Circulation on the Run: Recent Episodes
Carolyn Lam, MBBS, PhD
Each 15-minute podcast begins with an overview of the issue’s contents and main take-home messages for busy clinicians on the run. This is followed by a deep dive into a featured article of particular clinical significance: views will be heard from both author and editor teams for a “behind the scenes” look at the publication. Expect a fun, highly conversational and clinically-focused session each week!
This week, please join Brad and Mercedes as they welcome Deputy Editor Ryan J. Tedford and they discuss the advance of SGLT-2, non-steroidal MRA, and GLP-1 therapies that provide clinicians options to treat patients and HFpEF comorbidities. Then, Associate Editor Mark Chandy joins the podcast to discuss highlights from the recent BCVS Scientific Sessions in Boston, as well as how he prioritizes different types of basic and scientific manuscripts at Circulation.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260810.584625
Each week, join Editor-in-Chief Brad Maron, along with cohosts Mercedes Carnethon and Jane Wilcox for the new iteration of Circulation on the Run.
This week, please join Brad and Jane as they welcome author Zahra Raisi-Estabragh as the three discuss her review article regarding 10 Years of Scientific Discovery with the UK Biobank CMR Imaging Study. Then, Brad and Jane chat with Specialty Associate Editor Betty Raman as she discusses her Clinician Lighthouse, a new article type at Circulation, and what prospective authors should consider when submitting their own Clinician Lighthouse manuscript to Circulation.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260803.13306
Each week, join Editor-in-Chief Brad Maron, along with cohosts Mercedes Carnethon and Jane Wilcox for the new iteration of Circulation on the Run.
This week, join Mercedes and Brad as Fatima Rodriguez joins the podcast for a discussion on the recently released CKM Guidelines. Then, Mercedes welcomes Deputy Editor Tiffany Powell-Wiley as they discuss the Clinician's Corner article type and what prospective authors should consider when submitting a manuscript for this article type.
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260727.885623
Each week, join Editor-in-Chief Brad Maron, along with cohosts Mercedes Carnethon and Jane Wilcox for the new iteration of Circulation on the Run.
This week, join Brad on location at BCVS Scientific Sessions in Boston as he sits down with the new BCVS Council Chair, Sean Wu. Brad and Sean discuss the priorities for BCVS, the standards for high-quality and actionable science in the era of multi-omics, how cardiovascular science can adapt to growing emphasis on acquired determinants of disease, and finally, find ways to improve the clinical translational relevance of basic science.
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260717.271223
On this week's episode of Circulation on the Run, join Editor-in-Chief Bradley Maron and Deputy Editor Mercedes Carnethon as they welcome Circulation's Executive Editor, Karen E. Joynt Maddox. Karen discussed health services and health care policy, and what prospective authors should consider when submitting manuscripts to Circulation. Then, Brad and Mercedes welcome authors Marc Humbert and Jason Weatherald as they discuss their review article regarding pulmonary arterial hypertension in the July 14th issue of Circulation.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260713.392409
Circulation on the Run welcomes Circulation's new Editor-in-Chief, Bradley A. Maron, MD. Join Brad Maron, along with cohosts Mercedes Carnethon and Jane Wilcox for the new iteration of Circulation on the Run. This week join Brad, Mercedes and Jane as they first welcome Vice Chair Pamela B. Morris as she discusses the 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia. Then join author Hertzel Gerstein as he discusses his article "Cardiovascular Risk Reduction with GLP-1 RA Drugs." Besides gaining insight about leading science research, learn more about the scientific researchers in Circulation on the Run's newest feature, "Get to Know Our Guests." Don't miss this newly revamped podcast!
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260706.284480
This week marks the final Circulation on the Run under Dr. Joseph Hill's tenure. For this episode, please join our current hosts along with former host Carolyn Lam, Executive Editor James de Lemos, and Editor-in-Chief Joseph Hill as they remember the legacy of the podcast started a decade ago, the important scientific research discussed, and fond memories after 520 episodes.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260629.459176
This week, join Circulation's Disparities Editors Mercedes Carnethon, Karol Watson, and Guest Editor Eric J. Brandt as they host this week's Circulation on the Run episode. First, they speak with authors Rishi K. Wadhera and Prihatha R. Narasimmaraj as they discuss their article "The Cardiovascular Cost of Medicaid Cuts Under H.R. 1." Then Mercedes speaks with author Yi-Yun "Crystal" Chen as she discusses her original research article "Multidimensional Social Adversity and Mortality in People With HIV and Heart Failure: Insights From NYC Health + Hospitals HIV–Heart Failure Cohort."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260615.699938
This week, please join authors Rasha K. Al-Lamee and Fiyyaz Ahmed-Jushuf as well as Associate Editor Emmanouil Brilakis as they discuss the article "Determining the Physiological Threshold for Angina (ORBITA-FIRE): A Double-Blind, Randomized, Placebo-Controlled Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260608.559074
This week, please join author Sreekanth Vemulapalli as he discusses the article "Adaptive AI for Cardiovascular Event Adjudication: Cardiovascular Event Adjudication Across Different Definitions in the ODYSSEY OUTCOMES and EUCLID Trials."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260601.995930
This week, please join author Harmony R. Reynolds and Associate Editor Nicholas Mills as they discuss the article " Multimodality Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women and Men."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260526.732262
This week, please join author Nicholas A. Marston and Section Editor Parag Joshi as they discuss the article "Effect of APOC3 Inhibition With Olezarsen on Coronary Atherosclerosis: Essence-TIMI 73b Imaging Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260518.156242
This week, please join author Jean-Luc Vachiery and Associate Editor Kelly Chin as they discuss the article "Sotatercept for Combined Post- and Precapillary Pulmonary Hypertension Associated With Heart Failure: Results From the Phase 2, Randomized, Placebo-controlled CADENCE Study."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260511.411136
This week, please join authors Gregory D. Lewis and Ravi V. Shah as they discuss the article "Multiorgan Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure With Preserved Ejection Fraction."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260504.789757
This week, please join Chair Roger Blumenthal and author Gregg Fonarow as they discuss the recently published "2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia" along with an accompanying commentary "The 2026 American College of Cardiology/American Heart Association Multisociety Guideline on the Management of Dyslipidemia: A More Precise—But More Complicated—Framework for Atherosclerotic Cardiovascular Disease Prevention and Treatment."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260427.104601
This week, please join author Alexander "Sasha" Opotowsky as he discusses the article "The Fontan Outcomes Network: Findings After 2 Years and 1121 Participants."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260420.342132
This week, please join author Edouard L. Fu and Associate Editor Dhruv Kazi as they discuss the article "Risk of Heart Failure Hospitalization for GLP-1 Receptor Agonists Versus DPP-4 Inhibitors or SGLT-2 Inhibitors in Patients With Type 2 Diabetes: A Target Trial Emulation."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260413.101706
This week, please join author Rik Pauwels as he discusses the article "Wearable-Derived Training Load and Coronary Atherosclerosis in Middle-Aged and Older Athletes and Physically Active Controls: A New Perspective From the Master@Heart Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260406.965700
This week, please join authors Charles Khouri and Clément Jambon-Barbara as well as Associate Editor Kelly Chin as they discuss the article "Second- and Third-Generation BCR-ABL Tyrosine Kinase Inhibitors and the Risk of Pulmonary Arterial Hypertension: A Prevalent New-User Design."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260330.77255
This week, please join author Ivo Roca-Luque and Editorialist Andrew Arai as they discuss the article "PAM-VT 2 Study: Long-Term Scar Evolution and Ablation Lesion Assessment by Late Gadolinium Enhancement Cardiac Magnetic Resonance After Ventricular Tachycardia Ablation" and the accompanying editorial " Cardiac Magnetic Resonance Before Ventricular Tachycardia Ablation and During Follow-Up."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260323.157498
This week, please join author Niklas Dyrby Johansen and Associate Editor Sandeep Das as they discuss the article "High-Dose Versus Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: The FLUNITY-HD Prespecified Pooled Analysis."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260316.180799
This week, please join author Michael J. Blaha as he discusses his article "Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross Cohort Collaboration."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260309.22779
This week, join author Enrico Ammirati and Associate Editor Justin Ezekowitz as they discuss their article "Natural History of Patients With Histologically Proven Acute Eosinophilic Myocarditis."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260302.497755
This week, join author Moritz J. Hundertmark and Associate Editor Vlad Zaha as they discuss their article "IMPROVE-DiCE, a 2-Part, Open-Label, Phase 2a Trial Evaluating the Safety and Effectiveness of Ninerafaxstat in Patients With Cardiometabolic Syndromes."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260223.163027
This week, please join guest hosts Sana Al-Khatib and Mercedes Carnethon as first, they briefly introduce Circulation's annual Go Red for Women® issue. Then, our hosts welcome author Emilia Benjamin and Section Editor Maryjane Farr as they discuss the unique challenges women cardiologists have faced in the past and still encounter, and the importance of mentors and mentees in the field of cardiology. Finally, our hosts welcome Ju-Young (Judy) Shin to discuss her article "Association of Statin Discontinuation in Pregnancy With Maternal Cardiovascular Health and Birth Outcomes: A Nationwide Cohort Study." Don't miss this important podcast!
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260213.424527
This week, join authors Shaan Khurshid and Julian S. Haimovich as they discuss their article "Incidence, Risk Factors, and Outcomes in Stressor-Associated Atrial Fibrillation: Insights From the VITAL-AF Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20260209.180892
This week, join author Chao Jiang as he discusses the article "Dapagliflozin to Reduce Early Recurrence After Catheter Ablation for Atrial Fibrillation: The DARE-AF Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260202.172048
This week, join authors Xiangbin Pan and Jie Dong, as well as Associate Editor Dharam Kumbhani as they discuss the article "Transcatheter Closure of Patent Foramen Ovale with a Novel Biodegradable Device: A Prospective, Multicenter, Randomized Controlled Clinical Trial."
For the episode transcript, please visit: https://www.ahajournals.org/do/10.1161/podcast.20260112.347892
This week, please join author Mathew S. Maurer as he discusses the article "Coramitug, a Humanized Monoclonal Antibody for the Treatment of Transthyretin Amyloid Cardiomyopathy: A Phase 2, Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260126.13097
This week, join author Albert Ariza-Solé and Associate Editor Parag Joshi as they discuss the article "Triple versus Dual Lipid Lowering Therapy in Acute Coronary Syndrome: The ES-BempedACS Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20260120.624282
This week, please join author Robert Lookstein and Associate Editor Joshua Beckman as they discuss the article "Randomized Controlled Trial of Mechanical Thrombectomy With Anticoagulation Versus Anticoagulation Alone for Acute Intermediate-High Risk Pulmonary Embolism: Primary Outcomes From the STORM-PE Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/10.1161/podcast.20260105.594056
This week, please join our guest hosts Peter Kennel and Gurleen Kaur as they interview the recipient of the 2025 James T. Willerson Award, Michael Waight and discuss his article, "Personalized Heart Digital Twins Detect Substrate Abnormalities in Scar-Dependent Ventricular Tachycardia."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251229.893259
This week, join author Marcely Bonatto and Associate Editor Torbjørn Omland as they discuss the article "Sacubitril-Valsartan for the Prevention of Anthracycline Cardiotoxicity in Patients With Elevated Cardiac Troponin I Concentration During Chemotherapy: A Double-Blind Randomized Placebo-Controlled Clinical Trial: The SARAH Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251222.180775
This week, join author Vivek Reddy and Senior Associate Editor Sana Al-Khatib as they discuss the article "High-Voltage Focal Pulsed Field Ablation to Treat Scar-Related Ventricular Tachycardia: The First-in-Human VCAS Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251215.75602
This week, join author Sara Moura-Ferreira and Associate Editor Ntobeko Ntusi as they discuss the article "Prognostic Value of Exercise Right Ventricular-Pulmonary Arterial Coupling in Primary Mitral Regurgitation."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20251208.238882
This week, join author Hans-Josef Feistritzer and Associate Editor Stefan James as they discuss the article "Peri-Interventional Anesthesia Strategies for Transcatheter Aortic Valve Implantation: A Multicenter, Randomized, Controlled, Noninferiority Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251201.586148
This week, join author Jonas Oldgren and Associate Editor Torbjørn Omland as they discuss the article "Biomarker-Based ABC-AF Risk Scores for Personalized Treatment to Reduce Stroke or Death in Atrial Fibrillation: A Registry-Based Multicenter, Randomized, Controlled Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251124.61165
This week, join Associate Editor and Editorialist Graeme Hankey as he discusses the article "Bailout Intracranial Angioplasty or Stenting After Thrombectomy for Acute Large Vessel Occlusion: 1-Year Outcomes of ANGEL-REBOOT and the editorial "Unsuccessful Thrombectomy During Acute Ischemic Stroke: Can It Be Rescued by Angioplasty and/or Stenting?"
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251117.229007
This week, please join authors Shingo Fukuma and Yuichiro Mori as well as Associate Editor Shinya Goto as they discuss the article "Screening-Detected Atrial Fibrillation and Cardiovascular Outcomes in Working-Age Adults."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251110.703752
This week, join author Rohan Khera and Associate Editor Nicholas Mills as they discuss the article "Phenotypic Selectivity of Artificial Intelligence-enhanced Electrocardiography in Cardiovascular Diagnosis and Risk Prediction."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20251103.917420
This week, Marc Ruel guest-hosts in this episode of Circulation on the Run as it features the annual Surgery Issue for Circulation. First, Marc is joined by author Duk-Hyun Kang as they discuss his article "Comparison of Long-Term Outcomes of Early Surgery Versus Conventional Treatment for Asymptomatic Severe Mitral Regurgitation: A Propensity Analysis." Then Marc is joined by authors Enoch Akowuah and Janelle Wagnild as they discuss their article "Accelerometer-Measured Physical Activity After Mitral Valve Surgery: An Analysis of the UK Mini Mitral Randomized Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251027.193601
This week, please join author Torbjørn Omland, as he discusses the article "Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251020.442597
This week, please join author Emily Lau, editorialist Sadiya Khan, and Associate Editor Kelly Chin as they discuss the article "Contemporary Burden of Cardiovascular Disease in Pregnancy: Insights From a Real-World Pregnancy Electronic Health Record Cohort" and the editorial "Bending the Curve in Maternal Mortality: Pregnancy as a Moment for Cardiovascular Disease Prevention."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251013.381115
This week, please join author Emily Lau, editorialist Sadiya Khan, and Associate Editor Kelly Chin as they discuss the article "Contemporary Burden of Cardiovascular Disease in Pregnancy: Insights From a Real-World Pregnancy Electronic Health Record Cohort" and the editorial "Bending the Curve in Maternal Mortality: Pregnancy as a Moment for Cardiovascular Disease Prevention."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251013.381115
This week, please join authors Joseph Campain and Gregory Lewis, as well as Section Editor Satyam "Tom" Sarma as they discuss the article "Characterization and Application of Novel Exercise Recovery Patterns That Reflect Cardiac Performance: A Substudy of the SEQUOIA-HCM Randomized Trial."
For the episode transcript, visit: https://staging.www.ahajournals.org/do/10.1161/podcast.20251006.208532
This week please join author Gregory Hundemer, Editorialist Wanpen Vonpatanasin, and Associate Editor Torbjørn Omland as they discuss the article "Subclinical Primary Aldosteronism and Major Adverse Cardiovascular Events: A Longitudinal Population-Based Cohort Study" and the editorial "Subclinical Primary Aldosteronism: A Potential New Target in Cardiovascular Prevention?"
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20250929.481570
This week please join author Chetan Huded as he discusses the article "Health Status Outcomes with Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting in ISCHEMIA."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250922.194514
This week, please join Daniel W. Jones as he discusses updates found in the 2025 AHA/ACC High Blood Pressure Guideline. This is an important episode to learn of the changes in guidelines and recommended practices in treating high blood pressure.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250912.590432
This week please join author Daniele Giacoppo as he discusses the article "Transcatheter Aortic Valve Replacement With Balloon- Versus Self-Expandable Bioprostheses for the Treatment of Bicuspid Aortic Valve Stenosis."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250908.794818
This week please join author Rebecca Lawn and Associate Editor Mercedes Carnethon as they discuss the article "Experiences of Stalking and Obtaining a Restraining Order Are Associated With Onset of Cardiovascular Events in Women: A Prospective Analysis in the Nurses’ Health Study II."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250902.860161
This week please join author Sheri Hartman and Associate Editor Jarett Berry as they discuss the article "Impacts of Reducing Sitting Time or Increasing Sit-to-Stand Transitions on Blood Pressure and Glucose Regulation in Postmenopausal Women: Three-Arm Randomized Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250825.890592
This week please join authors Eric Olson and Qianqian Ding, and Senior Guest Editor Gianluigi Condorelli as they discuss the article "Genomic Editing of a Pathogenic Sequence Variant in ACTA2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome in Mice."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250818.61174
This week please join author Joachim Skovbo and Associate Editor Brendan Everett as they discuss the article "Association of Statin Treatment and Dose With the Clinical Course of Small Abdominal Aortic Aneurysms in Men: A 5-Year Prospective Cohort Study From 2 Population-Based Screening Trials."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250812.716960
This week please join author Christian Ruff and Associate Editor Andrea Russo as they discuss the article "Abelacimab Versus Rivaroxaban in Patients With Atrial Fibrillation on Antiplatelet Therapy: A Prespecified Analysis of the AZALEA-TIMI 71 Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20250804.510827
This week please join author Boyoung Joung and Associate Editor Svati Shah as they discuss the article "Proteomic Signatures for Risk Prediction of Atrial Fibrillation."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250728.351486
This week please join author Marek Hozman and Associate Editor Andrea Russo as they discuss the Original Research Article "COOPERATIVE-PFA: A Three-Arm Randomized Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250721.6011
This week's podcast is dedicated to Circulation's fifth annual Disparities issue. First, please join Associate Editor Karol Watson and Guest Editor Nilay Shah as they discuss the article "Centering Diné (Navajo) Voices: Barriers, Facilitators, and Perceptions of Cardiac Care Among Patients With Heart Failure in Rural Navajo Nation" with corresponding author Lauren Eberly. Then, Associate Editor Mercedes Carnethon and Guest Editor Nilay Shah discuss the Frame of Reference article "Health Equity: Are We There Yet?" with author Clyde Yancy. Don't miss this important episode!
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250710.251438
This week please join guest author Adam Griesemer and Associate Editor and Digital Strategies Editor Maryjane Farr as they discuss the Review Article "Cardiac Xenotransplantation: Current State and Future Directions."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250707.102697
This week please join guest host Susmita Sahoo and author Huize Pan as they discuss the article "Atherosclerosis Is a Smooth Muscle Cell–Driven Tumor-Like Disease." Dr Pan and his coauthors are the recipients of the 2025 Joseph Loscalzo Award. This award recognizes the best basic/translational article published in Circulation in the preceding 12 months.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250629.645452
This week please join author Yuxiang Dai and Associate Editor Esther Lutgens as they discuss the article "Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2–Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250623.661904
This week please join author Robert Clarke and Associate Editor Wendy Post as they discuss the article "Causal Relevance of Lp(a) for Coronary Heart Disease and Stroke Types in East Asian and European Ancestry Populations: A Mendelian Randomization Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250617.454324
This week please join author Nikolaus Marx as he discusses the article "Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250609.351110
This week please join author Brian Lindman and Executive Editor and Editorialist James de Lemos as they discuss the article "Cardiac Biomarkers in Patients With Asymptomatic Severe Aortic Stenosis: Analysis From the EARLY TAVR Trial" and the accompanying editorial "Biomarkers to Guide the Timing of Aortic Valve Replacement in Asymptomatic Aortic Stenosis: Where Do We Stand After Early TAVR?"
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250529.497472
This week please join author Varsha Tanguturi and Associate Editor Dharam Kumbhani as they discuss the article "Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis: A Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250528.505920
This week please join author André Zimerman and Associate Editor Amit Khera as they discuss the article "Intensive Lowering of LDL Cholesterol Levels With Evolocumab in Autoimmune or Inflammatory Diseases: An Analysis of the FOURIER Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250519.268826
This week please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results From VALOR-HCM."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250512.476310
This week please join author Jarett Berry as well as Guest Editor and Editorialist Paul Thompson as they discuss the article "High-Volume Physical Activity and Clinical Coronary Artery Disease Outcomes: Findings From the Cooper Center Longitudinal Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250505.656863
This week please join author Bin Zhou and Associate Editor Zhao Wang as they discuss the article "Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250428.805646
This week please join author Signe Glargaard and Associate Editor Justin Ezekowitz as they discuss the article "A Randomized Controlled Trial of Thoracentesis in Acute Heart Failure."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250421.239148
This week please join author Emmanuel Stamatakis and Associate Editor Jarett Berry as they discuss the article "Dose Response of Incidental Physical Activity Against Cardiovascular Events and Mortality."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250414.213483
This week please join author Barry Borlaug and Associate Editor Torbjørn Omland as they discuss the article "Evidence-Based Application of Natriuretic Peptides in the Evaluation of Chronic Heart Failure With Preserved Ejection Fraction in the Ambulatory Outpatient Setting."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250407.806254
This week please join author Josef Stehlik as he discusses the article "Clinical Outcomes With Normothermic Pulsatile Organ Perfusion in Heart Transplantation: A Report From the OCS Heart Perfusion Registry."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250331.87307
This week please join author Josefine Windfeld-Mathiasen and Associate Editor Ntobeko Ntusi as they discuss the article "Cardiovascular Disease in Anabolic Androgenic Steroid Users."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250324.957173
This week please join author Eric Rosenthal and Associate Editor Gerald Greil as they discuss the article "Covered Stent Correction for Sinus Venosus Atrial Septal Defects, an Emerging Alternative to Surgical Repair: Results of an International Registry."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250317.309077
This week please join author Michael Zile and Associate Editor Justin Ezekowitz as they discuss the article "Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250307.892170
This week please join author Yugo Yamashita and Associate Editor Joshua Beckman as they discuss the article "Rivaroxaban for 18 Months Versus 6 Months in Patients With Cancer and Acute Low-Risk Pulmonary Embolism: An Open-Label, Multicenter, Randomized Clinical Trial (ONCO PE Trial)."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250303.648421
This week please join author Carl Johann Hansen and Associate Editor Mark Link as they discuss the article "Declining Trend of Sudden Cardiac Death in Younger Individuals: A 20-Year Nationwide Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250224.873552
This week, Circulation celebrates Go Red for Women with its 9th annual special issue. Guest hosts Sana Al-Khatib and Mercedes Carnethon welcome authors Upasana (Paz) Tayal as well as Thais Coutinho and coauthors. Circulation on the Run also welcomes the American Heart Association's President Keith Churchwell.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250217.870159
This week please join author Michael Zhang and Guest Editor Paul Gurbel as they discuss the article "Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS."
For the episode transcript, visit: https://www.ahajournals.org/do/110.1161/podcast.20250210.487047
This week please join author Paul Welsh and Guest Editor Manuel Mayr as they discuss the article "A Proteomics-Based Approach for Prediction of Different Cardiovascular Diseases and Dementia."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250203.163969
This week please join author Hayley Dillon and Editorialist Justin Canada as they discuss the article "Preventing Allogeneic Stem Cell Transplant−Related Cardiovascular Dysfunction: The ALLO-Active Trial" and the Editorial "Cardiorespiratory Fitness Assessment in Stem Cell Transplant Recipients: Getting to the Heart of the Problem."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250127.949759
This week please join author Olaf Bergmann as he discusses the article "A Latent Cardiomyocyte Regeneration Potential in Human Heart Disease."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20250121.427979
This week please join author Helga Gudmundsdottir and Editorialist James MacNamara as they discuss the article "Exercise Training in Patients With Hypertrophic Cardiomyopathy Without Left Ventricular Outflow Tract Obstruction: A Randomized Clinical Trial" and the accompanying Editorial "Cardiac Plasticity in Hypertrophic Cardiomyopathy: Exercise as Medicine?"
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250113.568188
This week please join author Kieran Docherty and Associate Editor Justin Ezekowitz as they discuss the article "Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the FINEARTS-HF Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20250106.356679
This New Year's week, please join Social Media Editor Pishoy Gouda as he interviews corresponding author Alexander Fanaroff to discuss the 2024 Willerson Award-winning article "Effect of Gamification, Financial Incentives, or Both to Increase Physical Activity Among Patients at High Risk of Cardiovascular Events: The BE ACTIVE Randomized Controlled Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20241227.771393
This week please join Circulation on the Run's newest host, Anezi Uzendu, author Boris Schmidt, and Associate Editor Andrea Russo as they discuss the article "Ablation Strategies for Repeat Procedures in Atrial Fibrillation Recurrences Despite Durable Pulmonary Vein Isolation: The Prospective Randomized ASTRO AF Multicenter Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20241216.546751
This week offers a double-feature of author interviews. First, please join author Gregg Stone as he discusses the article "Interatrial Shunt Treatment for Heart Failure: The Randomized RELIEVE-HF Trial." Then, please join author Sung-Min Cho and our Circulation on the Run podcast host Greg Hundley as they discuss the article "Clinical Use of Bedside Portable Ultra-Low-Field Brain Magnetic Resonance Imaging in Patients on Extracorporeal Membrane Oxygenation: The Results From the Multicenter SAFE MRI ECMO Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241209.320025
This week, please join authors Amil Shah and our own Peder Myhre, as well as Guest Editor Allan Jaffe as they discuss the article "NT-proBNP and Cardiac Troponin I, but Not Cardiac Troponin T, Are Associated With 7-Year Changes in Cardiac Structure and Function in Older Adults: The ARIC Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241202.603271
This week, please join author Robert Shaddy and Senior Associate Editor Victoria Delgado as they discuss the article "Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-blind Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20241125.19126
This week, please join author Gilles Montalescot, Editorialist John Carroll, and Associate Editor Dharam Kumbhani as they discuss the article "Flecainide to Prevent Atrial Arrhythmia after Patent Foramen Ovale Closure, the AFLOAT Study: A Randomized Clinical Trial" and the Editorial "Atrial Arrhythmias After PFO Device Closure: Common, Clinically Important, and Preventable?".
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241115.222442
This week, please join author Nigopan Gopalasingam, Editorialist B. Daan Westenbrink, and Associate Editor Justin Ezekowitz as they discuss the article "A Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction" and the editorial "Ketone Treatment in Heart Failure With Preserved Ejection Fraction: Recharging the Heart or Reducing Filling Pressures?".
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241111.585567
This week, please join author Kashish Goel and Associate Editor Dharam Kumbhani as they discuss the article "Contemporary Outcomes and Trends for the Transseptal Mitral Valve-in-Valve Procedure Using Balloon Expandable Transcatheter Valves in the United States."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241104.791174
This week, please join authors Regina Royan and Tracy Madsen as well as Associate Editor Deborah Diercks as they discuss the article "Disparities in Emergency Medical Services Use, Prehospital Notification, and Symptom Onset to Arrival in Patients with Acute Stroke."
For the episode transcript, visit: https://www.ahajournals.org/do/110.1161/podcast.20241028.477927
This week, join Associate Editor Marc Ruel who briefly summarizes Circulation's annual Surgery Issue. Then he is joined by author André Lamy and they discuss the article "Topical Versus Intravenous Tranexamic Acid in Patients Undergoing Cardiac Surgery: The DEPOSITION Randomized Controlled Trial." Then Marc is joined by author Niccolò Maurizi and they discuss the article "Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHARE Registry."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20241018.445322
This week, please join authors Shaan Khurshid and Shinwan Kany as they discuss the article "Associations of ‘Weekend Warrior’ Physical Activity With Incident Disease and Cardiometabolic Health."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241003.112753
This week, please join author Luigi Di Biase as he discusses the article "Pulsed Field Ablation to Treat Paroxysmal Atrial Fibrillation: Safety and Effectiveness in the ADMIRE Pivotal Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20241003.273130
This week, please join author Marcelo Di Carli and Associate Editor Vlad Zaha as they discuss the article "Relationship of Subendocardial Perfusion to Myocardial Injury, Cardiac Structure, and Clinical Outcomes Among Patients With Hypertension."
This week, please join author Chen Chen and Associate Editor Sergio Lavandero as they discuss the article "LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240920.99651
This week, please join a panel session with authors Timothy Poterucha and David Ouyang, Editorialist Anna Sannino, and Senior Associate Editor Victoria Delgado as they discuss the Original Research Articles "Deep Learning for Echo Analysis, Tracking, and Evaluation of Mitral Regurgitation (DELINEATE-MR)" and "High-Throughput Deep Learning Detection of Mitral Regurgitation."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240916.127413
This week, please join author Bruce Wasserman and Associate Editor Mercedes Carnethon as they discuss the article "Intracranial Atherosclerotic Disease and Incident Dementia: the Atherosclerosis Risk in Communities Study (ARIC)."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240906.944975
This week, please join author Gregory Wyant and Associate Editor Gabriele Schiattarella as they discuss the article "Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240830.316198
This week, please join author Gary Owens and Associate Editor Iris Jaffe as they discuss the article "A Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240825.966308
This week, please join author Marius Hoeper and Associate Editor Kelly Chin as they discuss the article "Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized, Controlled Phase 3 Study."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240816.125469
This week, please join author Rachel Lampert as she discusses the article "Vigorous Exercise in Patients with the Congenital Long-QT Syndrome: Results of the Prospective, Observational, Multinational, LIVE-LQTS Study.”
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240809.114150
This week, please join author Hiroyuki Daida and Associate Editor Amit Khera as they discuss the article "A Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy−Statin and Eicosapentaenoic Acid (RESPECT-EPA)."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240804.906883
This week, please join author Rod Passman and Associate Editor Mark Link as they discuss the article "Association of Atrial Fibrillation Burden and Mortality Among Patients With Cardiac Implantable Electronic Devices."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240729.689092
This week, please join author John J.V. McMurray and Guest Editor Frank Ruschitzka as they discuss the article "Effect of Sacubitril/Valsartan on Cognitive Function in Patients With HFpEF: A Prespecified Analysis of PARAGON-HF."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240719.555489
This week, Circulation is proud to present the 4th annual Disparities issue. First, Guest Editor Latha Palaniappan leads the interview with author Jennifer Green as they discuss the article "Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial." Then, Disparities Editor Mercedes Carnethon talks with author Benjamin Zielonka about his article "Childhood Opportunity and Acute Interstage Outcomes: A National Pediatric Cardiology Quality Improvement Collaborative Analysis." Finally, Dr. Karol Watson leads the discussion with author Lisa Cooper regarding her article "Equitable Care for Hypertension: Blood Pressure and Patient-Reported Outcomes of the RICH LIFE Cluster Randomized Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240712.517573
This week, please join first author Heerajnarain Bulluck as he discusses the article "Effect of Cangrelor on Infarct Size in ST-Segment−Elevation Myocardial Infarction Treated By Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial)."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240703.90241
This week, please join authors Reza Nezafat, Shiro Nakamori, and Amine Amyar as they discuss the article "Cardiovascular Magnetic Resonance Radiomics to Identify Components of the Extracellular Matrix in Dilated Cardiomyopathy."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240628.66549
This week, please join Social Media Editors Shirin Doroudgar and Susmita Sahoo as they speak with the 2024 Loscalzo Award recipient, Mark C. Blaser, regarding his article "Multiomics of Tissue Extracellular Vesicles Identifies Unique Modulators of Atherosclerosis and Calcific Aortic Valve Stenosis." The Loscalzo Award recognizes the best Basic/Translational article published in Circulation in the preceding 12 months.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240621.715149
This week, please join author Laura Galian-Gay and Associate Editor Joshua Beckman as they discuss the article "Atorvastatin Effect on Aortic Dilatation and Valvular Calcification Progression in Bicuspid Aortic Valve (BICATOR): A Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240614.566029
This week, please join author David Kandzari and Associate Editor Wanpen Vongpatanasin as they discuss the article "Effect of Alcohol-Mediated Renal Denervation on Blood Pressure in the Presence of Antihypertensive Medications: Primary Results From the TARGET BP I Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240607.177703
This week, please join author Siddharth Patel and Guest Editor Ileana Piña as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240531.705195
This week, please join authors Jonathan Leor and Tal Caller, as well as Associate Editor Gabriele Schiattarella as they discuss the article "Small Extracellular Vesicles From Infarcted and Failing Heart Accelerate Tumor Growth."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240524.921966
This week, please join author Adrian Hernandez as he discusses the article "Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240515.717282
This week, please join author Stephan Rosenkranz, Editorialist Lewis Rubin, and Associate Editor Kelly Chin as they discuss the article "Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era" and the Editorial "Is There a Role for Calcium Channel Blockers in the Contemporary Treatment Paradigm for Pulmonary Arterial Hypertension?"
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240510.641533
This week, please join author Kristoffer Berg-Hansen and Section Editor and Editorialist Stayam "Tom" Sarma as they discuss the article "Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240503.968091
This week, please join author Amy Lin and Statistical Editor Dan (Amanda) Tong as they discuss the article "Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240426.766271
This week, please join author Prakriti Gaba as she discusses the article "Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With Left Main Disease With and Without Diabetes: Findings From a Pooled Analysis of 4 Randomized Clinical Trials."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240422.957293
This week, please join author Gilles Montalescot as he discusses the article "Postprocedural Anticoagulation After Primary Percutaneous Coronary Intervention for ST-Segment−Elevation Myocardial Infarction: A Multicenter, Randomized, Double-Blind Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240412.432949
This week, please join author Hanjoong Jo, editorialist M. Luisa Iruela-Arispe, and Associate Editor Charles Lowenstein as they discuss the article "HEG1 Protects Against Atherosclerosis by Regulating Stable Flow-Induced KLF2/4 Expression in Endothelial Cells," as well as the Editorial "Hemodynamic Forces and Atherosclerosis: HEG1 at the Center of the Jigsaw Puzzle."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240408.470208
This week, please join author Nicholas Mills as he discusses the article "Machine Learning for Myocardial Infarction Compared With Guideline Recommended Diagnostic Pathways.
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240329.877789
This week, please join author William McIntyre, Editorialist Christian Ruff, and Associate Editor Shinya Goto as they discuss the article "Direct Oral Anticoagulants for Stroke Prevention in Patients With Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240322.70604
This week, please join author John Triedman and Associate Editor Gerald Greil as they discuss the article "Pediatric ECG-Based Deep Learning to Predict Left Ventricular Dysfunction and Remodeling."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240315.583656
This week, please join author Kieran Docherty and Associate Editor Justin Grodin as they discuss the article "Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240306.916294
This week, please join author Samir Kapadia and Editorialist Neil Kleiman as they discuss the article "Concomitant Left Atrial Appendage Occlusion and Transcatheter Aortic Valve Replacement Among Patients With Atrial Fibrillation."
For the episode transcript: https://www.ahajournals.org/do/10.1161/podcast.20240301.133854
This week, please join author Josep Rodés-Cabau and Associate Editor Dharam Kumbhani as they discuss the article "Transcatheter or Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Small Aortic Annulus: A Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240226.780348
This week's podcast features a panel discussion. Please join authors Masahiro Natsuaki, Myeong-Ki Hong, and Robert Storey, as well as Associate Editor Stefan James as they discuss the Original Research Articles "An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial" and "Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial" and the Editorial "Antiplatelet Therapy After PCI: The Art and Science of De-Escalation."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240220.712469
This week is Circulation's annual Go Red for Women issue. Please join Special Issue Editors Sana Al-Khatib and Mercedes R. Carnethon as they discuss the issue. Then they interview authors Jaime Kitt and Shanshan Sheehy as they discuss the articles "Cardiac Remodeling After Hypertensive Pregnancy Following Physician-Optimized Blood Pressure Self-Management: The POP-HT Randomized Clinical Trial Imaging Substudy" and "Perceived Interpersonal Racism in Relation to Incident Coronary Heart Disease Among Black Women."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240212.130685
This week, please join author Brendon Neuen and Editor Sandeep Das as they discuss the original research article "Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240205.184727
We have a panel discussion with authors Albert Wiegman and Frederick Raal and Editorialist Raul Santos as they discuss the original research articles "Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia" and "Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/110.1161/podcast.20240129.812328
This week, please join author Geert-Jan Geersing he discusses the article "Safety of Switching From a Vitamin K Antagonist to a Non–Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240122.313687
This week, please join author Mikhail Kosiborod and Associate Editor Brendan Everett as they discuss the article "Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20240116.96740
This week, please join author Kimberly Harmon and Associate Editor Mark Link as they discuss the article "Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240108.684387
This week, please join author Colin Berry and Associate Editor Emmanouil Brilakis as they discuss the article "Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240102.447846
This week, the Social Media Editors of Circulation interview the recipients for the 2023 Loscalzo and Willerson Awards. Please join Maryjane Farr, Susmita Sahoo, Shirin Doroudgar, Pishoy Gouda and Peter Kennel as they talk with authors Zihan Ma, Chenfeng Mao, and Alexander Sandhu.
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20231222.991468
This week, please join author Cristina Basso and Associate Editor Mark Link as they discuss the Research Letter, "Rate and Cause of Sudden Cardiac Death in the Young During the COVID-19 Pandemic and Vaccination."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20231218.67540
This week, please join author Jennifer Rymer and Editorialist Alexander Chaitoff as they discuss the article "Rivaroxaban Plus Aspirin Versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights from VOYAGER PAD."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231211.181332
This week, please join author Ahamed Idris as he discusses the article "Bag-Valve-Mask Ventilation and Survival From Out-of-Hospital Cardiac Arrest: A Multicenter Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231204.859686
This week, please join author Jan Vincent Beltran and Associate Editor Charles Lowenstein as they discuss the article "Single-Cell Meta-Analysis of Neutrophil Activation in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Reveals Potential Shared Immunological Drivers."
For episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231127.335747
This week, please join author Peter Henriksen and Guest Editor Ileana Piña as they discuss the article "A Multicenter, Prospective, Randomized Controlled Trial of High Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20231120.338829
This week, please join author Sameed Ahmed Khatana and Associate Editor Mark Link as they discuss "Projected Change in the Burden of Excess Cardiovascular Deaths Associated with Extreme Heat by Midcentury (2036–2065) in the Contiguous United States."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231113.953480
This week, please join author Jung-Im Shin and Senior Associate Editor Sana Al-Khatib as they discuss "Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231106.465546
This week, please join author Daniel Jones and Associate Editor Dharam Kumbhani as they discuss "Computed Tomography Cardiac Angiography Before Invasive Coronary Angiography in Patients With Previous Bypass Surgery: The BYPASS-CTCA Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20231030.705281
This week is a very special podcast: please join Circulation's Executive Editor James de Lemos and Associate Editor Marc Ruel as they discuss the articles in this year's Surgery Issue.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231023.446837
This week, please join author Sebastian Reinstadler and Senior Associate Editor Victoria Delgado as they discuss "Cardiac Magnetic Resonance Imaging Versus Computed Tomography to Guide Transcatheter Aortic Valve Replacement: A Randomized, Open-Label, Noninferiority Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20231016.898440
This week, please join senior author Nathaniel Smilowitz and Associate Editor Joshua Beckman as they discuss the article "Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES)."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/10.1161/podcast.20231009.345628
This week, please join author Karen Joynt Maddox and Associate Editor Sandeep Das as they discuss the article "Changes in Cardiovascular Spending, Care Utilization, and Clinical Outcomes Associated With Participation in Bundled Payments for Care Improvement−Advanced."
For the episode transcript, visit: https://www.ahajournals.org/do10.1161/podcast.20231002.799650
This week, please join author Milton Packer and Associate Editor Brendan Everett as they discuss the article "Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230925.181139
This week, please join authors Robert Yeh, Rahul Aggarwal, as well as Associate Editor Mark Link as they discuss the article "Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230918.938511
This week, please join author Mark Hofmeyer and Guest Editor Mauro Giacca as they discuss the article "Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230911.59229
This week, please join Guest Host Pishoy Gouda, author Kiran Khush, and Associate Editor Maryjane Farr as they discuss the article "Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230905.6639
This week, please join Carolyn Lam and author Frans Van de Werf as they discuss the article "STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment−Elevation Myocardial Infarction: A Randomized, Open-Label Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230828.941314
This week, please join author Jason Glotzbach and Associate Editor Wendy Post as they discuss the article "Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230821.396745
This week, please join Guest Host Pishoy Gouda, author Xin Du, and Guest Editor Walter Paulus as they discuss the article "The Effect of Frailty on the Efficacy and Safety of Intensive Blood Pressure Control: A Post Hoc Analysis of SPRINT Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230813.441244
This week, please join author Joe-Elie Salem and Guest Editor Allan Jaffe as they discuss the article "Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230807.753501
This week, please join author Susmita Sahoo and Associate Editor Thomas Eschenhagen as they discuss the article "Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230731.330982
This week, please author Markus Schlaich as he discusses the Research Letter "Effect of Initial Treatment With a Single Pill Containing Quadruple Combination of Quarter Doses of Blood Pressure Medicines Versus Standard Dose Monotherapy in Patients With Hypertension on Ambulatory Blood Pressure Indices: Results From the QUARTET Study."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230724.155005
This week, please join our very special panel discussion to accompany Circulation's 2023 Disparities Issue. Please join Guest Host Mercedes Carnethon as she leads a discussion of equity, diversity, and inclusion in scientific research with panelists Karol Watson, Rishi Wadhera, and author Ambarish Pandey.
For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230709.293635
This week, please join author Douglas Johns and Associate Editor Thomas Eschenhagen as they discuss the article "An Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor."
For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230709.411427
This week, please join author Vivek Reddy and Associate Editor Mark Link as they discuss the article "Safety and Effectiveness of Pulsed Field Ablation to Treat Atrial Fibrillation: One-Year Outcomes From the MANIFEST-PF Registry."
For the episode transcript, visit: https://ahajournals.org/do10.1161/podcast.20230630.576031
This week, Digital Strategies Editor Maryjane Farr welcomes two guests, Joshua Beckman and Esther Kim, as they discuss vascular medicine, the current state of vascular medicine research, and two recently published vascular medicine articles in Circulation.
For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230626.231366
This week, please join author Aidin Rawshani and Guest Editor Todd Brown as they discuss the article "Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study."
For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230619.624297
This week, please join authors Emmy Okello and Andrea Beaton as they discuss the articles "Rheumatic Heart Disease Research Collaborative in Uganda" and "Refining Risk Stratification Among Children With Latent Rheumatic Heart Disease."
For the episode transcript, visit:
https://ahajournals.org/do/10.1161/podcast.20230612.642952
This week, please join author Leslie Gordon and Associate Editor Torbjørn Omland as they discuss the article "Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230601.394643
This week, please join author Ewa Jankowska and Associate Editor Justin Ezekowitz as they discuss the article "Association Between Hemoglobin Level and the Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230526.118098
This week, please join author David Cohen and Associate Editor Stefan James as they discuss the article "Economic Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Low Surgical Risk: Results From the PARTNER 3 Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230519.961111
This week, please join author Braden Manns and Associate Editor and Editorialist Sandeep Das as they discuss 2 articles: "Self-Management Support Using Advertising Principles for Older Low Income Adults at High Cardiovascular Risk: A Randomized Controlled Trial" and "Eliminating Medication Copayments for Low-Income Older Adults at High Cardiovascular Risk: A Randomized Controlled Trial."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230515.95172
This week, Carolyn, Greg, and Peder welcome podcast hosts Laxmi Mehta and Eva Rocha of The Journal of the American Heart Association's new podast "Aha! With JAHA."
Then, please join author Leopoldo Pérez de Isla and Associate Editor Stefan James as they discuss the article "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study.
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230508.620091
This week, please join author Hyo-Soo Kim and Associate Editor Stefan James as they discuss the article "Comparison of 3- to 6-Month Versus 12-Month Dual Antiplatelet Therapy After Coronary Intervention Using the Contemporary Drug-Eluting Stents With Ultrathin Struts: The HOST-IDEA Randomized Clinical Trial."
For the episode transcript, visit:
https://www.ahajournals.org/do/10.1161/podcast.20230428.322841
This week on Circulation: On the Run, please join author Charles Hong and Associate Editor Gabriele Schiattarella as they discuss the article "Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230421.342161
This week, please join authors Marc Sabatine and Prakriti Gaba, as well as Associate Editor Amit Khera, as they discuss the article "Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE."
Dr Greg Hundley:
Welcome listeners, to this April 18th issue of Circulation on the Run and I am Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Peder Myhre:
And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo.
Dr Greg Hundley:
Peder, today's feature discussion, very interesting. We're going to evaluate the association between what's achieved with LDL cholesterol lowering, and then also long-term cardiovascular and safety outcomes. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first?
Dr Peder Myhre:
Yes, Greg. I would love to. And the first paper is from the World of Preclinical Science and it comes to us from corresponding author, Jan Magnus Aronsen from University of Oslo in Norway. And perhaps, as you know, Greg, cardiomyocyte contraction and relaxation depend on the activity of the sarcoplasmic reticulum CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced activity of SERCA2, as seen in chronic heart failure, weakens contractile force and delays relaxation and no available therapy involves direct manipulation of the SERCA2 activity. And Greg, phosphodiesterase 3A is proposed to be present in the SERCA2 interactome limit SERCA2 activity and disruption of phosphodiesterase 3A from SERCA2 might thus be a strategy to develop SERCA2 activators. And in this study, the authors investigated and mapped SERCA2 and phosphodiesterase 3A and assessed this in experiments assessing the binding between these two in cardiomyocytes and in vesicles.
Dr Greg Hundley:
Wow Peder, sounds very interesting. So what did they find and how about the clinical implications of the findings?
Dr Peder Myhre:
So Greg phosphodiesterase 3A bounded directly to SERCA2 in the cardiomyocyte. So that's the first finding. Second, they demonstrated that SERCA2 phosphodiesterase 3A disruption increased SERCA2 activity independently of the catalytic activity of phosphodiesterase 3A in both normal and failing cardiomyocytes. And third, SERCA2 activity by the optimized SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced mortality and improved contractility after aortic binding in mice. So the clinical implication is that direct targeting of phosphodiesterase 3A binding to SERCA2 could be a novel approach to increase SERCA2 activity and thus cardiac contractility in patients with heart failure.
Dr Greg Hundley:
Very nice Peder. What a great new finding in the world of preclinical science. Well my paper is going to delve into the world of clinical science and involves patients with stroke. So Peder in this study led by corresponding author, Dr. Dileep Yavagal from University of Miami Miller School of Medicine performed a survey in 75 countries through the Mission Thrombectomy 2020+ Global Network between November of 2020 and February of 2021 to determine the availability of mechanical thrombectomy for large vessel occlusion in patients with stroke. Now Peder, the primary endpoints were the current annual mechanical thrombectomy availability, the mechanical thrombectomy operator availability and the mechanical thrombectomy center availability. All of these availabilities were defined as the proportion of estimated large vessel occlusion for patients receiving mechanical thrombectomy in a given region annually.
Dr Peder Myhre:
Okay, Greg, so this is really an access question. So in essence, what is the availability of mechanical thrombectomy worldwide? So what did they find?
Dr Greg Hundley:
Right, great Peder. So what they found, the authors received 887 responses from 67 countries and low-income countries had 88% lower mechanical thrombectomy availability compared to high-income countries. The global mechanical thrombectomy operator availability was 16.5% of optimal, and the mechanical thrombectomy center availability was only 20.8% optimal. And with these results, the authors indicate that global cooperation and targeted region-specific public health interventions, including all stakeholders involved in stroke care delivery, are really needed to rapidly increase access to this brain-saving and disability-sparing treatment with mechanical thrombectomy really worldwide.
Dr Peder Myhre:
Oh wow. What a beautiful summary, Greg. Thank you so much. And we also have some other interesting papers in the mailbag today. We have an exchange of letters between Dr. Yang and Dr. O'Donoghue regarding the article “Long Term evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease.”
Dr Greg Hundley:
Great Peder, and also Professor Perera has a Frontiers article entitled “Unloading the Left Ventricle in Venoarterial ECMO in Who, When and How?” and then finally there's a Research Letter from Professor Verma entitled “Prevalence of Diabetes and Cardiovascular Risk in the Middle East and Africa: The Primary results of the PACT-MEA Study.” Well Peder, how about we jump to that feature discussion?
Dr Peder Myhre:
Can't wait.
Dr Greg Hundley:
Welcome listeners to this feature discussion on April 18th and we have with us today Prakriti Gaba and Marc Sabatine from Brigham and Women's Hospital and our own associate editor, Dr. Amit Khera. Welcome everyone. Well Marc, we'll start with you. Can you describe for us some of the background information that really helps constitute the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Marc Sabatine:
Yeah, thanks Greg and thanks for having us. So we've seen in a variety of epidemiologic cohorts the association between LDL cholesterol and the risk of adverse cardiovascular events like in Framingham Heart Study and UK Biobank. But in those cohorts, in these industrial societies, we don't have the benefit of lots of data in individuals with very low levels of LDL cholesterol and so we had the opportunity with the FOURIER study that was the randomized comparison of evolocumab PCSK9 inhibitor versus placebo to get patients down to extremely low levels of LDL cholesterol and evolocumab. We were able to get individuals down to about 30 mg/dL. And so in addition to all the studies we've done showing the comparison of evolocumab to placebo, we also then had the chance to use FOURIER, and as you'll hear from PK, FOURIER-OLE, the open-label extension, as a cohort to then examine patients' new baseline, if you will, their new achieved LDL cholesterol and then it's association not only with cardiovascular events but safety events.
And so the hypothesis is that there would be a relationship with the lower the LDL cholesterol, the lower the risk of cardiovascular events and we wanted to explore how far down that went. And then the second one for safety would be that there wouldn't be any association between low levels of LDL cholesterol and a variety of safety outcomes that rightly or wrongly people have ascribed to low levels of LDL cholesterol.
Dr Greg Hundley:
Thanks so much, Marc. Well listeners, now we're going to turn to PK, the first author, on this very interesting paper and PK, Marc mentioned to us the FOURIER-OLE study. Maybe describe for us here your study design and then what specifically was your study population?
Dr. Prakriti Gaba (PK):
Yeah, definitely. Thanks so much for the introduction. So the study population included 27,564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels that were greater than or equal to 70 mg/dL or non-HDL cholesterol greater than or equal to a 100 mg/dL on statin therapy. The patients who then went on to the FOURIER-OLE or the open-label extension part of the trial consisted of about 6,635 patients. And so in this study we essentially evaluated the combination of those populations in 2 separate analyses. We then categorized patients according to 6 pre-specified bins based on their achieved LDL cholesterol levels at designated time points and those ranged from LDL levels of less than 20 mg/dL all the way up to 100 mg/dL. And then we looked at their baseline characteristics and evaluated the cardiovascular and safety outcomes that Dr. Sabatine mentioned earlier.
Dr Greg Hundley:
Very nice PK. Well we've got a great listening audience today and they're anxious to hear your study results, so can you share those with us please?
Dr. Prakriti Gaba (PK):
Definitely. So over the course of more than 77,000 patient years of follow-up, we found that there was a monotonic relationship between achieving lower LDL cholesterol levels down to very low levels of less than 20 mg/dL and a lower annualized risk of the primary efficacy endpoint, which was a composite of 5 individual endpoints. We also found that there was a similar relationship observed between lower LDL achieved, LDL cholesterol levels and a lower annualized risk of the secondary efficacy endpoint, and then when we looked at safety, there were actually no clear monotonic trends between lower achieved LDL levels and the risk of any of the 8 adverse events and these included things like serious adverse events, hemorrhagic stroke or muscle related events.
Dr Greg Hundley:
Very nice PK and I'm sure our listeners are wanting to know, did you find any discrepancy in your results based on either age or gender?
Dr. Prakriti Gaba (PK):
That's an excellent question, and we did look at age and gender throughout. I think across the board the results were pretty consistent, but additional subanalyses will further address this question.
Dr Greg Hundley:
Very good. Well listeners now we're going to turn to one of our associate editors, Dr. Amit Khera, who has helped move this article through the process of evaluation with the editorial team. Amit, you have many papers come across your desk, what attracted you to this paper and then how do we put this study's results really in the context of other studies that have sought to dramatically lower LDL cholesterol?
Dr. Amit Khera:
Well first thanks a lot Greg for allowing me to participate today. I want to congratulate Drs. Gaba and Sabatine on a fantastic paper and the minute I saw it, and you know can tell when you've done this for a while what's a great paper, and this one certainly is and we work closely with them to try to make it better and enhance the analyses and as a group, I think we achieved that. I was fortunate to write an accompanying editorial that you'll see.
So I got to take a pretty deep dive in this paper and I want to just talk about sort of what's important here, why is this important, and I think as Dr. Gaba mentioned, there's two sides to this. There's the efficacy side where you talk about LDL lowering and getting to very low levels. Now mind you, they got to, what I call, ultra low levels, even explored for a down to a median of 7 mg/dL, so really, really low. And first I think what our listeners need to know when we look at guidelines, these numbers of 70 or 55, these are completely arbitrary and they're based on what was observed in clinical trials, what was achieved in high intensity versus moderate intensity statins in IMPROVE-IT.
There's no biology behind that, and I think what this study does is reminds us there is no biology behind how low we need to go. This group previously published their shorter-term data approximately 2 years with this construct of lower is better and I think that's fine, but people worry, particularly on the safety side about extension, and we'll get to that in a minute, so where this fits is it gives us even more reassurance that lower is better, reminds us there's no biologic basis of that even down to very low levels. And so what does that mean? I think that comes back to guidelines. We have some discrepancy between European, ACC, Multisociety Guidelines that are around 55 and so from a guideline perspective, I think we'll see a little bit more enthusiasm about lower cut points or lower thresholds. And from a clinical standpoint, as a clinician it reminds me that when I see someone that's very high risk, there's no magic to achieving a number that if the risk is high, we need to be quite intensive and get their LDL down as low as possible and as safely as possible.
I do want to also acknowledge, there's not, to your point about context, the IMPROVE-IT study also showed very low levels show additional efficacy and there's also a lot of other data, genetics and ecologic data supporting this. So this is... we look at Bayesian analysis that this is consistent that we're seeing across different platforms.
I do want to talk about safety too, Greg. That's really important because honestly this is when it comes to patient level, the safety part of it. We as clinicians may have comfort with very low levels, but the safety is important. I also want to, just from a steady design, this is post-hoc, so those that achieve very low levels are different. You can see that in their table 1, but these investigators did lots of things. They did pretty extensive multi-variable analysis, they looked at time-dependent LDLs, they looked at it multiple different ways, but as mentioned, there really did not seem to be a safety signal. And this is where time matters.
Safety in two years, interesting, but safety 5 to 8 years really offers us much more reassurance. So I think that's where this really comes in about that safety piece with the extended analysis. So again, I think from a guideline perspective, from a clinical perspective, there's so many implications from this paper and I really hope people take the time to take a deep dive and also put it in context, like you said, to the other literature where this is not standalone, but it's corroborating what we're seeing.
Dr Greg Hundley:
Very nice, amit. Marc, I want to come back to you, just two quick questions thinking about the preparation of your study. One, did you sample cognition? One thing we hear about frequently in dramatic lowering of LDL cholesterol are questions around cognition, particularly in the elderly?
Dr. Marc Sabatine:
Yeah, it's a great question Greg. So first of all, in the FOURIER study itself, there was an embedded study called EBBINGHAUS that Bob Giugliano from our group led that actually did formal neurocognitive testing in individuals using basically a iPad-like test. We also collected the usual neurocognitive adverse events as part of safety collecting. So 2 ways, the general asking about any adverse events and then the specific neurocognitive testing. We had previously reported out the results of EBBINGHAUS that there wasn't any relationship between evolocumab and the low LDL cholesterol and the risk of any neurocognitive AEs. We just were able to recently do this OLE analysis over time for the major adverse cardiovascular events and for the general safety events including cognition, so all that looked good. As PK indicated, we're now digging into the EBBINGHAUS formal neurocognitive testing, which was also extended out. So stay tuned for those results.
Dr Greg Hundley:
Very nice. And then eligibility, maybe just walk us through that really quickly. Patients that are going to be randomized to this form of therapy, were they already on high-dose statins? Who exactly did we randomize in this trial?
Dr. Marc Sabatine:
Yeah, so at the get-go, as PK indicated, these are patients with atherosclerotic cardiovascular disease, so they had a prior MI, prior stroke, symptomatic PAD. They were to be on an optimized lipid-lowering regimen, optimized statin therapy, so for close to 70%, that was a high-intensity statin. We had a small percentage on ezetimibe, but that's because we hadn't yet published the results of the IMPROVE-IT trial that Amit mentioned when we were enrolling in FOURIER, but it was a well-treated population on statin therapy. So these results would apply to your typical patient with ASCVD who's on a good statin regimen.
Dr Greg Hundley:
Very nice. Well, listeners now we're going to go back to both of our authors and investigators, as well as Dr. Khera. PK we'll start with you. What do you see as the next study to really be performed in this sphere of research?
Dr. Prakriti Gaba (PK):
I think that's an excellent question. I think with the data presented here now we know that the lower the LDL, the lower the risk of adverse cardiovascular events and that having a low LDL is safe in the long term. I think moving forward, as Dr. Khera mentioned, there needs to be a shift of these recommendations into the guidelines. So I think additional studies confirming these findings is what we need, but we do have the evidence available.
Dr Greg Hundley:
Very nice. And Marc?
Dr. Marc Sabatine:
Yeah, and I agree with PK of course. I think there's a couple things that we want to look at. We had looked in the parent FOURIER trial and found some groups who were higher risk, who seemed to have a bigger benefit early on, and those by and large were people who had a lot of athero. But as Amit indicated that the parent FOURIER trial was relatively short at about in two and a quarter years median follow up, and so now we have the benefit of an additional half decade of follow up in a subset of people and so now we're starting to look through and see the subgroups where we saw some differential benefit and this was a paper we published in circulation soon after we published the primary results of FOURIER.
Now we have the ability to go through and look at those same subgroups and see what happens now with an additional 5 years. And so that'll be quite interesting, I think, to see how those groups play out now over time. I think as Amit indicated, time is critical. We know the benefit of lipid lowering really tends to grow with time. We saw that in FOURIER, we saw that in FOURIER-OLE and then as Amit indicated, I think for safety also it's now very reassuring, being able to go out to not two and a half years, but 5, 6, 7, 8 years of safety follow up.
Dr Greg Hundley:
Very nice. Well, listeners we're next going to turn to Dr. Khera. I'm going to put him on the spot a little bit. I don't know if many of you know he's a cardiologist with expertise in primary prevention. So here we've really focused today, I think, on a very unique set of results in secondary prevention. Amit, as you think about studies to be performed in the future, is there a role for really lowering LDL cholesterol as a primary prevention target?
Dr. Amit Khera:
The short answer is absolutely. I think, to be fair, you can't necessarily directly extrapolate these results 'cause it's a secondary prevention population, but I think if we step back for a second, is there any reason I think this wouldn't work in primary prevention, there's not, and I think there's tons of genetic data, tons of other long-term data that suggests that lower is better than primary prevention. I think the challenge, as you know, is just from primary prevention is it's just about the number that you need to treat and primary prevention is pretty profound in terms of to lower events. So this is where the trade-off comes.
I think even in their study, we do have to appreciate while lower is better, when you have very low levels and you're going to even lower, let's say when you go from in secondary prevention from 50 to 40, as much as that sounds valuable, that delta's pretty small and then the absolute risk reduction is still going to be pretty small for those individuals and that's only magnified in primary prevention. So the short answer is I have no reason to believe that lower is better is not applicable in primary prevention, but I do know that the cost and what entails to get there, you don't get as much return on investment.
I do want to say one last thing though. We're talking about lower is better, and I know these investigators know this well, but it's not only just how low but how long and I think that's where primary prevention about to go to clinic and I play the long game for primary prevention that we know we've magnified these benefits over the long term and even a little bit early in life can pay off long dividends. So that's how I look at it.
Dr Greg Hundley:
Very nice. Well, listeners we want to thank Dr. Prakriti Gaba, Dr. Marc Sabatine, both from Brigham and Women's Hospital and also our own associate editor, Dr. Amit Khera from University of Texas Southwestern Medical Center for bringing us this study involving patients with arteriosclerotic cardiovascular disease indicating that long-term achievement of lower LDL cholesterol levels down to values less than 20 mg/dL was associated with a lower risk of cardiovascular outcomes and not and not an increase in the risk of significant safety related events.
Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Kavita Sharma and Associate Editor Svati Shah as they discuss the article "Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction."
Dr. Greg Hundley:
Welcome listeners, to this April 11th issue of Circulation on the Run. And I am one of your cohosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I am Dr. Peder Myhre from Akershus University Hospital, and the University of Oslo in Norway.
Dr. Greg Hundley:
Well, Peder, wow. This week's feature discussion, very interesting. We spend a lot of time, especially with our colleague, Dr. Carolyn Lam, on heart failure preserved ejection fraction. But this week's feature discussion, it's going to focus on some of the myocardial metabolomics in this condition. But before we get to that, how about we grab a cup of coffee, and jump into some of the other articles in the issue? How about if I go first?
Dr. Peder Myhre:
Let's go, Greg.
Dr. Greg Hundley:
Okay. So Peder, some believe that cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. And so, the American Heart Association, as you know, recently released an updated algorithm for evaluating cardiovascular health. Life's Essential 8, and it has a very nice score. So these authors, led by Dr. Lu Qi, from Tulane University, aimed to quantify the associations of the Life Essential 8 scores with life expectancy in a nationally representative sample of US adults. And the team included 23,000 non-pregnant non- institutionalized participants who were age 20 to 79 years, who participated in the National Health and Nutrition Examination survey, or NHANES, from 2005 to 2018. And whose mortality was identified through linkage to the National Death Index, from the period extending through December of 2019.
Dr. Peder Myhre:
Oh wow. So really, a validation of the Life's Essential 8. Greg, that's so interesting. What did they find?
Dr. Greg Hundley:
Right Peder, as you say, very interesting. So here are some of the data, and let's itemize them. So, during a median of 7.8 years of follow up, 1,359 total deaths occurred. Now, the estimated life expectancy at age 50 was 27.3 years, 32.9 years, and 36.2 years, in participants with low Life's Essential 8 scores, less than 50. Moderate, so Life's Essential 8 scores of greater than or equal to 50, but less than 80. And then, high scores, greater than 80. Okay? So equivalently, participants with high Life's Essential 8 scores had an average of 8.9 more years of life expectancy at age 50, compared to those with low scores.
Next, on average, 42.6% of the gained life expectancy at age 50, from adhering to sort of that cardiovascular health, those recommendations, was attributable to reduced cardiovascular death.
Next, significant associations with the Life's Essential 8 score and life expectancy were observed in both men and women.
Next, similarly significant associations of cardiovascular health, Life's Essential 8, with life expectancy were observed in non-Hispanic Whites and non-Hispanic Blacks, but not in those originating from the country of Mexico.
So Peder, finally, in summarizing all of this, adhering to the cardiovascular health lifestyle, defined by the Life's Essential 8 score, it was related to a considerably increased life expectancy. However, because of the findings from the individuals from the country of Mexico, more research is needed to be done in some of these minority groups, and particularly, those of Hispanic ethnicity, and perhaps other races.
Dr. Peder Myhre:
Oh, wow. Very interesting. And I would love to learn more about this subgroup analysis in future studies.
So Greg, the next paper is about the hospitalization for heart failure measures. Because contemporary measures of hospital performance for heart failure hospitalization, the 30-day risk standardized readmission and mortality rate, are estimated using the same risk adjusted model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial ethnic groups, and may not adequately represent the hospital performance for patients of Black or other races. And in this study, led by co-corresponding authors, Mentias from Cleveland Clinic and Pandey from University of Texas Southwestern Medical Center, the authors used fee for service Medicare beneficiaries from 2014 to 2019 hospitalized with heart failure, in hospital level 30 day risk standardized remission and mortality rates were estimated using traditional race agnostic models and the race specific approach, with measures derived separately for each race ethnicity group.
Dr. Greg Hundley:
Ah, very interesting, Peder. So what did they find from this study?
Dr. Peder Myhre:
So the study included more than 1.9 million patients, comprising of 75% White patients, 15% Black patients, and 10% patients of other races, with heart failure from 1,860 hospitals. And compared with the race agnostic model, composite race-specific metrics for all patients demonstrated stronger correlation with 30 days readmissions. And that is correlation coefficient 0.78 versus 0.63, and 30 day mortality rate 0.52 versus 0.29 for Black patients. In concordance in hospital performance was for all patients and patients of Black race was also higher with race specific as compared to race agnostic metrics.
So Greg, the authors conclude that among patients hospitalized with heart failure race specific 30 day risk standardized remission and mortality rates are more equitable in representing hospital performance for patients of Black and other races.
Dr. Greg Hundley:
Very nice, Peder. What a beautiful summary in a very elegant study. Peder, myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlining molecular mechanisms for this relationship remain unclear. Now, recent studies demonstrate, that the diabetic heart is resistant to several cardioprotective interventions, including adiponectin and pre-conditioning. The universal quote, unquote, resistance to multiple therapeutic interventions suggest, impairment of the requisite molecule, or molecules, involved in broad pro survival signaling cascades. Now caveolin is a scaffolding protein coordinating trans-membrane signaling transduction. However, the role of caveolin-3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. And so these investigators, led by Dr. Xinliang Ma, from Thomas Jefferson University, studied mice fed a normal diet or high fat diet for two to 12 weeks, and subjected them to myocardial ischemia and reperfusion.
Dr. Peder Myhre:
Oh wow. What an interesting preclinical science paper, Greg. What did they find?
Dr. Greg Hundley:
Right. So the authors found that nitration of caveolin-3 at tyrosine 73 and resulted signal complex dissociation was responsible for cardiac insulin adiponectin resistance in the pre-diabetic heart. And this contributed to ischemic heart failure progression. Now, early interventions preserving caveolin-3 centered signal zone integrity was found to be an effective novel strategy against diabetic exacerbation of ischemic heart failure. And Peder, I think these very exciting results suggest that this is a new area of research and further experiments are warranted.
And there's a very nice editorial by Professor Heidenreich, entitled “Pursuing Equity in Performance Measurement.
Well Peder, there's some other articles in this issue, and we'll dip in this week to the mail bag, for a Research Letter from Professor Hibbert, entitled “Utility of a Smartphone Application in Assessing Palmar Circulation Prior to Radial Artery Harvesting for Coronary Artery Bypass Grafting.”
Dr. Peder Myhre:
That is so cool. And we also have a Letter from Dr. Kim, regarding the article entitled, “Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study.”
Dr. Greg Hundley:
Very nice. Well, how about we get along to one of Carolyn's favorite topics, heart failure with preserved ejection fraction, and learn more about myocardial metabolomics?
Dr. Peder Myhre:
Can't wait.
Dr. Carolyn Lam:
Today's feature discussion is on my favorite topic, heart failure with preserved ejection fraction, or HFpEF. But today, what we're focusing on is truly novel. We are looking at the myocardial metabolomics of human HFpEF, very, very valuable data and insights. We're so pleased to have with us the corresponding author of today's feature paper, Dr. Kavita Sharma, who's from the Johns Hopkins University School of Medicine, and our associate editor, Dr. Svati Shah, who's, of course, from Duke University School of Medicine.
So welcome Kavita and Svati. Kavita, if I could start by, please put us and bring us all to the same level of knowledge, by perhaps explaining in simple terms, what is metabolomics? And what is normal versus perhaps abnormal metabolomics, in a known condition, like systolic heart failure or heart failure with reduced ejection fraction?
Dr. Kavita Sharma:
Sure. Well thank you, Carolyn, for the opportunity to chat around this topic. And it's great to be with you and Svati this morning. Metabolomics is a broad general study of essentially, all the chemical processes involving metabolites, or small molecule substrates, their intermediates, and even the products of cellular metabolism. This can be studied in really, any organ system, in any organ. What is really unique, I think, to this particular paper in our project is that, it has yet to have been defined or described in human HFpEF from the myocardial tissue. We call this heart failure with preserved ejection fraction, and inherent to that name in this complicated syndrome is that, there is something probably wrong with the heart, yet we have not really had much insight to what that might be from direct myocardial tissue.
We are also still learning about what metabolomics looks like in, for example, the heart failure with reduced ejection fraction state. Though, there is more published in this space than in HFpEF. From the limited knowledge that we have, it does appear that heart failure with reduced ejection fraction hearts, and this is certainly seen in the plasma, which is where most of metabolomic studies have generated from, those hearts tend to utilize various forms of energy banks, if you will. Whether that's fatty acid oxidation, whether that is glucose utilization or intermediates and so on. And our primary interest was to understand, how do the preserved EF parts in patients fare in comparison?
Dr. Carolyn Lam:
Oh, thank you so much, Kavita. That was beautifully explained. And indeed, what's so special about your paper is, it's not just circulating metabolites but myocardial metabolites. And you have the control groups that are so important to study at the same time. So patients with HFpEF, but also those with HFrEF and versus controls. And thank you for establishing too, that if I'm not wrong, fatty acid metabolism accounts for the majority of ATP generation in the normal heart. Whereas, this declines a little in the HFrEF heart. And now, I think we're about to find out what happens in the HFpEF heart. So if you could explain what you did and what you find.
Dr. Kavita Sharma:
Yes, absolutely. So we examined, again, tissue and plasma metabolomics from 38 subjects with HFpEF. These are patients referred to the Hopkins HFpEF Clinic. And so they have been essentially, clinically evaluated, and have what we define as HFpEF, based on hemodynamic testing. So a right heart catheterization, often with exercise, that meets criteria for diagnosis of the syndrome.
As you stated, we compared our HFpEF patient tissue and plasma samples to samples coming from patients with HFrEF, dilated cardiomyopathy, and non-failing controls. And the latter two sources were a tissue bank from the University of Pennsylvania, that is long-standing, where patients with endstage dilated cardiomyopathy are able to have tissue banked at the University of Pennsylvania at the time of explant prior to transplant. So albeit, we are comparing to fairly advanced end stage dilated cardiomyopathy, and control tissue comes from unused donor hearts, essentially. So presumably, normal heart function patients, likely in a brain death state, who for whatever reason, the hearts were not utilized for transplantation. Again, not an entirely perfect controlled state, but again, given the nature of the work, the fact that it's myocardial tissue, the closest that we have found we've been able to come to for a control comparison.
We started out performing what we call quantitative targeted metabolomics. We measured organic acids, amino acids, and acylcarnitines in the myocardium. And that was totaling around 72 metabolites. And we did the same in plasma, so close to 69 metabolites. And our metabolomics work was actually completed at the University of Pennsylvania. And so, I wish to credit Dr. Zoltan Arany and Dr. Dan Kelly for their great collaboration in this study.
Dr. Carolyn Lam:
That's wonderful. Kavita, if you could tell us a little bit more about the patients with HFpEF. We understand it was end stage dilated cardiomyopathy, HFrEF, and donor hearts as the controls, but the patients with HFpEF, in relation to obesity, diabetes, and how that may impact the interpretation of the results.
Dr. Kavita Sharma:
Sure. So these are HFpEF patients that are in an ambulatory state outpatient setting. They have many of the comorbidities we know are intrinsic today to HFpEF. Out of our HFpEF population, the majority were women. So 71%, that's 27 out of the 38 we serve. And we're very fortunate to serve a African-American enriched population in Baltimore that's intrinsic to our center. And so, over half of our patients were Black. The remaining Caucasian, one non-Caucasian. Over half had been hospitalized, for example, in the prior one year. So these are certainly symptomatic patients. And all had NYHA II or greater symptoms.
We do have a rather obese cohort at Hopkins. And so, our median BMI, for example, was 39, our mean is very similar. And the majority have, as we see often in HFpEF, the majority with hypertension, over half with diabetes. In fact, it was actually 70% or so. Rather few with coronary disease, and this is a trend we're seeing in general in HFpEF in the present day kind of common phenotypes, and about a third with atrial fibrillation. So really, representative, I think, of this kind of cardiometabolic as we call it, phenotype of HFpEF, that is the predominant phenotype we're seeing, at least in North America.
Dr. Carolyn Lam:
Oh, that's perfect. And then, maybe just a few words about the results before I bring Svati in for her thoughts. Thanks.
Dr. Kavita Sharma:
Sure, absolutely. So we conducted this study in a couple different stages. We first started with performing a principal component analysis and hierarchical clustering analysis, to see whether the myocardial metabolites and the plasma metabolites, respectively, would they distinguish these three patient groups? So HFpEF from HFrEF and controls. And interestingly, in the myocardial tissue, our PCA analysis and our hierarchical clustering analysis show that actually, in fact, as few as 70 metabolites in the myocardium really distinctly differentiate these three subgroups. The top contributors that separated HF from controls, for example, and HFrEF, were mostly related to amino acids, including branched chain amino acids and their catabolites, as well as medium and long chain acylcarnitines, which are byproducts of fatty acid oxidation.
When it came to the plasma metabolome, on the other hand, there was far less distinguishing between the groups, and significant overlap, both in PCA and hierarchal clustering. And really, the take home there is that, the myocardial tissue and the plasma were really quite distinct for the overall metabolite analysis. But then, even as we broke it down by fatty acid oxidation, by glucose metabolism, and even branched chain amino acids, we saw this trend continue, that the plasma was quite distinct from the myocardial tissue.
Now, which of the two is more representative of the disease state? Which is the one that we should be paying more attention to? I think that remains to be fully understood further. And of course, it would be really nice to replicate these findings in another cohort. But that is something that, I think, is a first, that certainly, that we have seen and important for the community.
Dr. Carolyn Lam:
Indeed. Oh, Kavita, we could go on talking forever, but I'd really love Svati's thoughts. Why was this paper so special? What does it tell us clinically with any implications?
Dr. Svati Shah:
Yeah. I just want to commend Dr. Hahn, Dr. Sharma, on this incredible work. If you can just imagine how much painstaking work this took for Dr. Sharma and Dr. Hahn. It's a very careful phenotyping of HFpEF. These are true HFpEF patients. The ability to get tissue, and to pair the tissue to the plasma, so that we can really understand. When we measure things in the circulation, and we think they're telling us about the heart, are they actually telling us about the heart? So I really want to commend this incredible work.
And Carolyn, I love talking about cardiac metabolism, because the heart is an incredible organ, right? The heart is a metabolic omnivore. It'll eat many different kinds of fuels, and a lot of different things determine which fuels it uses. And as you nicely outlined, Carolyn, earlier, in the normal heart, the heart prefers to use fatty acids.
But what we are not completely certain of is, what happens in HFpEF? So in HFrEF, we know that the heart switches to glucose, which is not a great fuel, actually. It's actually, a metabolically inefficient fuel. And so we know in HFrEF, that the heart has this metabolic inflexibility. All of a sudden, it's not an omnivore, and it's kind of stuck with certain fuels, which are not very healthy for it.
But what Dr. Sharma and Dr. Hahn have shown, for the first time really, is what happens in HFpEF? And so, I think it's really cool that, actually, it just highlights how complex HFpEF is as a disease. So they were able to show that in some ways, HFpEF is similar to HFrEF, including that there's impairments in use of these fatty acids, which is what the normal heart does.
But, they also show that HFpEF may be different than HFrEF in many ways, including, because of these branched chain amino acids. And that may be because of some of the clinical differences that we know exist in patients with HFpEF, including the obesity and diabetes, that Dr. Sharma nicely outlined. Although, I want to point out, they were very careful about trying to take these clinical factors into account when they looked at differences in the metabolites.
So really incredible work, highlighting that the HFpEF heart also has this metabolic inflexibility. It also is not a metabolic omnivore like the normal heart is, but highlighting important differences, potentially, between HFpEF and HFrEF.
Dr. Carolyn Lam:
Oh, Svati, thank you for putting that so clearly.
Dr. Kavita Sharma:
No, I think that was a really elegant summary of the findings, Svati. And thank you for your kind words and support in allowing us to share our work through Circulation. I really couldn't say it better, but that's exactly what we seem to find is that, when we look at various sort of stores or banks of energy resource, what we really found is that these HFpEF hearts are energy inflexible, as Svati said, that begins with fatty acid metabolism. And so, when we look at, for example, medium and launching acylcarnitines, what we find is that these are markedly reduced in HFpEF myocardial tissue, quite similar to HFrEF. Again, both of them reduced compared to controls. And again, these are byproducts of fatty acid oxidation, and that is really responsible for almost 80% of generally what we think of energy metabolism in the normal state.
In the plasma, however, again, back to that theme where we don't see that reproduced in the plasma, we find that HFpEF is actually not too dissimilar from controls for certain medium and long chain acylcarnitines, and then closer to HFrEF in some cases. And interestingly, we compared our metabolomics study to our prior report of our RNA sequencing paper, that was also published in Circulation now two years ago. And what we found is that, there is reduced gene expression of many of the proteins involved with fatty acid uptake and oxidation, when we compare them to control states. So the story is sort of, fits with what we have seen previously, and when we focus in on this group of genes.
Our analysis of glucose metabolism though, did not include glycolysis or glucose oxidation intermediates. We still found that, majority of the TCA cycle intermediate, so succinate, for example, fumarate, malate, were all reduced in HFpEF versus control. It was really only pyruvate in isolation that was increased in HFpEF myocardium, compared to controls. And again, a number of genes implicated in glucose metabolism in general, we found to be lower in HFpEF versus control, including gluten 1, or SLC2A1, which is involved in glucose uptake.
So again, this theme of, we have patients with significant obesity, many in the diabetic state, we would think that these hearts would utilize these energy stores, but they don't seem to be. And finally, we see distinct differences in the tissue and branched chain amino acid pathways as well. There appears to be some sort of a block between the branched chain amino acids, and then sort of byproducts, as you continue down through ketoacids and further. And we don't fully understand where those blocks are, but that was certainly notable.
And then lastly, I'll say, one interest that we've had, and really, what led to much of this work in the tissue, is to pursue what we call deep phenotyping. Can these molecular signatures, whether it's gene expression, or metabolomics, or what we're working on now, which is proteomics, can these really help us identify unique subgroups within HFpEF? And so, we've tried to do that with the metabolomics, and we found that, using various sort of clustering analytical methods, in fact, there is significant overlap, as it turns out, within HFpEF, when it comes to the metabolomic signatures. And we only found, really, two subgroups within HFpEF. And even these two really did not have much that distinguished them, beyond branched chain amino acids.
And so, this is the first time, at least that our group has seen, at a tissue level, that there is actually a fair bit of homogeneity now in the metabolomic signatures, compared to our RNA sequencing work. And that may be reflective of now, this increasingly cardiometabolic phenotype of HFpEF. And now, we may be seeing signs of that at the clinical and at the treatment level, where we have therapies like SGLT2 inhibitors, that are showing benefit to what seems to be a much broader spectrum of HFpEF, compared to prior therapies. So a lot of questions that have been generated from the work, and we're looking forward to exploring much of this in more detail.
Dr. Carolyn Lam:
And Svati, may I give you the last word? Where do you think this field is headed next?
Dr. Svati Shah:
I think there's so much to do, and I think Dr. Sharma and Dr. Hahn have highlighted how much work there is to do in this space. We're brushing the surface and understanding cardiac metabolism with this really important paper. But Carolyn, as you pointed out, we really need to understand what happens to these patients over time? What happens to, not just cardiac metabolism, but molecular biology more broadly, in patients with HFpEF with these various treatments? Including now, thank goodness, we have SGLT2 inhibitors as a therapeutic intervention for patients with HFpEF. And in fact, we published in Circulation a few months ago, a paper led by a very talented junior faculty, Senthil Selvaraj, where we actually showed that these acetylcarnitine levels that reflect fatty acid oxidation actually are changed by SGLT2 inhibitors, and are associated with changes in clinical outcomes in HFpEF. So we really need larger sample sizes, being able to look at these patients in a longitudinal fashion. But really, doing what Dr. Sharma and Dr Hahn have done, which is careful, careful phenotyping and multidisciplinary teams, so that we can understand the molecular biology, as well as the clinical implications.
Dr. Carolyn Lam:
Oh, wow. Thank you so much, Kavita and Svati, for this incredible interview. I learned so much, and enjoyed it so thoroughly, as I'm sure our listeners did as well.
Well, listeners, you've been listening to Circulation on the Run. Thank you for joining us today, and don't forget to tune in again next week.
Dr. Greg Hundley:
This program is Copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Tatsuhiko Naito and Kosuke Inoue as well as Associate Editor Wendy Post as they discuss the article "Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Study."
Dr. Greg Hundley:
Welcome listeners, to this April 4th discussion of Circulation on the Run. I am one of your co-hosts, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre from Akershus University Hospital and the University of Oslo in Norway. So Greg, today we have the feature paper, discussing the genetic risk of primary aldosteronism and its contribution to hypertension. So this is such an interesting topic and av very important cost on hypertension. And in this paper, they use cross-ancestry meta-analysis from GWAS studies to assess this very interesting discussion.
But first, Greg, I have a paper that comes to us from the DELIVER trial, and it is about dapagliflozin to patients with HFpEF, and assessing the association with the duration of the heart failure.
So Greg, it is important to understand how the effects of new treatments vary by the duration of heart failure. Because on one hand, physicians may think that a patient who has longer standing heart failure represents a stable survivor where new treatment is unnecessary. On the other hand, the view has been expressed that patients with long-standing heart failure may have more advanced disease, and there may come a point where they no longer respond to or tolerate the addition of new therapies, particularly because of hypotension, kidney dysfunctional and electrolyte abnormality. So the investigators from the DELIVER trial, led by corresponding all author John McMurray from University of Glasgow, therefore, aimed to assess the efficacy and safety of the SGLT2 inhibitor dapagliflozin, according to the duration of heart failure with EF above 40%. So that is mildly reduced or preserved.
Dr. Greg Hundley:
Wow, Peder, very timely, very timely article. So what did they find?
Dr. Peder Myhre:
So Greg, the authors categorized patients by duration of heart failure, one category less than six months, and then six to 12 months, and then one to two years, two to five years, and finally, more than five years. And longer duration heart failure patients were older, and more comorbid with worse symptoms, and the rate of the primary outcome increased with heart failure duration. And so, the benefit of dapagliflozin was consistent across heart failure duration categories with hazard ratios 0.67, 0.78, 0.81, 0.97, and 0.78. And that gives a P4 interaction of 0.41. So the absolute benefit was therefore since there was no P4 interaction, greatest among those with highest risk, and that it was the longest duration heart failure. So there was a number needed to create for heart failure above five years of 24, versus 32 for those with the shortest duration of heart failure. And the authors therefore conclude, that even in patients with long-standing heart failure and generally mild symptoms cannot be considered stable, and it is not too late for such patients to benefit from an SGLT2 inhibitor.
Dr. Greg Hundley:
Ah, very practical information, Peder, beautiful description. Well Peder, this next paper comes to us evaluating low density lipoprotein cholesterol. And as you know, low density lipoprotein cholesterol is an important causal risk factor for atherosclerotic cardiovascular disease. However, a sizable proportion of middle-aged individuals have not developed coronary atherosclerosis as assessed by the presence of coronary artery calcification. Now whether the presence of coronary artery calcification modifies the association of LDL cholesterol with atherosclerotic cardiovascular disease risk, well, that's unknown. So these authors, led by the corresponding author of Martin Mortensen from Aarhus University Hospital, evaluated the association of LDL cholesterol with future atherosclerotic cardiovascular disease events, in patients with and without coronary artery calcium, from 23,132 consecutive symptomatic patients evaluated for coronary artery disease, using coronary commuted tomography angiography, or CTA, that were included in the Western Denmark Heart Registry, which is a semi-national multi-center based registry with longitudinal registration of both patient and procedural data.
Dr. Peder Myhre:
Oh, that is so important, Greg. So we're looking at LDL cholesterol and the association with ASCVD in patients with and without coronary artery calcification. So what did they find?
Dr. Greg Hundley:
Right, Peder. So during a median follow up of 4.3 years, 552 patients experienced a first cardiovascular disease event. In the overall population, LDL cholesterol per 38.7 milligrams per deciliter increase, was associated with cardiovascular disease events during the follow-up period. Now, when stratified by the presence or absence of a baseline coronary artery calcium score, LDL cholesterol was only associated with a cardiovascular disease event in the 47% of patients with a coronary CAC score greater than zero. While no association was observed in the 53% of individuals with a coronary artery calcium score equal to zero.
Now similarly, very high LDL cholesterol, so greater than 193 milligrams per deciliter, versus an LDL cholesterol of less than 116 milligrams per deciliter, was associated with a cardiovascular disease event in patients with a CAC score greater than zero, but not in those without coronary artery calcium. Next, Peder, in patients with coronary artery calcium equal to zero, diabetes, current smoking, and low HDL cholesterol levels, were associated with future cardiovascular disease events. This principle finding was replicated in the multiethnic study of atherosclerosis.
And so, Peder, LDL cholesterol appears almost exclusively associated with a cardiovascular disease event over the ensuing five years of follow-up in middle-aged patients with versus without evidence of coronary atherosclerosis, as identified by coronary artery calcium scores. This information is quite valuable for individualized risk assessment among middle-aged patients.
Dr. Peder Myhre:
Oh, that is so important, Greg. So really, LDL seems to be more predictive of atherosclerotic cardiovascular disease than those with calcium in their coronaries, while there was no association in those with no calcium in their coronaries. Very interesting.
Dr. Greg Hundley:
Absolutely. And there's a very nice editorial by Professor Sniderman entitled, “Cholesterol Coronary Calcification and Cardiovascular Prevention: Lessons We Can Learn from the Western Denmark Heart Registry.”
Dr. Peder Myhre:
Thank you, Greg, that was a beautiful summary. And we are going to stay in clinical science, but we're going to move to aortic disease and look at gut microbiota. Now, Greg, large scale human and mechanistic mouse studies indicate a strong relationship between the microbiome dependent metabolyte, Trimethylamine-N-oxide, abbreviated TMAO, and several cardiometabolic diseases. And in this study, which comes to us from corresponding author Philip Owens from University of Cincinnati, the investigators aim to assess TMAO's role in the pathogenesis of AAA and targeting its parent microbes as a potential pharmacologic intervention.
Dr. Greg Hundley:
Ah, very interesting, Peder. So what methodology did they use?
Dr. Peder Myhre:
So Greg, this is one of those fantastic studies combining clinical and preclinical science. And the investigator measured TMAO in two independent patient cohorts, with a total of 2,129. And in addition, they used the murine AAA model, and fed the mice a high choline diet, which is a diet that markedly augment plasma levels of TMAO. And these mice were then treated with broad spectrum antibiotics, targeted inhibition of a gut microbial enzyme with fluorometer chloroquine, called FMC, or utilizing mice genetically deficient of Fmo3.
Dr. Greg Hundley:
Very nice. So what did they find, Peder?
Dr. Peder Myhre:
So the authors found that elevated TMAO was associated with increased AAA incidence and growth in both patient cohort studies. And dietary colon supplementations augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad spectrum antibiotics. In treatment with FMC ablated TMAO production attenuated colon augmented aneurysm in the initiation, and halted progression of an established aneurysm model. And additionally, the Fmo3 knockout mice had reduced plasma TMAO, aortic diameters, and were protected from AAA rupture compared to wild type mice.
So Greg, in conclusion, this study defined a role for gut microbiota generated TMAO in AAA formation, and additionally, increased microbiome derived TMAO may serve as a novel therapeutic approach for AAA treatment where non currently exists.
Dr. Greg Hundley:
Beautifully described, Peder. And another one of their articles in Circulation that, as you indicated, very nicely complying the world of preclinical and clinical science.
Well, we've got some other articles in the issue, and how about we jump into some of those? So first, there's a very nice Letter to the Editor from Professor Wong entitled, “Frailty and Age Correlation in Clinical Trials.” And there is another reply to a prior Letter to the Editor from Professor McMurray entitled, “Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure, a Pre-specified Analysis of the DELIVER Trial.” And then next, Peder, Michelle A. Albert has a very nice synopsis of the American Heart Association Presidential Address, entitled, “Economic Adversity and Healthcare.”
Dr. Peder Myhre:
Nice. And finally, there's a Research Letter from Dr. Baggish entitled, “Association Between Concussion Burden During Professional American-style Football and Post-career Hypertension.”
Dr. Greg Hundley:
Very good, Peder. Well, what a packed issue we have this week, and how about we jump next to that feature discussion with our colleague Carolyn? Ah.
Dr. Peder Myhre:
Let's go.
Dr. Carolyn Lam:
Primary aldosteronism, or, we're going to say PA for this discussion, is one of the most common causes of secondary hypertension, and it is also a particularly morbid form of secondary hypertension. So identifying this subgroup of hypertensive patients with primary aldosteronism, again PA, would allow us to perhaps, direct more aggressive management to their cardiometabolic risk. Now, is a genetic approach the way to do it? Well, we're about to find out in today's very special paper.
We're very honored to have the first author, Dr. Tatsuhiko Naito, from Osaka University Graduate School of Medicine, and his second and co-author Dr. Kosuke Inoue, from the Graduate School of Medicine in Kyoto University, as well as our associate editor, Dr. Wendy Post, from Johns Hopkins University School of Medicine, here to discuss this very important paper. Perhaps I could start with you, Dr. Tatsuhiko. Could you please, perhaps, tell us a little bit about what made you do this study, what you did, and what you found?
Dr. Tatsuhiko Naito:
I would like to thank you for inviting us to present the information from our paper. In terms of genetic, germline genetic factors behind the development of PA has not been isolated. And in addition, the PA is the cause of hypertension, but the genetic relationship between hypertension and PA has not been discussed previously. That is why we conducted a genome-wide association study, GWAS, of PA here. Our GWAS consisted of three defined cohorts of our Japanese cohort, UK Biobank, and FinnGen. In our Japanese cohort, we collected samples in Hiroshima University, and we used controls from Biobank Japan, which is the largest Japanese biobank. And we also used two publicly available biobanks, UK Biobank and FinnGen. So they can be used upon registration. By utilizing these resources, we conducted a cross-ancestry, meta-analysis of GWAS.
Dr. Carolyn Lam:
Thank you. And the results, please?
Dr. Tatsuhiko Naito:
In the meta-analysis, we identified five genetic loci that were significantly associated with the risk of PA satisfied in the genome world significant threshold. The strongest association was observed at WNT2B, which is located in chromosome 1. And in addition, we identified one near the genome-wide association locus CYP11B1 and B2, which is located on chromosome 8. So CYP11B2 is the key enzyme that acts in producing aldosterone in the adrenal gland, thus, we consider that resource. This locus would be also our PA risk associated locus with a high probability.
Of interest, these loci were reported to be associated with hypertension, but we thought this results is resemble, because PA occupies around five to 10% of causes of hypertension. Does the PA associated loci could be reported as hypertension associated loci in previous GWAS with large sample size?
So to support our assumption, we compared the risk effect of these genetic loci between PA and hypertension. So if there are risk effects who are coming from PA, these loci should present higher effect on PA than on hypertension. And expectedly, these loci presented significantly higher effect on PA here.
And lastly, inspired by these results, we hypothesized that some of other loci, that had been reported to be associated with hypertension, might come from the primary effects on PA. To investigate this, we picked up blood pressure rated genetic loci from previous GWAS of blood pressure, and compared their risk effects between PA and hypertension. The result was that, 66.7% presented a higher risk effect for PA than for hypertension. And two strictly demonstrates the result. We also performed the adjustment of blood pressure values, and even in this adjustment, 61.9% showed a higher effect on PA than on hypertension. So considering the prevalence of PA among hypertensive individuals, this result is little bit surprising, we think. So PA may explain an unexpectedly large amount of genetic background of hypertension, we think.
Dr. Carolyn Lam:
Wow, thank you so much, Tatsuhiko. So first, genome-wide evidence for genetic predisposition to PA susceptibility, and then, revealing that two thirds of previously established BP associated variants were in fact a higher risk effect for PA than for hypertension. Wow. So Wendy, could you help us put these findings into perspective, please?
Dr. Wendy Post:
Thank you, Carolyn. Congratulations to the authors. This was a really interesting paper that we enjoyed discussing in our meetings. We were especially interested in the clinical potential, clinical implications of your study. We all see patients with hypertension, whether we're cardiologists, or endocrinologists, or primary care physicians. And so, trying to understand more about what is potentially the underlying causes for hypertension, from a biological standpoint, that might help us to identify and treat our patients appropriately, is really so important. And so, I was wondering, Kosuke, if you could tell us, from your perspective as an endocrinologist and a researcher, how you interpret these studies in a way that our readers might be able to use these results to think about the next patient we're seeing in our clinic with hypertension?
Dr. Kosuke Inoue:
Yeah. Thank you very much for asking this important point, Wendy. We're, first of all, I'm very pleased that our research is published in Circulation, and thank you very much for your consideration. And I think there are two major implications of our findings, treatment and a diagnosis.
First of all, for treatment, well, our findings advance our current state of knowledge about PA pathogenesis. Like Wendy said, what is the causes? And what is the genetic causes of primary aldosteronism ? And particularly, it'll be helpful for better precision medicine in the future. And therapy involving genetic information, this may not be the clinical practice tomorrow, but this would advance our clinical practice in the future.
And the second point is diagnosis. Well, primary aldosteronism is really important to diagnose, because treating only blood pressure, or hypertension, is not enough for patients with primary aldosteronism. Like Tatsu said, aldosteronism itself has a direct effect on organ damage beyond blood pressure, elevated blood pressure. So diagnosis of primary aldosteronism is critical, and our findings showed 10%, the current percentage of 10% primary aldosteronism, may not be fully diagnosed patients, given that 67% of PA associated variants presented higher alteration for the PA. So I think, we needed to be more careful about diagnosing primary aldosteronism. So for those who have a resistant hypertension, or who are suspected to have primary aldosteronism, we needed to screen more for such patients.
Dr. Wendy Post:
Thank you, that was really helpful. Can I ask you a little bit more about what you recommend in clinical practice? I've been asking around, we actually just had our American College of Cardiology meeting in New Orleans, and I knew this paper had just been published online, and the editorial is about to come out. And so, I noticed that there's a lot of variability in practice, as to whether we screen for PA, or just treat with aldosterone blocking medications, such as spironalactone. So can you tell me a little bit more about what you recommend? And maybe your practice is different as an endocrinologist, but should we just presume people have primary aldo, and aldosteronism, and treat them for that? Or should we be searching for aldosterone producing adenomas, and surgically removing them? If you could, tell us a little bit more about what you recommend.
Dr. Kosuke Inoue:
Thank you very much for asking this, Wendy. So to be honest, I don't think we can conclude something only from our result, of course. But what I can recommend is, from our findings, it is better to always thinking about primary aldosteronism when treating patients with hypertension. So those may have and those may not have that. I think thinking about primary aldosteronism is important, and if there's a possibility they have, or if their clinicians have trouble treating hypertension, then I would recommend screening for such patients about primary aldosteronism.
Dr. Wendy Post:
In order to find an adenoma, is that the purpose of the screening?
Dr. Kosuke Inoue:
I think, whether they have an adenoma or, there are two types of primary aldosteronism, aldosteronism producing adenoma, and BAH bilateral adrenal hypocardia. And rather does not have adenoma itself, but they have a hyper aldosteronism in their blood. So we cannot tell whether they have a PA or BAH. But anyway, we needed to think about whether they have excess level of aldosterone, and if they have, we needed to think about the proper treatment, such as medication therapy or surgical treatment.
Dr. Wendy Post:
Thank you. So if they have bilateral adrenal hyperplasia, then medical therapy.
Dr. Kosuke Inoue:
Yes.
Dr. Wendy Post:
If they had an adenoma, you might consider surgical excision.
Dr. Kosuke Inoue:
Generally, yes.
Dr. Wendy Post:
Thank you.
Dr. Carolyn Lam:
Wendy, I love that clinical focus, because much as PA is a highly morbid cause of secondary hypertension, it's also sometimes seen as potentially curable, or at least targetable with specific medical therapy. And thank you for inviting that beautiful editorial, I'd love to quote from it. Because the final sentence of it really does say that this paper really reminds everyone treating hypertension, to maintain a high clinical suspicion for PA, and hopefully, such a high clinical suspicion will lower the threshold for biochemical testing. Will motivate the pursuit of localization studies, to determine if a surgical cure is possible. And at minimum, allow for early initiation of mineralocorticoid-receptor blockade. How beautifully put, huh?
So thank you for inviting that editorial. And if I may, are there any final take home messages from anyone? May I start with Dr. Tatsuhiko? Any take home messages or next steps you'd like to mention?
Dr. Tatsuhiko Naito:
Okay. Yeah. I think the future advances in this study first, as Kosuke said, of PA is mainly classified into aldosterone producing adenoma and bilateral adrenal hyperplasia. However, we couldn't identify subtype specific risk associated loci, due to the lack of statistical power. And specifically, we know that histopathological features of aldosterone producing adenoma are reported, vary depending on the causative somatic mutations. So further insights may be obtained by investigating the genetic risk of aldosterone producing adenoma, according to the causative somatic mutations. But anyways, we are happy to present the genome-wide association genetic loci that associated with PA in the cross-ancestry cohort for the first time. Thank you.
Dr. Carolyn Lam:
Thank you. Kosuke?
Kosuke Inoue:
Sure. So I totally agree with what Tatshu said, and also, aldosterone is a nasty hormone. So as a clinician, I would recommend, for all clinicians who treat patients with hypertension, please always consider aldosterone, and whether their aldosterone should be treated or not. And thank you.
Dr. Carolyn Lam:
Wendy?
Dr. Wendy Post:
I also wanted to get back to your statements, Kosuke, about precision medicine. And this was a genetic study, and you did mention how this could potentially lead to precision medicine, practical approaches to identifying patients who might be treated with specific therapies, based on their genetics. And of course, we're not there yet, but thanks for helping us to get closer to that vision in the future.
Dr. Carolyn Lam:
Indeed, thank you so much for publishing this very important paper in Circulation, and for coming online to discuss it today.
You've been listening to Circulation on the Run. Thank you listeners for joining us today, and don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study."
Dr. Gregory Hundley:
Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion.
Dr. Gregory Hundley:
Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966.
Dr. Peder Myhre:
Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find?
Dr. Gregory Hundley:
Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery.
Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race.
So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients.
Dr. Peder Myhre:
Well, that is really interesting, Greg. Are you ready for the next paper?
Dr. Gregory Hundley:
Absolutely.
Dr. Peder Myhre:
So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events.
Dr. Gregory Hundley:
Interesting, Peder. So what did they find?
Dr. Peder Myhre:
So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits.
Dr. Gregory Hundley:
Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses.
Dr. Peder Myhre:
Oh, this is really interesting, Greg. So what did they find?
Dr. Gregory Hundley:
Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction.
So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.
Dr. Peder Myhre:
Oh wow. That was really impressive.
Dr. Gregory Hundley:
Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled “A Mouse Model of Atrial Fibrillation in Sepsis.” And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled “Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure.” And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled “Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes.” And that particular paper is published in Nature.
Dr. Peder Myhre:
That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.” And finally we have On My Mind by Bertram Pitt entitled “Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension.” Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes.
Dr. Gregory Hundley:
Very good. Let's go.
Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Vincent Aengevaeren:
So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis.
And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density.
Dr. Gregory Hundley:
Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here?
Dr. Vincent Aengevaeren:
The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics.
So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise.
Dr. Gregory Hundley:
Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here.
Dr. Vincent Aengevaeren:
So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes.
Dr. Gregory Hundley:
Very nice. So Vince, describe for us your study results.
Dr. Vincent Aengevaeren:
During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings.
Dr. Gregory Hundley:
And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples.
Dr. Vincent Aengevaeren:
So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher intensity, for example spinning on a spinning bike, it's traditionally at a higher exercise intensity. So that was counted as a very vigorous intensity exercise. And I have to say this was based on questionnaire data, so I did not have six-year or lifelong heart rate data. So it is based on questionnaire data, the categorization of exercise intensity. That's a good example. Other things of [inaudible 00:19:03] intensives, for example, soccer, hockey, I don't know how popular those sports are in America, but those are pretty popular in Netherlands as well.
Dr. Gregory Hundley:
When you mean very vigorous for some of our runners out there, I mean for the casual runner that might run two or three miles a day, is that very vigorous or are you talking about someone that's training periodically for marathons and running three or four marathons a year?
Dr. Vincent Aengevaeren:
That is really more, I guess, about volume. So if people do a lot of marathons, that can actually be at a lower intensity. Like, with intensity, we really, really mean the heart rate intensity and not the intensity of the volume. So I have to specify that. It's really exercise intensity such as for oxygen consumption or heart rate and not the volume in the hours per week. So typically the runners that we had were mostly very vigorous runners. So couple hours per week traditionally they did like trainings of one and a half hour, which is usually at a higher intensity.
Dr. Gregory Hundley:
Very nice. Well listeners, now we're going to turn to one of our associate editors, Dr. Jarett Berry, who really has some expertise in this area. And Jarett, you see many papers in circulation. What do you find is unique about this particular study and then how do you put its results really in the context of other studies that have focused on exercise both in duration as well as intensity?
Dr. Jarett Berry:
Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege to be able to visit with both of you today about this important paper. I think if you take a step back here, challenges I think we all have as physicians is dealing with these uncertain questions that arise clinically where you encounter patients who are exercising at these extreme levels. And although it's not super common, we do encounter these scenarios clinically. And what we need in context like this is we need some data and understanding of what's happening clinically to be able to provide guidance. And so we're really in a context like this in a scenario where we have the common clinical problem of incomplete information. And I think it's studies like this that really help us move the needle to help us understand how to think about those patients of ours that exercise at very high levels.
I do think it's important to put it into context, about 10% of the participants in this study exercised below 1,000 minutes per week. And so for those of you taking notes at home, that's the guidelines in 500 and 1,000 minutes per week would be, I mean you'd be hitting the guidelines. And two-thirds of these individuals were exercising at 2,000 minutes per week. So I think it's important to put it into context when we think about applying and understanding the question about toxicity of exercise, putting that into context that most of the patients that we encounter are not exercising at these high levels. However, as I mentioned, we do encounter this and we have to know what to do with it.
The key here I think is... The other context is with a point that's been raised already in some of the questions and discussion is the heterogeneity that we see in individuals who exercise at these high levels. When you're trying to think about dose of exercise, we have to think about not just intensity but volume. And I think what the study's done here has done a really nice job of trying to parse that out because we can achieve the dose of exercise that's recommended or the dose of exercise that we want to achieve for personal reasons, but we can get there through different ways. We can get there through more hours or we can get there through a higher intensity. And then of course, obviously combinations of the two.
And I think this study here does two things for us. Number one, it gives us a delta question. We've seen this before with just looking cross-sectionally and we have all the challenges that come with that with regard to recall of exercise. Here we have a prospective cohort that we're following or that events followed. And secondly, the ability to parse out both volume and intensity over time. And I think that for me, the finding that really sticks out is that in addition to all the complexities that are right here, we see that the story with regard the components of the dose may not be uniform. That intensity or exercising at very high intensity may be a different part of the equation beyond just volume.
And I think that as we think about counseling our patients as they are engaging in this type of high level of exercise, I think it's one additional component of our way of interpreting this and providing counsel to these patients about how to think about volume and intensity. And maybe these data suggests the hypothesis that the volume part of the dose equation may be safer or maybe something that's more palatable for the heart perhaps over time than the intensity. I think the big elephant in the room, of course, is the fundamental question is that we're dealing with an intermediate phenotype and we know lots of observational data showing that more atheros bad. We all recognize that, but you can get to athero through different mechanisms here.
And I think that these data and others suggest that exercise is one mechanism perhaps that though you can get athero, the question is what is the true clinical significance from a [inaudible 00:24:32] standpoint down the road as we try to extrapolate the intermediate phenotype into the future. And I think there's controversy, I think agreement about what the intermediate phenotype means in these high volume exercisers. And I think that question remains unknown, I think.
But in the interim, as I said in the beginning, that as we think about putting all this into context, we don't have perfect information and we do have to take the information that we do have to provide the counsel that we need to provide if these patients. And I think I take away from this that when providing counsel, maybe I lean more towards volume and less towards this really high volume, sorry, this really high intensity for those individuals whose coronary calcium or their athero burden is particularly high. But a fantastic study. Another step in the road and it's really trying to understand an incredibly complex story and one that will continue to unfold.
Dr. Gregory Hundley:
Very nice, Jarett. And listeners, we're going to turn back to both Vince and Jarett here each in 30 seconds. Vince, what do you see as the next study that your group or others might want to be considering in this sphere of research?
Dr. Vincent Aengevaeren:
For me personally, the next big thing that we should do is really cardiovascular risk. So what's the clinical relevance of this finding? So coronary calcification is strongly associated with cardiovascular risk, but how that is in these athletes in which we see increased coronary calcification, that's still pretty much the question. I mean, any plaque is worse than no plaque, but how is this for the very vigorous exercisers who may show some more calcification and whether that risk is different. I mean, that's the question that all the athletes that email me after this type of publication have the question. And also the mechanisms. Like, what are the underlying mechanisms? That's also a next lead study for me.
Dr. Gregory Hundley:
Very nice. And Jarett?
Dr. Jarett Berry:
Yeah, I think the ultimate question is, I completely agree, is what is the clinical significance. I think that's going to be... That's a challenging question to answer just because of the on average these individuals are more rare. And so following these individuals over time to really tease out the clinical significance of this type of athero in these athletes, I think, is a challenge. I think for me the next step would be more studies like this where we can get more granular with regard to measured exercise intensity. I think wearable devices, things that Vince alluded to with regard to heart rate, really trying to get more quantitative to try to parse out the contribution of more objectively measured exercise intensities, I think would probably, for me, represents kind of probably the next step, is digging a little deeper into the phenotype and being a little bit more precise perhaps with studies like this to help us begin to understand the significance of these findings.
Dr. Gregory Hundley:
Very nice. Well, listeners, we want to thank Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands, and our own associated editor, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas for bringing us this study highlighting that exercise intensity but not volume was associated with progression of coronary atherosclerosis during a six-year follow-up of this cohort of really trained athletes and intriguingly the very vigorous. So we want to distinguish that. The very vigorous intensity exercise was associated with greater coronary artery calcium calcified plaque progression, whereas simply just vigorous intensity exercise, casual riding of the bike, casual running, et cetera, was associated with less coronary artery calcium progression.
Well, on behalf of Peder and Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age."
Dr. Greg Hundley:
Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway.
Dr. Greg Hundley:
Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?
Dr. Peder Myhre:
I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts.
Dr. Greg Hundley:
Wow, Peder, so a very large gene-wide association study. So what did they find?
Dr. Peder Myhre:
So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease.
Dr. Greg Hundley:
Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development.
Dr. Peder Myhre:
Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find?
Dr. Greg Hundley:
Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.
So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects.
Dr. Peder Myhre:
Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first?
Dr. Greg Hundley:
Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study."
Dr. Peder Myhre:
And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions.
And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century."
And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that?
Dr. Greg Hundley:
Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion?
Dr. Peder Myhre:
Let's go.
Dr. Mercedes Carnethon:
Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found.
Professor Mikael Dellborg:
Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor.
Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD.
Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline.
So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed.
Dr. Mercedes Carnethon:
Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you?
Professor Mikael Dellborg:
What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age.
Dr. Mercedes Carnethon:
Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation?
Dr. Gerald Greil:
Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future?
Professor Mikael Dellborg:
Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years.
The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet.
It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers.
We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper.
Dr. Gerald Greil:
Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients?
Professor Mikael Dellborg:
I think they relate to our paper in a nice way, because one of the things we also could show was that the morbidities of patients with adult congenital heart disease are significant. The risk of heart failure, atrial fibrillation, stroke, nonfatal MI, diabetes, and so on, is much larger in that group. And the cumulative risk of having any such adverse event is about 75% at age 68 after 50 years of follow-up. The letter by Bergh et al. focuses on, as you say, heart failure. And during a follow-up or 25 years, there was an overall, like you said, 8.7 times higher risk for patients with CHD to develop heart failure. The most, I think, important factor from this is not only that the risk is increased, it has been described before and it's obvious and quite intuitive, but there was a dramatic difference in the age of onset of heart failure, which was about 40 years in patients with CHD compared to 66 years of age for the controls who developed heart failure.
And again, it was obvious that it was highest among the most complex CHD. The risk was 20 to 40 times higher. But also among non-complex CHD, the atrial receptor defects, the ventricular receptor defects, the risk was significantly higher, five to 10 times. One thing we saw there was that... That could be seen there was that the risk was particularly high in the youngest age group, the youngest patients, as compared to controls. And not so much, although still significant, it increased also in the higher age groups. We could also see that the risk of heart failure seemed to increase. It was higher among those born after 1970 as compared to those before 1930 to '69.
And I have two explanations for that. One is that a lot of patients born in 1930 and so on were not captured by our registers, because they have died before that. But it also reflects that the most complex patients, the most likely to develop heart failure, they survive these days. They did not survive in their thirties, forties, fifties, sixties and early seventies and so on, so that's why. So things haven't been worse, but we do have a much sicker group of patients with congenital heart disease that are alive today.
Dr. Mercedes Carnethon:
That's very hopeful. When I hear that and I think about the impact that treatment and therapy has had on these improvements in survival, it's really exciting to hear. We were really enthusiastic because our colleagues, Dr. Rosenthal and Qureshi from London, submitted an editorial to discuss your piece as well as Dr. Bergh's piece. And they're discussing in it some of the complexity in providing this care and what it has taken to get us to this point where survival is better. Can you tell us a little bit based on the findings from your study and what you know of the field, how do you envision the future care of adults with congenital heart disease?
Professor Mikael Dellborg:
Yes, Mercedes, thank you. I think this is a very nice editorial. It summarizes very well where we are today, and I think they see the future very much along the same lines as I do and as we do. But the large number of patients with CHD living into their sixties, seventies, and eighties, they will not only live longer, they will also have more comorbidities. And I think that's what our data shown and what the editorial is discussing. This will require some changes to be made to the care of adults with congenital heart disease. We will clearly, as pointed out, need large, highly specialized, very competent ACHD centers located close to, or at least in close corporation with pediatric centers. There's no doubt about that building such centers need to continue and you need roughly one large complete such center with outpatient clinic, surgical interventions, structured transfer, specialized physicians, physiotherapists, nurses, education research, et cetera.
You need about one such center per 5 million people. But over time the need of ACHD patients will also change and this will have impact also on the large specialized centers. For instance, if you have an adult patient with say, tetrology of Fallot, fairly common disease in this setting, well operated on a early childhood, well-functioning, modest right ventricular dysfunction, modest pulmonary valve insufficiency, and it's followed by a large centralized ACHD unit. You will keep track of the right ventricle size waiting for the proper time to intervene and replace the right ventricular outflow tract by surgery or catheter. This waiting is probably 10, 15, maybe 20 years before anything needs to be done. But during that time the patient develops hypertension, type 2 diabetes, AFib, and the chances of this happening at some time are fairly substantial. So either the ACHD unit needs to take care of also these comorbidities and that's not always the case today.
And I think it's unrealistic to expect primary care GPs to do this. I mean, would you as primary... As a GP start the SGLT2 treatment? Is that okay for a patient with Fallot? Or the indications for anticoagulation the same as... And that's not easy patients to handle. So on the other hand, if the ACHD unit will take care also of all these comorbidities, they will, I think, have too much to do and I think they will find it difficult to completely cope with this. So as in increasing role for cardiologists who are knowledgeable on ACHD care, but who perhaps spend most of the time caring for the usual patients with heart failure and AFib, post-MI, type 2 diabetes and who are confident in using novel anti-diabetic medications, but at the same time they know about Fallot. They know enough to understand the do's and don'ts, and they can interact on a regular basis with the local ACHD units. So patients will see their general cardiologist twice a year perhaps, and the ACHD center every two years, something like that. I think there's a great need for that.
Dr. Mercedes Carnethon:
I really appreciate having your insights on that. Do you have anything, Gerald, that you'd like to follow up with? I think the feedback that you've shared with us, Mikael, about where you see the treatment field going for adults has been very comprehensive and it's fantastic to be able to have these conversations with you, because obviously these discussions go beyond what you can share in the original research article, which is why we really enjoy this opportunity with the podcast. So Gerald, I'd really like to turn it to you for a final wrap up, given your expertise in this area.
Dr. Gerald Greil:
Yeah, I mean, Mikael, thank you so much to you and your colleagues just giving us this great overview, and even more importantly giving us the perspective how this field is going. I think we are getting more and more aware that there are more patients with and adults with congenital heart disease we need to take care of. We need to find new strategies, as you correctly pointed out, to cope with the enormous burden of disease and providing these patients good quality of life and excellent outcome after sometimes a very difficult start in their lives. And we need to be aware of the pediatricians and adult cardiologists and other subspecialties are forming a team and working together and not working as separate entities. So thank you so much for giving us this perspective. And I would hand over to Mercedes to wrap up the whole discussion please.
Dr. Mercedes Carnethon:
Well, yes, I just really want to thank our listeners for tuning in with us today. It was such a delight to have you here with us, Dr. Dellborg, and thank you as well for sharing your insights.
Thank you for joining us again for this episode of Circulation on the Run Podcast. It's meant to whet your appetite and turn you towards the journal so that you can read more. So thank you very much.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first.
I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs.
Dr. Greg Hundley:
Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study.
Dr. Carolyn Lam:
Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy.
Dr. Greg Hundley:
Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination.
Dr. Carolyn Lam:
Wow. Wow. Important question. Everyone's interested in the results. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis.
Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science.
Dr. Carolyn Lam:
Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, “Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction.” That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we?
Dr. Greg Hundley:
Absolutely.
Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address?
Dr. Milind Desai:
Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers.
So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today.
Dr. Greg Hundley:
Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll?
Dr. Milind Desai:
Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients.
Dr. Greg Hundley:
Very nice. So Milind, what were your study results?
Dr. Milind Desai:
Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers.
But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT.
Dr. Greg Hundley:
And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex?
Dr. Milind Desai:
No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders.
Dr. Greg Hundley:
And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there?
Dr. Milind Desai:
There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity.
Dr. Greg Hundley:
And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles?
Dr. Milind Desai:
The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy.
Dr. Greg Hundley:
Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy?
Dr. Mark Link:
Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper.
Dr. Greg Hundley:
Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research?
Dr. Milind Desai:
Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out.
Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging.
Dr. Greg Hundley:
Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about?
Dr. Milind Desai:
So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very careful about over inhibition of the cardiac myosin and a drop in ejection fraction and its downstream ramifications including heart failure. The other aspect is drug-drug interaction because of its pathway of metabolism. So these are the two key things we have to be on the careful about.
Now you asked my clinical experience. So we have been prescribing this for almost six, seven months, and we have dozens of patients on this using the REMS strategy, careful echocardiographic monitoring and clinical decision making. So far, we have been very successfully able to navigate these patients without any major adverse events. And the vast majority of the patients, true to form as we have shown in the clinical trial, are doing very, very well in terms of their symptoms, their need for SRT, as well as their markers, including outflow tract gradient.
Dr. Greg Hundley:
Very nice. And Mark, turning to you from the perspective of an electrophysiologist, what potential future studies do you see forming in this space?
Dr. Mark Link:
Yeah, very similar to Milind. And I think the long term efficacy and safety really has to be looked at. There's a signal for potential harm in that the EF can drop, and Milind mentioned that too, that we have to learn how to deal with that. The way to prescribe it now, you have to be in a special program. You have to be trained, you have to agree to get echoes every three months, I believe it is, essentially for the rest of their life. So we need to see what happens long term with these drugs and we need to know how to dose them and how to do it safely.
Dr. Greg Hundley:
Very nice. So for our listeners, really a class of drugs that is emerging and at this time only under really strictly supervise protocols. Well, from the perspective of our listeners, we want to thank Dr. Milind Desai and our own associate editor, Dr. Mark Link, for bringing us this informative new early randomized trial study results indicating that in severely symptomatic patients with obstructive hypertrophic cardiomyopathy, 32 weeks of mavacampten treatment showed sustained reduction in the proportion proceeding to septal reduction therapy.
Well, on behalf of Petter, Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume.
Dr. Greg Hundley:
Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform?
Dr. Carolyn Lam:
So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment.
Dr. Greg Hundley:
Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative.
Dr. Carolyn Lam:
Oh wow. So a new gene variant. So what was the relationship?
Dr. Greg Hundley:
Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials.
And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling.
Dr. Carolyn Lam:
Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go.
So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes.
Dr. Greg Hundley:
Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find?
Dr. Carolyn Lam:
They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar.
In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration.
So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more.
Dr. Greg Hundley:
Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals."
Dr. Carolyn Lam:
There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare.
Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion?
Dr. Greg Hundley:
You bet.
Dr. Mercedes Carnethon:
Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine.
I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us.
Dr. Xuerong Wen:
Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone.
Dr. Mercedes Carnethon:
Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth.
Dr. Sandeep Das:
Thanks Mercedes. It's great to be with you.
Dr. Mercedes Carnethon:
Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found?
Dr. Xuerong Wen:
So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population.
So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results.
Dr. Mercedes Carnethon:
Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team?
Dr. Xuerong Wen:
That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population.
Dr. Mercedes Carnethon:
Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation?
Dr. Sandeep Das:
Yeah, absolutely. Thanks for the question.
So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question.
Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello.
Dr. Mercedes Carnethon:
Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well.
Dr. Sandeep Das:
Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients?
Dr. Xuerong Wen:
I would say yes. Okay.
Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced.
And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist.
And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease.
Dr. Sandeep Das:
Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice.
Dr. Mercedes Carnethon:
I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular?
Dr. Xuerong Wen:
That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that.
Dr. Mercedes Carnethon:
Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions?
Dr. Sandeep Das:
No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing.
Dr. Mercedes Carnethon:
Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work?
Dr. Xuerong Wen:
Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical.
Dr. Mercedes Carnethon:
Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen.
Dr. Xuerong Wen:
Thanks for this great opportunity to disseminate my study with us, thank you.
Dr. Sandeep Das:
Thanks Mercedes.
Dr. Mercedes Carnethon:
Thank you for joining us for this episode of Circulation on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Jennifer Conway as she discusses the article "The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Carolyn, wow. We're closing out the month of February, this is February 28th. And the feature discussion today, very interesting. So in patients with hypertrophic cardiomyopathy, we often see them as adults, and guidelines are very clear on how to manage them. What about patients' children that present with hypertrophic cardiomyopathy? How do we manage them? Should we do exercise testing? Well, to get the answers to some of those questions, you'll have to wait listeners to our feature discussion today. But first we're going to grab a cup of coffee and jump into some of the other articles in the issue. Carolyn, would you like to start?
Dr. Carolyn Lam:
I would love to. With this first paper, which is a preclinical study revealing a novel signaling axis in cardiorenal interaction.
Dr. Greg Hundley:
Wow. Pray tell.
Dr. Carolyn Lam:
I will. So this paper is from Dr. Molkentin and colleagues from University of Cincinnati. And using mouse models of ischemia reperfusion acute kidney injury and unilateral ureteral obstruction, these authors found that interleukin 33 release from the kidney endothelium during acute kidney injury communicates with the heart through the suppression of tumorigenicity 2 or ST2L receptor on cardiomyocytes. And that's where it causes hypertrophy, fibrosis, and loss of cardiac function. Mice lacking interleukin 33 or mice lacking the gene encoding this ST2L receptor on cardiomyocytes, but not endothelial cells or fibroblasts, were protected from acute kidney injury induced hypertrophy and cardiomyopathy. Indeed, inhibition of acute interleukin 33 release from the kidney after acute kidney injury with a monoclonal antibody prevented cardiomyopathy. So the interleukin 33 ST2L signaling axis is a novel potential therapeutic target to protect the heart during kidney injury.
Dr. Greg Hundley:
Wow, Carolyn, really interesting preclinical science relating acute kidney industry and cardiomyopathy. Well, I have another paper from the World of Preclinical Science. And, Carolyn, this pertains to the metalloprotease ADAMTS7, and it is a novel locus associated with human coronary atherosclerosis. ADAMTS7 deletion protects against atherosclerosis and vascular restenosis in rodents. Carolyn, these authors led by Professor Wei Kong from Peking University designed three potential vaccines consisting of distinct B-cell epitopic peptides derived from ADAMTS7 and conjugated with the carrier protein KLH as well as aluminum hydroxide as an adjuvant. And they tested the efficacy of the vaccines to evaluate coronary intimal hyperplasia in mirroring wire models and after stent implantation in porcine models.
Dr. Carolyn Lam:
Oh, wow. So a vaccine against atherosclerosis? Cool.
Dr. Greg Hundley:
Yeah, it is really a vaccine concept against restenosis. Carolyn, this peptide vaccine against metalloproteinase ADAMTS7 efficiently mitigated atherosclerosis in vaccinated hyperlipidemic mice without lowering lipid levels and impeded intimal hyperplasia in both the murine wired injured arteries and the swine stented coronary arteries without any significant immune related organ injuries. Carolyn, the clinical implications are that the vaccine against the metalloproteinase ADAMTS7 is a novel atherosclerosis vaccine, mainly targeting vascular remodeling, thereby also alleviating instent restenosis. And perhaps in the future the application of this vaccine would be a complimentary therapeutic avenue to current lipid loading strategies for atherosclerotic disease. And this is nicely followed by an editorial from Professors Heribert Schunkert and Thorsten Kessler.
Dr. Carolyn Lam:
Cool, thanks, Greg. Well, this next paper asks the question that if coronary artery calcium can be identified on non-gated chest CTs, can this finding be effectively incorporated into care with the help of AI? So the Notify One was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease or a prior statin prescription were screened for coronary arterial calcium on a prior nongated chest CT from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental coronary artery calcium were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient specific image of coronary artery calcium and guideline recommendations regarding statin use. And the primary outcome was statin prescription within six months.
Dr. Greg Hundley:
Really interesting, Carolyn. So coronary artery calcium observed when a patient might happen to come in for another chest CT scan or actually randomizing a patient population to being notified and maybe doctors act on it versus not. So what did they find?
Dr. Carolyn Lam:
Yep, beautifully summarized. And this is from Dr. Sandhu and colleagues from Stanford University. And what they found was among more than 2000 patients who met initial and clinical inclusion criteria, coronary artery calcium was identified by the algorithm in 424 patients and confirmed by a radiologist in 89% who were randomized to notification or usual care. At six months, the statin prescription rate was 51% in the notification arm versus 7% with usual care. Thus, opportunistic coronary artery calcium screening of prior nongated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is of course needed to determine whether this approach can actually reduce atherosclerotic cardiovascular disease events. This is discussed in an editorial by Doctors Joshi, Nasser, and Navar.
Dr. Greg Hundley:
Wow, Carolyn, you know, this all fits with behavioral science. When we see something, then often we change our behavior much more readily. And so, gosh, boy, just a perfect example of that in this last paper. Well, there's some other articles in the issue, and I see again, just as it was last week, you've got a whole list here to describe.
Dr. Carolyn Lam:
Oh, you bet Greg. First, there's an exchange of letters between Doctors Du and Lee on physical activity has no significant association with stroke. There's a primer by Dr. Leyva on “Declining Risk of Sudden Cardiac Death in Heart Failures, Is that a Fact or a Myth?” There's a Research Letter by Dr. Soehnlein on “Time Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice.” There's also Highlights from the Circulation Family of Journals by Molly Robbins. The characteristics of patients with recurrent sudden cardiac death are described in circulation arrhythmia and electrophysiology. A proof of principle gene therapy for correction of long QT two and short QT one syndromes is presented in circulation, genomic and precision medicine.
The impact of food insecurity on heart failure mortality is reported in circulation heart failure. The associations of hypertension and hypertension treatment with differences in sexual identities are presented in circulation, cardiovascular quality and outcomes. A multi-modality imaging and biomarker strategy to detect early decompensation with chronic aortic regurgitation is reported in circulation cardiovascular imaging, and an analysis of revascularization at the time of TAVR on cardiovascular outcomes is reported in circulation cardiovascular interventions. Finally, that's a Perspective piece by Dr. Turer on cardiac myosin inhibitors unlocking potential to improve treatment in hypertrophic cardiomyopathy.
Dr. Greg Hundley:
Wow, Carolyn, just another issue that's so rich with both preclinical and clinical science. Well, how about we get off to that feature discussion and learn more about management of children and young adults with hypertrophic cardiomyopathy?
Dr. Carolyn Lam:
So important. Let's go.
Dr. Greg Hundley:
Welcome listeners to this February 28th feature discussion where we're going to work into the world of hypertrophic cardiomyopathy in children. And we have with us today Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta. Welcome Jennifer. And maybe Jennifer, let's start off, could you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Jennifer Conway:
Sure. And I would just like to start by thank you for inviting us to really present the information from our paper. We think it's a very exciting paper and are excited to share our results. When you think about hypertrophic cardiomyopathy in children, a lot of the information in the past has really been extrapolated from adults. And we know from the recent 2020 guidelines that exercise testing is really no longer part of risk stratification for adults. It's mostly used to look at functional outcomes and really when assessing patients more for heart failure related symptoms. So we wanted to see whether or not exercise testing in children had a different role because we know the recent risk stratifying calculators such as the primacy calculator that's come from this cohort of patients or HCM risk kids, has different risk factors that have been identified for sudden events, for instance, than in the adult population. And that's really kind of sparked us to see, well, maybe exercise has a different role in children than it does in adults.
Dr. Greg Hundley:
And so we wanted to investigate the role of exercise testing in children with hypertrophic cardiomyopathy. So how did you arrange your study design, and what was your study population?
Dr. Jennifer Conway:
This is an international cohort of 20 centers from the US, Canada, and Australia. And it's an observational cohort, and there is over 724 patients' information that has been collected within this cohort of patients. And for this particular study, 630 of them had an exercise test and therefore were included in the study to look at.
Dr. Greg Hundley:
And in the study population, I know it's a pediatric population, what was the age range?
Dr. Jennifer Conway:
The average range was about 13 years old with probably the youngest being around eight because that's really where you can do an exercise test with and that's up to 18 years of age. So that's kind of the general age range of patients.
Dr. Greg Hundley:
And of these pediatric populations, what percentage were, I guess, boys versus girls?
Dr. Jennifer Conway:
Yeah, so just over 75% were males within this study population.
Dr. Greg Hundley:
Okay. And then now Jennifer, can you describe for us your study results?
Dr. Jennifer Conway:
Sure. I think the first main result is that we can really think about what we defined as an abnormal exercise test so maybe we'll start with that and kind of explain our findings there. So abnormal exercise test in this study was really a threefold one if you had an abnormal blood pressure response. The other one is if you had ventricular ectopy or if you had ST-T wave changes, which we described as ischemia. And so taking those three together, about 28% of our pediatric patients had an abnormal finding on their exercise test. So that's kind of the first main finding. So then we took those abnormal exercise patients and compared those with a normal exercise test to try to look for outcomes. And the two outcomes that we mainly focused on all cause mortality and transplantation is one outcome and the other one was sudden cardiac death events.
So when we looked at the five-year freedom for all cause mortality and transplant, we found that those who had an abnormal exercise test had a lower five-year freedom from all cause mortality and transplantation. And when we sub-analyzed the different abnormalities in the exercise test, we found that ischemia and an abnormal blood pressure response were both associated with kind of a higher risk of mortality and transplantation. And then when we went on to look at sudden cardiac death events, there was really no difference seen between those with an abnormal or normal exercise test in terms of sudden cardiac death events. But when we looked at the individual factors once again exercise induced ischemia was associated with a lower freedom from a sudden cardiac death event.
Dr. Greg Hundley:
Jennifer, frequently in adults we're often examining with exercise how the intracavitary or left ventricular outflow tract gradient may change with exercise. What did you find in children in regards to that parameter?
Dr. Jennifer Conway:
Yeah, so we couldn't actually study that because this was a compilation of different types of exercise tests. So not everybody at each institution did the same form of exercise tests. So some patients had an exercise echo, some had a CPET test, and some had an exercise stress test. And so we took the common parameters from all of those to study, so we weren't specifically able to look at LV outflow tract gradients for instance.
Dr. Greg Hundley:
Jennifer, as a pediatrician managing a patient with hypertrophic cardiomyopathy, how do we use the results of your study to influence how we might manage patients moving forward?
Dr. Jennifer Conway:
I think this is an excellent question, and there's probably really two things that we can think about. The first is, what is the role of exercise testing in pediatrics? And just as we're starting to discover what our risk factors are for sudden cardiac death events, I think we have to do a little bit more to discover what our role is truly going to be with exercise test. So one of the things that we're doing as part of the primacy group is trying to decide is if we add exercise testing abnormalities to the already developed primacy calculator, does it change its power at all? That's one of the things kind of for the future to see with the current kind of sudden death risk factor calculators, can exercise, add to them? The second thing is I think that there is probably a role in exercise testing in general with patients that you see in your clinic to look at these predictive outcomes, and that is not standard across centers.
We know that because not everybody in this cohort had an exercise test. I think there are some higher risk patients that likely are not suitable for exercise tests, but I think a majority of the patients that we see likely can undergo exercise testing. And although it's not published in this paper, of the 630 patients, there's only one patient who had a kind of aborted arrest during the exercise test. And that patient was a higher risk patient who had a previous reported aborted arrest. And this actually corresponds with two other papers in the literature, one from CHOP in Boston where it's a very low event rate when exercise testing is done in a controlled environment with professionals around and have a lab set up to specifically do that. The other aspect of this I think is that as we're starting to understand hypertrophic cardiomyopathy in general better, I think using exercise tests to try to help design exercise interventions is going to be important.
Another study that I'm doing that's not part of this is looking at the cardiovascular health of children with hypertrophic cardiomyopathy across Canada. And we are finding that there's a high level of obesity, sedentary lifestyle, high lipid profiles for instance, all of which put people at risk for cardiovascular disease as adults. And so I think as we're getting more comfortable potentially with looking at exercise prescriptions for hypertrophic cardiomyopathy patients and understanding risks a bit better, then exercise testings going to be a key in trying to design maybe some of that programming for patients.
Dr. Greg Hundley:
Wow, Jennifer, just a beautiful explanation of where we need to move with your research results in the future. One thing that kind of caught my attention as you were speaking, really safety. So for all our listeners, in terms of exercising children with this condition or young adults, would you recommend a specialized center or what would you describe in that, at least in terms of safety precautions?
Dr. Jennifer Conway:
Well, if you look at all the... There's not a lot of studies that have been published, but the ones that have, they're in a lab that commonly exercises children. They have protocols of who they will exercise and who they won't and when you would stop an exercise test. For instance, the paper from CHOP nicely describes how they approach the exercise in hypertrophic cardiomyopathy, and they have clear guidelines of when they stop testing. So in their 140 patients, for instance, they stop testing in two patients, one who had, I think ST segment changes and the other one who developed some ventricular ectopy. I think it needs to be in a controlled environment where you have safety measures in place and you have guidelines to direct you in terms of if this happens, this is the response to that. I think that's all very important when you're kind of thinking about exercising what has been deemed as higher risk patients.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta for sharing with us these really interesting results, highlighting that exercise abnormalities are common in childhood hypertrophic cardiomyopathy, and an abnormal exercise test was independently associated with lower transplant free survival especially in those with ischemic or abnormal blood pressure responses during that exercise testing.
Well, on behalf of Peter, Carolyn and myself, we want to wish you a great week, and we will catch you next week on The Run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia.
Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis?
Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion.
Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address?
Dr. Carolyn Lam:
Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine.
And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan.
However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials.
Dr. Greg Hundley:
Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find?
Dr. Carolyn Lam:
In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure.
Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña.
Dr. Greg Hundley:
Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis.
So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition.
And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage.
So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression.
Dr. Carolyn Lam:
Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex.
They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models.
So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression.
Dr. Carolyn Lam:
Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension.
So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence.
Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development.
As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age.
So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results.
Dr. Greg Hundley:
Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models?
Dr. Carolyn Lam:
Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension.
The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration."
So lots of translational implications of this paper.
Dr. Greg Hundley:
Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe.
Dr. Carolyn Lam:
Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants."
There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea."
In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature.
Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity.
There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study.
Dr. Greg Hundley:
Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion?
Dr. Carolyn Lam:
Let's go. Thanks.
Dr. Greg Hundley:
Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen.
Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Amil Shah:
Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today.
So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality.
Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes.
Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation.
Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction.
And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals.
But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults.
And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease.
To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life.
Dr. Greg Hundley:
So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population?
Dr. Amil Shah:
Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota.
Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age.
We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally.
And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion.
Dr. Greg Hundley:
Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results?
Dr. Amil Shah:
So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair.
And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort.
And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes.
Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest.
Dr. Greg Hundley:
Now, did you find similar results for men and for women?
Dr. Amil Shah:
So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar.
Dr. Greg Hundley:
And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions?
Dr. Amil Shah:
Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages.
So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly.
So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings.
For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that.
Dr. Greg Hundley:
Very nice. Well, thank you so much, Amil.
And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper?
Dr. Ntobeko Ntusi:
Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle.
And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms.
We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex.
And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution.
The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease.
And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations.
So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg.
Dr. Greg Hundley:
Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research?
Dr. Amil Shah:
So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life.
And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in.
I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients.
Dr. Greg Hundley:
Very nice. Ntobeko, do you have anything to add?
Dr. Ntobeko Ntusi:
Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward.
The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease.
Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time.
And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg.
Dr. Greg Hundley:
Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events.
Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join Circulation Senior Associate Editor Sana Al-Khatib and Associate Editor Mercedes Carnethon as they discuss the seventh Go Red for Women issue of the journal.
Dr. Sana Al-Khatib:
Hello and welcome to the Special Circulation on the Run podcast focused on the seventh Go Red for Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I had the pleasure of co-leading this issue with a colleague and friend, Dr.
Dr. Mercedes Carnethon:
Well, I am so pleased to be with you today, Sana. My name is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine. I'm an associate editor at the journal Circulation and extremely excited to join you this year on the seventh issue, as a guest editor for our Go Red for Women Issue. And we've got so many great pieces today, so let's get going.
Dr. Sana Al-Khatib:
Wonderful. So we're very excited to provide you with some highlights of the issue that covers a broad range of topics related to cardiovascular disease in women. In this particular issue, the content is presented as five original research articles, three research letters, five online articles, and one in-depth review article. And like prior podcasts, this year's podcast will only focus on the original research articles, so let's get to it.
The first original research article is titled Exercise for the Prevention of Anthracycline Induced Functional Disability and Cardiac Dysfunction. This was the breast cancer randomized exercise intervention Brexit study. In this trial, the investigators enrolled 104 women who were between 40 and 75 years old and had stage one to three breast cancer. And these women were scheduled for anthracycline based chemotherapy and they randomized them to three to four days per week of aerobic and resistance exercise training for 12 months and they were randomized in one-to-one ratio to either do the exercise or really usual care. Very interesting study Merci, don't you think?
Dr. Mercedes Carnethon:
Absolutely. This is such an important issue, particularly for survivors of breast cancer.
Dr. Sana Al-Khatib:
Exactly. And in this trial, they focused on looking at the following measures, cardiopulmonary exercise testing to quantify the peak VO2 and functional disability, cardiac reserve, quantified using exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output stock volume, standard-of-care echocardiography-derived resting LVEF and global longitudinal strain.
And exercise training was found to attenuate functional disability at four months, which was really interesting, but not at 12 months. But when they looked at it, Merci, in a per protocol analysis, functional disability was found to be entirely prevented at 12 months among participants who adhered to exercise training.
Dr. Mercedes Carnethon:
That is so exciting to hear, especially with the potential to intervene for better outcomes.
Dr. Sana Al-Khatib:
Exactly. And then listen to this, as compared with usual care at 12 months, exercise training was associated with a net plus 3.5 milliliter per kilogram per minute improvement in the peak VO2 that coincided with improvements in cardiac output, stroke volume, LVEF and RVEF reserve, all of them improved, Merci.
Dr. Mercedes Carnethon:
That is such great news. What did the authors have to say about these findings?
Dr. Sana Al-Khatib:
Well, of course they were really excited about these findings because hopefully this will help a lot of patients. Now, when they looked at the exercise training in relation to resting measures of LV function, there didn't seem to be an effect. So they concluded that in women with early stage breast cancer undergoing anthracycline based chemotherapy, 12 months of exercise training did not attenuate functional disability, but it certainly provided clinically meaningful benefits in relation to the peak VO2 and cardiac reserve. So really interesting findings. Obviously I personally would like to see these findings replicated by other studies, but I think these results are promising.
Dr. Mercedes Carnethon:
I'm so excited to be able to feature that important piece in here, especially as more women are living and being treated for breast cancer.
Dr. Sana Al-Khatib:
Indeed. So Merci, I'll turn it over to you to tell us about a couple of your articles.
Dr. Mercedes Carnethon:
Well, I'd love to do two of mine back to back if that's okay with you because they address similar issues. So in one of the first from Dr. Yuan, Liu, and colleagues, they studied the influence of maternal exposure to particulate matter, small, fine, particular matter, and how that influenced the risk of congenital heart defects. We certainly know that congenital heart disease is a significant problem. And what's even more interesting is that the author's site that more than 80% of congenital heart disease has no known cause.
However, prior research does suggest that particulate matter is a plausible environmental exposure that could damage follicular development, disrupt hormone homeostasis, cause inflammation and glucose intolerance. All of those processes could lead to abnormal placentation and fetal development. And so I thought it was really exciting that they would pull together this very large study. And in fact, this isn't the first study to ask this question, but it is one of the largest. It was carried out in China, which is an area with relatively higher levels of pollution.
And the authors did some really cool things. I can't wait to tell you Sana, because I feel as though I rarely get to say NASA was involved in a study that we're featuring here in Circulation. So let me tell you about it.
Not just cardiologists, not just obstetricians and gynecologists, but environmental scientists were involved here and the mean monthly measures of PM 2.5, which is small fine particulate matter, were made via satellite, NASA satellites, and imputation procedures were used that combined a number of meteorologic variables, land use types, road network information, elevations and emissions to train models using machine learning to make estimates of the burden of PM 2.5. Isn't this cool?
Dr. Sana Al-Khatib:
Wow. How interesting. Absolutely.
Dr. Mercedes Carnethon:
Yes. It's probably not something you do every day in your cardiology practice, but it's particularly important for us to be able to get these precise measures of PM 2.5 exposure and what the authors were doing were matching up these units of exposure with the preconception period three months before pregnancy, the first trimester three months after pregnancy, and the entire window to determine how exposures to PM 2.5 during those critical periods for fetal development influenced congenital heart disease and they studied the major causes of congenital heart disease, the major classes using ICD 10 codes.
Dr. Sana Al-Khatib:
Wow. Well, I can't wait to hear the results.
Dr. Mercedes Carnethon:
So the results suggested that in general, the risk of delivering a baby with a congenital heart defect increased by 2% for each 10 nanogram per meter cubed in maternal exposure to PM 2.5 during the preconception period. And this relationship was even stronger preconception than it was during the first trimester. And when they studied different types of congenital heart diseases, the strongest associations were with septal defects. And this was regardless of the exposure window, this was preconception, the first trimester and the entire peri-conception window. I think another really compelling thing about a study of this size, and did I mention that it was 1.4 million births that were studied here during a period of time between 2014 and 2017? 1.4 million births.
Dr. Sana Al-Khatib:
That's a very large study.
Dr. Mercedes Carnethon:
Yes, and one of the benefits of having a study of that size is that you have the opportunity to look at subgroup effects to determine whether there are other characteristics that modify the relationship of the exposure and the outcome in this case PM 2.5 exposure. And what they found was that the relationship of PM 2.5 exposure with congenital heart disease was even stronger for births that took place in northern China or births that happened in areas with a low per capita disposable income. And even more surprising, and I'm not sure if this surprised you, but the relationships were even stronger in births to mothers who were younger than age 35. And that's particularly telling given that many births are obviously happening when women are below age 35.
So I think these findings are just so compelling. I think they are important certainly for our cardiology community, but I think they're also important for policy makers as they consider the implications of air quality and how that affects our long-term health.
Dr. Sana Al-Khatib:
Yeah, no, absolutely. Very important implications here, Merci. I agree.
Dr. Mercedes Carnethon:
Yes. Well, so I was really pleased to feature that article and then in the same issue, if I can continue to hold the microphone here.
Dr. Sana Al-Khatib:
Yes, please.
Dr. Mercedes Carnethon:
In the same issue, we have another paper led by authors from China, Zhang and colleagues, who carried out a study of what happens when women grow up with congenital heart disease and they have their own pregnancies? And so the goal of this particular paper was to look at the influence of pulmonary hypertension, which is a common complication of women with congenital heart disease when they become pregnant, to see how the severity of pulmonary hypertension influences pregnancy outcomes in these women.
Dr. Sana Al-Khatib:
A very important topic. Yeah, I agree, Merci.
Dr. Mercedes Carnethon:
Yes. And so this was carried out in over 2000 pregnant women with congenital heart disease who had completed pregnancies. This was a retrospective analysis. And of those a significant portions, 729 women, had pulmonary hypertension. And these range from mild to moderate to severe. And unfortunately, maternal mortality was an outcome in this study along with birth outcomes among the babies. And what the authors found, I guess, consistent with what one might hypothesize, is that the severity of pulmonary hypertension was associated with adverse outcomes. Those women who had more severe pulmonary hypertension were more likely to experience maternal mortality. They were more likely to experience heart failure and other cardiac complications.
And unfortunately, those risks were as well passed along to the babies where there were more obstetric complications and other adverse events. So it's an unfortunate finding, but I would say that there were a number of bright spots and a few bright spots to this particular study. And their findings were that those women who had follow-up care with a multidisciplinary team, strict antenatal supervision, tended to have a lower likelihood of these adverse events.
Dr. Sana Al-Khatib:
That is so good to know. Of course, I mean, we have thought of that to be the case, but now to have a study showing that is really impactful.
Dr. Mercedes Carnethon:
It certainly is. And especially such a well done study. These aren't common. And so this team managed to find a relatively large sample size so that they could produce robust estimates that we can use and consider when we consider helping women with congenital heart disease manage their developing families. So I really thank you for letting me talk about two of these studies back to back, but I can't hog the microphone. We have so much good work in this episode.
Dr. Sana Al-Khatib:
Yeah, no problem. But it's so good to see more work being done on the adult congenital heart disease, by the way, because this is a growing patient population, and it's great that we were able to feature it in two articles, Merci. So let me present the second paper that I had the pleasure of handling in many ways, this particular paper. First of all, it is a topic that's near and dear to my heart as I am an electrophysiologist and the paper provides data on the comparative effectiveness of left atrial appendage occlusion versus oral anticoagulation bisects in patients with atrial fibrillation. And not only am I interested in the topic, but I actually was the senior author on this paper, and so I really need to acknowledge that and would like to share some highlights of the paper with you.
So in this particular paper, Merci, we analyzed Medicare claims data from 2015 through 2019, and we really focused on patients who were deemed to be eligible for left atrial appendage occlusion.
And we divided them into sex subgroups. And of course, we had to apply robust statistical methodology first in terms of making sure that patients with left atrial appendage occlusion were well-matched in one-to-one ratio to those receiving anticoagulant therapy. Obviously, a lot of selection bias goes into those assignments in clinical practice, and so we needed to make sure to match those groups, and we did that for women and we did that for men. And we were really interested in looking at the risks of mortality stroke or systemic embolism as well as bleeding between these matched groups, so we wanted to compare those risks.
And so among females, we had 4,085 left atrial appendage occlusion recipients, and those were again matched in one-to-one ratio to women who were receiving anticoagulant therapy. And if you look at the subgroup of males, 5,378 were left atrial appendage occlusion recipients. And again, those were similarly matched to men who received oral anticoagulation.
And so of course, after doing the matching, we applied the further adjustment to take care of remaining differences between the groups. So what did we find? We found that left atrial appendage occlusion was indeed associated with a significant reduction in the risk of mortality as well as stroke or systemic embolism and this was true for females and males. And when we looked at the bleeding risk, we found that that risk was significantly greater in left atrial appendage occlusion recipients early after implantation, because as you know, Merci, those people for the first six weeks have to be treated either with anticoagulation or a combination of aspirin and Plavix, and so it's not surprising that bleeding was actually high early on, but really lower after the six week per procedural period for both females and males.
And so what we concluded in this study, which was a real world study, and that's the significance of this because several trials had been conducted, but many of us always raised the questions of, well do the results of the clinical trials apply to the average patient that we see in clinical practice? So many of us would like to see comparative effectiveness analysis being conducted in real world populations, and here we were able to show that left atrial appendage occlusion was associated with a reduction in the risk of death, stroke, or systemic embolism as well as long-term bleeding both in females and males. So really very interesting results that I think should help inform shared decision making discussions with patients.
Dr. Mercedes Carnethon:
Oh, absolutely. I have to say I'm not biased. It's not because you are the senior author, it's because this is just truly excellent work, really a creative design. And I agree with your assessment that doing this sort of real world work is critically important because sometimes we don't have the representation in clinical trials of a distribution of people who would ordinarily be the targets of these types of therapies. And so I really applaud you and your team for really leading an excellent study that I hope people will find extremely useful.
Dr. Sana Al-Khatib:
Well, thank you very much, and I really want to give a lot of credit to the first author, Dr. Zeitler, who has been mentee of mine for many years and has done a great job and really a lot of credit to the rest of the co-authors.
Dr. Mercedes Carnethon:
Well, that's fantastic. I'm glad that I chose the ordering that I did because the final study that I'd like to talk about is in fact a randomized trial. And I think similar to the one that you just described, this is another study that's comparing sex differences. So this particular study led by Coughlan and colleagues describes sex differences in 10-year outcomes after percutaneous coronary intervention with drug-eluting stents. And given the positive impact that drug-eluting stents have had on improving coronary artery disease, I think it's critically important for us to find out whether or not there are any disparities by sex and the types of outcomes that occur following percutaneous coronary intervention. And so in order to address this question, what the authors did was to carry out a pooled analysis of five individual patient data from trials of drug-eluting stints that had at least 10 years of follow up.
And the objective here was to really address the controversy in the field about whether the outcomes were worse for women, which was observed in some studies versus in other studies where there was no difference. And the benefit of using this pool design, again, this sample size, I'm an epidemiologist, I love big samples for what can be done. And in the 9,700 patients that were included in this trial, 24% of them were women. So really it required this type of a meta analytic design in order to have enough women to answer these questions. So the outcomes of interest here included death from all causes, death from cardiovascular disease, MI, stent thrombosis, and revascularization of the target lesion, the target vessel, and the non-target vessel.
So one of the challenges in interpreting findings from prior studies of this question are the concerns that the clinical characteristics of men versus women who underwent PCI were different.
And in fact, in this particular pooled analysis, men were more likely than women to have three vessel disease, and they had a lower, lower mean ejection fraction coming in the characteristics following angiogram and the procedure also showed some differences by sex groups, namely that women had smaller vessel reference diameters before PCI and a smaller minimal luminal diameter after PCI. But men had a longer total stinted length as compared with women. So I'm sure you want to know what ended up happening.
Dr. Sana Al-Khatib:
Please.
Dr. Mercedes Carnethon:
Yes. So when the authors tested their primary hypothesis of sex differences in tenure outcomes, they found that some of the very minor differences in the proportion of women versus men who experience the outcomes of interest were eliminated following adjustment for relevant characteristics, or in fact that women were slightly less likely to experience the outcomes of interest. Specifically women were less likely to experience death from any cause over 10 years, but there was no difference in cardiovascular death as compared with men.
Women though were significantly less likely than men to require repeat revascularization of the target legion, the target vessel, and the non-target vessels over 10 years. But unfortunately, the findings weren't all good. A notable exception was that when the offers examined the one-year event rates, women had a significantly increased likelihood of MI in the first 30 days after PCI. And I'm not sure why this is, but the authors did advance numerous hypotheses to explain their findings. One was that baseline and procedural characteristics varied markedly between men and women, and that the age was a primary confounder of these findings. And this was because they carried out a series of sensitivity analyses where they didn't account for age and when they didn't account for age, women had an increased risk of cardiovascular death through the entire 10 years of follow up. And it's curious why this would happen.
And the observation was thought to be attributable either to women developing CAD later than men in life, or because they're diagnosed later because of decreased physician awareness among women. And that's shocking to hear since we all know that cardiovascular disease is the leading cause of death among women. So I really think that the observations in this large pooled analysis do warrant further study and investigation. And a point that I think we discussed earlier is that the representation of women in clinical trials, we have to have more women in these trials and this was an argument that the authors advanced because then without more women in these trials, we don't have adequate power to investigate these sex differences and to explore reasons behind these sex differences. And so I hope that investigators will really heed these calls so that we can generate the best possible science to inform treatment options for women so that we can maximize our health outcomes.
Dr. Sana Al-Khatib:
No, absolutely. Those are excellent points, Merci, that you make. And we certainly need to make sure that we have more women participating in clinical trials and that to the extent that we can, that patients enrolled in clinical trials are representative of patients that we see in clinical practice. You bring up excellent points. Thank you for that great summary.
Dr. Mercedes Carnethon:
Thank you so much, and thank you really for letting me join you in this special issue. I'm so excited about all of our pieces, not just these original research pieces, but as well our research letters and the rest of our content. I think there's just a lot for our readers to dig into here.
Dr. Sana Al-Khatib:
Yeah, no, absolutely. Merci, it's been a pleasure for me to co-lead this issue with you and I agree while we focus this podcast on the original research articles, the other articles are equally interesting and impactful. So a lot for our readers to enjoy here. So in closing, we want to wholeheartedly thank Dr. Joe Hill, the editor-in-chief for Circulation, Dr. James De Lemos, the executive editor of the Journal and all authors who submitted the research for this issue. We also want to thank the Circulation associate editors and staff who worked so hard to deliver what you are about to experience. We're very excited about this issue and know you will find it very informative and interesting.
This concludes our Go Red for Women issue Circulation on the Run podcast. Thank you so much for listening.
Dr. Mercedes Carnethon:
Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join author Petr Ostadal and Associate Editor Dharam Kumbhani as they discuss the article "Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today Carolyn will have such an interesting feature discussion. We are going to look into the use of ECMO to treat patients with cardiogenic shock, the results of the ECMO-CS randomized clinical trial. Isn't that interesting?
Dr. Carolyn Lam:
Awesome. Can't wait. But I suppose you're going to tell us about some papers in the issue first. I'm getting my coffee.
Dr. Peder Myhre:
Yeah, go ahead. Because first we're going to talk about a very interesting paper that relates to diabetes and the progression of coronary artery disease. So as you know, Carolyn, diabetes remains associated with an increased risk of cardiovascular morbidity and mortality. And although the absolute risk difference between patients with and without diabetes have declined over the past 20 years, we still don't know what is the diabetes associated differences in coronary plaque morphology and lipid content.
Dr. Carolyn Lam:
It's true. That's a very interesting question. And will you tell us more?
Dr. Peder Myhre:
Yeah. So the investigators in the prospect two study who enrolled patients exclusively from Denmark, Norway in Sweden who presented with biomarker positive MI and assessed both culprit lesions and untreated non-culprit lesions in these patients. And then they stratified the patients by diabetes status and examined with three vessel quantitative coronary angiography and near infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention.
Dr. Carolyn Lam:
Okay, that's deep investigation. And what did they find?
Dr. Peder Myhre:
So diabetes was present in about 12% of patients and during a median or 3.7 year follow up, MACE occurred almost twice as free frequently in patients with versus without diabetes. And that was primarily due to an increased risk of MI related to culprit lesion stenosis and non-culprit relation related spontaneous MI. However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes, concerning culprit and the non-culprit lesions and in multi-variable models, diabetes was associated with MACE in lesions but not with prevalence of high-risk plaque characteristics. So Carolyn, the authors conclude that diabetes related plaque characteristics that might underlie the increased risk were not identified by multimodal imaging.
Dr. Carolyn Lam:
Oh, I just love studies like that so elegant with just a really, really intriguing results that make us ask more important questions. Love it. Thank you. Well, the next paper is also about myocardial infarction, but this time looking at the fibrotic remodeling after myocardial infarction because we know that MI induces a repair response that ultimately generates a stable fibrotic scar. And although the scar is important to prevent cardiac rupture, excessive pro-fibrotic response impairs optimal recovery because it promotes a development of non-contractual fibrotic areas. So would it be possible to regulate the expansion of cardiac fibroblast after MI through a paracrine action on the cardiac stromal cells? So the authors led by corresponding author Dr. Hulot from University of Paris performed a bioinformatic secretome analysis of cardiac stromal PW1 positive cells isolated from normal and post MI mouse hearts to identify novel secreted proteins.
And they found that first cardiac PW1 positive stromal cells responded to myocardial infarction by secreting factors that promoted the proliferation and activation of resident fibroblasts and one such factor growth differentiation factor three or GDF3 was highly upregulated in the ischemic hearts and promoted a high induction of fibroblast proliferation via interaction with TGF beta receptors and activation of SMAD1/5 and SMAD2/3 signaling cascades. The upregulation of GDF3 was detected in the plasma of mice and humans following MI and high levels of plasma GDF3 in the days following MI predicted adverse outcomes measured six months later including cardiac dilation and limited recovery of contractile function in humans.
Dr. Peder Myhre:
Oh, that's so interesting. We already know GDF15 were very well, but now we hear about GDF3 in predicting fibrotic remodeling post myocardial infarction. So Carolyn, what are the clinical implications of these findings?
Dr. Carolyn Lam:
Exactly, Peder, in fact you said it. So the detection of high circulating GDF3 in plasma may serve as a novel biomarker of adverse fibrotic remodeling in heart tissue. That's one. And next the measurement of GDF3 plasma levels in the early post MI phase may allow for the identification of patients within an increased risk of severe myocardial fibrosis and heart failure and therefore could guide specific disease management.
Dr. Peder Myhre:
Thank you. That was an excellent summary of the paper, Carolyn. And now I'm going to look into a paper that relates to the important issue of arteriosclerosis following heart transplantation because as you know, transplant arteriosclerosis characterized by concentric and diffuse narrowing of vastly lumen is a major complication in long-term survivors of heart transplant patients. And increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis. But how lymphangiogenesis affects this process is unknown. The authors of this paper, which comes to us from corresponding author Sue from Sejong University, transplanted vascular allografts between various combinations of mice including mice with severe combined immune deficiency and studied the lymphatic vessels within the grafted arteries.
Dr. Carolyn Lam:
Wow, that is really cool. Studying lymphatics and lymphangiogenesis in atherosclerosis. Interesting. What did they find, and what are the clinical implications?
Dr. Peder Myhre:
So Carolyn, lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 were associated with these immune structures. Fibroblasts in the vascular allografts released VEGFC, which stimulated lymphangiogenesis into the grafts and inhibition of VEGFC signaling inhibited lymphangiogenesis, neointima formation and adventitial fibrosis of vascular allografts. And these studies identified VEGFC released from fibroblasts as signal stimulating lymphangiogenesis extending from the host into the vascular allografts. So, Carolyn, the authors conclude that the formation of lymphatic vessels play a key role in the immune response to vascular transplantation and inhibition of lymphangiogenesis may be a novel approach to prevent transplant atherosclerosis.
Dr. Carolyn Lam:
Wow, that is super interesting. Thanks, Peder. While also in this issue, there's an exchange of letters between Drs. Tanaka and Schulze regarding SGLT2 inhibitor treatment in acute decompensated heart failure. Why do we initiate it early? There's also a really nice On My Mind paper by Dr. Schiattarella on Cardiometabolic HFpEF. Is it the NASH of the heart?
Dr. Peder Myhre:
Oh, that's interesting. We also have some cardiology news by our own Bridget Kuehn entitled “No Benefit Seen for Nighttime Dosing Over Morning Dosing for Antihypertensive Medications.” And this is a summary of the time trial, which was presented at European Society of Cardiology Congress in 2022. And finally, Carolyn, we have a Research Letter entitled “Stepwise Generation of Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to Model Coronary Microvascular Dysfunction” by Dr. Joseph Wu from Stanford University School of Medicine.
Dr. Carolyn Lam:
While cool, Peder. But now I'm so excited to hear about the ECMO-CS randomized trial. Let's go.
Dr. Greg Hundley:
Welcome listeners to this February 7th feature discussion and we have with us today Dr. Petr Ostadal from Na Homolce Hospital in Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome, gentlemen. Well, Petr, we'll start with you. Can you describe for us some of the background information that really led you to perform this study, and what was the hypothesis that you wanted to address?
Dr. Petr Ostadal:
According to the current guidelines from the management for the management of cariogenic shock, it should be considered administration of inotropes and vasopressor for hemodynamic stabilization, or it may be considered administration of inotropes and vasopressors and it should be considered the use of short-term mechanical circulatory support. And the aim of the ECMO-CS trial was to compare early conservative therapy with inotropes and vasopressors and immediate implementation of ECMO in patients with the rapidly deteriorating or severe cardiogenic shock. The hypothesis of the ECMO-CS trial was that immediate implantation of ECMO in patients with cardiogenic shock and critical hemodynamic condition will be associated with improved outcomes.
Dr. Greg Hundley:
Very nice. Can you describe for us this study population and then also what study design did you use to address your hypothesis?
Dr. Petr Ostadal:
We try to select patients who can really profit from the early ECMO implantation, and we define two categories of patients. First category where the patients with rapidly deteriorating cardiogenic shock corresponding to current sky stage D or E. This patient should have evidence of left ventricle pump failure as left ventricle ejection fraction below 35% or ejection fraction 35 to 55 in case of severe mitral regurgitation or aortic stenosis. And this patient also should require a repeated both of vasopressors to maintain mean arterial pressure about 50 millimeters of mercury. The second category where the patients with severe cardiogenic shock corresponding to current sky stage D and this patient should have the criterion of a hemodynamic conditions which was cardiac index less than 2.2 or systemic blood pressure below 100 millimeters of mercury in both situation with higher doses of inotropes and vasopressors. And in case of a low systolic blood pressure, also the evidence of left ventricle pump failure based on ejection fractional below 35 or ejection fraction 35 to 55 in case of severe mitral regurgitation of aortic stenosis.
The second criteria for the metabolic criteria, that was the evidence of tissue hypoperfusion and this was defined as a higher lactate above three millimeters per litter or low ScvO2 below 50%. And the third criterion was exclusion of hypovolemia, and this was based on central venous pressure or pulmonary artery wedge pressure. So this was the major inclusion criteria in the ECMO trial. The study population was not defined based on theology of cardiogenic shock, but just on severity of cardiogenic shock.
Dr. Greg Hundley:
Very nice. And so your design, did you have a one-to-one randomization, or how did that work? And then also how many subjects did you include in this important trial?
Dr. Petr Ostadal:
The patients were randomized in one-to-one ratio to immediate implementation of ECMO or to early conservative therapy. But it is important to point out that in the early conservative therapy downstream use of ECMO was allowed in case of further hemodynamic worsening defined as increase of what lactate by three millimeters per litter. We enrolled 122 patients, 61 were randomized to early ECMO and 61 to early conservative strategy. Five patients were excluded due to absence of informed consent and finally 58 patients were analyzed in the early ECMO or immediate ECMO arm and 59 patients were analyzed in the early conservative arm.
Dr. Greg Hundley:
Sounds great Petr. And then tell us and describe your study results.
Dr. Petr Ostadal:
The primary endpoint was composite of death from any cause, resuscitated circulatory RS and implementation of another mechanical circulatory support including ECMO in the early conservative arm at 30 days. And there was no difference in the primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95% confidence in interval 0.46 to 1.12. There was also no difference in the incidence of death from any cause. 50% in the immediate ECMO arm and 28%, 47.5% in the early conservative arm. There was no difference in the incidence of resuscitated circulatory arrest, 10.3 in the immediate ECMO arm and 13.6 in the early conservative arm. Less patient required another mechanical circulatory support in the early ECMO arm through 17.2 in comparison with 42.4% in the early conservative arm and downstream ECMO was used in 39% of patients in the early conservative arm.
Dr. Greg Hundley:
Very nice. So similar results both immediately and then 30 days later for both arms. And I think that last point that you make is very interesting. 39% of the individuals randomized to the conservative arm went on to receive VA-ECMO. Well, listeners next, we're going to turn to one of our associate editors and Dharam, you have many papers that you see. How do we put the results that Petr has just described really in the context of management of shock and results that have been published previously?
Dr. Dharam Kumbhani:
Yeah, Greg, thank you. And Petr, thank you for this important paper and again, I'm really honored to be here on behalf of Circulation on the Run. So again, want to congratulate the authors for really an important study. I think in terms of context, what is really interesting is the use of ECMO, particularly VA-ECMO for patients with shock has really skyrocketed. And it is interesting that this expansion has occurred in the absence despite, I guess high quality clinical trials, this trial certainly fills an important void. Although it is a small patient population, it is randomized, it is a largest randomized trial to date on this important population. And so I think most of the studies that have been done so far have been done using observational data sets which have sort of inherent limitations. So I certainly want to congratulate you on trying to study this very challenging population because in sort of that acute setting, it's frequently very hard to get patients randomized.
So just broadly in that context, I think at the same time this study does sort of pose some important questions and sort of perhaps leads, just given the limitations of the sample size does sort of leave a few unanswered questions. So one question I have is, Petr, in addition to the 40% crossover rate is obviously important as Greg pointed out. The other thing is it appears that the use of other mechanical support during the conduct of this trial was also close to 40%, about 42%. So pretty much everybody in the conservative arm ended up with some kind of mechanical support. Now, at least in the last few years, a concept that has gained a lot of traction is a concept of a shock team where a number of providers with particular expertise from different disciplines would get together and sort of decide next steps was a shock team sort of part of the decision-making, especially for the conservative arm.
Dr. Petr Ostadal:
Thank you for this question. The situation is maybe a little bit more simple in the Czech Republic here, the cardiologist are responsible for the acute cardiac care, usually competent and experience not only for the diagnosis and examinations and monitoring of patients in cardiogenic shock, but also experience in insertion and management of the mechanical circulatory support. So here this attending cardiologist competent to manage this patient from different sites from the manage not only the conservative therapy but also the mechanical circulatory support therapy in these patients. So in this respect, this is more simple situation in the Czech Republic.
Dr. Dharam Kumbhani:
I just had a very quick question about, and I don't know if you want to include this, but Petr, I was curious, were patients with cardiac arrest, I know you mentioned sky shocks in were patients with cardiac arrest on the field or in the hospital included?
Dr. Petr Ostadal:
Thank you for this excellent question. And in comparison, with other trials comparing the or focusing on patients with cardiogenic shock in the ECMO-CS trials, cardiac arrest survivors were excluded. And the reason was that the brain damage, which is the major cause of death in these patients cannot be influenced by ECMO insertion. And second, in majority of patients after cardiac arrest, if there is a presence of shock, there is frequently combined shock with important peripheral component. And again, it cannot be assumed that this peripheral component can be reversed by ECMO implantation. So in the ECMO-CS trial, the cardiac arrest survivors were excluded from that enrollment.
Dr. Greg Hundley:
Well, thank you so much Petr. Petr, what do you think is the next study to be performed really in this area of research?
Dr. Petr Ostadal:
I think that we are happy because several other clinical trials focusing on the mechanical circulatory support in patients with cardiogenic shock underway. And there are other trials focused on ECMO and trials a bit focused on combination of ECMO with balloon pump and trials focused on Impella. So I think in the very close time we will be able to see the results of these current running trials1.
Dr. Greg Hundley:
And Dharam, do you have anything to add?
Dr. Dharam Kumbhani:
No, I agree completely with Petr. I think this is a very exciting field. I know there's a lot of interest in doing well conducted clinical trials in this space. And so certainly, I think the future is bright for investigation in this field.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Petr Ostadal from Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from Dallas, Texas for bringing us this study highlighting that immediate implementation of VA-ECMO in patients with rapidly deteriorating, or severe cardiogenic shock did not improve clinical outcomes compared to an early conservative strategy that permitted downstream use of VA-ECMO in the case when the patient's hemodynamic status worsened.
Well, on behalf of Carolyn, and Peder, and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join Guest Host Maryjane Farr, authors Sarah Franklin and Stavros G. Drakos, as well as Associate Editor Hesham Sadek as they discuss the article "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo.
Dr. Carolyn Lam:
Peder, today's featured paper is very, very important in the heart failure world. It is such a deep dive into the transcriptomic and proteomic profile that specifies heart failure and the potential of myocardial recovery with mechanical unloading and circulatory support.
Dr. Peder Myhre:
Can't wait for that feature discussion today, Carolyn.
Dr. Carolyn Lam:
But you have to wait because I insist on telling you about yet another really important paper, of course in my favorite subject, heart failure with preserved ejection fraction or HFpEF. Now you know that exercise intolerance is a defining characteristic of HFpEF and a marked rise in pulmonary capillary wedge pressure during exertion is pethepneumonic for HFpEF and it's thought to be a key cause of the exercise intolerance. Now if that is true, acutely lowering the wedge pressure should improve exercise capacity, right? Well, don't assume this because to test this hypothesis, authors led by corresponding author Dr. Ben Levine from UT Southwestern evaluated peak exercise capacity with and without nitroglycerin, which was used to acutely lower pulmonary capillary wedge pressure during exercise in patients with HFpEF.
Dr. Peder Myhre:
Oh, that's so cool. What an amazing research question and Carolyn, you're the best to summarize this. Please tell us what did they find?
Dr. Carolyn Lam:
Well, they studied 30 patients with HFpEF and get this. They underwent two bouts of upright seated cycle exercise dosed with sublingual nitroglycerin or a placebo every 15 minutes in a single blind randomized crossover design. So really well done. Wedge pressure, VO2 and cardiac output were assessed at rest with 20 watts exercise and at peak exercise during both the placebo and nitroglycerin conditions and the principle finding of the study (singing) acutely lowering pulmonary capillary wedge pressure during upright exercise with nitroglycerin in HFpEF did not improve peak exercise performance. So peak VO2 was practically identical with a 1% difference despite a 17% drop in peak wedge pressure. Peak cardiac output and peak peripheral oxygen extraction were unchanged, again, despite the drop in peak wedge pressure suggesting that oxygen delivery and utilization were unaffected. Exercise performance variables including peak wattage, peak ventilation and peak RER were unchanged, suggesting that again, reductions in peak wedge were insufficient to improve exercise tolerance.
All these results suggest acute reductions in wedge pressure are insufficient to improve exercise capacity and provide convincing evidence that a high wedge during exercise by itself is an epiphenomenon perhaps rather than a primary limiting factor for exercise performance in patients with HFpEF. Now of course this is incredibly interesting contrary to hypothesis and so please read the paper. The discussion is very rich.
Dr. Peder Myhre:
Oh wow, Carolyn. That is such a great paper. I can't wait to pick it up and read it from start to finish and now Carolyn, we're going to look into research within cardiovascular disease from COVID-19 and we have learned so much and so quickly about COVID-19 and its effects on the heart and we have really come a long way from the first case reports reported in the beginning of the pandemic and this paper, which comes to us from corresponding author Professor JP Greenwood, really adds important knowledge to this field. The COVID heart study was a prospective longitudinal multi-center observational cohort study of patients hospitalized with COVID-19 and at elevated serum troponin levels across 25 hospitals in the UK and these investigators aim to characterize myocardial injury, its association and sequela in convalescent patients following hospitalization with COVID-19 utilizing appropriately matched contemporary controls.
Dr. Carolyn Lam:
Ooh, important stuff. So what did they find?
Dr. Peder Myhre:
So these authors included in total 519 patients comprising 342 patients with COVID-19 and an elevated troponin, 64 patients with COVID-19 and a normal troponin and 113 age and comorbidity matched controls without COVID-19 and the frequency of any heart abnormality defined as left or right ventricular impairment, scar or pericardial disease was two full greater in patients with COVID positive and troponin positive, so 61% compared to the control groups and that is 36% for COVID positive and troponin negative and 31% for COVID negative and comorbidity positive and the myocardial injury pattern was different for these patients with COVID and an elevated troponin more likely than controls to have infarction and micro infarction. But there was no difference in non-ischemic scar and using the late MRI criteria, the prevalence of probable recent myocarditis was almost 7% for those with COVID and elevated troponin compared to only 2% for the controls without COVID-19 and myocardial scar is but not prior COVID-19 infection or troponin was an independent predictor of MACE.
So Carolyn, these authors discussed their findings in light of previously reported studies and these authors identified a lower prevalence of probable recent myocarditis than previously described and a higher proportion of myocardial infarction and this newly described pattern of micro infarction following COVID-19 and Carolyn, there is a brilliant editorial really summarizing this by Dr. Stuber and Baggish entitled "Acute Myocardial Injury in the COVID Heart Study Emphasizing Scars While Reassuring Scarce." I really recommend everyone to pick this up and read the editorial as well.
Dr. Carolyn Lam:
Very clever title. Thank you. For the last original paper in today's issue, it focuses on the crosstalk between sterile metabolism and inflammatory pathways, which have been demonstrated to significantly impact the development of atherosclerosis. Authors today are featuring and focusing on 25 hydroxy cholesterol, which is produced as an oxidation product of cholesterol and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. So these authors with co-corresponding authors, Dr. Suárez and Fernández-Hernando from Yale University School of Medicine, they showed beautifully that first, 25 hydroxy cholesterol accumulates in human coronary atherosclerosis. Next, that 25 hydroxy cholesterol produced by macrophages accelerated atherosclerosis progression and promoted plaque instability by promoting the inflammatory response in macrophages and also via paracrine actions on smooth muscle cell migratory responses.
Dr. Peder Myhre:
Wow, that is so interesting, Carolyn. What are the therapeutic implications of these findings?
Dr. Carolyn Lam:
Yes, I'm glad you asked because it was summarizing a lot of work in those findings with the very important implications that inhibition of 25 hydroxy cholesterol production might therefore delay atherosclerosis progression and promote plaque stability. So this study actually opens a door to explore the role of 25 hydroxy cholesterol as a target to control inflammation and plaque stability in human atherosclerosis.
Dr. Peder Myhre:
Oh, that is so important. Thank you so much and there is more in this issue as well, Carolyn. We have another issue of Circulation Global Rounds and this time we're going to France in a paper written by Dr. Danchin and Bouleti. We also have an exchange of letters by Dr. Yang and Dr. Schultze regarding the article, "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation" and an ECG Challenge by Drs. Manickavasagam, Dar and Jacob entitled "Syncope After Transcatheter Aortic Valve Implantation: Pace or Not."
Dr. Carolyn Lam:
Interesting. There's a Frontiers paper also by Dr. Dimopoulos on “Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus,” a Research Letter by Dr. Kimenai on the impact of patient selection on performance of an early rule out pathway for myocardial infarction from research to the real world. Nice. Well let's carry on to that feature discussion on heart failure, transcriptomics and proteomic, shall we?
Dr. Peder Myhre:
Can't wait.
Dr. Maryjane Farr:
Welcome everybody to Circulation on the Run. We are so pleased to be talking with Dr. Stavros Drakos and Dr. Sarah Franklin from the University of Utah. My name is Maryjane Farr and I am the heart failure section chief at UT Southwestern and Digital Strategies editor for circulation. Myself and Hesham Sadek will be talking with them about their new paper and circulation called "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients with Potential of Myocardial Recovery Upon Mechanical Unloading and Circulatory Support." Just briefly, Dr. Stavros Drakos is the director of cardiovascular research for the division of cardiology at Utah and co-director of the Heart Failure Mechanical Circulatory Support and Heart Transplant Program. Dr. Sarah Franklin is associate professor of medicine at the University of Utah whose lab has a specific expertise in the applications of proteomics to heart disease. Welcome, Stavros and Sarah.
Dr. Sarah Franklin:
Thank you.
Dr. Stavros Drakos:
Thank you. Thank you for having us.
Dr. Maryjane Farr:
This paper is exciting for clinicians. It's exciting for translational scientists. Hesham, why don't you start digging into this paper and tell us one or then the other of you tell us what this paper is about, what's the background and let's get into the science. Let's go there and then we'll pull back and look at some of the big picture stuff. Hesham.
Hesham Sadek:
Well, thank you. So I've been fascinated by the field of cardiac recovery for some time now and obviously Stavros is as an expert and one of the leaders of that field and what struck me about this is that we are starting to see some distinct molecular signature of patients that can experience recovery as opposed to patients undergoing the same procedures with the same profile that do not manifest evidence of myocardial recovery and specifically, the study was conducted very rigorously and the signature was very clear in that they saw primarily interest for someone like me who's interested in cardiac regeneration, a signature of cell cycle in the patients that experience recovery as well as ECM signature which could suggest reverse remodeling and also there's some evidence that ECM might impact cardiomyocyte and myocardial regeneration. So my interest in this for selfish reasons is primarily that this supports the hypothesis that perhaps there is a molecular signature of regeneration that occurs in patients that experience myocardial recovery with LVAD.
Dr. Maryjane Farr:
So Stavros, let's start with you. Give us the reason why to do this study. You mentioned some of the background. It'd be great to sort of talk for a moment about re-stage heart failure and then how it brought you to this study.
Dr. Stavros Drakos:
Thank you, Jane. So again, thank you for the opportunity to talk about the findings and the implications of this study. I like the way you are asking us to look a little bit at what led to this study and as you mentioned, the re-stage is a multi-center study that was performed in six US sites which showed in a reproducible fashion now given that we had single center studies from all over the world suggesting that, advanced heart failure is not an irreversible process that has to lead to end stage, an irreversible disease and what a re-stage demonstrated was that there is a subset of patients which if you select them based on clinical characteristics that we derived from other studies that were performed previously, you can achieve reverse remodeling, essentially a bad heart looking much better by every clinical, functional, structural characteristic in up to 50% of the selected patients. That's what re-stage showed.
So having this finding now in a multicenter study, what made this study very timely was to be able to understand what drives this remarkable response. What are some of the mechanisms, as Hesham said, that we can if uncover take advantage of and expand this paradigm and enhance it and achieve reverse remodeling and recovery of even more patients and even go earlier in the disease process. So that's kind of how I would link the clinical findings that preceded this study with the motivation to perform the study and the implications of these findings for the ongoing translational and basic science research.
Hesham Sadek:
I'd like to ask a question here. So Stavros, do you think it's too early to sort of redefine the term reverse remodeling in this context to include perhaps some evidence of regeneration? Is there evidence of regeneration in this field or that's too premature to say?
Dr. Stavros Drakos:
I think the data are directing us towards the direction you just mentioned. I think that we can begin talking about it and planting the seed. We do have other evidence from work that you and others have performed indicating that this indeed is one of the mechanisms that drives this phenomenon and I think that the findings, especially in the cell cycle that we identified add to and contribute even more to that body of work that you and others have done. At this point, I will turn it to Sarah who can talk a little bit more about the findings related to the cell cycle that we identified in our study and I think that these may complete the answer to you, Hesham.
Dr. Sarah Franklin:
Yeah, I would love to comment. I think it's a really interesting phenomenon and really in these patient samples we were trying to understand molecularly what the difference is between individuals that respond positively to therapy and individuals that receive the same exact therapy and do not respond positively. So these are termed responders and non-responders and in our analysis we combined two platforms where we could molecularly interrogate what's different in these two tissues and try to see what is differentiating these populations. So what's consistent and reproducible different in responders and non-responders on a molecular level and in both the transcriptomic data and the phospho proteomic data, we saw clear patterns with cell cycle regulation and extracellular matrix or focal adhesion molecules and the interesting thing about cell cycle is cardiomyocytes have typically been thought to exit the cell cycle not long after birth and we see some interesting phenomenon either in humans or mice where we can have nuclei that have either multiple sets of chromosomes or multiple nuclei and there's some differences that have been observed in the nucleus with regards to disease, so hypertrophy, heart failure.
So the molecules that we've identified, we saw a large difference in proteins involved in cell cycle regulation. Now the interesting thing is not all of those molecules are increasing or decreasing. We see a combination of molecules that are increasing or decreasing. But I think the other thing that's interesting is that these molecules, even though we are seeing changes in expression or changes in phosphorylation, exactly how that contributes to either cell cycle or cell cycle reentry or just nuclear function and transcription of proteins or genes or DNA regions is still what we need to continue to study. So exactly how these changes in proteins or transcripts related to the cell cycle, how they are exactly contributing to the physiological improvements that we're seeing is something that still needs to be investigated but is really important that that is a highlight of this study and as Stavros mentioned of previous work.
Dr. Maryjane Farr:
Stavros, tell us the design of the study.
Dr. Stavros Drakos:
Okay. So this study was performed in 93 patients that were prospectively enrolled in the Utah transplant affiliated hospitals here in Salt Lake City between the University of Utah, Intermountain Medical Center and the VA and these people came from all over the mountain west, the surrounding states of Utah and through our VA, through the state, from all over the west and south, from Alaska and Hawaii to Texas and we think it's a very representative population of our country's patient population and then we followed prospectively these people with serial echocardiograms so we can tell who will respond as Sarah said before, which essentially means which hearts are going to get better by echocardiographic criteria functionally and structurally, the dimensions of the heart shrinking and the ejection fraction improving to more than 40% and the dimension shrinking to normal range and then we compare these people, the subset of patients that have responded to the majority of patients actually that they have not responded. As we know these are advanced end stage patients and there is only a subset of those that they will favor respondents.
As we said earlier, these subset can increase if you go selectively and pick these patients based on baseline characteristics. So then we analyze the tissue we got from these people when the LVAD went in, which is the core of the apex of the heart and compare that to the tissue we receive when the patients got transplanted and we got the whole heart. So in the meantime, as we just discussed, we phenotyped these people so we knew who were responders and non-responders and then we went back in the lab and tried to marry two basic processes, analyzing the transcriptome and the proteome and by doing that we were able to see some overlapping changes between the transcriptome and the proteome and we felt that by doing this overlapping analysis, we will increase the likelihood that what we are seeing, exponential mechanistic drivers will be the real mechanism and not just associations that you can frequently find when you do studies in humans and that's kind of a rough, brief summary of the design. Sarah, would you add something to that?
Dr. Sarah Franklin:
No, I think that's a great overview of it. I think what excites me about it is that this was first clinically observed that these patients were recovering and so I think the exciting part is the hypothesis was that there was some molecular underpinnings that could molecularly define these patients that were responding or not responding and so with that hypothesis we then carried out these analyses hoping that we would see a difference and we're very excited. It's very successful in that we found very clear, molecular differences that are reproducible between these patient populations.
Dr. Maryjane Farr:
So obviously there's lots of implications. Let me start with one very simple clinical one and that is, so based on some of the differences in the signatures and pathways that you saw for the next patient who needs LVAD therapy and you're trying to predict in some way whether they may be a responder or a non-responder, could you look at a biopsy sample and try to make some sort of prediction based on some of your findings so that they can choose a VAD over a transplant? That's a very clinical question and then I guess the second question is would it have to be a left ventricular myocardial sample? So are the differences? What do you think about that question? Or it's just too much too, far beyond? This is obviously a mechanistic study. But I'm just asking.
Dr. Stavros Drakos:
No, that's a great question and I'll start and Sarah can add later. So obviously it will be great if we can have a practical way to predict before the intervention who are the people that they will respond and that's one of the motivations for this study. It was not just to find the mechanism so we can make this phenomenon better and enhance it and find the mechanism, create new therapies. It was also the practical approach that you suggested, Jane, and I think that yes, this adds to the clinical predictors that we have already identified from other studies and yes, we could theoretically take the tissue and do this analysis. Is this the most practical thing we can say to the patient to biopsy the heart, right? It would've been better to be able to identify a biomarker in the plaque and we've done that. We started in other studies, identifying what's going on in the tissue and then going targeted in the blood and that's how we identified two cytokines and a two cytokines model, interferon gamma and TNF alpha being predictive as circulating biome.
In this study we identify changes that can also inform future studies of biomarkers in the blood. But if we had a way to easily get the tissue and analyze the genes, yes, we could have done that as a predictor as well. The practical issue is that asking a patient for a biopsy just to predict the response to therapy may be something that most patients and most clinicians will consider way too advanced and complicated, right?that's why more work should and could be done to identify circulating biomarkers or other modalities that can help us interrogate what's going on in the heart related with these findings. But not that we cannot also do what you said. It's just more complicated. I don't know if Sarah would like to add to this.
Dr. Sarah Franklin:
I'd love to. I think that's a great overview. I think the only thing that I would add is that there are a number of conditions whether in the heart or otherwise in the body that you can use a single biomarker and it can be very predictive of conditions. Heart failure is so complex that often individual biomarkers are not sufficient enough to cover an entire population and all the nuances that can go into heart failure symptoms or syndromes and I think the exciting part about this study is it is one of the largest cohorts of patients that have been examined in this manner, which is exciting, but also that we have a multi-factor panel that is made up of multiple biomarkers that with the number of individuals that we examined is completely predictive of all of these patients.
So these biomarkers are consistent and reproducible across all of these patients between responders and non-responders regardless of some of the nuances in the heart failure that they have and so it's very exciting because it's possible that a multifactorial panel could be much more applicable and last the test of time more so than an individual biomarker. I think the one other thing that is exciting like Stavros mentioned is that we did initially identify these in the left ventricle and it will be really exciting to see how far these biomarkers can be used if they can be used in potentially other aspects of the heart or blood, which obviously is less invasive and so that's not something that we've applied this panel to yet, but I think is a really wonderful extension of now saying, can we also identify some of these biomarkers in the blood which would be less invasive even if it's a fraction of them. That would still be wonderful.
Dr. Maryjane Farr:
I have so many clinical questions. But Hesham, what questions do you have?
Hesham Sadek:
Yeah, so the elephant in the room here obviously is that the variable is that these patients have an unloaded heart and there is evidence that unloading can reverse some of the changes that occur after birth with increasing ventricular load and initiate cascade of molecular events that may allow myocytes to proliferate. So this begs the question, is there a difference in how these ventricles of patients that recover versus those that do not recover see load? Are we able to measure load appropriately and is there a difference in load between these patients and if so, can this be improved or detection or measuring unloading or the degree of unloading clinically, can this be improved?
Dr. Stavros Drakos:
No, that's a great question and it provides the opportunity to talk about some of the things we can do on the clinical arena to further enhance this phenomenon. Yes, there are ways that we can use to tailor the mechanical unloading that we can provide in order to enhance this phenomenon. One way, and that's a study that we are proposing, is to use sensors, pressure sensors that can guide the way you function the machines, the devices, right? The way you remove part of the load and these sensors, some of them are clinically approved like cardioments and then without doing invasive procedures you can follow chronically how these patients are being unloaded and how the heart is responding to this unloading. We know that a lot of LVAD patients, despite doing clinically well, we know this from snapshot evaluations in right-heart cath studies, they are not optimally unloaded. They are feeling pressures left and right are not always optimized and so by doing this kind of prospective assessment of the mechanical unloading, you can tailor what you offer and the hypothesis generated is that by doing that you may be able to recover even more people.
You can do this as we said, with approved sensors like cardioments or with other sensors that they are under investigation. You can also do more invasive stuff like PV loops. Of course these will require cathing these patients, which is a little bit more complicated. But it will provide more accurate assessment and it will also interrogate how the heart is improving and provide to you in-depth investigation and in-depth insights on also how the recovery process and the reverse remodeling process is being, I would say, digested by the heart and translated to functional response instead of just looking at it with an echocardiogram or the findings of a right-heart cath and these are studies that others have performed and have published and we know that they can give you a real good look into the systolic and diastolic function of the heart and how this is changing and improving down the road. So yes, that's the short answer. We can do that and we can tailor the unloading and potentially that's the hypothesis, maximize the effect that we saw here.
Hesham Sadek:
So this begs the question, maybe two questions here. One, is there evidence that patients who recover not from this study only but from other studies, is there evidence that patients who recover are more unloaded than patients that do not recover and the second question is: is it time to standardize assessment of mechanical load in patients with LVAD, especially those that will undergo or would be considered for recovery?
Dr. Stavros Drakos:
Yes. So that's a great opportunity to share with our audience what we know and what we don't know in this field in relation to your question about whether we know what is the optimum degree of unloading and the answer I think is that we need to know and understand more. What do I mean by that? There's this idea that the heart as every other organ after being unloaded and not working for some time may it lazy, may get atrophic and may need some rehab like the skeletal muscle when we put it in the cast and get atrophic and we need to rehab it when we remove the cast. So you can imagine that the LVAD and the unloading that provides, which in many cases may take over a significant part of the function of the heart may need gradual reloading as a second phase after the first phase of unloading and that's something that we've done. We have an ongoing study on this and also others have published that it may be beneficial.
Of course, it needs to be validated and investigated further and to discuss about the degree of unloading in the first phase and what is the optimum degree of unloading, I would say even there, there is room for us to understand better what's going on and I think that we can investigate with ongoing studies right now whether full unloading versus partial unloading and measure the pressures using these sensors can translate to better changes functionally and structurally. I think that's something that is very doable and it would be very beneficial. What was the second part of your question, Hesham?
Hesham Sadek:
I was asking whether it's time to start standardizing some measure of unloading if these patients are planned for recovery?
Dr. Stavros Drakos:
Yes, and that's what we are doing. In all of these people, we report from the get-go what is their recovery score based on the intermixed ICARS derived score and when we have patients that they have high likelihood of recovery, we monitor them very closely and clinically what we do is just looking at the echo and whenever we do a right heart cath for clinical reasons. But in a prospective research study we could do more than just looking at the echo and occasional right heart cath and using the sensors we just discussed previously, you can tailor the unloading and begin prospectively unloading them in a more I would say well monitored wave. Yes.
Hesham Sadek:
So this is unloading or device specific parameters. Now are there patient specific parameters with regards to type of heart failure? So we talked initially about whether there's an element of regeneration specifically when it comes to cell cycle. But many patients with non-ischemic cardiomyopathy for example, don't have large scars and don't have lot of myocytes as the underlying cause of cardiomyopathy. Would you foresee that there is different mechanisms, for example, in these patients that don't have myocyte loss, that perhaps maybe it's not cardio myocyte proliferation and not regeneration?
Dr. Stavros Drakos:
Yes. So I think that the differential responses we get based on the heart failure theology warrant further investigation. Sarah and I have discussed that and actually we are following on our findings with larger number of patients so we can tease out these and I'll let Sarah talk a little bit more about it in a minute. But to answer the clinical part of this question, we don't know yet whether different parts of heart failure should be prescribed different modes of unloading. But the way you described it of course invites the hypothesis that of course different substrates, different injuries of the heart, as you said, it's a completely different failing heart if you have a big scar there versus a patient who has a mode of heart failure, another type of injury and would this be treated better and more effectively in terms of reverse remodeling by applying a different mode of unloading? That's things that we need to investigate further. But Sarah, would you like to comment on the potential on the effect of the different heart failure theologies on some of the findings we saw?
Dr. Sarah Franklin:
Yeah, definitely. So I think it's a really interesting question and in this analysis we included ischemic and non-ischemic samples in the patient populations and really we're just stratifying them based on responders and non-responders. When we start layering additional levels onto that, then we're effectively kind of reducing the potential numbers. So if we have 25 responders and we start breaking that down into ischemic and non-ischemic to see if there's another layer of biomarkers there, we actually did that we did not include it in this study. It's something that we're working on to add that. But we do reduce the number overall of patients in those two populations. So it would be fine to share that we were seeing stratification between ischemic and non-ischemic. But we did not feel like the numbers might be high enough within the responder and non-responder categories that warrant including that in this manuscript. So it's very intriguing that just responders and non-responders alone stratify as well as they do.
They separate based on these biomarkers and it looks like it will also be possible in the future for us to even separate these samples further based on similar or additional biomarkers based on more specific factors in the etiology. So I think that will be another really exciting next step for future research.
Hesham Sadek:
My final question would be maybe a little bit broader than LVAD population, but definitely informed by this study. The term non-ischemic cardiomyopathy, do you think it's too broad and too vague for us to use in this setting because this encompasses many different types of cardiomyopathy that really are not nuanced enough by this definition.
Dr. Stavros Drakos:
Well, Jane was smiling while you were asking this question because we all as heart failure clinicians need to accept that it was not a good idea to name all of these different diseases non-ischemic cardiomyopathy when we did it or when this happened many moons ago. As you said, Hesham, and I couldn't agree more, these are completely different diseases. We need to understand them better and I think that the way we treat nowadays, chronic heart failure, many years down the road when people will look back, they will consider it a little bit, I would say, surprising that we were treating all of these the same way.
We need more studies like the one we just did, that they will have enough numbers and that's when the issue becomes that you need enough numbers to be able to tell the differences between all of these non-ischemic cardiomyopathy types, theologies and if you go upstream, motivated and inspired by findings like this, we hope that we will be able to identify how to go and do a root cause analysis and treat these diseases, not down, down, downstream the same way, but going upstream, finding what really went wrong and treating them earlier in the molecular or other pathophysiological mechanism pathway that led to the heart failure and so yes, it was a bad idea to do that. But of course sometimes we do things because we don't understand it better, right? As one of our keynote speakers here in the recovery symposium said a few years ago, Jay Khan, the founder of Heart Failure Strata of America, some things look complicated until you understand them. Then when you understand them, they look simple.
So here we don't really understand non-ischemic cardiomyopathy and how all these theologies lead there and I think studies like these can help us really inform the field better. But we will need, as Sarah said, more numbers.
Dr. Maryjane Farr:
So that was a great conversation. I wanted to just raise one last thing and that is what's so interesting about this cohort relative to re-stage heart failure is these were older patients and for re-stage heart failure, I think the average age was 35. So you would imagine there might have been one etiology for cardiomyopathy, uncontrolled hypertension or peripartum. But for cohorts in their fifties, there's probably an accumulation of different insults over many years time and so I thought that was particularly interesting from the point of view of that you were probably dealing with, again, a mixed bag of pressure overload, volume overload, maybe a genetic underpinning, whatever the life trajectory of some of these patients were and then lastly, the decision to try to go to recovery rather than to transplant, which would be the real world experience of why this wet pathway than the other. These are people truly in their fifties where they may have one or two surgeries in their lifetime left and so it's the relevant population that you're studying and so I'll leave it at that. That's a comment rather than a question, I think.
But I think for heart failure clinicians, this is why the bench to bedside piece is so relevant to understanding this because it actually does change clinical practice, even if the mechanistic pathways may take still many more years to truly understand. It helps understand what's possible from an accrued clinical decision-making level.
Dr. Sarah Franklin:
Jane, if I might just comment on that, I actually think that's one of the most exciting parts about this dataset is that, as you mentioned, these patients have complex diseases. They are older. But yet we are still able to see consistent and reproducible differences between the patient populations that respond and don't respond and to me that suggests that at the end of the day there are consistent differences or reproducible or consistent molecular changes in cardiac tissue and in response to stress and I think that that gives us hope that we could potentially not only predict who would respond or not respond, but that as we get better at understanding the differences, that there could be potential therapeutic targets or therapies that would still be beneficial regardless of the complexity of the heart failure.
Dr. Maryjane Farr:
Okay. So Sarah, Stavros, thank you so much for spending time with Hesham and myself and look forward to EUCORS--I'm allowed to say that.
Dr. Stavros Drakos:
Of course.
Dr. Maryjane Farr:
Thanks so much. Bye.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway.
Dr. Carolyn Lam:
Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question.
Dr. Peder Myhre:
That is so interesting, Carolyn. I can't wait to hear this discussion.
Dr. Carolyn Lam:
Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis.
Dr. Peder Myhre:
Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn.
Dr. Carolyn Lam:
Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157.
How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis.
Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed.
Dr. Peder Myhre:
Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP.
Dr. Carolyn Lam:
Cool. That's interesting. So how did they do this, and what did they find?
Dr. Peder Myhre:
So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm.
And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies.
Dr. Carolyn Lam:
Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction.
Dr. Peder Myhre:
Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain.
Dr. Carolyn Lam:
I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study.
This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload.
So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh?
Dr. Peder Myhre:
Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury.
Dr. Carolyn Lam:
Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find?
Dr. Peder Myhre:
Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study.
Dr. Carolyn Lam:
Indeed.
Dr. Peder Myhre:
And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury.
Dr. Carolyn Lam:
Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature.
Dr. Peder Myhre:
And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles."
And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy."
Dr. Carolyn Lam:
Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we?
Dr. Peder Myhre:
Let's go.
Dr. Greg Hundley:
Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Subodh Verma:
First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes.
Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described.
Dr. Greg Hundley:
Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population?
Dr. Subodh Verma:
So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity.
Dr. Greg Hundley:
And how many subjects did you randomize?
Dr. Subodh Verma:
So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups.
Dr. Greg Hundley:
Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results?
Dr. Subodh Verma:
So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%.
Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant.
Dr. Greg Hundley:
And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age?
Dr. Subodh Verma:
Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se.
Dr. Greg Hundley:
Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes?
Dr. Christopher Granger:
Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes.
But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure.
And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits.
Dr. Greg Hundley:
Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research?
Dr. Subodh Verma:
Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working.
And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further.
So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards.
Dr. Greg Hundley:
Very nice. And Chris, do you have anything to add?
Dr. Christopher Granger:
Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months.
Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join author Pieter Martens and Associate Editor Justin Grodin as they discuss the article "Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial."
Dr. Greg Hundley:
Welcome listeners to this January 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo, in Norway. And today, Greg, we have such an exciting feature paper. It comes to us from the ADVOR trialists. And the ADVOR trial examined the effect of acetazolamide in acute decompensated heart failure. And in this paper we're going to discuss how that treatment effect was across the left ventricular ejection fraction, across the spectrum. Greg, what do you think?
Dr. Greg Hundley:
Oh, wow. Sounds very interesting. But we might have some other articles in the issue. How about we grab a cup of coffee and Peder maybe this week, I'll go first and we'll start with preclinical science. How about that?
Dr. Peder Myhre:
Let's do preclinical science, Greg.
Dr. Greg Hundley:
Well, Peder, this particular paper focuses on the relationship between cardiac fibroblasts and cardiomyocytes. Remember that myocytes sit on a lattice of network of fibroblasts. And when the myocytes die, the fibroblasts then proliferates, secrete collagen and form this thick scar. Now, if we're going to try to regenerate, how are we going to get myocytes to get back into that thick scar when there's really a complete absence?
And so as adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts synthesize extracellular matrix, post myocardial infarction to form fibrosis, leading to cardiac dysfunction and heart failure. And therapies that can regenerate the myocardium and reverse fibrosis in the setting of a chronic myocardial infarction are lacking. Now, these investigators led by Professor Masaki Ieda from University of Tsukuba, were going to evaluate this process. The overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, Han2, all combined as MGTH. They can directly reprogram cardiac fibroblasts into induced cardiomyocytes and improve cardiac function in and under the setting of an acute myocardial infarction. However, the ability of an in vivo cardiac reprogramming to repair chronic myocardial infarction with established scars, well, that is really undetermined.
Dr. Peder Myhre:
Oh, what a wonderful introduction, Greg. And the way you described to us how cardiomyocytes and fibroblasts interact was really fascinating. Thank you. And now let's hear what the authors found and don't forget the clinical implications.
Dr. Greg Hundley:
Thanks, Peder. So these authors developed a novel transgenic mouse system where cardiac reprogramming and fibroblasts lineage tracing could be regulated spatiotemporally with tamoxifen treatment to analyze in vivo cardiac reprogramming in the setting of chronic MI. Then with this new model, the authors found in vivo cardiac reprogramming generates new induced cardiomyocytes from resident cardiac fibroblasts that improves cardiac function and reduces fibrosis in chronic myocardial infarction in mice. Wow.
And additionally, they found that overexpression of cardiac reprogramming factors converts profibrotic cardio fibroblasts to a quiescent state, and that reverses fibrosis in chronic myocardial infarction. And therefore, Peder, direct cardiac reprogramming may be a promising therapy for chronic ischemic cardiomyopathies and heart failure. Really exciting work, converting scar tissue to actual functional cardiomyocytes.
Dr. Peder Myhre:
That was such a fantastic summary, Greg, and a very interesting paper. And I'm now going to take us back to clinical science and epidemiology. Because Greg, we all know that social and psychosocial factors are associated with cardiovascular disease risk. But the relative contributions of these factors to racial and ethnic differences in cardiovascular health has not been quantified. So these authors, led by the corresponding author, Nilay Shah from Northwestern University Feinberg School of Medicine in Chicago, used data from NHANES to examine the contributions of individual level social and psychosocial factors to racial and ethnic differences in population cardiovascular health. And that was measured by something called the cardiovascular health score, CVH score, which ranges from zero to 14, and it counts for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, and blood glucose.
Dr. Greg Hundley:
Wow, really interesting, Peder. So what did they find here?
Dr. Peder Myhre:
So Greg, among males, the mean cardiovascular health score was 7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic black, and 7.6 in non-Hispanic white adults. And the authors found that the education explained the largest component of cardiovascular health differences among males. And now what about females? In females, the mean score was 8.0 in Hispanic, 9.3 in non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in non-Hispanic white adults. And for women, education explained the largest competence of cardiovascular health difference in non-Hispanic black. And place of birth, and that is US born versus born outside the US, explained the largest component of cardiovascular health difference in Hispanic and non-Hispanic Asian females. So Greg, the authors conclude that education and place of birth conferred the largest statistical contributions to the racial and ethnic differences in cardiovascular health among US adults.
Dr. Greg Hundley:
Very nice, Peder. What a beautiful description and outline that so well highlighting the differences in men versus women. Well, now we're going to turn back to the world of preclinical science, listeners. And we will continue with the paper by Dr. Amit Khera from Verve Therapeutics. Now, Peder, VERVE-101, this is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene. And that permanently turns off hepatic protein production and thereby, durably lowers LDL cholesterol. In this study, the investigators tested the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and also in a murine F1 progeny study.
Dr. Peder Myhre:
So more on PCSK9s, and this time CRISPR technology. Very exciting. Greg, what did they find?
Dr. Greg Hundley:
Right, Peder. So VERVE-101 was well tolerated in non-human primates and led to, listen to this, an 83% lower blood PCSK9 protein and 69% lowering of LDL-C with durable effects up to 476 days following the dosing. These results have supported initiation of a first inhuman clinical trial. That's what needs to come next in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Wow.
Dr. Peder Myhre:
Even greater reductions from this therapy on PCSK9 than the previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we go from one fascinating study to another. And this time we actually have the primary results from a large randomized clinical trial, Greg. Isn't that exciting?
Dr. Greg Hundley:
Yes.
Dr. Peder Myhre:
And this paper describes the primary results of a trial testing in Indobufen versus aspirin on top of clopidogrel in patients undergoing PCI with drug-eluting stent DES who did not have elevated troponin. So that is patients without mycardial infarction. And in fact, fact, this is the first large randomized control trial to explore the efficacy and safety of aspirin replacement on top of P2Y12 inhibitor in patients receiving PCI with death. And Greg, I suppose you like I wonder what Indobufen is, and I just learned that that is a reversible inhibitor of platelet Cox-1 activity and it has comparable biochemical and functional effects to dose of aspirin. And previous data indicate that Indobufen could lessen the unwanted side effects of aspirin and that includes allergy intolerance and most importantly, aspirin resistance, while it retains the antithrombotic efficacy.
Dr. Greg Hundley:
Wow, Peder. Really interesting and great explanation. Indobufen. So how did they design this trial and what were the primary results?
Dr. Peder Myhre:
So Greg, the investigators of this trial, called OPTION, led by corresponding authors, Drs. Ge, Quian, and Wu from Fudan University in Shanghai, randomized 4,551 patients from 103 center to either indobufen based DAPT or conventional, and that is aspirin based DAPT for 12 months after DES implementation. And the trial was open label and with a non-inferiority design, which is important to keep in mind. And the primary endpoint was a one year composite of cardiovascular death, non-fatal MI, ischemic stroke, definite or probable stent thrombosis or bleeding, defined as BARC criteria type 2, 3, or 5.
And now Greg, the primary endpoint occurred in 101, that is 4.5% of patients in the indobufen based DAPT group compared to 140, that is 6.1% patients, in the conventional DAPT group. And that yields an absolute difference of 1.6%. And the P for non-inferiority was less than 0.01. And the hazard ratio was 0.73 with confidence intervals ranging from 0.56 to 0.94.
And Greg, the occurrence of bleeding was particularly interesting and that was also lower in the indobufen based DAPT group compared to the conventional DAPT group. And that was 3.0% versus 4.0% with the hazard ratio of 0.63. And that was primarily driven by a decrease in BARC type two bleeding.
So Greg, the authors conclude that in Chinese patients with negative cardiac troponin undergoing DES implementation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of one year net clinical outcomes, which was mainly driven by reduction in bleeding events without an increase in ischemic events.
Dr. Greg Hundley:
Very nice, Peder. So another reversible inhibitor of platelet COX-1 activity, indobufen. And seems to be very, have high utility in individuals of Chinese ethnicity and Asian race. Well, perhaps more to come on that particular drug. Peder, how about we dive into some of the other articles in the issue? And I'll go first. So first, there's a Frontiers article by Professor Beatty entitled “A New Era and Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies and Priorities.” And then there's a Research Letter by Professor Zuurbier entitled, “SGLT-2 inhibitor, Empagliflozin, reduces Infarct Size Independent of SGLT-2.”
Dr. Peder Myhre:
And then Greg, we have a new ECG challenge by Drs. Haghighat, Goldschlager and Oesterle entitled, “AV Block or Something Else?” And then there is a Perspective piece by Dr. Patrick Lawler entitled, “Models for Evidence Generation During the COVID-19 Pandemic: New Opportunities for Clinical Trials in Cardiovascular Medicine.” And Greg, there's definitely so much to learn from all the research that has been done through the pandemic. And finally, we have our own Molly Robbins giving us Highlights from the Circulation Family of Journals. And first, there is a paper describing the characteristics of postoperative heart block in patients undergoing congenital heart surgery described in Circulation: Arrhythmia Electrophysiology. Next, the impact of socioeconomic disadvantages on heart failure outcomes reported in Circulation: Heart Failure. Then there is social and physical barriers to healthy food explored in circulation, cardiovascular quality and outcomes. And then there is the association of culprit-plaque morphology with varying degrees of infarct, myocardial injury size reported in Circulation: Cardiovascular Imaging. And finally, the impact of optical coherence tomography on PCI decisions reported in circulation cardiovascular interventions.
Dr. Greg Hundley:
Fantastic, Peder. Well, how about we get off to that feature discussion?
Dr. Peder Myhre:
Let's go.
Dr. Mercedes Carnethon:
Well, thank you and welcome to this episode of the Circulation on the Run Podcast. I'm really excited today to host this show. My name is Mercedes Carnethon. I'm an associate editor at Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm really excited to learn from the lead author of a new study on decongestion with Acetazolamide and acute decompensated heart failure across the spectrum of LV ejection fraction. And I've got the lead author with me today, Pieter Martens, as well as my colleague and associate editor Justin Grodin, who handled the paper. So I'd love to start off with just welcoming you, Dr. Martens.
Dr. Pieter Martens:
Thank you for having me. It's a pleasure to be here today.
Dr. Mercedes Carnethon:
Yes. And thank you so much for submitting your important work to the journal, Circulation. I'd love to start to hear a little bit about what was your rationale for carrying out this trial and tell us a little bit about what you found.
Dr. Pieter Martens:
So the ADVOR trial was a double blind placebo controlled randomized trial, which was performed in Belgium. And it set out to assess the effect of acetazolamide in acute decompensated heart failure and this on top of standardized loop diuretic therapy and patients with heart failure. And the goal of the current analysis was to assess whether the treatment effect of acetazolamide in acute heart failure differs amongst patients with a different ejection fraction at baseline at randomization. So we looked specifically at patients with heart failure, reduced, mildly reduced and preserved ejection fraction to determine whether acetazolamide works equally well in those patients.
Dr. Mercedes Carnethon:
Well, thank you so much. Tell me a little more. What did you find? Did your findings surprise you?
Dr. Pieter Martens:
All patients that were randomized in the ADVOR trial, we registered a baseline left ventricular ejection fraction at baseline. And what we saw was at the multiple endpoints that we collected in the ADVOR trial, that randomization towards acetazolamide was associated with a pronounced and preserved treatment effect. And different endpoints that we looked at was a primary endpoint which was successful, which is an important endpoint, which we all strive towards in acute decompensated heart failure. And we saw that irrespective of what your baseline ejection fraction was, that randomization towards acetazolamide was associated with a higher odds ratio for having successful decongestion.
And also looking at other endpoints which we find important in the treatment of patients with acute compensated heart failure, such as renal endpoints such as the diuresis, the amount of urine that they make, or the natruresis, the amount of sodium that they excrete, we again saw that randomization towards acetazolamide was associated with a higher treatment effect, so more diuresis, more natruresis, which was not effective, whether you had heart failure, reduced, mildly reduced or preserved eject fraction. We did see a slight increase in the creatinine, which was a little bit more pronounced in patients with heart failure with reduced ejection fraction.
Dr. Mercedes Carnethon:
Thank you so much for that excellent summary. I'm an epidemiologist, so I'm certainly aware that of the cardiovascular diseases and their changes over time, heart failure is one that is going up over time and affecting more of the population. So I know I really enjoyed hearing about an additional therapy that helps to improve quality of life and improve clinical outcomes in individuals who are experiencing heart failure. And I'm really curious as I turn to you, Justin, what attracted you to this particular article and why did you find it to be such a good fit for our audience here at Circulation?
Dr. Justin Grodin:
Well, Mercedes, I mean, I think you hit the nail on the head with your comment. And clearly when we look at Medicare beneficiaries in the United States, hospitalization for decompensated heart failure is the number one or most common cause for hospitalization. And up to this time, we really haven't had any multi-center randomized control clinical trials that have really informed clinical care with a positive result or a novel strategy that says, "Hey, this might be a better way to treat someone in comparison with something else."
And so when we have a clinical trial like ADVOR, one of the crucial things that we want to understand is how does this work and does it work for everybody? And now when we look at the population hospitalized with heart failure, we know that approximately half of them have a weak heart or low ejection fraction, and the other half have a stiff heart, a normal ejection fraction. And so since we've got this 50/50 makeup, it is a crucially important question to understand if we have an important study like ADVOR, does this apply? Are these benefits enjoyed by all these individuals across the spectrum?
Dr. Mercedes Carnethon:
Thank you so much for really putting that in context. And I believe you had some additional questions for Dr. Martens.
Dr. Justin Grodin:
Yes. Yeah, thank you. So Pieter, I mean obviously this was a terrific study. One question I had for you guys is, you and your colleagues and the ADVOR research team is whether you had expected these results. Because we know at least historically, that there might be different cardiorenal implications for individuals that have a weak heart or heart failure with reduced ejection fraction in comparison with a stiff heart or heart failure with preserved ejection fraction.
Dr. Pieter Martens:
Thank you for that comment. And thank you also for the nice feedback on the paper. I think we were not really completely surprised by the results. I think from a pathophysiologic perspective, we do wonder whether heart failure with reduced ejection fraction from a kind of renal perspective is different from heart failure with preserved ejection fraction. Clearly, there are a lot of pathophysiological differences between heart failure with reduced, mildly reduced and preserved ejection fraction. But when it comes to congestion and acute heart failure, they seem to behave, or at least similarly in terms of response to acetazolamide, which was very interesting. We do think there are neurohormonal differences between heart failure reduced ejection fraction, preserved ejection fraction. But at least how acetazolamide works seems relatively unaffected by the ejection fraction.
Dr. Justin Grodin:
And Pieter, another question that comes to mind, and this is getting a little bit technical, but there have been studies that have shown that people that present to the hospital with decompensated heart failure, that have HFpEF, have a very different perhaps congestion phenotype where they might not have as much blood volume expansion. And so I, for one, was pretty curious as to how these results were going to play out. And I wonder what your thoughts are on that, or maybe that's perhaps more niche and less widely applicable than what you observed.
Dr. Pieter Martens:
Now, I can completely agree that when we are thinking about congestion, the congestion itself is a sort of pressure based phenomenon. And the pressure based phenomenon is based on what your volume is and the compliance within your cardiovascular system. But I think one of the important things to remember is that how we enrolled patients in the ADVOR trial was that we enrolled patients who had clear signs of volume overload. Remember, we used a volume score to assess clinical decongestion or actually getting rid of the volume. Volume assessment isn't really necessarily a pressure based assessment. And pressures might be the genesis of elevated pressures might be different amongst heart failure with reduced versus preserved ejection fraction.
But what was really clear was that all these patients were volume overloaded. And when you think about the volume axis, then it's really about getting rid of that additional sodium, water, and that's where really acetazolamide works. So I do think we differ a little bit from historical acute decompensated heart failure trials in which they sometimes use signs and symptoms of more congestion, a pressure based phenomenon, where our endpoint was truly at volume endpoint. And we do believe that diuretics work really on a volume component of heart failure.
Dr. Mercedes Carnethon:
Thank you so much, especially for explaining that in a way that even non-clinicians such as myself can understand the potential implications. A big picture question that I have, and I really enjoy these discussions because they give us an opportunity to speculate beyond what we read in the paper. And that question is we do clinical trials and we identify effective therapies. And one of the bigger challenges we often face is getting those therapies out to the people who need them. Do you perceive any barriers in uptake of the use of acetazolamide in clinical practice?
Dr. Pieter Martens:
That's an excellent question. So one of the, I think beauties about acetazolamide is that this drug has been on the market for about 70 years. So I think everybody has access to it. This is not a novel compound which needs to go through different steps of getting marketing approval and getting a sort of reimbursement before it becomes available in clinical practice. And in theory, everybody should have access to this relatively cheap agent and can use it in its clinical practice. And I think it was very interested when we came out with the initial paper. I think already the day afterwards, we were getting messages from across the world that people have been using acetazolamide. So I think it is an agent which is available in current clinical practice and should not be too many barriers to its current implementation and clinical practice.
Dr. Mercedes Carnethon:
Well, that's fantastic to hear. So I hope Justin, that you will certainly help to ring the bell to get the information out about this wonderful study. I do want to turn to you, Pieter, to find out whether or not there are any final points that you didn't have an opportunity to discuss with us today.
Dr. Pieter Martens:
Think some of the other end points we didn't discuss were the effect, for instance, on length of stay. I think length of stay is a very important endpoint because hospital admissions, like Justin said, heart failure is the number one reason why elderly patients are being admitted. And just shortening the length of stay from a financial perspective might be important. So it was also very interesting to see that the use of acetazolamide in the study also translated into a shorter length of stay, which was also was unaffected, whether you had heart failure, reduced, mildly reduced or preserved ejection fraction,
Dr. Mercedes Carnethon:
Well, I certainly know people appreciate being in their own homes and being able to discharge is certainly a major benefit. So thank you so much for sharing that final point. I really want to thank you so much for a stimulating discussion today. I know that I learned a lot from you, Pieter, and the hard work of your research team as well as from you, Justin, for putting these findings in context and really helping our listeners and the readers of our journal understand why this paper is so important and how it's really moving the field forward for a clinically important problem. So thank you both so much for joining us here today on Circulation on the Run.
Dr. Justin Grodin:
Thank you.
Dr. Pieter Martens:
Thank you for having me.
Dr. Mercedes Carnethon:
I really want to thank our listeners for joining us today for this episode of Circulation on the Run. I hope you will join us again next week for more exciting discussions with our authors.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join authors Loren Field and Sean Reuter, as well as Associate Editor Thomas Eschenhagen as they discuss the article "Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity But Not Cardiomyocyte Proliferation."
Dr. Greg Hundley:
Welcome listeners, to this January 10th issue of Circulation on the Run, and I am Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.
Dr. Greg Hundley:
Well, listeners, this week's feature discussion delves into the world of preclinical science and evaluates cardiac troponin I and its impact on S phase activity in cardiomyocytes, and does that relate to cardiomyocyte proliferation. But before we get to that, how about we grab a cup of coffee and Peder and I will work through some of the other articles in the issue. Peder, how about this week I go first?
Dr. Peder Myhre:
Go ahead, Greg.
Dr. Greg Hundley:
Right. So Peder, this first study evaluated whether the burden of positive coronary artery calcification on cardiovascular disease differed by multidimensional individual characteristics, and so the investigators led by Dr. Kosuke Inoue from Kyoto University sought to investigate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease. And so Peder, to examine this question, the authors implemented a cohort study design that included adults aged greater than 45 years, free of cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis, or MESA, and after propensity score matching in a one-to-one ratio, they applied a machine learning causal forest model to, first, evaluate the heterogeneity in the association between positive coronary artery calcium and incident cardiovascular disease and then, second, to predict the increase in cardiovascular disease risk at 10 years when the coronary artery calcium score was greater than zero, so versus is it zero at all at the individual level?
Dr. Peder Myhre:
Oh, Greg, that is so cool, so using machine learning for coronary artery calcium and risk prediction, I'm very excited. What did they find?
Dr. Greg Hundley:
Right, Peder, so the expected increases in cardiovascular disease risk when the coronary artery calcium score was greater than zero were heterogeneous across individuals. Moreover, nearly 70% of people with low atherosclerotic cardiovascular disease risk showed a large increase in cardiovascular disease risk when the coronary calcium score was greater than zero, highlighting the need for coronary artery calcium screening among such low-risk individuals. And Peder, future studies are really needed to assess whether targeting individuals for coronary artery calcium measurements based on not only the absolute ASCVD risk, but also the expected increase in CVD risk when a CAC score is greater than zero and whether that improves overall assessment of cardiovascular outcomes.
Dr. Peder Myhre:
Wow, that is so clinically relevant and very interesting. And we're actually going to stay clinically relevant with the next paper which is about anti-platelet therapy after PCI. And this paper describes the long-term results of the HOST-EXAM trial. To remind you, Greg, the HOST-EXAM trial was an investigator-initiated prospective, randomized, open label, multicenter trial done at 37 sites in Korea. They enrolled patients who had undergone PCI with DES and maintained dual anti-platelet therapy without any clinical event for a mean 12 months and then they were randomized one to-one to either clopidogrel, 75 milligrams once daily, or aspirin, 100 milligram once daily. The primary results of this trial was published in Lancet in 2021 and showed superiority of clopidogrel over aspirin in prevention of the composite of MACE and major bleeding during 24 months of followup. And then, through the current paper, this describes the results of the post trial extended followup of about five years.
Dr. Greg Hundley:
Very nice, Peder, so aspirin versus clopidogrel and looking at the maintenance of that monotherapy and cardiovascular outcomes. Wow, so what did they find?
Dr. Peder Myhre:
Yeah, Greg. They, in this extended followup study, had a total of 5.8 years median followup, and the primary endpoint occurred in 12.8% in the clopidogrel group versus 16.9% in the aspirin group, and that has a range of 0.74 with a 95% conference interval ranging from 0.63 to 0.86. So also the clopidogrel group had lower risk of the secondary thrombotic endpoint and the secondary bleeding endpoint while there was no significant difference in the incident on all caused death. So Greg, to conclude, these very interesting results from the primary analysis of the HOST-EXAM trial was consistent through the longer followup, and this support the use of clopidogrel over aspirin monotherapy from 12 months onwards after PCI.
Dr. Greg Hundley:
Very nice Peder, beautiful description and sounds like long-term clopidogrel use over aspirin was quite beneficial. Well, the next study comes to us from the world of preclinical science, and it is from the investigative group led by Dr. Yunzeng Zou from Shanghai Institute of Cardiovascular Diseases and the Zhongshan Hospital and Fudan University. Peder, the study pertains to diabetes. So diabetic heart dysfunction is a common complication of diabetes mellitus and cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise intervening time of particular cell death type remained largely unknown in diabetic hearts. And so, Peder, this study aimed to identify the particular cell death type that is responsible for diabetic heart dysfunction and propose a promising therapeutic strategy by intervening in this cell death pathway.
Dr. Peder Myhre:
Wow, Greg, that is really interesting. Heart dysfunction in diabetes is something that we really have to learn more about and I'm so excited to hear what these authors found, Greg.
Dr. Greg Hundley:
Right. So first, Peder, the authors identified necroptosis as the predominant cell death type at later stages in the diabetic heart. And then second, Peder, the CB2 receptor, and we'll call that CB2-R, recruits transcription factor Bach2 to repress necroptosis and protects against diabetic heart injury while hyperglycemia and MLKL in turn phosphorylates CB2-R to promote ubiquitous dependent degradation of CB2-R, thus forming a CB2-R centric feedback loop of necroptosis. And finally, Peder, cardiac CB2-R or Bach2 expression negatively correlates with both MLKL 10 expression and the extent of diabetic heart injuries in humans. And so the clinical implications of these findings, Peder, are that the CB2-R centric necrotic loop represents a promising target for the clinical treatment of diabetic heart injuries.
Dr. Peder Myhre:
So Greg, this paper that comes to us from corresponding author Amanda Paluch from University of Massachusetts Amherst, is a meta-analysis of eight prospective studies with device measured steps including more than 20,000 adults who were followed for CVD events. And the mean age of participants in this study was 63 years and 52% were women. And the participants were followed for a median of 6.2 years and 1,523 cardiovascular events occurred.
So first, Greg, there was a significant difference in the association of steps per day in cardiovascular disease between older, that is greater or equal to 60 years, and younger, that is less than 60 years adults. So for older adults that has the ratio for cardiovascular disease using Q1 as reference was 0.80 for Q2, 0.62 for Q3, and 0.51 for Q4. And for younger adults that has ratio for cardiovascular disease using Q1 as reference was 0.79 for Q2, 0.90 for Q3, and 0.95 for Q4. And in the paper, Greg, there are some beautiful, restricted cubic lines that really illustrate the association between daily steps and the risk of cardiovascular disease among older adults and in younger adults.
So the authors conclude that for older adults taking more daily steps is associated with a progressively lower risk of cardiovascular disease. And monitoring and promoting steps per day is a simple metric for clinician patient communication and population health to reduce the risk of cardiovascular disease.
Dr. Greg Hundley:
Well, Peder, we've got some other very interesting articles in this issue and how about we dive into that mail bag and discuss a few of those. So I'll go first. The first is a Perspective piece by Professor Powell-Wiley entitled “Centering Patient Voices through Community Engagement in Cardiovascular Research.” A very important topic where can those in the community actually help us design meaningful outcomes for our research initiatives? And next Peder, there is a Research Letter from Professor Evans entitled “Increasing Mononuclear deployed Cardiomyocytes by Loss of E2F7/8, and does that fail to improve cardiac regeneration post myocardial infarction?”
Dr. Peder Myhre:
Thanks, Greg. We also have an ECG Challenge by Dr. Li entitled, “What Is The Truth Behind Abnormal ECG Changes?” And this is describing a very rare and interesting cause of ST segment elevation. I recommend everyone to read that case. We also have our own Nick Murphy who gives us the Highlights from the Circulation Family of Journals where he summarizes five papers from the Circulation subspecialty journals. First, the experience with a novel visually assisted ablation catheter is reported in circulation A and E. The impact of various exercise training approaches on skeletal muscle in heart failure with preserved the F is presented in circulation heart failure. Gaps in heart failure treatment over a decade are reported in circulation cardiovascular quality and outcomes, and the associations of machine learning approaches to plaque morphology from coronary CTA with ischemia are reported in circulation cardiovascular imaging. And finally, Greg, an observational study of left main PCI at sites with and without surgical backup is reported in circulation cardiovascular interventions. Let's go on to the feature paper today describing the cardiac troponin I interacting kinase and the impact on cardiomyocyte S phase activity.
Dr. Greg Hundley:
Great, let's go.
Welcome listeners to this January 10th feature discussion. Very interesting today as we are going to delve into the world of preclinical science. And we have with us today Dr. Loren Field and Dr. Sean Reuter from University of Indiana in Indianapolis, Indiana. And our own associate editor, Dr. Thomas Eschenhagen from University Medical Center of Hamburg in Hamburg, Germany. Welcome gentlemen. Well, Loren, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Loren Field:
Sure. This study actually came about in a rather roundabout fashion. We were doing a study with Kai Wollert in Hanover, Germany, where we were looking at the impact of a CXCR4 antagonist, which is used to mobilize stem cells from the bone marrow. And we had sent our mice over to Kai's lab and we have a mouse model that allows us to track S phase activity in cardiac myocytes, so these are cells are starting to replicate. And Kai crossed them into a different genetic background. And when he sent the mice back to us to analyze the hearts, we observed that we saw things that we never saw before in our experiments here.
His injury model was different than ours and now the mouse also had a genetic background, so we had to spend about a year to figure out if it was the injury model or the background. It turned out to be the genetic background, and the phenotype was these mice had about a 15-fold elevated level of cell cycle reentry. So then it became a relatively simple genetics game where we took the progenitor mice, made F1 animals, looked for the phenotype, did backcross animals, and basically identified the gene responsible for the phenotype.
Dr. Greg Hundley:
Very nice. And so in this study moving forward, what hypothesis did you want to address?
Dr. Loren Field:
Well, the main hypothesis was to figure out what the gene was and then secondarily to figure out the degree of cell cycle progression. When the cell is proliferating, the first task is to replicate its genome, which is S phase activity that's followed by the nuclei dividing and then finally by the cell itself becoming two cells. So our task was to identify, first, the gene and secondly, how far through the cell cycles the cells progressed.
Dr. Greg Hundley:
Very nice. And how did you construct your experiment?
Dr. Loren Field:
It was, again, very straightforward. It was simply setting up the appropriate genetic crosses to produce the animals. For the past 10, 15 years, we've been developing a computer assisted assay that allows us to identify the anatomical position of S phase positive cardiac myocytes in sections of the heart. And basically, we apply that program to the different genetic backgrounds and after that it's a ball of mapping studies, QTL mapping.
Dr. Greg Hundley:
So really mechanistic understanding. Well listeners, we're next going to turn to Sean, and Sean, can you describe for us your study results?
Dr. Sean Reuter:
Yes, as Loren stated, we saw a 15-fold increase in the S phase activity within the remote zone. Now we partition the heart in three different zones after injury, so the scar, the border zone, and then the remote zone or injury. And as Loren stated, we saw a 15-fold increase in the S phase activity, cell cycle activity, in the remote zone. And it's only because we have this system in hand that we can anatomically map the S phase activity within the heart that we were able to detect and also quantify this. And I think that's the reason we discovered this particular phenotype. But in addition to that, we performed RNA-seq or Exome sequencing and discovered that TNNI3K was the responsible gene for elevated S phase activity within the remote zone and border zone, but interestingly not in the scar.
Dr. Greg Hundley:
Very interesting, Sean, and so describe for us the importance of the TNNI3K and its relationship to this S phase.
Dr. Sean Reuter:
Sure. This particular gene was first discovered around 2000, and it's been studied for a while now, but the targets of this kinase specifically expressed in the heart, and it does get elevated after injury, but the actual targets are not well described or well known. It's believed that it phosphorylates some mild filament fibers and structural proteins, but the actual mechanism and the consequence of this is not known. So when we saw this in the remote zone, the elevated S phase, our current theory is that we believe that it's probably increasing oxidative stress that would basically further out from the at-risk zone or the border zone and then it now is in the remote zone. So we think it's just causing the heart, a pathological area of the heart, basically to expand. And so that's our current theory. Other groups have published on the oxidative stress in over expression of TNNI3K as well.
Dr. Greg Hundley:
Very nice. Well listeners, next we are going to turn to our associate editor, Thomas many articles come your way and come across your desk. What attracted you to this particular article, and how do we put its results really in the context of cardiac regeneration?
Dr. Thomas Eschenhagen:
Indeed, there were several arguments. It's a cool paper and the whole field is still very important. As probably most of you know, the field have a rough ride over the last 20 years, went up and down, lots of bad findings. And in the end it turns out that we are there where we have been 20 years ago, the mammalian heart essentially doesn't regenerate. So anything which would improve that would be of very major importance. Why is it a good paper? Because it starts from a very clear finding, one mouse, which looks like strongly regenerating after MI, another mouse line, which doesn't. And so by applying, let's say, classical genetic, very stringent methodology, Loren Field and his group identified this troponin I kinase to be the culprit. And they also proved it, because putting it back in the strain with a low, so-called, regeneration brought it back to the other level. So it's a very clear, nice methodology.
And finally, it's also a bit provocative because others in a very prominent paper, actually, have shown that this kinase... Or they concluded more or less just the opposite. The reason for the discrepancy is not quite clear and I was very happy to learn that the two groups actually discussed about it. So it's not just a bad controversy, but something which brings forward science.
And finally, I think something we didn't talk about yet today, what I particularly liked, maybe the most, on this paper is that this group didn't stop at the point of DNA synthesis. Everybody else would've probably said, "Okay, here we are, one regenerate the other doesn't." But in the very important extra finding of this paper is that this is just increased DNA synthesis and not more myocytes. And this distinction is so critical to the field because people forget that adult mammalian cardiomyocytes often have several nuclei and individual nuclei have more than one set of chromosomes, so this polyploid. And so if you see DNA synthesis like in this paper, it doesn't necessarily mean more myocytes. And actually here it was shown that it is not more myocytes but more polyploidization and making this difference so clear, I think it's a very important contribution to the field.
Dr. Greg Hundley:
Very nice. Well, listeners, we're going to turn back to each of our guests today and we'll start with you Loren. Based on your results, what do you see as the next study moving forward in this sphere of research?
Dr. Loren Field:
I think these results made me appreciate for the first time that the intrinsic level of cell cycle reentry, that's just the S phase, not the cell division, is actually much higher than I had thought previously. And this was because we just fortuitously, or I guess anti-fortuitously, we're using a strain that had low levels of S phase induction. If you calculate the turnover, if every nucleus that it synthesized DNA actually went on to have that cell divide, you could replace a 50% loss of myocytes over the course of about 550 days, give or take. And to me, that's actually telling me that if we could push those cells from just being polypoid, as Thomas was saying, to actually go through cytokinesis, there would be enough intrinsic activity to go forward. So this really tells me that what we should be focusing on is now not trying to induce cell cycle, but to allow the cells that are entering the cell cycle to actually progress through it.
Dr. Greg Hundley:
Very nice. And Sean?
Dr. Sean Reuter:
Yes, well, echoing Loren's point there, it's really not necessarily cell cycle induction, it's cell cycle completion to the cytokinetic fate. And that's the key. If we can get to that point, if we can figure out the mechanism to get to that point, then we have a wonderful discovery. However, we're not quite there yet, but we hope to be.
Dr. Greg Hundley:
And Thomas.
Dr. Thomas Eschenhagen:
Well, nothing to add really from my side, except that I would like to know what this Troponin I kinase does, because that is somehow still a missing link. How does this kinase lead to more DNA synthesis or the initiation of cell cycling? That would be an important finding and I'm sure there will be more research going on. Particularly also, to solve this discrepancy, I mean, there must be something in it and we don't quite yet know how, but I think we are in a good way. I'm sure there will be papers showing that soon. So I think that's, again, a very good start for this discussion.
Dr. Greg Hundley:
Well, listeners, we want to thank Dr. Loren Field, Dr. Sean Reuter and Dr. Thomas Eschenhagen for bringing us this really informative study in mammalian myocellular regeneration, highlighting that the level of cardiomyocyte cell cycle reentry in hearts expressing TNNI3 kinase would lead to significant regenerative growth if each cardiomyocyte exhibiting S phase activity was able to progress through cytokinesis. And this in turn suggests that identification of factors which facilitate cardiomyocyte cell cycle progression beyond S phase will be key to unlocking the intrinsic regenerative capacity of the heart.
Well, on behalf of Carolyn, Peder and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Judith Hochman, Editorialist Steven Bradley, and Guest Host Mercedes Carnethon as they discuss the article " Survival After Invasive or Conservative Management of Stable Coronary Disease" and editorial “If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.”
Dr. Greg Hundley:
Welcome everyone to our new year 2023, and we are here on this January 3rd edition of Circulation on the Run. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
I am Dr. Peder Myhre, Social Media Editor and doctor at the Akershus University Hospital and University of Oslo.
Dr. Greg Hundley:
Very nice. Well, welcome listeners and this week's feature, ah, very interesting. You know many times patients with stable coronary artery disease, we're seeing a lot in the literature about an invasive strategy versus a conservative strategy. But what happens long term for these patients? What's their prognosis? Well, more to come in the feature discussion. But first, how about we grab a cup of coffee and we discuss some of the other issues in this session. Peder, would you like to go first?
Dr. Peder Myhre:
Yes, Greg I would love to and the first paper today is very interesting and relates to one of the most important challenges globally, namely climate changes and extreme temperatures. And in this paper, which comes to us from corresponding author, Barrak Alahmad from Harvard Chan School of Public Health in the United States, together with a large international group of authors, investigated the associations between extreme temperatures and cardiovascular cause-specific mortality in 567 cities in 27 countries from 1979 to 2019.
Dr. Greg Hundley:
Wow Peder, that is a really large comprehensive study. So, how did they perform this analysis? What did they find?
Dr. Peder Myhre:
So Greg, the investigators collected city-specific daily ambient temperatures from weather stations and analyzed cause-specific cardiovascular mortality and excess deaths in association with extreme hot and extreme cold temperatures. And in total, the analysis included more than 32 million deaths from any cardiovascular cause, which were subdivided into deaths from ischemic heart disease, stroke, heart failure and arrhythmia and at extreme temperature percentiles. And that is defined as heat above the 99th percentile and as cold below the first percentile were associated with a high risk of dying from any cardiovascular cause, ischemic heart disease, stroke and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality.
And Greg, across a range of extreme temperatures, hot days above the 97.5 percentile and cold days below the 2.5 percentile accounted for more than two and more than nine excess deaths for every thousand cardiovascular death respectively. And heart failure was associated with the highest excess death proportions from extreme hot and cold days. So Greg, it seems like extreme temperatures really impact the cardiovascular mortality across the globe.
Dr. Greg Hundley:
Yeah, beautiful description Peder. And I think what was really exciting about that particular article is you had results from 27 countries. Wow, so really quite a global study and very informative.
Dr. Peder Myhre:
Yes, indeed very impressive.
Dr. Greg Hundley:
Well, Peder my next study comes to us from the world of preclinical science. And Peder, these investigators led by Professor Jose Luis de la Pompa from CNIC, evaluated two structural cardiac diseases, left ventricular non-compaction and bicuspid aortic valve. And they wanted to determine if those two conditions were caused by a set of inherited heterozygous gene mutations affecting the notch ligand regulator, Mind bomb-1 and co-segregating genes.
Dr. Peder Myhre:
Okay Greg, so we are looking at mechanisms for non-compaction and bicuspid aortic valve. What did they find?
Dr. Greg Hundley:
Right Peder, so whole exome sequencing of the left ventricular non-compaction families identified heterozygous missense mutations in five genes co-segregating with E3 ubiquitin protein ligase-1 Mib-1 as well as left ventricular non-compaction. And corresponding mouse models showed that left ventricular non-compaction or bicuspid aortic valve in a notch-sensitized genetic background. Now, also gene profiling showed that increased cardiomyocyte proliferation and defective morphological and metabolic maturation in mouse hearts and human pluripotent stem cell cardiomyopathy. Biochemistry suggested a direct interaction between notch and some of the identified gene products.
And so, these data Peder support a shared genetic basis for left ventricular non-compaction and bicuspid aortic valve with Mib-1 notch playing a crucial role. And thus, identification of heterozygous mutations leading to left ventricular non-compaction or bicuspid aortic valve may allow us to expand the genetic testing panel repertoire for better diagnosis and or risk stratification of both of these conditions, left ventricular non-compaction and bicuspid aortic valve.
Dr. Peder Myhre:
All right, that is really great and novel linking left ventricular non-compaction to bicuspid aortic valve, really great. And now Greg, we're going to go back to clinical science and we're going to talk about lipoprotein(a) or Lp(a). And as you know, elevated Lp(a) is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. And the authors of this next paper coming to us from corresponding author Olli Raitakari from University of Turku in Finland, examined Lp(a)'s potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease, ASCVD. And they did this by measuring Lp(a) in youths nine to 24 years old and linking that to a diagnosis of ASCVD as adults and also linking it to carotid intermediate thickness in the Young Finns Study. And in addition, these results were validated in the Bogalusa Heart Study.
Dr. Greg Hundley:
Oh, very nice Peder. So, what did they find?
Dr. Peder Myhre:
So Greg, those who have been exposed to high Lp(a) levels in youth and that was defined as greater than or equal to 30 milligrams per deciliter, had about two times greater risk of developing adult ASCVD compared to non-exposed individuals. In fact, all the following youth risk factors were independently associated with a higher risk. Lp(a), LD, cholesterol, body mass index and smoking all independently associated with ASCVD. And similar findings were made in the validation cohort who were participants with a high Lp(a) had 2.5 times greater risk of developing adult ASCVD compared to non-exposed individuals. And this also persisted in adjusted models. Now, what about the carotid intermediate thickness? In that analysis, there were no associations detected to youth Lp(a) levels in either of the cohorts.
Dr. Greg Hundley:
Very nice, Peder. So, great description of the utility of lipoprotein(a) measurements in the youth and for predicting future major cardiovascular events. Well, the next paper goes back to the world of preclinical science. And Peder, cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum. Now, these misfolded proteins can be removed via the adaptive retro-translocation, poly-ubiquitylation and a proteasome mediated degradation process. The endoplasmic reticulum-associated degradation, ERAD, which altogether as a biological process and rate has not been studied in vivo.
So, these investigators led by Dr. Christopher Glembotski from University of Arizona College of Medicine, investigated the role of ERAD in a pathophysiological model and they examined the function of the functional initiator of ERAD, VCP-interacting membrane protein and positing that the VCP-interacting membrane protein would be adaptive in pathological cardiac hypertrophy in mice.
Dr. Peder Myhre:
Thanks Greg. So, we're talking about degradation of the endoplasmatic reticulum and the association to hypertrophy. So, what did these investigators find, Greg?
Dr. Greg Hundley:
Right, Peder. So, this was really the first study to demonstrate that endoplasmic reticulum-associated protein degradation or ERAD is responsible for degrading and thus, regulating the levels of a cytosolic non-endoplasmic reticular protein. The results reported here describe a new mechanism mediating the pathological growth of the heart, such that in the healthy heart SGK-1 levels are low due to ERAD-mediated degradation. While in the setting of pathology, ERAD-mediated degradation of SGK-1 is disrupted, allowing the pro-growth kinase to accumulate and contribute to pathological cardiac hypertrophy.
And so Peder, the clinical relevance of these findings is that the investigators found that a variety of proteins that constitute the ERAD machinery were decreased in both mouse and human heart failure samples while SGK-1 was increased, supporting the possibility that SGK-1 is a contributor to the disease phenotype. And this is notable and that these studies could lead to the development of new therapeutic approaches for managing pathological cardiac hypertrophy and heart failure that target the ERAD to restore efficient SGK-1 degradation.
Dr. Peder Myhre:
That was an excellent explanation of a very difficult topic. Thank you, Greg.
Dr. Greg Hundley:
Well, Peder how about we take a look and see what else is in the issue? And now I'll go first. Well, first there's an In Depth by Professor Ntsekhe entitled, "Cardiovascular Disease Among Persons Living with HIV: New Insights into Pathogenesis and Clinical Manifestations within the Global Context." And then, there's a Research Letter by Professor Verma entitled, "Empagliflozin in Black Patients Versus White Patients With Heart Failure: Analysis of EMPEROR results-Pooled."
Dr. Peder Myhre:
Great Greg and there is an On My Mind by Gabriel Steg entitled, "Do We Need Ischemia Testing to Monitor Asymptomatic Patients With Chronic Coronary Syndromes?" Very timely and interesting. And finally, there is an AHA Update from Michelle Albert, the President of the AHA entitled, "Tackling Adversity and Cardiovascular Health: It is About Time."
Dr. Greg Hundley:
All right. Well Peder, how about we get onto that feature discussion looking at survival after invasive or conservative management in stable coronary heart disease?
Dr. Mercedes Carnethon:
Thank you so much for joining us for this episode of Circulation on the Run. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. And I'm very excited today to have as a guest, Dr. Judith Hochman, who is going to be discussing the long-awaited findings from the ISCHEMIA-EXTEND trial that are looking at survival after invasive or conservative management of stable coronary disease. Really pleased to have you with us today, Judy to hear about these findings.
Dr. Judith Hochman:
It's a pleasure to be here.
Dr. Mercedes Carnethon:
Thank you. So, just to start off, can you tell us about this study? What motivated this long-term follow-up of this particular trial?
Dr. Judith Hochman:
Yeah, so as I think the viewers or the listeners will recall, we built on a wealth of data from COURAGE and BARI 2D, some of the landmark trials that looked at revascularization versus optimal medical therapy or guideline-directed medical therapy alone. We tested an invasive strategy versus a conservative strategy dating back already to 2012 is when we started. And we had a five component primary outcome, which included cardiovascular death, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. And at the end of 3.2 median years of follow-up, we saw no difference in the primary outcome in that the curves crossed with some excess risk upfront due to periprocedural MI and decreased risk of spontaneous MI long-term. But the net overall timeframe spent free of event was similar between the groups.
So, we did observe improved quality of life for the invasive strategy, but in terms of clinical outcomes there was no difference. So, cardiovascular death at the end of that time period was no different between the groups, all-cause mortality was no different, non-cardiovascular death, there was actually an increase in the invasive group, which was somewhat of a mystery. We can get into that a little bit later because I think that becomes important. But 3.2 years meeting and follow-up is relatively short. So, everyone was very interested in what would the long-term outcomes be. So, we had another grant from the National Heart, Lung and Blood Institute to follow these patients long-term. And this is an interim report with seven years of follow-up, a median of 5.7 years.
And the bottom line is that all-cause mortality was the same at seven years but for the first time, an invasive strategy resulted in lower cardiovascular mortality, which was very interesting and very exciting except that it was offset, exactly offset by the continued excess that we had previously observed in non-cardiovascular mortality. And that's basically the upshot of what we just reported and why we continue to follow patients and why we're going to continue to follow patients and have a final report in 2026.
Dr. Mercedes Carnethon:
This is really fantastic work. As you point out, the initial follow-up was fairly short and the findings were so critically important demonstrating that there were subtle differences between the two approaches but that overall, things appeared relatively similar. Did it surprise you? Oh, please correct me.
Dr. Judith Hochman:
I should point out that because there were less spontaneous MIs during follow-up and spontaneous MIs are associated with a heightened risk of subsequent death more so than the periprocedural MIs, we did hypothesize and we're very interested in longer term cardiovascular and all-cause mortality thinking that those reduced spontaneous MIs in the invasive group would be associated with reduced cardiovascular death and perhaps reduced mortality. As I did indicate, cardiovascular death mortality was reduced but all-cause mortality was the same with a hazard ratio of 1.0.
Dr. Mercedes Carnethon:
Well, nothing seems more clear than a hazard ratio of 1.0 with those very tight confidence limits so thank you so much. I'm really pleased that our editorialist, Dr. Steve Bradley was also able to join us today because to hear his thoughts about where this fits in the context of what we know can be really insightful. So, I'd really love to turn to you, Dr. Bradley. In your opinion, why was this study question so important and tell us a little bit about how you think the clinical field should use these findings.
Dr. Steven Bradley:
Absolutely and thanks for having me. I think there were some indication that perhaps the farther we follow the patients out from the original ISCHEMIA trial that we might start to see some evidence of benefit for revascularization. I think Dr. Hochman spoke about the evidence of more of these spontaneous myocardial infarctions that were happening in the non-revascularization arm of the study and an association with worse cardiovascular outcomes in patients that experience spontaneous events. And so, the thoughts might be that over time we would see the benefit of that. And certainly if you parse out cardiovascular versus non- cardiovascular outcomes, we do, we see lower rates of cardiovascular death in the patients who undergo revascularization but it's balanced out by non-cardiovascular death. And so, it becomes a zero sum game for a patient. They want to be alive, it doesn't matter by what mechanism.
So, if we have a therapy that doesn't actually prolong their life but it leads to different mechanisms by which they have an outcome, that's important for us to understand. This adds to an already robust evidence-based that ISCHEMIA really did inform and it gives us that long-term trajectory to help us understand for patients what the implications are. I will note that and we've commented in the editorial and this is something that was shown in the original ISCHEMIA trial, that it's not just about mortality for patients, it's important that we help them live better as well. And certainly we know that revascularization is associated with quality of life improvement so that's an important part of the conversation with patients. But again, continuing to refine our understanding of what the implications of revascularization are for mortality is where this study leads us now.
Dr. Mercedes Carnethon:
Thank you so much. One of the things that I find so impressive about clinical trials of this scale are that you incorporate such a broad audience. I note that 36 countries contributed data to this particular trial. I wonder whether, did you have an opportunity to investigate whether these findings were similar in low and middle income countries as compared with higher income countries? And how would you expect clinicians in low and middle income countries to use this information?
Dr. Judith Hochman:
That's a great question and yes, the treatment effect was similar across regions, didn't really have any very low income regions but we did have India was in the study and a number of South American countries. And I think it's incredibly important for those countries where there are very limited resources to reassure them, the practitioners and their patients that just because they can't afford an expensive invasive procedure, stenting or bypass, does not mean it's going to cut their life shorter, it's not going to make them survive for a shorter amount of time. Therefore, they can limit the use of scarce resources to the most severely impaired in terms of quality of life, the patients with the most frequent angina. It also became extremely relevant during COVID.
Dr. Mercedes Carnethon:
Tell me more.
Dr. Judith Hochman:
Well, elective procedures were shut down during COVID and more publications that cited the ISCHEMIA trial to say that they felt comfortable not being able to do elective stenting in patients with stable ischemic heart disease that would've met the ISCHEMIA trial criteria, which by the way we should add was preserved ejection fraction, we excluded ejection fraction less than 35, patients had to be stable. They could not have had two coronary syndrome within the last few months. They could not have had angina refractory to medical therapy and they could not have had left main disease. So, those are key. There are other exclusion criteria but those are the key exclusion criteria.
Dr. Mercedes Carnethon:
Thank you for that. And I can really see a corollary and I appreciate the messaging around similar outcomes and preserving resources. And I think certainly even within our own country where we see vast differences in access to intensive medical therapies or tertiary care medical centers who do these procedures on a higher volume, at least we can feel reassured that outcomes may be quite similar as far as mortality. What do you-
Dr. Judith Hochman:
If they take their guideline-directed medical therapy.
Dr. Mercedes Carnethon:
Thank you for pointing that out.
Dr. Judith Hochman:
It's incredibly important. John Curtis' group looked at adherent patients by the modified Morisky score versus non-adherent patients. Non-adherent patients don't have as good a health status as adherent patients. So, just that also adds to a wealth of literature that you have much better outcomes if you actually take your medications.
Dr. Mercedes Carnethon:
No, I think that's a very good point. What are your thoughts, Steve on what the next steps might be?
Dr. Steven Bradley:
Well, I know that as was pointed out earlier, there's going to be the opportunity to see additional longer term follow-up beyond this interim analysis. So, it'll be interesting to see what that continues to show us in terms of understanding applications on mortality. I'll pose a question that we posed within our editorial around trying to identify non-fatal outcomes to see if there are any opportunity to capture those non-fatal outcomes to give us an understanding of potential mechanisms for why there is this cardiovascular versus non- cardiovascular mortality difference by treatment arm? Certainly, that may be helpful.
Dr. Judith Hochman:
Sorry. We're very, very interested in the excess in non-cardiovascular death. So, we are as a result of this interim analysis, revising our case report form, which was very lean, pragmatic because the funding is relatively limited to include especially collection of data around malignancy. Because as we reported before, the non-cardiovascular deaths were largely malignancy and to some extent infection. And what was driving the difference, the excess in non-cardiovascular death as we published in American Heart Journal in the invasive group was excess malignancy.
Dr. Mercedes Carnethon:
That's really interesting.
Dr. Judith Hochman:
To our deep surprise and shock, it appeared that the only variable associated with that excess risk was the number of tests or procedures you had that involve radiation. And of course, we're talking about medical doses of radiation. And this short timeframe, three and a half to seven years, which is when the curve started to diverge to three and a half, we filed to seven years is not thought to ... it's thought to be too short a timeframe for exposure to radiation to lead to excess malignancy.
So, we have partnered with some radiation experts, we are adding much more details to our case report form, not only in terms of death from malignancy but just the occurrence of malignancy. Did you get malignancy during the course of follow-up? And that's really critically important. We are not adding information about additional myocardial infarctions. We think that the key, if we're going to focus on site burden and how much they can actually collect, is to look at the mechanisms of death and the occurrence of malignancy, whether that leads to death or not, those are our top priorities at this point.
Dr. Mercedes Carnethon:
I could go on and on, I'm learning so much speaking with the two of you. And again, that really is the primary goal of our podcast to really have an opportunity to extend beyond what's written in the paper and really hear directly from the authors who led the study to hear your thoughts as well as those of the editorialists on where this is going. I really want to thank you both for the time you've spent today to share with our audience of the Circulation on the Run podcast.
Dr. Judith Hochman:
You're very welcome.
Dr. Steven Bradley:
My pleasure.
Dr. Mercedes Carnethon:
I just want to thank all of our listeners for joining us on this really stimulating discussion today on this episode of Circulation on the Run.
Please tune in next week where we will have more exciting discussions like this one. Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
In this week’s Circulation on the Run podcast, we turn the show over to Circulation’s Social Media Editors Dr. Pishoy Gouda and Dr. Peder Myhre. They interview the 2022 recipients of the Joseph Loscalzo Award for Best Basic Science Article, and the 2022 recipients of the James T. Willerson Award for Best Clinical Article.
Dr. Maryjane Farr:
Welcome everybody to Circulation on the Run. My name is Maryjane Farr, and I'm the digital strategies editor at Circulation. Carolyn and Greg are on break this week. And as part of the Circulation tradition, we turn the stage over to two of our social media editors, Dr. Peder Myhre from Oslo and Dr. Pishoy Gouda from Edmonton. They're going to be interviewing the 2022 winners of the Loscalzo Award and the Willerson Award. Take it away, Peter and Pishoy.
Dr. Peder Myhre:
Today. Pishoy, we have a very exciting issue of Circulation on the Run. We are going-
Dr. Pishoy Gouda:
We certainly do.
Dr. Peder Myhre:
Yeah. We're going to discuss two amazing papers that are award-winning and we're going to talk to the first authors who really know these papers and conducted the amazing work that we're going to display here today.
Dr. Pishoy Gouda:
Yeah, I'm excited.
Peter. And with us today, we'll start talking about the recipients of the Loscalzo Award. So I wanted to start off by introducing Dr. Leo and Dr. Suvorava, who are the very proud recipients of the Loscalzo Award for their paper entitled Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure. So welcome Doctors Leo and Suvorava. How are you guys doing today?
Dr. Francesca Leo:
Hi, thank you for the introduction and pretty well, I'm currently in Italy for my winter Christmas holidays, but I'm really excited and happy to be here today with you.
Dr. Pishoy Gouda:
Excellent.
Dr. Suvorava:
Hello. I'm also very happy to be here today. Thank you for your invitation and for your congratulations. It's a privilege and honor for me to be a recipient of this Dr. Loscalzo Award. Thank you.
Dr. Pishoy Gouda:
Well, I just wanted to start off by taking another second here to congratulate you both on this award. We all know the sheer amount of work and dedications to get these projects going, so congratulations. And I'm going to start off with a really easy question for you guys. When you found out that you were a recipient of the Loscalzo Award, who is the first person that you told?
Dr. Francesca Leo:
As I mentioned, I'm Italian and as a good Italian I need to say that. Of course, the first people I told were my parents because we all know that Italian and parents are just one thing. So they were the first ones. And then all of course, my partner and friends came second, parents first, family first.
Dr. Pishoy Gouda:
Very good. What about yourself, Tatsiana?
Dr. Tatsiana Suvorava:
Hi. Yeah. I had to think back like seven years ago and I very good remember one day when I was really excited about the results, what we found, I was in the lab, I was developing a western blood to check the functional ability of our models and it showed that it was very successful that we couldn't knock out our protein of interest almost completely. And at that day exactly, we had a lab meeting. So I directly pulled this image on my USB stick and then showed it on the lab meeting. So actually these were my colleagues who first hear about this.
Dr. Pishoy Gouda:
That's awesome. That's lovely. Well, after I got married, sometimes my parents get bumped to the second phone call and they weren't very happy about that and they let me know very clearly. But let's switch gears a little bit and tell us a little bit about how you made the decision to pursue academics. It's such a daunting career and a daunting topic sometimes. And how did you get interested in research and how did you find yourself coming into this research project?
Dr. Francesca Leo:
If I can start first. Well, I decided to pursue an academical career at the beginning following my master thesis that I did at the University of Pisa here. And I've always wanted to go abroad and gain experience, get to know different realities apart from Italy. And I was actually really lucky that I got the opportunity to work in the laboratory Professor Cortese-Krott because that gave me the opportunity to grow a lot, both personally and professionally, of course. I learned new techniques and together with our great team, we managed to achieve many goals. In particular, this paper, I must say that was my last satisfaction before my doctoral exam. So I think the feeling that you get after any also small achievement is something that you can really, I cannot find it hard to explain to people that are not in research or not in science in general.
Dr. Pishoy Gouda:
No, I totally agree. When I get a new data set, I get so excited and my wife is telling me, what are you doing is I just got new data and I'm like a little child on Christmas day. She doesn't understand it, but she appreciates that some people like that. What about yourself? What about yourself?
Dr. Tatsiana Suvorava:
Yeah, well my decision to pursue academic career started with as probably for many researchers, started from intense fascination from one discovery. I was at the beginning of my bachelors' science studies and then the Nobel Prize was given for the discovery of nitric oxide as a signaling molecule in a cardiovascular system. And I was so fascinated that the gaseous molecule so simple has so lots of responsibility in the body. And since that time, that was always in the focus of my research and this is for me, a lifelong journey. I'm still on the way.
Dr. Pishoy Gouda:
That's amazing, Tatsiana. And that sort of sets us up nicely. And as you guys know, I'm a interventional cardiologist. Basic science is a little bit farther from my memory. So I'll start off by admitting that my basic science research is not where it should be. But with that in mind, I was wondering if you could just tell our listeners a little bit about your research and why this question is so important and explain it to you like you were lowly clinicians that don't really understand basic science.
Dr. Francesca Leo:
I always take over Tanya, but yes, I have less to say than you. I must admit.
Dr. Tatsiana Suvorava:
Okay so let’s start. No problem.
Dr. Pishoy Gouda:
It's a team effort. It's a team effort.
Dr. Tatsiana Suvorava:
Its a team effort and yeah. Ok.
Dr. Francesca Leo:
It's been a really teamwork, I must say from the really, really, really beginning. So this paper was, as I said, the central focus of my doctoral thesis. I just take two small part of it, of course, in particular, what is really important on the paper, I think that is we use really new mice models that Tanya and my Professor Cortese-Krott really and highly characterized at the really beginning, so developed completely from new, and they are mice that are expressing or not eNOS this protein that is responsible for nitric oxide production in the endothelium or in red blood cells. So the importance of this research was to demonstrate the role or pivotal role of eNOS expressed in the red blood cells in the modulation of blood pressure as well as circulating nitric oxide metabolites. And we actually did it with this paper. And considering that cardiovascular disease are one of the major causes of death nowadays, this results can really have important clinical and therapeutical implications for future research and real life, let's say.
Dr. Tatsiana Suvorava:
Yeah, maybe I could add to Francesca.
Dr. Francesca Leo:
Sure,
Dr. Tatsiana Suvorava:
Yeah.
Dr. Pishoy Gouda:
Of course.
Dr. Tatsiana Suvorava:
I think our research was especially important because it's identified the existence of previously unrecognized and actually non-canonical pathway, how the red blood cells can regulate blood pressure. And it was so exciting about this.
Dr. Pishoy Gouda:
Right. So trying to find out if the red blood cell, nitric oxide synthase can actually regulate blood pressure. And this has obviously lots of clinical implications. So in practice, how did you guys set up your experiments? How did you try to test the significance of the Enos red blood cells effects?
Dr. Francesca Leo:
Just if I can add something, what was really important. So what is known is that Enos expressing the endothelium plays an important role in the modulation of blood pressure. What we actually found out is that the one in the red blood cells also is involved and played a role that seems to be independent from the one played from the eNOS expressed in the endothelium. For answering your question, I also, I need to say I'm not the right candidate because this is a huge project that started about 10 years ago. So I was really, I repeated and I will always repeat it, I was really lucky to take part to this project and to get the opportunity to take part to this journey because it was really a journey and it gave me the opportunity to work with very different people and get in touch with very different realities, academical realities.
And I can say that this project started from my previous boss and Tanya that they had this idea and started this whole project together with, of course Tanya is the one that is involved since the really beginning. So she can definitely better answer to this question.
Dr. Tatsiana Suvorava:
Yeah, thank you, Francesca. It's a long way actually what we did, and actually I started this particular project on the level of postdoc and eNOS and hypertension have been already in a center of my research interest for several years. And in a previous project what I had, I also had a transgenic mice, which were generated by conventional genetic approach by micro injection of D N a. And at that time we observed a significant contribution of external endothelial component into the blood pressure regulated. However, at that time we were not able to identify the exact extracellular allocation of this component. There were several candidates which were suggested, and one of them there were red blood cells. And everyone was kind of skeptical about this because the level of eNOS protein in red blood cells is extremely low. And furthermore, there were a lot of doubts how eNOS activity can be exported from the red blood cells because it's red blood cells are full of heme, which is a scavenger of nitric oxide.
Furthermore, actually it was not clear how they transported and how it is released this activity. But now if we think that red blood cells are the largest component contributor to overall cell number in the body, so maybe then we can more critically think and then think that the total amount of red blood cells maybe compensate for this very low eNOS protein expression. And actually because they have a high density and their shape is erase high, so they provide a very sufficient release of this inactivity from red blood cells. But this idea was doubted for many years, although there it was reported that eNOS is expressed in red blood cells in 2006 was a paper.
Dr. Pishoy Gouda:
Well that's very exciting. So what we really learned is that eNOS system in both red blood cells and endothelial cells contribute to blood pressure regulation. Now I might direct this to you, Francesca. Well what does that mean for the clinicians in our audience? Well, what does that mean for a hypertension patients?
Dr. Francesca Leo:
So for clinicians, so, I must say these findings may have really important pathophysiological implication in the understanding of the interrelationships between hematologic and cardiovascular disease and may reveal the really novel therapeutic approaches to improve tissue perfusion. Moreover, our data and models may also help in understanding how red blood cells eNOS signaling can really affect red blood cells function, the scavenging of nitric oxide, as Tanya had previously said, as well as the crosstalk between nitric oxide and the sulfides that are of highly present in the bloodstream and in the body as well as oxygen transport. And may also enable us to refine the criteria for blood banking transfusion and to also try to develop new strategies or therapies for many diseases and pathologies where red blood cells are involved.
For example, coronary artery disease, chronic kidney disease that normally are pathologists that show a decrease in the expression of eNOS expressed in the red blood cells or hematologic disease hemoglobinopathies, which are normally characterized by a systemic decrease in nitric oxide bioavailability or one of the most common diseases, sickle cell disease. Cause of course the shape of red blood cells is definitely also responsible of their functioning. And it can also determine, of course, an impairment or more alteration in the release of nitric oxide in the body.
Dr. Tatsiana Suvorava:
Yeah, maybe I'll just add few words. So actually that's open as a perspective that impairment of red blood cells, eNOS may contribute to the pathogenesis of hypertension. So this is the most important thing I think here in clinician point of view.
Dr. Pishoy Gouda:
Yeah, absolutely. Lots of different ways that this research might be heading. And like you were saying earlier, Tatiana research is really a longitudinal process. You started this almost a decade ago and I'm sure that there's more projects and plans that you have with this for the future. What are you working on now?
Dr. Tatsiana Suvorava:
Well, I'm still in academia and I'm still doing academic career, actually. We continued our study and we also studied pathophysiological significance of red blood cells eNOS for cardio protection. For example, in regulation of coronary blood flow, myocardial performance in myocardial infarction, acute myocardial infarction in vivo. We recently published this and here we could also see involvement of red blood cells eNOS, which limit infarct size in acute myocardial infarction. In a pipeline is also a manuscript about red blood cells and endothelial cells eNOS in exercise induced cardio protection and of course the other focus would be the role of red blood cells eNOS in other disease conditions and a chronicle kidney disease for example. It will be also investigated. So we are full of plans, however, I changed department, but I'm still having eNOS in focus and hypertension as well.
Dr. Pishoy Gouda:
Well that's really exciting stuff and yes, I just wanted to congratulate you both again Dr. Leo and Suvorava and thank you for taking the time to share with us your very clear passion for this topic and I wish you guys both the best of luck. Congratulations again.
Dr. Francesca Leo:
Thank you so much.
Dr. Tatsiana Suvorava:
Thank you so much.
Dr. Pishoy Gouda:
Well congratulations again to our award recipients and Peter, why don't you tell us a little bit about what article we're going to be talking about next?
Dr. Peder Myhre:
Yes, thank you so much Pishoy. And first, I must say it was so much fun to listen to you guys discuss the paper. You can really feel the passion for the science coming through the microphone. And that was for me as a clinician as well. I learned a lot. And now we're going to actually take a step and move over back to clinical science and we are going to talk to the winners of the James T. Willerson Award. So welcome doctors, Jeanne du Fey and Dr. Alexandra Prepoudis.
Dr. Jeanna du Fay de Lavallaz:
Thank you very much for having us on the podcast. It's a pleasure to be here and we're also very happy to be able to discuss this paper with you. And of course we were extremely glad to receive this award, so we're excited about the discussion.
Dr. Peder Myhre:
And so for the listeners who are not familiar with the Willerson Award, this award recognizes the best clinical paper published in circulation in the preceding 12 months. And this award honors Dr. Willerson, who was a major leader within American Heart Association. And among his roles, he served for over a decade as the editor-in-chief of circulation. And during his tenure, the journal transitioned away from a once monthly format, vastly expanded its international footprints and rose substantially in stature and impact. And speaking of international footprint, today we have authors from all over the world and I know both of you, Jeanne and Alexandra are from the amazing biomarker group in Basel led by Christian Mueller. So Alexandra, if we can start with you, I just want to learn a little bit more about you. Where do you work, where are you in your career and your areas of interest?
Dr. Alexandra Prepoudis:
Good evening and thank you for the introduction. My name is Alexandra Prepoudis and I'm currently a cardiology fellow at the University Hospital of Basel in Switzerland. I have always been very interested in clinical research, so I decided to join the group of Professor Christian Mueller in Basel for a year prior my residency in internal medicine. And that's how I met Jeanne and the whole study team.
Dr. Peder Myhre:
Very nice. And Jeanne, what about you?
Dr. Jeanna du Fay de Lavallaz:
So my name is Jeanne du Fey and I'm currently also a cardiology fellow at the hospital in Zurich. I moved a little bit, but my main research is still based in Basel. You don't leave Professor Mueller's group once you're in it. So I sticked around. So I am undertook physician scientist track after med school and for my MD PhD I was very lucky to integrate Dr. Mueller's group into the paper we are going to discuss tonight is actually the very first study that I designed during my PhD of course with a lot of help from the whole group of Professor Mueller, professor Mueller himself and of course Alexandra who joined a little bit later and really helped us tackle quite a big piece of the biomarker research that I'm very excited to talk about.
Dr. Peder Myhre:
So that is amazing. So this is the first paper you designed and what a wonderful debut because today we're going to discuss this award-winning paper and it is entitled Skeletal Muscle Disorder and Non-Cardiac Source of Cardiac Troponin T. And of course we are within the field of troponin and I must admit Jeanne and Alexandra that I myself is a troponin nerd myself. I love research and learning more about troponin and for me this paper was really something I was eager to learn more about because we've all been questioning what is the impact of skeletal muscle disease on troponin. So perhaps Jeanne, if you could start to explain the background for this study, and what was the research question?
Dr. Jeanna du Fay de Lavallaz:
So in the past years, I think there were quite a few reports. These were mostly case series of what you have just mentioned. So it's this observation that skeletal muscle disease might actually have an impact on some troponin measurements and we were not exactly sure which. So there are these two main isophones of troponin, the troponin T and the troponin I. Depending on the hospital, depending on the country, one of both might be measured either the troponin I or the troponin T. And then for troponin T we have only one essay and then for troponin I there are several of them. So there is kind of a big mix up there of what is possibly obtainable to assess cardiovascular health and basically also more coronary health, well cardiovascular health in patients that we see every day in the clinic.
And well, as you just mentioned, we had noticed in the past that sometimes it's troponin T was behaving in weird way in patients that were also suffering of some muscle skeletal muscle disease. So Prof. Mueller is leading a very large group biomarkers on troponin research and this is something that we decide to tackle in a very structured way in order to be able to rehab an answer and bring something to the field that might be maybe a little bit more consistent than this, however very interesting case series, but that were maybe a little bit done on very specific disease and a little bit all over the place.
Dr. Peder Myhre:
Exactly, and this is exactly what really made this paper so amazing is that first of all, you structured the clinical part of it with a prospective cohort. You did multiple essays on the patients and you even included some translational work on top of that, which is truly amazing. So I was wondering, Alexandra, if you perhaps could start with explaining the clinical part of the study, the patient cohort, the mythology use, et cetera. So please, Alexandra.
Dr. Alexandra Prepoudis:
We enrolled patients with muscle complaints. So for example, muscle pain, weakness, stiffness or fasciculations. And we enrolled them at four sites in two countries, most of them during ambulatory visits. And from each patient we collected a blood sample and we measured four different high sensitivity cardiac troponin assays. So one for troponin T and three for troponin I. Then patients underwent the cardiac workup including E C T, echo cardiography and cardiac M R I depending on the clinical indication. As a control group, we used patients from a prior study where patients who presented to the emergency department with the leading symptom of chest pain were enrolled. So of these we analyzed patients without skeletal muscle disease in whom a cardiac cause of chest pain could be excluded.
Dr. Peder Myhre:
Great. So really a big and well pheno typed group of patients. And before we go to the results, we're going to also learn a little bit about the experimental part of the study that you conducted. So Jeanne, if you would just explain what was, this was something with the gene expression in the muscles, right.
Dr. Jeanna du Fay de Lavallaz:
So we decided to be a little bit original and to bring it back to the bench instead of bringing it to the bedside as we usually do. And-
Dr. Peder Myhre:
I love it.
Dr. Jeanna du Fay de Lavallaz:
We will soon. We were also very lucky to have amazing collaborators because that allowed us to collaborate with a rheumatologist with neurologists. And these doctors might have in the past collected some muscle tissue for completely different muscle analysis. So in order to phenotype the diseases that the patients were actually suffering of and we're also lucky enough so that there was sometimes some of this muscle tissue is still available and we basically extracted mRNA from these skeletal muscle samples. And what we looked at was the mRNA of the different troponin genes that we could find in there. So as you probably know, there is some genes coding for skeletal troponin and there are some genes coding for cardiac troponin. And what we could see that was, we might come to that in the results, but basically our goal was to look at the expression of the different skeletal or cardiac troponin in these skeletal muscle samples.
Dr. Peder Myhre:
Exactly. And the next question is going to be difficult because I want you to summarize the findings and there are so many findings to supplement. This is really, it's like pressure. But please Alexandra, can you try to summarize the primary results of this paper?
Dr. Alexandra Prepoudis:
Yes, of course. I will try my best. So maybe first about half of the cohort showed the cardiac disease IE the coronary heart disease, atrial fibrillation, or chronic heart failure. So cardiomyocyte injury resulting from cardiac disease was a major contributor to elevated troponin T and I concentrations even in these patients with skeletal muscle disorders. But troponin T concentrations were above the upper limit of normal in about 55% and the concentrations were significantly higher compared with control subs checked. While troponin I concentrations were elevated to a significantly lower percentage, which were also comparable to the concentrations in the control group. Also, we found that the elevated troponin T concentrations were restricted largely to patients with non-inflammatory myosis and myositis. And maybe one thing to the gene expression regarding the gene expression analysis, we found the eightfold up regulation for the gene and coding for cardiac troponin T in skeletal muscle compared with controls without skeletal muscle disease.
Dr. Peder Myhre:
Wow, that is so great. So please let me try to summarize these important findings to the listeners. So you actually found in patients with skeletal muscle disease, a much higher level of troponin T compared to healthy controls or at least controls without myocardial infarction. And for troponin, these differences were not that pronounced. So that means gene, that troponin T in patients with certain types of skeletal muscle disease may be falsely positive. Is that correct? And how would you put these findings in relation to previous studies in the field and also perhaps some clinical implications of the findings?
Dr. Jeanna du Fay de Lavallaz:
So yeah, I think we can say that in the patient where that was the case, this is actually falsely positive because when we talk about cardiac troponin T, cardiac troponin, we expect it coming from the heart, certainly not from the muscle of the patients or at least it's what cardiologists have been trying to not diagnose in the past years by refining also the assays that we were using so that it doesn't cross-react with anything coming from a skeletal muscle. And I think regarding previous studies in the field, so we tackled, I believe several aspect with this paper that hadn't really been well investigated before. And our study design helped with that a lot. So first we included patients based on their complaints that was not a specific cohort with a certain type of disease. We really enrolled them if they presented with some muscle complaints, so not a specific already diagnosed disease.
So this was the first point. And then second also, we investigated several troponin I assays, which also allowed us to have a broader observation of how this assay are actually interacting also with each other or how they relate to this troponin T assay, which is the only one existing. And then finally, I think this translational part with the MRN analysis really helped us to go back to the primary hypothesis, how does that work? Why is this the case at all? And finding this re-expression of the cardiac troponin T in the skeletal muscle really tells us that this might actually not be a problem with the assay itself but might really be that we have some cardiac troponin T circling in the blood and being measured by a perfectly well working assay, which is a totally different mechanism than for instance, cross reaction that we might sometimes observe for instance, with troponin I assays.
Dr. Peder Myhre:
Exactly. And the findings were so consistent across the 3 troponin I assays and supported by the biopsy findings, I think they were so robust. And you know, we're talking about how this might impact adjudication of a suspected myocardial infarction, but also troponin is a very strong prognostic marker within chronic conditions and in ambulatory patients. And even there it may really impact the utility of troponin as a risk marker. Alexandra, don't you think so?
Dr. Alexandra Prepoudis:
So, to come back to the first part of your question, what about patients with myocardial infarction? Our study did not directly investigate the impact of these unexpected troponin T concentrations on the diagnosis of myocardial infarction. But we believe that it's reasonable to say that if patients with a known chronic skeletal muscle disease present with chest pain to for example the emergency department and the first troponin T comes back elevated, the clinician should be aware that the skeletal muscle can be a possible source of this biomarker. So if possible, a troponin I should be obtained in these patients.
Dr. Peder Myhre:
Excellent. And that brings us to the last question of today, I think Jeanne, and that is the future direction of this field. We now know, I think for certain that some skeletal muscle disease have an elevated cardiac troponin T, or perhaps not cardiac, but at least troponin T. So what do we need to learn more about this? And is there any way we can improve the assays? Please, Jeanne, let me know your thoughts about the future.
Dr. Jeanna du Fay de Lavallaz:
So that's a complex question. I think already we are kind of running into troubles when we already just see the current situation with these assays. Depending on the countries, depending on the hospitals, depending on the laboratory background that all the laboratory measurement system that we might have. Some hospitals have a total different approach on which troponin to measure and what's troponin to make available for their physicians. But I think these biomarkers haven't finished to surprise us and also most likely to bring us some very good prognostic tools. And I believe once we can really refine the exact origin of which elevation in which patient and what this does imply for their prognosis, we might also be able to just predict much better where with our patients are going, what kind of diagnostic or treatments that we need to use in order to improve their life on the short and long term. So I have quite a lot of hope for these different assays to be better understood in the coming years.
Dr. Peder Myhre:
What a wonderful way to finalize this podcast. Jeanne and Alexandra, thank you so much for participating and for sharing your knowledge in the field and to learn about your current situation with work and your choices of career. And also a big thank you to Francesca and Tanya for the winners of the LOSCALZO Award for sharing their research. So on behalf of Pishoy and myself, I want to thank everyone for listening and thank you to the amazing authors and winners of the awards. This is Peter Myra, and on behalf of myself and Pishoy Gouda, we thank you for listening.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Mads Liisberg and Guest Host Mercedes Carnethon as they discuss the article "Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study from 1996 to 2016."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke, National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, today's feature paper is about aortic dissections and it's the first nationwide population based study investigating the clinical characteristic, incidents, and mortality based on validated diagnosis of aortic dissection in a national patient registry. You want to hear more? Well, you have to just keep listening. Let's go on though first to discuss the other really important papers in today's issue, shall we?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
You know what, Greg? I'm going to start while you grab a coffee. I want to talk about high sensitivity cardiac troponins and how they have allowed the use of strategies in the emergency department, for example, to rapidly rule out acute MI within one to three hours and potentially facilitate early discharge of low-risk patients. Now, the ability to rapidly rule out MI of course depends on the turnaround time of these high sensitivity cardiac troponin results from the central laboratory, which is often delayed due to specimen transport and handling and all these things.
So, point-of-care assays can reduce this turnaround time by even 40 minutes, and early studies have actually used frozen plasma bio banks to assess these point-of-care assays... But no study has evaluated these point-of-care assays with fresh whole blood to safely rule out MI in the emergency department. That is until today's paper. So in today's study led by corresponding other Doctor Fred Apple from Hennepin Medical Center in Minneapolis, Minnesota and his team, they aimed to derive and validate an optimal high sensitivity cardiac troponin threshold concentration using whole blood point-of-care troponin eye assay on a single sample at presentation in the emergency department to identify patients at low risk of index MI for potential early discharge.
Dr. Greg Hundley:
Fascinating study Carolyn. So point-of-care testing, high sensitivity troponin from whole blood in the ED. So what did they find?
Dr. Carolyn Lam:
Among consecutive emergency department patients from two prospective observational studies with suspected acute coronary syndrome, a point-of-care, whole blood, high sensitivity cardiac troponin eye assay, the Atellica VTli provided a sensitivity of 98.9% and a negative predictive value of 99.5% for ruling out MI. A single measurement using a cutoff of less than four nanograms per liter for whole blood was successful in rapidly identifying patients at low risk of MI cardiac and all cause death and unplanned revascularization at 30 days.
Dr. Greg Hundley:
Very nice Carolyn, and could be quite practical. So Carolyn, my next paper comes to us from the world of preclinical science and it pertains to cardiac regeneration. So cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes. However, certain animals readily regenerate lost myocardium via process involving dedifferentiation, which unlocks their proliferative capacities. So inspired by this concept, these investigators led by Professor Patrick Hsieh from Academic Sinica, generated mice with inducible cardiomyocyte specific expression of the Yamanaka factors enabling adult cardiomyocyte reprogramming and dedifferentiation in vivo.
Dr. Carolyn Lam:
Wow. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So two days following induction, adult cardiomyocytes presented with a dedifferentiated phenotype, an increase proliferation in vivo. Microarray analysis revealed that the up-regulation of ketogenesis was central to this process. Now adenovirus driven HMGCS2 over-expression induced ketogenesis in adult cardiomyocytes and recapitulated cardiomyocyte dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue. And HMGCS2 knockout mice showed impaired cardiac function and response to injury, and so in summary, Carolyn, these data demonstrated the importance of HMGCS2 induced ketogenesis as a means to regulate metabolic response to cardiomyocyte injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.
Dr. Carolyn Lam:
Wow, that's so cool. From cell regeneration to autoimmunity in this next paper. Now autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. However, the functional features of cardiac autoimmunity in humans remain undefined due to the challenge of studying immune responses in situ. Now, these authors previously described a subset of c-Met expressing memory T lymphocytes, which preferentially migrate to cardiac tissue in mice and humans. In today's study, these authors led by co-corresponding authors, Dr. Federica Marielli-Berg and Saidi Mohidden from William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, and Queen Mary University of London, and their colleagues performed in-depth phenotyping of peripheral blood T cells in groups of patients with inflammatory and non-inflammatory cardiomyopathies, patients with non-cardiac autoimmunity and healthy controls... And they found that c-Met positive T cells were selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies.
The phenotype and function of c-Met positive T-cells were distinct from c-Met negative T cells, including preferential proliferation to cardiac myosin and co-production of multiple cytokines. Further, circulating c-Met positive T cell subpopulations in different heart muscle diseases identified distinct and overlapping mechanisms of heart inflammation. Furthermore, validation studies in experimental autoimmune myocarditis showed that elevations of auto-antigens specific c-Met positive T cells in peripheral blood, marked the loss of immune tolerance to the heart. Importantly, disease development could be halted by pharmacologic c-Met inhibition indicating a positive role for these c-Met positive T cells.
Dr. Greg Hundley:
All right, Carolyn, as you always ask me. So what's the take home message here?
Dr. Carolyn Lam:
This study demonstrates that the detection of circulating c-Met positive T cells may have utility in the diagnosis and monitoring of adaptive cardiac inflammation and additionally defined new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury... And this is discussed in an editorial by doctors at Abplanalp, Merten, and Dimmeler.
Dr. Greg Hundley:
Very nice, Carolyn. Wow. More fantastic preclinical science. Well, in the mail of the bag today, there is a Research Letter by Professor Burr entitled “Cannabis Inhalation Acutely Reduces Muscle Sympathetic Nerve Activity in Humans.”
Dr. Carolyn Lam:
There's an ECG Challenge by Dr. Reddy entitled “Shortness of Breath and Near Syncope During Exertion In a Child, When Patient Worry Syndrome.” There's also a Perspective by Dr. Weitz on what is the future of Factor 11 inhibitors.
Dr. Greg Hundley:
Well Carolyn, I'm looking forward to learning more about aortic dissections and that large Danish population-based study. Wow.
Dr. Carolyn Lam:
That's great. Let's go Greg.
Dr. Mercedes Carnethon:
Well, welcome to this episode of Circulation on the Run. My name is Mercedes Carnethon, an Associate Editor of Circulation, and Professor and Vice Chair of Preventive Medicine at Northwestern University. I'm really excited today to be here with the senior author of a really exciting paper that we're featuring on clinical characteristics, incidences and mortality rates for aortic dissections type A and B, a nationwide Danish population-based cohort study, and we have with us today Mads Liisberg. So welcome today.
Dr. Mads Liisberg:
Thank you.
Dr. Mercedes Carnethon:
So thank you so much for joining us and really thank you for sharing your important research with Circulation. This topic is so critically important, particularly given the high mortality rates associated with aortic dissections. Can you tell us a little bit about the work that you and your co-authors did in this important space?
Dr. Mads Liisberg:
Yes. Well actually the work originated when I started my PhD thesis and we got a registry data dump from the Danish medical registries and we found that almost none of our patients in the registry were registered with a specific aortic dissection code.
So we did a validation study on the same time period from 1999 to 2006 where we went through all these medical records to ensure that we had the right aortic dissection TC 10 codes on population. Then we went a bit further and looked at the clinical characteristics of this patient, 'cause that's one of the really major things about Danish medical registries in our country, is that we have access to not only every patient's specific in hospital contacts, but also their medicine abuse, their drug use based on a TC code. So we can go really deep into each and everyone's drug history. When we did this study, we wanted to find out if the incidence rates during this timeframe had changed, which we find that it did, but also looking at mortality rates because, as you said, it's really high risk disease to be diagnosed with. So that's more the rationale for this study.
Dr. Mercedes Carnethon:
Thank you so much for sharing that. Certainly we know that the mortality rates from this are very high. I note that you report some changes over time between 1996 and 2016 in the incidents of these types of aortic dissections. So what did you find about the patterns of change in type A aortic dissections?
Dr. Mads Liisberg:
We found that it almost doubled from the beginning of our time period to the last, and the question is why is this? 'Cause that's one of the thing that the data doesn't reveal. We are only able to see that the incidence actually rises, but is it because that they are underdiagnosed in the beginning? Or is it because that we are better diagnosing in the end of the study that really are progressed?
Dr. Mercedes Carnethon:
That's a good question. I noted that when you studied the correlates of aortic dissection, you identified a number of characteristics and what stood out to me was the finding about the strong association of hypertension. I'm less aware of patterns of hypertension in the Danish population. Do you think that the changes in the prevalence of hypertension in the population contributed at all to these findings?
Dr. Mads Liisberg:
Well, most certainly, 'cause when you look at the prevalence of hypertension throughout any person's lifespan, the older they get the more likely they are to suffer from hypertension, and the Danish population has aged quite a lot in recent years. So I think that's one of the main reasons we find this, and also that most of our arctic dissection patients are actually quite old, which would correlate with hypertension as well.
Dr. Mercedes Carnethon:
One thing I really like, and you pointed this out, is really the richness of the data that you have in your health system, and I wonder, just going even a little deeper on the hypertension question, given that it is the most common medical diagnosis worldwide, were you able to study characteristics of hypertension that would be more strongly associated with aortic dissection? So for example, duration of hypertension, severity, prevalence of hypertension control?
Dr. Mads Liisberg:
That's actually a funny question 'cause the last study of my thesis, which hasn't been published yet or even submitted for that fact, examines the correlation between use and the risk of arctic dissection. On a very specific level, the way that hypertension is treated mostly in Denmark is with your general practitioner. So the way that we examine in studies like these, is that we look at prescription drug use. So if we find that an individual has a TC codes corresponding with anti-hypertensive drugs, then we are able to code them as hypertensive patients.
Dr. Mercedes Carnethon:
Okay, thank you for that. I always... I'm an epidemiologist myself, so I really love to see great population science studies and this registry is large, you have long-term follow up and you've got a great deal of data, but those people who feel as though it's obviously not appropriate to make causal conclusions around epidemiology and that perhaps epidemiologic findings shouldn't be driving clinical decision-making. In response to that, I think I would pose the question to you, which is how do you see clinicians and providers using this information from your observational study?
Dr. Mads Liisberg:
I think that's rather difficult. One of the findings that we present is to pose it over mortality for type B dissections when we exclude the 30-day mortality, but then we show that type A dissections have almost a corresponding mortality rate compared to a hypertensive cohort... And this finding is difficult to draw any clinical conclusions from, but there's actually a Danish randomized controlled trial just starting up in the next year. I think it's called the Sunday trial, where they will include all uncomplicated type B dissections and randomize them for treatment or no treatment, and the issue here is that you'll probably be over-treating some patients and under-treating others, but this discussion with the uncomplicated type B dissection has been ongoing for so many years. So it's difficult for me to just give one golden answer.
Dr. Mercedes Carnethon:
Certainly, and I appreciate the caution as we certainly don't want to overstep our findings. You did make a recommendation in the conclusion that it might be beneficial to treat type B aortic dissections more aggressively. Is this what you're alluding to, based on the other study that you're referencing?
Dr. Mads Liisberg:
Yes, yes, definitely. We see some clinicians being more cautious treating type B dissections with a TIVA or a surgery. So it's a difficult thing when they're uncomplicated, why treat them? But they can't be or become complicated quite easily and fast and then it's a difficult thing, because should you have treated them earlier? Or do you need to treat them now in their acute phase? Or wait for a chronic phase? It's a really good question.
Dr. Mercedes Carnethon:
No, I appreciate that and what I really love are the types of research studies that leave you with many more questions and next steps, and so I would like to really sort of bring us to a close with the big picture question, which is what do you see as the next steps in this line of research, given really what we all agree on is a very significant clinical problem.
Dr. Mads Liisberg:
We would really like to expand our database with even more clinical data as of now and include any image diagnostics for our cohort. So we're might be able to see any trends in our modulation before the dissection occurs. If any of our patients have any diagnostics done prior to being diagnosed.
Dr. Mercedes Carnethon:
I really want to thank you today for spending time talking with us. I know that our readers rarely have an opportunity to hear from everybody behind the scenes views on what the rationale was for carrying out a paper and really how the authors themselves hope that the paper will be used. So I really thank you for sharing that with us today, Matts, on behalf of your co-authors, this has been really a wonderful conversation, and thank you again for sharing your research with the journal, Circulation.
Dr. Mads Liisberg:
Oh, thank you for having me in for accepting our paper.
Dr. Mercedes Carnethon:
So thank you so much to our listeners for listening to us on this episode of Circulation on the Run. Please tune in next week as we will have more exciting insights.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Trisha Singh as she discusses her article "Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass for the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Carolyn, very interesting feature discussion this week. Many times we hear in magnetic resonance imaging the use of gadolinium contrast. And remember, gadolinium is an extracellular agent. And when we apply it in the heart, we look for infarcts, or areas of the heart that are perhaps dead, or scarred over. This week's feature discusses manganese as a contrast agent and it is an intracellular contrast agent. And very interestingly, it identifies calcium handling, so it's a marker of viability. And these authors are going to apply manganese as well as gadolinium in trying to understand mechanisms behind Takotsubo cardiomyopathy.
But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue?
Dr. Carolyn Lam:
Oh, I'd love to tell you about the other articles. But just have to first say, I loved your description of the feature paper. It's right up your alley and I can't wait to learn more.
But my first paper today I want to talk about pulse field ablation. Now, what is that? Pulse field ablation, or PFA, is a unique and novel technique to treat atrial fibrillation. It has a unique safety profile largely related to its preferentially for myocardial tissue ablation. And thus, sparing the esophagus and thus, deemed to have a unique safety profile. Now, a pentaspline catheter was the first such PFA system studied for AF ablation. And in the initial trials the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation.
However, following its regulatory approval in Europe, in clinical practice, physicians have ablated both these locations and expanded lesions that could be in closer proximity to the coronary arteries. Now, this is an unstudied important issue since preclinical and maybe some clinical data have raised the potential for coronary arterial spasm. Hence, the investigators led by Dr. Vivek Reddy from Icahn School of Medicine at Mount Sinai and colleagues studied the vasal spastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries.
Dr. Greg Hundley:
Wow, Carolyn, this is a really interesting question. So what did they find?
Dr. Carolyn Lam:
In this retrospective analysis of a series of 25 patients undergoing PFA for atrial fibrillation in whom coronary angiography was performed pre, during and post ablation, they found that during pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur. However, cavotricuspid isthmus ablation provoked severe subtotal vasospasm in five out of five consecutive patients. And this was relieved by in coronary nitroglycerin. ST elevation was not observed. No patient had severe spasm if first pretreated with parenteral nitroglycerin, either intracoronary or intravenous.
And so in summary, coronary vasospasm was not provoked during PFA at locations remote from the coronary arteries. But when the energy is delivered adjacent to a coronary artery, like in cavotricuspid isthmus ablation, PFA did provoke subclinical vasospasm. And the phenomenon was attenuated by nitroglycerine administered either post hoc to treat spasm or as prophylaxis. And this is discussed in accompanying editorial, I like it, “Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and Sundeep and Saba.
Dr. Greg Hundley:
Very nice Carolyn. Very important research in this area using that particular methodology.
Well Carolyn, my next study comes to us again from preclinical science. And Carolyn, this study evaluated mechanisms responsible for pulmonary hypertension.
So as background, pulmonary hypertension is associated with increased expression of VEGFA and it's receptor VEGFR-2. But whether and how activation of VEGFA signal participates in the pathogenesis of pulmonary hypertension, that's unclear. And so these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2 signal activation and VEGFR-2 Y949 dependent vascular leak in lung samples from patients with pulmonary hypertension as well as in mice exposed to hypoxia.
Dr. Carolyn Lam:
Another one of those excellent translational pieces, isn't it Greg? So what did they find?
Dr. Greg Hundley:
Right Carolyn. So these authors found that pulmonary hypertension led to excessive pulmonary vascular leak in both patients and hypoxic mice. And this was owing to over activated VEGFA and VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling via a specific point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure. This, in turn, led to alleviation of pulmonary hypertension manifestations including muscularization of distal pulmonary arterials, elevation of right ventricular systolic pressure and right ventricular hypertrophy.
And so Carolyn, in summary, these results suggest that VEGFA, VEGFR-2 Y949 dependent vascular permeability is an important determinant in the pathogenesis of pulmonary hypertension and might serve as an attractive therapeutic target pathway for this disease.
Dr. Carolyn Lam:
Aw, thanks Greg for explaining that so well.
The next paper talks about transcatheter aortic valve replacement of TAVR, recognizing that it is a well established treatment now for high and intermediate risk patients with severe symptomatic aortic stenosis. However, the question asked here is what makes some, but not all patients improve their left ventricular ejection fraction following TAVR associated after load reduction?
Now, hypothesizing that circulating microRNAs may play a role here, the authors led by corresponding authors, Dr. Hosen and Jansen from University of Bonn and their colleagues profiled the differential expression of microRNAs in circulating extracellular vesicles in patients after TAVR. And in particular, the novel role of circulating microRNA 1225p in cardiomyocytes.
Dr. Greg Hundley:
Oh wow. So Carolyn, important study. So what did they find?
Dr. Carolyn Lam:
Well, first aortic stenosis increases circulating microRNA 1225p, which correlated with a lack of improvement of the EF in patients after TAVR. Extracellular vesicles harbored microRNA 1225p and facilitated its startling into the cardiomyocytes. Vesicular shuttling of this particular microRNA was regulated by a direct interaction with a multifunctional RNA binding protein called heterogeneous nuclear ribonucleoprotein U in a sequence specific manner. Extracellular vesicles containing the specific microRNA post transcriptionally repressed BCL2 an anti-apoptotic gene, which is central to cell viability and apoptosis.
So in summary, Greg, an increase in extracellular vesicle microRNA 1225p in patients with aortic stenosis represents a novel mechanism for the deterioration of cardiac function in patients following TAVR. And pharmacological manipulation of this axis may improve ejection fraction and cardiac function in patients with aortic stenosis by improving the viability of cardiomyocytes, which opens the door to a potential therapeutic approach in patients with limited EF improvement following TAVR.
Dr. Greg Hundley:
Oh Carolyn, beautiful, beautiful description of that wonderful preclinical science.
Well, let's reach into the mail bag and see what else is in the issue. And first, there's a research letter by Professor van Raalte entitled “Kidney Hemodynamic Effects of Angiotensin Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition Alone and in Their Combination: A Crossover Randomized Trial in People with Type 2 Diabetes.”
And Carolyn, there's also an In Depth piece from Dr. Marx entitled “GLP1 Receptor Agonist for the Reduction of Atherosclerotic Cardiovascular Risk in Patients with Type 2 Diabetes.”
Dr. Carolyn Lam:
Very, very nice papers, those two. There's also an exchange of letters between Drs. Hou and Sedej regarding the article, “Fine Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.” As well as a Perspective by Dr. Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More Precision in Aortic Care.”
Now, let's go onto the feature discussion of all things MRI, shall we?
Dr. Greg Hundley:
You bet. More on manganese.
Welcome listeners to this very interesting feature discussion on December 13th. And we have with us Dr. Trisha Singh from the University of Edinburgh in Edinburgh, Scotland.
Welcome, Trisha. This is a fascinating study incorporating manganese cardiovascular magnetic resonance to study some of the mechanistic underpinnings of hypokinesis left ventricular hypokinesis in patients with Takotsubo syndrome. So maybe just describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Trisha Singh:
Yes, of course. So we know with patients with Takotsubo syndrome, it predominantly affects middle aged women, patients present with a degree of left ventricular dysfunction, which is transient. And, unfortunately, it can be quite difficult to diagnose because it can phenotypically present very similar to an acute coronary syndrome. We know from previous studies that these patients do have ongoing symptoms despite normalization of their LV function. And actually their outcomes are not as benign as previously thought.
In terms of manganese enhanced MRI imaging, we at Edinburgh University have imaged patients with other cardiac conditions such as hypertrophic cardiomyopathy, and dilated cardiomyopathy. And have established that it can be used as a surrogate marker of myocardial calcium uptake and handling. So we were very interested to see whether or not patients with acute Takotsubo syndrome have got a myocardial calcium dysfunction and more importantly whether or not this translates into long-term dysfunction and perhaps could explain their symptoms and worse prognosis in long-term.
Dr. Greg Hundley:
Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is manganese different? You mentioned it's a nice marker for calcium handling. Is this widely used clinically? What kind of contrast does it provide?
Dr. Trisha Singh:
So manganese was actually one of the first contrast agents to be used with magnetic resonance imaging. It kind of came about in the 1970s and 1980s. And previous animal models have looked at how it is essentially an intracellular contrast agent. And what I mean by that is manganese is a calcium analog and therefore, in cells where they are viable and there's intact cell function, they will be taken up through a voltage gated calcium channels. So, for example, in the heart. So the theory is that manganese, when you've got normal viability, manganese is taken up into the myocardium via voltage gate calcium channels. And several studies have shown that if you then have disease myocardium, these tissues do not take up the manganese as normal tissue would.
And the main difference between manganese and gadolinium is they are both paramagnetic, which is why they're helpful and useful in MRI. But gadolinium, as a compound, is too big and it cannot cross an intact cell membrane and therefore, gadolinium is more extracellular. And as, we know, accumulates in tissues where there is increased edema, or water content. So gadolinium, for all intents and purposes, is incredibly useful contrast agent, certainly what we use predominantly at the moment in clinical practice, but it is extracellular. So the theory behind manganese is that it is an intracellular contrast agent as opposed to gadolinium. And where gadolinium accumulates in disease tissue, manganese accumulates in viable tissue. So they behave almost kind of in contrast to each other.
And currently, manganese is not used in clinical practice. I think the only clinical compound contrast agent utilizing manganese was mangafodipir, otherwise known as Teslascan, which I believe came off the market in 2012 and that was predominantly used for imaging liver metastasis.
Dr. Greg Hundley:
Well Trisha, thank you for clarifying for us the difference between manganese, the intracellular contrast agent, and gadolinium, the extracellular contrast agent, that's so widely used clinically.
Well, with that description, can you describe for us now, your study population and your study design?
Dr. Trisha Singh:
Perfect. So the study population was we aimed to recruit 20 patients with acute Takotsubo syndrome. The diagnosis of Takotsubo syndrome was based on a clinical diagnosis, so all our patients underwent a baseline echocardiography and invasive coronary angiography.
Now, for us, the coronary angiography was quite important because we wanted to ensure we ruled out anyone with an acute myocardial infarction, which can often be tricky in this cohort of patients.
So after recruiting 20 patients during the acute phase of Takotsubo, they all underwent a baseline gadolinium enhanced MRI scan followed by a manganese enhanced MRI scan. And these were done at least 48 hours a part. And then about three months roughly after the acute index, they were all invited to participate in a second manganese enhanced MRI scan.
Dr. Greg Hundley:
Very good. So two exams separated longitudinally over time. What were your study results?
Dr. Trisha Singh:
Our results demonstrated that during the acute phase as one would expect, patients had a degree of left ventricular dysfunction. The majority of our patients had afibrillar Takotsubo, so had afibrillar ballooning with preservation of the basal segments. With this, we also noted that in the areas that were affected by Takotsubo, so kind of the mid ventricular wall and the apex that all patients had significantly elevated native T1 and associated T2 as well. And as we expected there was reduced uptake of manganese and therefore kind of reduced calcium uptake in the myocardium in the area affected by Takotsubo syndrome.
Interesting, what we also noticed was that all these patients had significantly elevated LV mass, which has been described in previous Takotsubo papers, certainly by Professor Dawson. And when you measured the left ventricular wall thickness, the LV wall thickness is elevated in the affected and actually not even in the non-affected areas, which I suspect explains why in the acute phase people almost doubles up which kind I guess fit with kind of acute myocardial edema and intense water content.
And then, three months later when these patients returned for their follow-up scan, a lot of the acute changes had resolved. So native T2 values had improved and gone back to baseline. Native T1 and post contrast T1 values had remained elevated compared to the control population. And what we found was that manganese uptake, though it had improved, it still remained abnormal and reduced compared to the control population, which is a finding that we weren't expecting to find.
Dr. Greg Hundley:
Very interesting. So acutely we've got extracellular water there, elevation of myocardial T2, and also impaired manganese uptake. So intracellular abnormalities with calcium handling. Then later, so three months later, we have restoration of myocardial T2 so the extra water content is absent, but we have impaired manganese uptake indicating an abnormality with calcium handling. So how do we put this all together mechanistically? What does this tell us about the pathophysiology of Takotsubo syndrome?
Dr. Trisha Singh:
For one thing, I think we can say that there is, as described before, there is obviously intense myocardial edema present in patients with acute Takotsubo. And I think the significant elevation in T2 and LV mass kind of all fits together. Actually interestingly, as native T2 improves in their follow-up scans, the LV mass actually all return back to normal baseline. So I think the acute edema does resolve.
And as you said, interestingly, despite all of these patients, their LV function completely recover. And despite that their myocardial calcium uptake, or handling remain normal. And I think that's not been demonstrated before. And I think it just points to that there is obviously, still something going on in the myocardium and it's not behaving completely normally despite completely normal kind of gross LV function. And potentially, this might point in the direction of why these patients have ongoing symptoms. So, certainly, from our observational cohort group, about 70% of patients had ongoing symptoms and this was predominantly breathlessness and palpitations. And potentially, might be related to why patients have worse outcomes compared to the general population.
Dr. Greg Hundley:
Very nice. And Trisha, can you describe, was there a therapeutic intervention between the acute and then the three month later measurements? Were these patients administered any type of medical therapy and were there differences in what those therapies may have been between different patients in your study?
Dr. Trisha Singh:
So predominantly, most of the patient population that were started on some combination of heart treatment due to the baseline LV dysfunction. And this kind of was a combination of most of them were on Ramipril, a few of them were also on spironolactone or eplerenone. And then, every single one was on furosemide. And interestingly, I mean I appreciate, I think the population group was quite small, so it's very difficult to compare those that were on kind of full heart failure treatment versus those who were just on beta blocker and ramipril therapy. But even in that cohort there was a split of about, I think predominantly, I think 17, 16 patients were on kind just beta blockers and ramipril as opposed to beta blocker, ramipril, spironolactone. And there was no difference kind of in the recovery in manganese uptake in that cohort. But, again, the numbers are quite small, so I think it's difficult to extrapolate any kind of true meaning in that.
Of course, we know there's a lack of randomized control trial data looking at how to best treat patients with acute Takotsubo syndrome and certainly, what treatment may prevent these patients from having a recurrence of Takotsubo. And I know some of the TACA registry data has looked at actually despite the fact patients of being on beta blocker, or ramipril therapy, they still go having recurrence of Takotsubo and certainly of our cohort, one of our patients went on having a recurrent episode of Takotsubo within a year of her index event and she was on aspirin, beta blocker, spironolactone as well.
Dr. Greg Hundley:
Very nice.
And then lastly, when you made these measurements looking at the manganese uptake or lack thereof, were these in the regions of myocardium where you mentioned many had apical LV wall motion abnormalities, were they in those regions or did you also measure regions remote to where the wall motion abnormality occurred?
Dr. Trisha Singh:
Of course. So we took measurements in the affected regions of the heart that kind of demonstrated spironolactone syndrome. And we also took measurements in kind of, so to speak, the remote segments of the heart.
Now, for the remote segments of the heart, we could only measure native T1 and post contrast T1 at 30 minutes and to measure manganese uptake well, unfortunately, what we have to do is take a measurement over time, so we'd do every two and a half minutes for 30 minutes after the manganese contrast. So we weren't able to calculate manganese uptake in the remote regions. But what we could do was measure the native T1 in the remote region, and then the post contrast T1 and see how it differed with the region of interest in the affected portion of the heart, so to speak.
Dr. Greg Hundley:
Very good.
Well, Trisha, with this really exciting research and very nice methodology, what do you see as the next study to be performed in patients with Takotsubo?
Dr. Trisha Singh:
So I think, in terms of manganese enhanced imaging, I think it'd be really interesting to re-scan these patients at one year or at two years. And the question there is whether or not their manganese uptake ever recovers really. I know we previously talked about this and thought about whether or not these patients who go onto developing Takotsubo syndrome might actually have a kind of an underlying cardiomyopathy that puts them at risk of developing Takotsubo with stress. So it'd be interesting to see whether or not actually their calcium uptake ever recovers in the long-term, or whether actually they have more of a chronic heart failure type like picture.
And I think another area of interest would be to see potentially using manganese imaging as a noninvasive measure of kind of myocardial calcium activity and to see whether or there's any changes with therapy over the course of months to years or so.
Dr. Greg Hundley:
Very nice.
Well listeners, we want to thank Dr. Trisha Singh from University of Edinburgh in Edinburgh, Scotland for bringing us this really interesting article in patients with Takotsubo syndrome demonstrating that there is a marked perturbation of myocardial manganese uptake, which is most evident in the acute phase of Takotsubo presentation, but also persists for at least three months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema. All of this suggesting that abnormal myocardial calcium handling may be implicated in the pathophysiology of Takotsubo syndrome.
Well, on behalf of Carolyn and myself, we want to wish you a great week. And we will catch you next week on the run.
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ajjournals.org.
This week, please join author Sean Pokorney and Associate Editor Shinya Goto as they discuss the article "Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial."
Dr Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and Backstage Pass of the journal and its editors. We're your cohost. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting topic. In patients that have end stage renal disease that require dialysis, questions emerged should we anticoagulate them to prevent stroke, but of course, there's a risk of excess bleeding. Well, this feature discussion today is a study comparing apixaban and warfarin for anticoagulation in exactly this patient population. But before we get to those results, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first?
Dr Carolyn Lam:
Absolutely, Greg. So my first paper is a pre-specified analysis of the Paradise MI trial and knowing you'll likely ask me what that was about, Greg, at least to summarize for everyone, the Paradise MI trial compared sacubitril/valsartan with ramipril and its effect on reducing heart failure events after an MI in more than 5,600 patients with an acute myocardial infarction complicated by LV systolic dysfunction, pulmonary congestion, or both. Now in today's paper, what Dr. Mehran and colleagues found was that among patients with a recent AMI and LV systolic dysfunction, heart failure are both, sacubitril/valsartan decreased the risk of coronary related events by 14% as compared with ramipril over a median follow-up of 22 months. The reduction in coronary events occurred with a favorable safety profile.
Dr Greg Hundley:
Wow, Carolyn, very interesting. Another indication perhaps for sacubitril/valsartan, especially relative to ACE inhibitors. So what does this mean for us clinically?
Dr Carolyn Lam:
Well, the results really cause us to consider if in addition to antiplatelets and lipid lowering therapies, sacubitril/valsartan may be explored as a potential agent to mitigate the residual risk in survivors of AMI. Of course, dedicated studies are necessary to confirm this finding and elucidate its mechanism.
Dr Greg Hundley:
Oh, very nice, Carolyn. Well, my first paper comes to us from the World of Preclinical Science and Carolyn, this study evaluated the scavenger receptors stabilin-1 and stabilin-2, proteins that are preferentially expressed by liver sinusoidal endothelial cells. Now, they mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. And studies suggest that stabilin-1 and stabilin-2 may impact atherosclerosis. So in this study, the investigative team led by Professor Cyrill Géraud from the University Medical Center and Medical Faculty in Mannheim, Heidelberg comprehensively studied how targeting stabilin-1 and stabilin-2 affects atherosclerosis.
Dr Carolyn Lam:
Huh. All right, nicely explained. And so what did they find, Greg?
Dr Greg Hundley:
Right, Carolyn. So inhibition of evolutionary conserved class H scavenger receptors, stabilin-1 and stabilin-2, reduced aortic plaque burden in preclinical models and athero protection was mediated likely through down regulation on transcriptional factor ERG1 in monocytes by multifaceted plasma protein changes. And then finally, Carolyn transforming growth factor beta induced periostin, reelin, and they are novel ligands of stabilin-1 and stabilin-2 and are implicated in the development of atherosclerosis.
Dr Carolyn Lam:
Okay. Wow. Could you give us a take home message, please Greg?
Dr Greg Hundley:
Right. Carolyn, I knew you had asked me this. So here we go. Monoclonal, anti-stabilin-1 and anti-stabilin-2 antibodies provide a novel approach for the future treatment of atherosclerosis. And in the future, perhaps the plasma proteome composition may serve as a predictive factor, biomarker or surrogate parameter for cardiovascular disease in patients.
Dr Carolyn Lam:
Wow. Thanks Greg. My next paper is a true story of discovery. Now I could ask you what you know about the condition hypertension with brachydactyly type E... Greg, I love that expression. I wouldn't be able to answer that too. So let me tell you the story. So hypertension with brachydactyly type E is an autosomal dominant Mendelian disease resembling essential hypertension. Untreated patients die of stroke by the age of 50 years. Now, these authors had previously demonstrated a gain of function phosphodiesterase 3A gene mutations that caused the condition by increasing peripheral vascular resistance.
They studied a large family with the condition earlier and were puzzled that cardiac hypertrophy and heart failure did not occur despite the decades of hypertension. And so they hypothesized that in the heart, this phosphodiesterase 3A or PDE3A mutations could be protective. Isn't that neat? And so corresponding authors, Doctors Bader, Klussmann, Bähring and Hübner, all from the Max Delbruck Center for Molecular Medicine in Berlin, Germany. So they studied new patients as well as CRISPR-Cas9 engineered rat models of this condition of hypertension with brachydactyly type E. And they comprehensively phenotyped all of them with the human induced pluripotent stem cells carrying these PDE3A mutations as well. So analyzing all of this from cells to new patients to CRISPR-Cas9 models.
Dr Greg Hundley:
Wow, Carolyn, what an interesting story. So what did they find?
Dr Carolyn Lam:
So while in vascular smooth muscle, the PDE3A mutations caused hypertension, in the hearts, they conferred protection against hypertension-induced cardiac damage, hypertrophy and heart failure. The mechanism involved long-term adaptations of mRNA and protein expression as well as calcium cycling. Non-selective PDE3A inhibition was a final short term option in heart failure treatment to increase cardiac cyclic AMP and improve contractility. So the data argued that mimicking the effect of PDE3A mutations in the heart rather than non-selective PDE3 inhibition was cardioprotective in the long term. And these findings could indeed facilitate the search for new treatments to prevent hypertension-induced cardiac damage. This is discussed in a really lovely editorial by Dr. Chiong, Houslay, and Lavandero.
Dr Greg Hundley:
Very nice, Carolyn. Wow. What another... we have such great articles from the World of Preclinical Science. Beautiful description as well. Well, we have some other articles in the issue, particularly from the Mailbag. And we have a Research Letter from Professor Thiagarajan entitled “Yield of Cardiac MRI in a pre-participation cohort of Young Asian males with T-Wave inversion.”
Dr Carolyn Lam:
Interesting. There's an exchange of letters between Dr. Xu and Huang regarding the article associations of dietary cholesterol, serum cholesterol and egg consumption with overall and cause-specific mortality with a systematic review and updated meta-analysis. There is a Perspective piece by Dr. Marcus on Smart watch detected atrial fibrillation, the value in positive predictive value. Isn't that interesting? And now onto that very, very important question of anticoagulation in patients with kidney disease. Can't wait. Let's go, shall we?
Dr Greg Hundley:
You bet. Carolyn. Welcome listeners to our December 6th feature discussion. And we have with us today Dr. Sean Pokorney from Duke University in Durham, North Carolina, and our associate editor, Dr. Shinya Goto from Tokai University in Isehara, Japan. Welcome gentlemen. Well, Sean, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Sean Pokorney:
Yeah, absolutely. Thanks for having me to discuss the renal AF trial. And so I would say that the background information to the study was that we know that atrial fibrillation is an incredibly common condition in patients with chronic kidney disease. And the decision of anticoagulation in patients with end-stage kidney disease, on hemodialysis is really quite complex because these patients are at high risk for stroke and they're at high risk for bleeding. There are concerns with warfarin around calcific uremic arteriolopathy or calciphylaxis and there have been some data including from the original Aristotle trial that apixaban was even more favorable in terms of bleeding reduction relative to warfarin in patients with more advanced chronic kidney disease.
Although patients with creatinine clearance less than 25 were excluded from Aristotle and really all patients with endstage kidney disease on hemodialysis have been excluded from all trials of atrial fibrillation in the past. And so we really wanted to evaluate the safety of apixaban versus warfarin in patients with end-stage kidney disease, on hemodialysis. And the hypothesis was that apixaban was going to be non-inferior to warfarin with respect to safety in terms of major or clinically relevant, non-major bleeding in these patients with atrial fibrillation and end stage kidney disease on hemodialysis.
Dr Greg Hundley:
Thanks so much, Sean. And you've mentioned the renal AF trial. So could you describe for us, for your, I guess, substudy, what was the study population? Who did you include and describe for us also your study design?
Dr. Sean Pokorney:
Yeah, absolutely. So the trial included patients who had end-stage kidney disease, and/or on hemodialysis, as well as having concomitant atrial fibrillation. And the patients had to have a CHA-VASc score greater than equal to two. All of the patients had to be on hemodialysis for at least three months. So these were chronic hemodialysis patients. And the study design was an open label randomized trial that was 1:1 randomization between apixaban and warfarin with blinded outcome evaluation. And again, the primary endpoint of the study was major or clinically relevant non-major bleeding based on ISTH definitions. And there were secondary endpoints looking at stroke, systemic embolism, death, medication adherence, and I think a really important sub-study looking at PK data. And the goal was to have 50 patients where we included PK data that was going to more represent what chronic apixaban dosing data would look like in these patients with end-stage kidney disease on hemodialysis.
And originally the goal of the trial was to include over 700 patients. Originally we were trying to include 762 patients based on our initial power calculations to achieve true non-inferiority. Unfortunately, the trial enrollment was low and so the trial was ultimately stopped prematurely at 154 patients, although we were able to include the original targeted 50 patients in the PK substudy. The dosing that we used in the renal AF trial was 5 mg of apixaban twice daily unless patients had a second dose-reduction criteria in addition to chronic kidney disease. So the fact that they had end-stage kidney disease and were on hemodialysis counted as one dose reduction criteria and patients that were under 60 kilograms or less were 80 years of age or older, who had then a second dose-reduction criteria were treated with the 2.5 mg twice daily dosage. And this was important to note because this is different than the dosage that was used in the AXADIA-AFNET trial.
Dr Greg Hundley:
Very nice. And so Sean, what did you find?
Dr. Sean Pokorney:
Yeah. So again, a lot of this data is really exploratory because of the limited sample size, we weren't really able to definitively conclude anything about the major or clinically relevant non-major bleeding rates. I would say that some of the key findings that we saw was that there were high rates of major or clinically relevant non-major bleeding in both arms of the trial and one year bleeding event rates were 25% in the warfarin arm and 31% in the apixaban arm. And again, there was no statistically significant difference, although again, this is really exploratory. I would say that some of the other interesting findings that we saw was that there were very low rates of ischemic and hemorrhagic stroke in this patient population. Again, there were 82 patients randomized to apixaban, 72 patients randomized to warfarin. And there was a difference in the randomization because of the stratification by site that was performed with the randomization.
And so within the 82 patients that were randomized to apixaban, the patients, there was one ischemic stroke and one hemorrhagic stroke. There were no hemorrhagic strokes in the warfarin population and two ischemic strokes. Another key finding was the high rates of mortality in this patient population. So 26% of the apixaban patients experienced a mortality event, 18% in the warfarin arm. So again, the mortality rates in these patient populations were extremely high. I would also emphasize some of the data from the PK analysis. So we looked at the PK analysis in two different ways. For the patients that were treated with the 5 mg dose of apixaban, the PK data showed that there was consistent overlap in the steady state concentration at one month compared to patients in the Aristotle trial that had really mild to moderate, moderate to severe and severe chronic kidney disease.
And so there was a consistent overlap in those steady state concentrations between the end-stage kidney disease population on hemodialysis and the chronic kidney disease population who benefited from a apixaban in the Aristotle trial. Similarly, in the 2.5 mg apixaban dose, the patient who had a second dose reduction criteria in addition to chronic kidney disease, those patients had consistent steady state concentrations of apixaban relative to patients with mild to severe chronic kidney disease.
Dr Greg Hundley:
Very nice. Well thank you so much, Sean. And listeners, now we're going to turn to our associate editor, Dr. Shinya Goto. Shinya, can you, sort of, highlight for us some of the interesting findings that you see from these study results that Sean just presented?
Dr. Shinya Goto:
Thank you, Greg. Thank you, Sean for your wonderful summary of your study. We had a great discussion with an editor for this paper. As Sean pointed out, this is a kind of underpowered trial or just terminated early, hypothesis was not tested in the trial. But this population of patient clearly needs a real-world clinical trial, patient with atrial fibrillation, end-stage kidney disease, on hemodialysis; things a clinician could do. In some country, nephology society defined warfarin contraindicated in this population. As Sean pointed out, whether the development of this trial include this high-risk population patient. So we had a discussion whether the underpowered trial provided something or nothing may be better than something just provided here. Our consensus finally reached was, this limited trial still provide something like, you have to make a decision to use the anticoagulation. I mean, that the apixaban might be still used due to the PK data. That is the kind of interesting point of this trial.
Dr Greg Hundley:
Very nice Shinya. Well, Sean, turning back to you and Shinya with that nice lead in really, Sean, what do you think is the next study that needs to be performed in this sphere of research?
Dr. Sean Pokorney:
Yeah, absolutely. I think this is a challenging patient population to study. And again, our trial, the renal AF trial stopped early. Unfortunately, the AXADIA-AFNET 8 study also stopped early, which was also looking at apixaban versus warfarin outside the US and Europe. And so again, it is a challenging patient population to study. But again, I also think it's a really important population to study because one of the main unanswered questions in this population is whether or not they should receive anticoagulation. And so I think that ultimately more work and additional studies trying to determine whether or not these patients truly benefit from anticoagulation or stroke prevention, I think is really one of the critical directions that we need to take the field in.
Dr Greg Hundley:
And Shinya, do you have anything to add?
Dr. Shinya Goto:
Well, I fully agree with Sean. I mean, this is a very challenging area and still raising the question whether anticoagulation is necessary or not by your study. Maybe next generation oral anticoagulant such as Factor XI inhibitor that is more elevated to contact pathway may be beneficial. So we really need a good clinical study in this very important and known answered area.
Dr Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Dr. Sean Pokorney from Duke University in Durham, North Carolina and our own associate editor, Dr. Shinya Goto from Tokai University in Japan for bringing us the results of this randomized open-label trial of apixaban versus warfarin in patients with chronic kidney disease on hemodialysis, revealing high rates of bleeding in both groups, but due to low enrollment, was unable to identify its non-inferiority endpoint. It's important to note, however, as both our author and editorialists have identified further research is really needed in this area to really examine the efficacy of anticoagulation for stroke prevention in this high-risk patient population.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please author Gemma Figtree and Associate Editor Nicholas Mills as they discuss the Frontiers article "Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development."
Dr. Greg Hundley:
Welcome listeners to this November 29th, 2022 issue of Circulation On the Run. I am one of your hosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.
Dr. Greg Hundley:
Well, Peder this week's feature discussion very interesting. It is a state of the art review and it involves noninvasive plaque imaging and really how we might assess plaques to evaluate whether coronary artery disease is accelerating. Very important information by a large group of clinician scientists that will develop programs that, maybe, can be used in therapeutic drug development.
Dr. Peder Myhre:
That's so interesting, Greg.
Dr. Greg Hundley:
Right. A great group of individuals all put together, but before we get to that interesting feature discussion how about we grab a cup of coffee and start with some of the other articles in the issue? How about this week I go first?
Dr. Peder Myhre:
Go ahead Greg.
Dr. Greg Hundley:
Peder, these authors led by Marianna Fontana from University College London Medical School sought to characterize changes in the clinical phenotype of 1,967 patients with a diagnosis of transthyretin cardiac amyloidosis over the last 20 years enrolled and participating in the National Amyloidosis Center from 2002 to 2021.
Dr. Peder Myhre:
Oh yes, Greg, please. This cardiac amyloidosis we have to learn more about it. Please, tell me what did they find.
Dr. Greg Hundley:
Right, Peder.
First, there's been a substantial increase in the number of patients diagnosed with transthyretin amyloid in recent years. This is associated with greater proportions of patients referred following cardiovascular magnetic resonance imaging and bone scintigraphy scans. Second, transthyretin amyloid patients are often now being diagnosed much earlier in their disease process, as evidenced by a shorter duration of symptoms prior to diagnosis, milder stages of disease, and more favorable structural and functional echocardiographic changes at the time of diagnosis. Then, finally, mortality in these transthyretin amyloids patients has improved substantially in recent times aside from any potential benefits from disease modifying treatment or participation in clinical trials.
Dr. Peder Myhre:
Wow. Greg, over the course of 20 years we have seen some differences in the diagnosis or cardiac ATTR amyloidosis, so what would you say are the take home messages from this paper, Greg?
Dr. Greg Hundley:
Right, Peder.
Transthyretin amyloid is now often diagnosed earlier in the disease process with improved prognosis. I think, more data needed to guide decisions on in whom and when to initiate treatment and then which treatments should be used at each stage of the disease. Peder, along with this article there's an excellent editorial by Doctors Patel and Maurer entitled “The Future for Patients with Transthyretin Cardiac Amyloid is, It's Looking Brighter.”
Dr. Peder Myhre:
Okay. Greg, I'm going to continue in the field of clinical research and this paper actually describes a new ablation technique for ventricular tachycardia. Isn't that exciting?
Dr. Greg Hundley:
Absolutely.
Dr. Peder Myhre:
The paper comes to us from corresponding author Miguel Valderrabano from Houston Methodist Hospital in Texas and is entitled “Substrate Ablation by Multi-vein, Multi-balloon Coronary Venous Ethanol for Refractory Ventricular Tachycardia and Structural Heart Disease.” Ablation of ventricular tachycardia, VT, in the setting of structural heart disease often requires extensive substrate elimination, which is not always achievable by endocardial radiofrequency ablation and epicardial ablation is not always feasible. The left ventricle venous circulation allows vascular access to reach intramural substrates of VT in the context of myocardial infarction or non-ischemic scar, where radiofrequency ablation has limited success. Greg, in this study the authors enroll patients with ablation refractory VT and used phonography and epicardial mapping to perform a double balloon venous ethanol ablation. That is, by blocking flow with one balloon and injecting ethnol via this second balloon.
Dr. Greg Hundley:
Peder, what a beautiful description and very interesting strategy to address this situation.
What did they find?
Dr. Peder Myhre:
Greg, after the venous ethanol ablation vein maps and epicardial maps showed elimination of abnormal electrograms of the VT substrate an intracardiac echocardiography demonstrated increased intramural echodensity at the target lesions of the 3D maps and at one year of follow up VT recurrence occurred in seven patients, which translates into a success rate of 84%. The authors conclude that multi-balloon multi-vein intramural ablation by venous ethanol ablation can provide effective substrate ablation in patients with ablation refractory VT in the setting of structural heart disease over a broad range of left ventricular locations.
Dr. Greg Hundley:
Very nice, Peder. What a beautiful description. Excellent.
Well, this next paper Peder comes to us from the world of preclinical science and these authors led by Professor Christine Sideman from the Harvard Medical School evaluated alpha-kinase 3. Now, alpha-kinase three is a muscle specific protein in which loss of function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults. At presence the muscular functions of alpha-kinase 3 remain poorly understood, so to address this dilemma these investigators explored the punitive kinase activity of alpha-kinase 3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell derived cardiomyocytes. Mice and human patient tissues.
Dr. Peder Myhre:
Okay, Greg.
This sounds like impressive basic science work, so what did the authors find.
Dr. Greg Hundley:
Right, Peder.
Damaging variance in alpha-kinase 3 encoding an abundant muscle specific protein caused both neonatal and adult onset cardiomyopathies and led to both ventricular dilation and hypertrophy. Now, although alpha-kinase three contain an alpha kinase domain the team showed that it lacks catalytic activity and is really a pseudo kinase. Then finally, Peder, alpha-kinase 3 localizes to both the nuclear envelope of cardiomyocytes and the M-band of the sarcomere where it regulates the expression and localization of myomesins, myomesin 1 and myomesin 2, and additional M-band proteins important for sarcomere protein turnover.
Dr. Peder Myhre:
That is a beautiful summary, Greg. Since you did so well at summarizing this difficult topic, I'm not going to ask you what a clinical implications, but rather to take home messages here.
Dr. Greg Hundley:
Very nice. Glad you asked Peder.
First, alpha-kinase 3 cardiomyopathy may cause impaired contractility and ventricular dilation due to miss localization and dysregulation of myomesin proteins which are critical for force buffering in cardiomyocytes. Next, alpha-kinase 3 cardiomyopathy may cause hypertrophy due to dysregulation of key M-band proteins, which are important for sarcomere protein turnover. Then finally, therapeutic strategies to restore cardiomyocyte force buffering functions and sarcomere protein turnover may ameliorate disease phenotypes in patients with alpha-kinase three cardiomyopathy.
Dr. Peder Myhre:
Thank you Greg.
The next paper is also from the field of preclinical science and it is about the Hippo-YAP signaling pathway which maintains sinal atrial node homeostasis. It comes to us from the corresponding author Jun Wang from the University of Texas Health Science Center at Houston. Greg, this paper is not about hippos, but it is about the Hippo signaling pathway, which is known to control organ size and growth in animals and humans. These authors sought to investigate this pathway in relation to the sinal atrial node, i.e. The sinus node. As you know Greg, the sinal atrial node functions as the pacemaker of the heart initiating rhythmic heartbeats. Despite its importance the sinal atrial node is one of the most poorly understood cardiac entities, because of its small size and complex composition and function. To uncover the function of Hippo signaling in sinal atrial node the authors use knockout mice and a series of physiological and molecular experiments including telemetry, electrocardiogram recording, echochoreography, calcium imaging, immunostaining, ANA scope, quantitative real time PCR, and western blotting.
Dr. Greg Hundley:
Wow, Peder, that sounds like quite an extensive series of experiments. What did they find?
Dr. Peder Myhre:
Deletion of essential Hippo kinases caused increased fibroblast proliferation and fibrosis in the sinal atrial node. They also found evidence suggesting that Hippo signaling regulates calcium hemostasis in pacemaker cells and that may be partially mediated by the regulation of genes and coding key calcium handling proteins such as RYR2. Finally, the demonstrated that deletion of Hippo effectors in the sin atrial node can rescue the defect previously described.
Greg, the take home messages is that Hippo signaling was found to be an important regulator of the sinal atrial node homeostasis and that this provide insights applicable to the treatment of patients with sinus node dysfunction.
Dr. Greg Hundley:
Ah, beautifully done Peder. Beautifully done.
We've got some other articles in this issue. Let me tell you about a Research Letter. It's from Professor Nazer entitled “Targeted Screening for Transthyretin Amyloid Cardiomyopathy in Patients with Atrial Fibrillation.” Then Tracy Hampton has a whole series of cardiology news highlighting first that primary cilia are critical for exercise induced muscle hypertrophy. This is from the proceedings of the National Academy of Sciences. Next, there's a discussion of whole body reperfusion techniques to restore function in pig organs after death, that comes to us from nature. Then lastly, there's a final article scientists identify diverse pathogenic gene variants that lead to heart failure from the journal science.
Dr. Peder Myhre:
Thank you, Greg.
Finally, there is one Perspective piece by Dr. Rajiv Agarwal from Indiana University School of Medicine entitled “Hydrochlorothiazide versus Chlorthalidone: What is the difference?”
Now, let's move on to the feature discussion that I know you are very excited about, Greg, to learn more about the non-invasive plaque imaging in our frontiers of medicine.
Dr. Greg Hundley:
You bet.
Well listeners, welcome to this feature discussion today on November 29th and we have with us Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. Welcome to you both. Listeners, this is a really interesting feature discussion. It's one of our Frontiers articles that combines where we are in the past, but also where we want to move in the future and a very nice comprehensive review with many articles.
Gemma, can you describe for us the genesis really of this article and what you've been working on?
Dr. Gemma Figtree:
Thanks so much, Greg. Look, I think it's very exciting times at the moment and it's a really important time for all of our community to actually get together in this space. We are driven by trying to make a more efficient process for drug discovery and translation to occur and to basically move into humans in the space of coronary artery disease. We've actually known, obviously, for a long time that the underlying process driving heart attack, but we've not been able to image and treat the actual underlying disease. What this article focuses on is how we actually merge top current technology with policy and approval of drugs. We are very excited about the team of over 20 different institutes around the world trying to work on the best measures of corona artery disease as the disease itself.
Dr. Greg Hundley:
Very nice. Now, help us understand different techniques and why is this a frontier?
Dr. Gemma Figtree:
Look, I think it's a mixture of the fact that, obviously, we're getting great advances in noninvasive imaging techniques that allow us to actually measure plaque burden, but also plaque characteristics. In the case of drug translation this is an absolutely fundamental piece. You can transform a clinical trial where you can look at the underlying pathology and be able to enrich trials or be able to look at the effect of trials of a new drug in humans.
It's really important to acknowledge the fact that humans are really the only animal on the planet that get corona artery disease itself. To be able to translate some of the exciting new drugs that target the plaque itself and work synergistically with some of our agents on cholesterol, and blood pressure, et cetera, we really need to have these measures of coronary artery disease itself. It's a combination of the technology, but also how we apply it to a clinical trial and then how do we work with our regulatory authorities and policy advisors around getting this into humans. We really aiming to try to accelerate the development of drugs that can try to tackle our greatest burden of cardiovascular disease around the world.
Dr. Greg Hundley:
I'm hearing cardiovascular disease, I also heard in their imaging and lots of different modalities, and then I heard regulatory bodies. Are you thinking maybe we need standards?
Dr. Gemma Figtree:
That's exactly right. I think, importantly, whilst there's a lot of exciting technology and a lot of us are pursuing potentially different avenues of this we also need to be able to coordinate and develop a simple and harmonized approach that's able to be applied across the world in an equitable fashion. Whilst we, obviously, have developing exciting new toys we have to make sure that a measure that we want to work with regulatory authorities is able to be applied in all of our countries around the world to make sure that the drug development is applied in an equitable fashion.
Dr. Greg Hundley:
Very nice. Well listeners, next we're going to turn to our associate editor, Dr. Nick Mills. Nick, you evaluate many manuscripts. What attracted you to this particular paper? Also, help us put it in the context of why you think it's a new frontier that is emerging or needs to emerge in cardiovascular disease.
Dr. Nick Mills:
Yeah, thanks Greg.
Three things, the expertise of this group, the focus and novelty of the topic, and the fact that it's a really timely issue Gemma just outlined. Gemma a phenomenal job bringing together people from all over the world to tackle this area that includes imaging expertise, drug development expertise, industry that gives it a very balanced and diverse range of views and marks it out from other reviews that focus on particular imaging modality. Novelty's really important, but timeliness as well. We've seen in the last five years major breakthroughs in the treatment of diabetes and heart failure. But, drug development of coronary heart disease is stalling. I cannot remember the last time I went to a really exciting late breaking trial on a new development for coronary heart disease that has changed the outcomes for patients. We do need to rethink.
Gemma's absolutely right, that requires us to work with regulators to stimulate industry involvement in drug discovery, and delivery, and testing. This is occurring at a time where we've got more fabulous imaging modalities then we've ever had before. Critically, they're noninvasive. They're easy for patients, they're easy for serial testing, and that really opens up many opportunities. It's the fact that it's timely, novel, great expertise, and also really exciting area for cardio of medicine.
Dr. Greg Hundley:
Very nice. Well listeners, we're going to go back to Gemma. Gemma, what do you think are some of the next research studies that we need to perform to support what we're trying to indicate today in this Frontiers article?
Dr. Gemma Figtree:
Yeah. Thanks very much, Greg.
I think, ultimately, the features that need to be taken into consideration for a surrogate endpoint to be approved by our regulatory authorities need to be considered. There are many drug companies, but also individual investigators with ideas of drugs to take forward. What we need to do is make sure for all those studies that we're actually working together and ideally having a harmonized endpoint for use there. I think, working early with regulatory authorities is going to be key.
I think, if you actually, within the tables that are presented in the paper we demonstrate very clearly that these measures of plaque, particularly, the CT coronary angiography measures of low attenuation plaque are pretty ready for consideration by regulatory authorities. I think, agents that we already know work to reduce mortality, such as statins, we know that they actually have direct effects on plaque both from a pathophysiological perspective, but also from these imaging studies. We know that that change in the plaque characteristics and volume predict the outcomes.
In a sense, we've got a fabulous array of data already. In fact, new agents that have come through have also demonstrated effects on these measures. I think, by bringing all of this together in this article we're already in a position to work with regulatory authorities to see what is needed next. I think, listening to that's going to be very important. I do think that the next steps are really going to be working with effectively, I guess, our colleagues to make sure that we don't continue to rapidly advance the measures whilst losing the opportunity to work with regulatory authorities.
In answer your question about the research side of things, I think, as we gather more and more information about this we have to make sure that phase two studies are then linked and we can retrospectively see how they predict the outcomes in phase three studies, but I firmly believe that we're in a position that over the next couple of years we should be able to do harmonized approaches at phase two studies and then as a whole community be able to look at how that predicts outcome and work with our regulatory authorities to get more confidence in these endpoints as key. This is all driven by my clinical observations and interest in people who look up and say, "Why me" when they're having a heart attack? In our community where we're getting very good primary prevention we see up to 25% of our heart attack patients having plaque events and catastrophic heart attacks without those traditional risk factors that would've worn them.
Part of this is also opening up avenues for driving new diagnostic tools that can pick up the disease itself. Picking up... Treating coronary disease as the disease and using that for diagnostic and therapeutic purposes, I think, is a great opportunity to tackle this great burden that we're currently not winning with.
Dr. Greg Hundley:
With the group that you had assembled were there any primary suggestions on how to unite some of these efforts on a global scale? I really liked, very early in our conversation today, you mentioned that and I wondered what this collective you assembled may have suggested.
Dr. Gemma Figtree:
Yeah. Look, I think at the moment it is a collection of experts. I haven't quite figured out the name for such a thing, but we are also working with some of the leading organizations now to try to also make sure we get their auspicing of the concepts and how to best do that. I think, by not coming out of one particular organization and evolving from the members itself, and in particular, having industry and regulatory authorities involve and drug discovery experts right from the beginning has been fantastic. Also, making sure that we have that pragmatic approach and that consideration of equitable access. Particularly, making sure that any phase two trial can be done or enrichment for phase three trial can be applied right around the globe and make sure we get diversity of patients enrolled in these studies.
Dr. Greg Hundley:
Very nice. Coming back to you, Nick, any additional thoughts to build on Gemma's comments here?
Dr. Nick Mills:
Well, to say as someone who's worked in the field of cardiac biomarkers for many years and felt that we could tackle this with the regulators and drug delivery, but I've seen inflammatory biomarkers, lipoproteins come and go without changing. I think, it's just a really exciting opportunity that we now have the ability to phenotype an image, coronary artery disease noninvasively, but a highly specific surrogate endpoint that we've never had before. It's why I'm starting to do research into DT.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills for bringing us this really provocative Frontiers article highlighting a new strategy. Bringing together regulators, leading researchers, and industry to advance new methodologies and trying to tackle globally how we might address atherosclerosis.
Well, on behalf of Peder, Carolyn, and myself we want to wish you a great week and we will catch you next week on The Run.
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please author Jung-Minh Ahn and Associate Editor Emmanouil Brilakis as they discuss the article "Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial."
Dr. Greg Hundley:
Welcome, listeners to this November 22 issue of Circulation on the Run. And I am Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway, and also a social media editor interpolation.
Dr. Greg Hundley:
Well Peder, our feature this week, we are reviewing a comparison between drug eluting stents and bypass surgery for multi vessel coronary artery disease. Really an extended follow up from the Vest trial.
Dr. Peder Myhre:
I can't wait, Greg.
Dr. Greg Hundley:
Right. But before we get onto that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first?
Dr. Peder Myhre:
Sure, I'd love to. And the first paper today is a clinical one and it is entitled, “Efficacy of a Drug Eluting Stent Versus Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease: Primary Results of the Eminent Randomized Trial.” And it comes to us from the corresponding author Yann Gouëffic from Groupe Hospitalier Paris St. Joseph in France. So Greg, a clear patency benefit of a drug eluting stent over bare metal stents for treating peripheral artery disease of the femoropopliteal segment has not been definitely demonstrated. But today's paper publishes the primary results of the eminent randomized trials, which was designed to evaluate the patency of the Eluvia drug eluting stent. And this stent is a polymer based paclitaxel eluting stent and it was compared with bare metal stents for the treatment of femoropopliteal artery lesions. In fact, with 775 patients, Eminent is the largest randomized trial of drug eluting stent treatment for symptomatic femoropopliteal arterial disease to report patency to dates.
Dr. Greg Hundley:
Very nice, Peder. So describe for us, what were the results of this very large randomized clinical trial?
Dr. Peder Myhre:
Sure, Greg. So the primary effectivity outcome was primary patency at 12 months, defined as independent core laboratory assessed duplex ultrasound peak systolic velocity ratio less than or equal to 2.4 in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesions. And primary effectiveness analysis from the Eminent randomized study demonstrated superior one year primary patency for the Eluvia drug eluting stent versus bare metal stent. And that is 83.2% versus 74.3% with a P value less than 0.01. And this treatment was associated with a greater incident of Rutherford classification improvement without the need for re-intervention, and functional parameters demonstrated improvements in both groups, and there were no statistical difference observed in one year mortality between patients treated with the Eluvia drug eluting stents and bare metal stents. So in summary, this high level evidence supports the one year benefit of polymer based paclitaxel elusion over bare metal stents to treat superficial femoral artery and/or proximal popliteal artery lesions. What'd you think of that, Greg?
Dr. Greg Hundley:
Very nice. So sounds like for peripheral arterial interventions, a benefit from the polymer based paclitaxel eluting stents.
Dr. Peder Myhre:
Exactly. And there's also an editorial putting these results in context from Doctors Mosarla and Secemsky entitled, “From Imperialism to Eminence: The Noble Rise of the Second Generation Peripheral Drug Eluting Stents.”
Dr. Greg Hundley:
Excellent, Peder. Well, my article comes to us, Peder, from the world of preclinical science. And Peder, these investigators led by Professor Volker Spindler from University of Basel evaluated arrhythmogenic cardiomyopathy. And as you know, arrhythmogenic cardiomyopathy is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life threatening arrhythmias. So a substantial proportion of arrhythmogenic cardiomyopathy is caused by mutations in genes of the desmosomal cell to cell adhesion complex, but the underlying mechanisms are not well understood. So to address this, the team mutated the binding site of desmoglein two, a crucial desmosomal adhesion molecule in cardiomyocytes. This desmoglein two W2A mutation abrogates the tryptophan swab, a central interaction mechanism of desmogenin two based on structural data. Now, the impaired adhesive function of this DSG2W2A was confirmed by cell to cell dissociation assays and for spectroscopy measurements by atomic force microscopy.
Dr. Peder Myhre:
Wow. We continue to learn more about this disease, arrhythmogenic cardiomyopathy. And this sounds so interesting. Greg, please tell me what did they find?
Dr. Greg Hundley:
Right, Peder. So they found that the DSG2W2A mutation impaired binding on the molecular level and compromised intercellular adhesive function. Now, mice bearing this mutation, developed a severe cardiac phenotype recalling the characteristics of arrhythmogenic cardiomyopathy including cardiac fibrosis, impaired systolic function, and arrhythmia. Now, a comparison of the transcriptome of the mutant mice with arrhythmogenic cardiomyopathy patient data suggested deregulated integrin alpha V beta six and subsequent TGF beta signaling as a driver of cardiac fibrosis. Now accordingly, blocking integrin alpha V beta six led to reduced expression of pro-fibrotic markers and reduced fibrosis formation in the mutant animals in vivo.
Dr. Peder Myhre:
Oh, this is so important mechanistically. And Greg, can you please tell us something about the clinical importance of these findings?
Dr. Greg Hundley:
Right Peder, just like Carolyn always driving at that clinical significance. So these authors show now that disruption of desmosomal adhesion is sufficient to induce a phenotype which fulfills the clinical criteria to establish the diagnosis of arrhythmogenic cardiomyopathy confirming the dysfunctional adhesion hypothesis. Now mechanistically, deregulation of integrin alpha V beta six and TGF beta signaling was identified as a central step in the process toward developing fibrosis. And then finally, a pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. So perhaps, new information leading to future therapeutic strategies to halt myocardial fibrosis in patients with arrhythmogenic cardiomyopathy.
Dr. Peder Myhre:
Oh wow. What an amazing issue this is, Greg, and we actually have even more in the mail bag. We have a Perspective piece by Dr. Prystowsky entitled “Rate versus Rhythm Control for Atrial Fibrillation, Has the Debate Been Settled?” And we have some Cardiology News by Bridget Kuehn entitled, “Fitness Rather than BMI Appears to be Better Predictor of Survival for Women with Heart Disease.” I'm sure Carolyn would love to read that one. And in this paper, Bridget Kuehn discusses a new study published in European Journal of Preventive Cardiology.
Dr. Greg Hundley:
Very nice, Peder. Well, I've got a couple other articles in the issue. First, Dr. Tonelli has a Primer entitled, “Increasing Societal Benefit from Cardiovascular Drugs.” And then Professor Januzzi has a Research Letter entitled, “Association Between Sacubitril/Valsartan Initiation in Mitral Regurgitation Severity and Heart Failure with Reduced Ejection Fraction: The PROVE HF Study.” Well, now let's get on to that feature discussion in this issue to discuss PCI versus CABG for multi vessel coronary artery disease.
Dr. Peder Myhre:
Let's go.
Dr. Greg Hundley:
Welcome listeners to this November 22nd feature discussion and we have with us today Dr. Jung-Min Ahn from Seoul, South Korea and our own associate editor, Dr. Manos Brilakis from Minneapolis, Minnesota. Welcome gentlemen. Jung-Min, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Jung-Min Ahn:
Thank you, Greg. So the everolimus-eluting stent Freedom trial, showed a higher mortality after PCI than after bypass surgery in multi vessel disease. However, these findings maybe delimited predictability in the contemporary practice because such trials use the first generation drug stent which may have higher rate of stent thrombosis. The Press trial is the first randomized trial using the second-generation drug eluting stent. The initial approach was published in New England Journal of Medicine five years ago. So they showed that the 4.6 years of follow the PCI with everolimus-eluting stents showed a significantly higher rate of prime endpoint deaths, MI, the target revascularization, but overall mortality, there was no significant difference. So the hypothesis that, in a long term follow, more than 10 years follow, so we want to see the mortality difference between the PCI with the second generation everolimus-eluting stent versus bypass surgery. So we designed this extended follow trial best studies.
Dr. Greg Hundley:
Very nice, Jung-Min. And can you describe for us the study design, and who was your study population, and how many subjects did you enroll?
Dr. Jung-Min Ahn:
Actually, this study is the extended follow original Press trial, enrolled 880 patients from mostly Korea, China, Malaysia, and Thailand. So the study population was Asian population with a symptomatic or symptomatic coronary artery disease with angiopathy confirming the multi vessel coronary artery disease population. One additional criteria is the patient with coronary artery disease should report PCI and bypass surgery decided by the attending physicians and surgeons.
Dr. Greg Hundley:
Thank you, Jung-Min. And so, can you describe for us your study results?
Dr. Jung-Min Ahn:
Yes. During the extended follow-up study we found that there is no significant difference between the PCI with everolimus-eluting stent and bypass surgery regarding prime endpoint deaths, MI, vascularization. In addition, more importantly, we reduced the compost endpoint of death, MI, stroke. There was no significant difference in addition regarding the mortality. Also, there is no significant difference during the long term follow.
Dr. Greg Hundley:
Really interesting results, Jung-Min. Did you notice any differences in men versus women or in younger versus older individuals?
Dr. Jung-Min Ahn:
In our sub-group analysis, there is no interaction according to the sub-groups except the diabetic sub-groups. In diabetics and long term outcomes, have interaction with the treatment assignment regarding the primary endpoint, prime endpoints, death, MI, target vascularization. Even though contrary to the Freedom trial, the overall mortality rate, there is no significant difference between the PCI versus the bypass surgery even in diabetic populations.
Dr. Greg Hundley:
Well thank you so much, Jung-Min. And now listeners, we're going to turn to our Associate Editor, our expert in the area of advanced percutaneous coronary artery interventions, Dr. Manos Brilakis from Minneapolis, Minnesota. Manos, you have many papers come across your desk. What attracted you to this particular paper and how do you put its results in the context of other studies that have been performed to compare multi vessel percutaneous coronary artery intervention versus coronary artery bypass grafting?
Dr. Manos Brilakis:
Yeah, thank you, Greg. And again, congratulations to Jung-Min for a great paper. And the reason we were very interested in this paper is because it is an area that is still debated clinically quite extensively. As Jung-Minh mentioned, there is the Syndex trial showing that there was higher mortality amongst the PCI group over long term, but that was done a long time ago with previous generation drug diluting stents, and the data, the contemporary data with recently the currently used DS, is much more limited. So I think the appeal for us, and I think frankly for the practicing interventionalist, is that this paper provides long term outcomes with contemporary drug eluting stents over a fairly large patient population, and it does so fairly well, but there are plus and minuses.
There was no difference in mortality, which continues to be debated. But this paper is fairly equivalent on this respect. And if we see the coupled myo curves, they also look very similar. And there was some differences in death in myocardial infarction to be taken into consideration. But all this information is important for deciding for each patient we treat right now, which is the best way to go in terms of coronary devascularization.
Dr. Greg Hundley:
Very nice. And so, let's circle back next to Jung-Min. What do you see as the next research study really to be performed in this sphere of investigation?
Dr. Jung-Min Ahn:
Thank you, Greg. So I'd like to talk about the future study, but I'd like to say something about the how to do PCI. So what is the difference between the Press trial and previous randomized trial? In the Pres trial, we used the intracoronary imaging in 72% of PCI population. This is a huge higher rate than what was used compared with the previous randomized trial. Only 10% or less than 10% PCI population used intracoronary imaging. So I think to get the comparable research to the bypass surgery, I think we have to optimize the PCR region. What is the best way shortcut to get optimizing PCR region? It could be intracoronary imaging guided PCI, could be one important way to get optimized PCR region. I think this is very important to take a message from the first trial.
Dr. Greg Hundley:
Well, Jung-Min, it sounds like from your description that the application of intracoronary imaging was very important in this study. Do you want to expand on that for our listeners? You know, what were maybe some subgroup analysis results of using intracoronary ultrasound? And then, how would you recommend to our listening audience that that particular technique be applied?
Dr. Jung-Min Ahn:
Thank you, Greg. So I mentioned that the Press trial used the intravascular ultrasound in 72% of PCI. So we analyzed the the PCI with I, without I. PCI with I showed a very comparable primary endpoint and overall mortality rate to the bypass surgery group. But PCI without I showed a significantly higher rate of primary endpoint and overall mortalities. So intravascular ultrasound guided PCI may improve the PCI outcomes and we can compare our clinical outcomes to the bypass surgery.
Dr. Greg Hundley:
Very nice. And Manos, do you have anything to add?
Dr. Manos Brilakis:
Yeah, I think the era of doing multiple huge mega trials may be tough to find these days. I think we may not have big trials comparing those two modalities, but I do agree with Junh Minh. I think the conclusion from this study as well as the previous studies is that you can choose which way to go. But if you're going to go with PCI for example, you do want to make sure that you do the best possible outcome so that you use intravascular imaging, you use physiology. We know from phase three, that use of intravascular imaging was very limited. So if you're going to go with PCI for a specific patient, the decision of course depends on the study's results and the previous studies and the patients' specific preferences. But if you're going to do PCI, you want to take your time to get the best possible result, make sure you can get as complete revascularization as possible because that will translate into better clinical outcomes as well.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank our main author today, Dr. Jung-Min Anh, and our own associate editor, Dr. Manos Brilakis, for bringing us this important study highlighting that in patients with multi vessel coronary artery disease, there were no significant differences between PCI and coronary artery bypass grafting in the incidence of major adverse cardiac events, the safety composite endpoint, and all cause mortality during an extended follow up period. Well, on behalf of Peder, Carolyn, and myself, we want to wish you a great week and we will catch you next week On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Qiang Zhang and Matthew Burrage as well as Senior Associate Editor Victoria Delgado as they discuss the article "Artificial Intelligence for Contrast-free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement."
Dr. Carolyn Lam:
Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre from University of Akershus University Hospital in Norway.
Dr. Carolyn Lam:
Peder, today's feature discussion is on AI for contrast-free MRI. Isn't that so cool, using AI to perhaps understand what we could see only with contrast, but now in a contrast-free manner. Now I know that sound a bit confusing, but I hope very, very enticing, because everyone's going to have to wait for a little while before we get to that interesting feature discussion. And for now, let's talk about some of the papers we have in today's issue, shall we?
Dr. Peder Myhre:
Yes, Carolyn, I can't wait for the feature discussion, but we're going to start with some of the other papers in this week's issue, and we're going to start in the world of preclinical science with a paper looking at human cardiac reprogramming, because Carolyn, direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as one of the promising strategies to remuscularize the injured myocardium. Yet it is still insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails and underlying molecular mechanisms are not really well understood.
Transcriptional factors often act in concert and form tightly controlled networks featuring with common targets among different transcriptional factors. Therefore, missing one component during heart development could lead to heart function defects and congenital heart disease. And in this study by corresponding author Yang Zhou from the University of Alabama at Birmingham, the authors perform transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes to assess additional factors that govern transcriptional activation of gene programs associated with sarcomere contractility.
Dr. Carolyn Lam:
Wow. Really nicely explained. Thanks, Peder. So what did they find?
Dr. Peder Myhre:
So Carolyn, through these computational analysis of transcriptomic data, the authors identified TBX20 as the most under expressed transcription factor in human induced cardiomyocytes compared to endogenous cardiomyocytes. They also demonstrated that TBX20 enhances human cardiac reprogramming and improves contractility and mitochondrial function in the reprogrammed cardiomyocytes.
Dr. Carolyn Lam:
Nice. Could you summarize the clinical implications, please?
Dr. Peder Myhre:
Yes. So the clinical implications are that enhancing the efficiency and quality of direct cardiac reprogramming for human fibroblast is a critical step in the clinical translation of this technology, and better understanding of this synergistic regulation of key cardiac transcription factors during reprogramming will provide new insights into the genetic basis in normal and diseased hearts. Well, Carolyn, please tell me about your next paper.
Dr. Carolyn Lam:
Thanks, and we're moving now to kidney disease. Now end stage renal disease is associated with a high risk of cardiovascular events, but what about mild to moderate kidney dysfunction? Is it causally related to coronary heart disease and stroke? Well, today's authors give us a clue, and it's from corresponding author Dr. Di Angelantonio from University of Cambridge and colleagues who took a very unique combined approach to answer this question.
They first conducted observational analyses using individual level data from four huge population based data sources, namely the emerging risk factors collaboration, Epic CVD, Jillion Veteran Program and UK Biobank. Can you imagine this comprised almost 650,000 participants with no history of cardiovascular disease or diabetes at baseline, yielding almost 43,000 and 15,700 incident coronary heart disease and stroke events respectively during a 6.8 million person years of follow up.
So huge observational study, which they then followed with a Mendelian randomization analyses using a genetic risk score of 218 variants for GFR and involving participants in Epic CVD Million Veterans Program and the UK Biobank.
Dr. Peder Myhre:
Wow, Carolyn, this is a topic that I think many of us have really been wondering and thinking about. The mild to moderate kidney dysfunction, what does it really mean? And what a beautiful study to answer this. So what did they find?
Dr. Carolyn Lam:
First, there was a U-shaped association of creatinine-based GFR with coronary heart disease and stroke with higher risk in participants with GFR values below 60 or more than 105 mills per minute per 1.73 meters squared. Mendelian randomization analyses for coronary heart disease showed an association among participants with GFR below 60, but not for those with GFR above 105.
Results were not materially different after adjustment for traditional cardiovascular risk factors and the Mendelian randomization results for stroke were nonsignificant but broadly similar to those for coronary heart disease. So in summary, in people without manifest cardiovascular disease or diabetes, mild to moderate kidney dysfunction is causally related to the risk of coronary heart disease, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
Dr. Peder Myhre:
Thank you, Carolyn, for such a great summary and an important result from that study. I'm going to now take us back to the world of preclinical science and talk about diabetic cardiomyopathy and exercise. And we both know that patients with diabetes are vulnerable to development of myocardial dysfunction, and that exercise, our favorite thing, for maintaining cardiovascular health, especially in patients with diabetes.
And despite a wealth of evidence supporting that cardiometabolic benefits of exercise, the precise exercise responsive signals that confer the beneficial effects of exercise in cardiomyocytes to remain poorly defined. And previous studies have identified fibroblast growth factor 21, FGF21, a peptide hormone with pleiotropic benefits on cardiometabolic hemostasis as an exercise responsive factor.
And in this study from Aimin Xu from the University of Hong Kong, the authors investigated a six-week exercise intervention program in FGF21 knockout mice and wild-type litter mates that all had diabetic cardiomyopathy induced by high fat diet and injection of streptozotocin.
Dr. Carolyn Lam:
Nice. So what did they find?
Dr. Peder Myhre:
Yeah, the authors found that exercise lowers circulating FGF21 levels, therefore remodeling the heart as an FGF21 sensitive target organ. And the protective effects of exercise against diabetic cardiomyopathy are therefore compromised in mice with deficiency of FGF21. They also identified Sirtuin-3 as an obligor downstream effector on FGF21, preserving mitochondrial integrity and cardiac function. Finally, the authors demonstrated that FGF21 induces Sirtuin-3 expression through AMPK-FOXO3 signaling access.
Dr. Carolyn Lam:
So could you put that together for us better? So what are the clinical implications?
Dr. Peder Myhre:
So the clinical implications from this paper is that circulating FGF21 is a potential biomarker for assessment of exercise efficacy in improving cardiac functions. And exercise is a potent FGF21 sensitizer in cardiomyocyte and has the potential to enhance the therapeutic benefits of FGF21 analogs in diabetic cardiomyopathy, and selective activation of FGF21 signal in cardiomyocytes may serve as exercise mimetics and represent a promising targeted intervention for precise management of diabetic cardiomyopathy.
Dr. Carolyn Lam:
Oh my goodness. That is fascinating. Thank you, Peder. Well let's wrap up with what else there is in today's issue. There's an On My Mind paper by Dr. Weir entitled, “The Emperor's New Clothes: Aren't We Just Treating Grades of Heart Failure with Reduced Ejection Fraction.”
Dr. Peder Myhre:
And there is a Research Letter by Dr. James Martin from Baylor College of Medicine entitled “Gene Therapy Knockdown of Hippo Signaling Resolves Arrhythmic Events in Pigs after Myocardial Infarction.”
Dr. Carolyn Lam:
Very nice. Thanks, Peder. So wow, let's go onto a featured discussion on AI for contrast-free MRI and a virtual native enhancement here coming right up.
Dr. Peder Myhre:
Awesome.
Dr. Carolyn Lam:
Now we all know that myocardial scar is currently assessed non-invasively using cardiac MRI with late gadolinium enhancement as what we would call the imaging gold standard. Wouldn't it be amazing to have a contrast-free approach, which could provide the same information with many advantages such as a faster or cheaper scan, and without contrast associated problems? Well guess what? We're about to discuss that today in a feature publication in today's issue, and I am so pleased to have the co first authors with us today. They are Dr. Qiang Zhang and Dr. Matthew Burridge, both from University of Oxford, and to discuss it as well, our senior associate editor, Dr. Victoria Delgado from Barcelona. So welcome, everyone.
Qiang Zhang, could I start with you and ask you, I understand you're a machine learning expert, which means you're probably smarter than all of us here. Could you maybe explain in simple terms what made you and Dr. Burridge do the study?
Dr. Qiang Zhang:
First? Thank you so much, Carolyn and Victoria, for the invitation. As you have mentioned, late gadolinium enhancement, or LGE, has been the imaging gold standard in clinical practice for myocardial catheterization including scar assessment for patients with myocardial infarction. However, LGE requires the injection for gadolinium contrast, and this is cautioned in some patient groups and increases the scan time and cost.
On the other hand, pre-contrast CMR such as Sydney T1-T2 mapping, a gadolinium-free alternative for myocardial catheterization. But their clinical use has been hindered by confounding factors and a lack of clear interpretation. So with our cross deceptor team at Oxford, we developed an artificial intelligence, virtual native enhancement technique VNE.
It can produce a sort of a virtual LGE image but without the need for gadolinium contrast. And we have previously tested it in patients with hypertrophic cardiomyopathy as published in this journal last year. And in this new study together with Matt here, we tested in patients with history of chronic or prior myocardial infarction.
Dr. Carolyn Lam:
Oh wow. Cool. So audience, you heard it. Instead of LGE, we now have VNE, virtual native enhancement. That's super cool. Thank you. Matt, could I bring you in here? So tell us a little bit more about the population you studied and what you both found.
Dr. Matthew Burrage:
Yeah, absolutely. And thank you so much for the invitation as well. So as Chang has said, this was a single sensor study that we performed at the University of Oxford and specifically targeting assessing myocardial scar in patients with a history of chronic or prior MI. So we had two sources for our population data. Well, first we used our real world clinical service data from our institution.
So we screened 11 years worth of patient data for presence of MI. So patients were included. There was a evidence of a previous MI based on an ischemic pattern of LGE, but we specifically excluded patients who had an acute presentation, or if there were features of acute MI on the CMR scan such as presence of myocardial edema or microvascular obstruction. The reason for this is we wanted to keep this as a clean population to avoid the potential confounding effects of myocardial edema or MVO on native T1 values. And so we also excluded other myocardial pathologies such as underlying cardiomyopathies and infiltrative diseases.
A second population dataset came from the OX Army study, which is a single center prospective study of patients presenting with acute MI. And for these patients we used their six month follow up scan to again avoid the confounding effects of edema and pathology. So overall we had a total of 912 patients who have contributed over 4,000 image data sets. The patient characteristics, 81% were male, they had a mean age of 64 years and there were cardiovascular risk factors such as diabetes melitis, hypertension, hypercholesterolemia in 20 to 40% of patients, while just over half had a history of previous revascularization.
We also separately applied the VNE technology to a pig model of myocardial infarction, which was thanks to our collaborator, Rohan Domakuma in the US. And so those were scans performed eight to nine weeks after an induced MI in the LAD territory in a series of pigs. And so this gave us the ability to provide a direct comparison between LGE, VNE, and histopathology in this model.
Dr. Carolyn Lam:
Wow. And results?
Dr. Matthew Burrage:
So what we found and the key results were firstly that VNE provided significantly better image quality than LGE, and this was on blinded analysis by five independent operators from our test data sets. Secondly, the VNE correlated strongly with LGE in terms of quantifying infarct size and the degree of transmurality, so the extent of the MIs in our test data set. We had pretty good overall accuracy of 84% for VNE in detecting scar compared to LGE with no false positive VNE cases.
And finally there was also excellent visuospatial agreement with the histopathology in the pig model of myocardial infarction. So really this, we think, is a technology that provides clinicians with images in a format that firstly they're familiar with, which looks like LGE, provides essentially the same information as LGE, but it can be achieved without the need for any gadolinium contrast agents and can be acquired in a fraction of the time.
So it takes less than one second to generate the VNE image. So as we've said before, we feel there's a lot of potential here for this technology to potentially eliminate the need for gadolinium contrast in a significant proportion of CMR scans, reduced scan times and costs, increased clinical throughput and hopefully improve the accessibility of CMR for patients in the near future.
Dr. Carolyn Lam:
Oh wow. That is tremendous. So first of all, congratulations to both of you. Before I ask Victoria for some thoughts, could I also just check with Qiang Zhang, because all AI algorithms need to be externally validated or surely there's some catch to it, or so-called limitations, or something else you may study. Could you maybe round up by saying is there anything that clinicians should not be applying it to or be aware of some limitations or?
Dr. Qiang Zhang:
Thank you, Carolyn. So a limitation of this study is that the dataset that is used for developing the models, the majority of them are patients around six month after the acute infarction. So where the myocardial infarction is still evolving, which may include residual edema and microvascular obstruction, and that is difficult to assess using the current VNE model.
And also we found it challenging to assess small sub endocardial infarction and actually to address those limitations, we are working on improving the VNE models, training it on even larger data sets and training it on LGE to detect small sub endocardial function. And we will further develop it to detect, for example, acute edema and a microvascular obstruction, and in the meantime develop quality control driven AI models to inform the clinical users of and unreliable results.
Dr. Carolyn Lam:
Wow, thank you. So Victoria, now I'm dying to hear your thoughts. How do you think this fits in the landscape of all AI imaging now?
Dr. Victoria Delgado:
I think that it's an excellent development and I congratulate the others for the article and the proof of concept that we can move away from the late enhancement and the use of gadolinium enhancement. I think that this is a major step forward because as Matt said, they are going to decrease very much the time of scanning and the post processing because is automatically done as far as I understand. So even if you can interpret yourself the amount of so-called virtual enhancement, the system gives you a value for that extension of the virtual in non-gadolinium enhancement. So that reduces very much the variability that can be in each observer if that is done automatically.
But my question to them is also if that can be influenced by the type of scanner that you use, for example on echocardiography, that's much more my field of interest, it depends very much sometimes how the images are processed of which are the vendors that we have used to acquire the images. Is this a limitation for your software? Can you foresee there some variability or is completely independent?
Dr. Qiang Zhang:
Thank you, Victoria. So we are aware of actually the difference of the data produced by different scan of vendors and the advantage of AI-driven methods is that it is data driven. So we plan to incorporate dataset from other vendors so that the trend that VNE models can work with like multiple scanner vendors. This actually will be done alongside the ongoing standardization program of T1 mapping in our group, which is the underpinned technology for VNE. And this is led by Professor Stephan Pitchnik and Vanessa Farrera. And we actually hope the VNE technology as AI driven methods could contribute to a solution to the CMO standardization between the scanner vendor.
Dr. Victoria Delgado:
And another question, if I may follow in this CMR, it has been proposed as a very valuable imaging technique to assess infarct size and to see the efficacy of some therapies to reduce the myocardial infarction size. How do you think that this new methods will impact in future trials and the way we have been interpreting the previous trials, like for example, the one that you use for the validation?
Dr. Matthew Burrage:
Yeah, thanks Victoria. It's a really, really excellent question. I think there's a lot of potential for the new VNE technology to also become a clinical endpoint in some of these trials in terms of reduction in infarct size, because the information that we get is more or less the same as we get from the LGE. So there's lots of potential that we can, again, use this as a biomarker in trials for looking at reduction in infarct size and reperfusion therapies. But it has the benefit that it can be done quicker and without gadolinium contrast.
Dr. Victoria Delgado:
This is amazing guideline and really I would have a lot of questions for them as well. And knowing the literature, for example, in the Scenic center in Madrid that they have been scanning the evolution of myocardial infarction from 0.02 weeks to see how this would translate with your technique. That will be amazing to understand how this can be done.
Dr. Carolyn Lam:
Oh wow, there you go. New research idea right there. Well how about if we end with a very quick question for each of the first authors. So maybe Matt, you could start, I mean is this ready for primetime and clinical use? And if it's not, what needs to be done to get there? In other words, where are you headed as the next step?
Dr. Matthew Burrage:
So again, thank you, Carolyn, that's a really excellent question and I think the next step before this becomes ready for primetime clinical use is validating this technology really across the spectrum of other myocardial pathologies. So the next work that we are developing this on is in patients with acute myocardial infarction, and then extending this to sort of acute inflammatory conditions like myocarditis, other non-ischemic cardiomyopathies, things like amyloidosis as well.
So this will be the next step into rollout and we are looking to track things like VNE burden and how that relates to clinical outcomes, similar to the previous LGE papers have done across different myocardial pathologies, but then ultimately aiming towards clinical rollout within the next few years.
Dr. Qiang Zhang:
Yeah, I think pretty much what Matt has said, we're going to develop the deep learning methods and test it further on pretty much the whole spectrum of commonly encountered diseases, and then more complex pathologies such as acute pathologies like edema, microvascular obstruction, and then we test on large population study like UK Biobank and other prospective clinical trials. And of course the most importantly is to roll out for real world clinical use. And as Matt said, we are aiming to do this within the next two to five years.
Dr. Carolyn Lam:
Wow, this is amazing. Both Victoria and I said thank you, congratulations on this landmark piece of work. Thank you for publishing it in circulation. Audience, thank you for joining us today from Greg, Peder, myself. You've been listening to Circulation on the Run, and don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. And...
Dr. Peder Myhre:
I'm Dr. Peder Myhre from Akershus University Hospital, and University of Oslo in Norway.
Dr. Carolyn Lam:
Peder, I'm so excited about our future discussion. It's about a very important topic of detecting atrial fibrillation in the population using wearable devices. It talks about the Fitbit Heart Study. So exciting, but we're going to keep the audience waiting a bit, because we're going to talk about some other things in the issue. And I would love to start with this now.
We know that fulminant myocarditis presentation is a rare and severe presentation of myocarditis. But, what is its natural history, and clinical features associated with poor outcomes? Peder, what do you think?
Dr. Peder Myhre:
Oh, that's a great question. We really don't know, because prior studies have been relatively small and selected. So Carolyn, let me know.
Dr. Carolyn Lam:
You're absolutely right. But today's paper from Professor Saito, from Nara Medical University in Japan and colleagues, is the largest nationwide cohort study of patients with histologically proven fulminant myocarditis presentation. They study 344 patients, hospitalized with histologically proven myocarditis, who underwent catecholamine and/or mechanical support from 235 cardiovascular training hospitals across Japan, between 2012 and 2017, and here's what they found.
Over a median follow up of 600 days, the accumulative risk of death or heart transplantation at 90 days was 29%. So, really high. These were the risk factors associated with a higher risk of death or heart transplantation, and they were non-sinus rhythm, older age, ventricular tachyarrhythmia, lower left ventricular ejection fraction. Severe histological damage was also associated with a worse 90 day outcome in lymphocytic myocarditis. Cool, huh?
Dr. Peder Myhre:
Oh wow. That was some really solid data. And now Carolyn, I'm going to take us over to the world of preclinical science. And the next paper entitled at “APIC Associated De Novo Purine Synthesis is Critically Involved in Proliferative Arterial Disease” by Yuqing Huo from Augusta University in Georgia.
Dr. Carolyn Lam:
Cool.
Dr. Peder Myhre:
And as you know, Carolyn, vascular smooth muscle cells are extremely important in vascular health. They're located in the medial layers of arteries, and normally exhibit a contractile phenotype that contributes to the regulation of blood vessel tone, blood flow distribution, and blood pressure in normal mature blood vessels. And in response to disease processes, the vascular smooth muscle cells are switched to an activated synthetic and proliferative phenotype, that contribute to the development of a variety of arterial diseases, including atherosclerosis, in-stent restenosis, and bypass graft occlusion. And nucleotides that we are familiar with, such as ATP and GTP, are essential for a large number of biological processes in cells, including proliferation.
And Carolyn, the previous studies have demonstrated that de novo synthesis of purine is a critical pathway for nucleotide synthesis. And in this study, the authors assessed the role of de novo synthesis of purine in vascular smooth muscle cells by using knockout mice.
Dr. Carolyn Lam:
Oh, that was beautifully explained. Thanks, Peder. So what did they find?
Dr. Peder Myhre:
So the authors found that the de novo purine synthesis was increased in proliferative vascular smooth muscle cells. Moreover, they identified an important enzyme in the process called A-P-I-C, APIC. Which was observed in the neointima of the injured vessels, and atherosclerotic lesions in both mice and humans.
Finally, they showed that in a mouse model with knocked out APIC, the atherosclerosis and arterial restenosis was attenuated.
Dr. Carolyn Lam:
Cool. So tell us what the clinical implications are.
Dr. Peder Myhre:
So these findings provide novel insights into the reprogramming of purine metabolism underlying vascular smooth muscle cells proliferation in the development of arterial disease. And that targeting APIC may be a promising therapeutic approach to combat arterial diseases.
So Carolyn, please tell me about your next paper.
Dr. Carolyn Lam:
Ah, thanks, Peder. Well, back to the clinical world, this time, talking about arrhythmogenic right ventricular cardiomyopathy. We know that is characterized by progressive cardiomyocyte loss and fibro fatty replacement. And we know that patients with this a ARVC are at risk for life-threatening ventricular arrhythmias and sudden cardiac death.
The placement of an ICD is a crucial component of ARVC management. But arrhythmic risk stratification and the selection of the optimal candidates for ICD, especially for primary prevention of sudden cardiac death, has, of course, been challenging.
As background, a ventricular arrhythmia risk calculator, in patients without previous sustained ventricular arrhythmias, has been proposed, and includes seven clinical variables derived from non-invasive tests that are routinely performed in these patients. However, the possibility of integrating additional parameters, such as ventricular tachycardia inducibility on programmed ventricular stimulation, with this risk calculator, has been suggested, but not conclusively investigated in a large cohort. And so, here comes corresponding author, Dr. Cadrin-Tourigny, from Montreal Heart Institute and colleagues, who studied 288 patients with a definite ARVC diagnosis, no history of ventricular arrhythmias at diagnosis, and programmed ventricular stimulation performed at baseline. And these patients were identified from six international ARVC registries.
Dr. Peder Myhre:
Oh wow. So we're talking risk stratification for patients with ARVC. Such an interesting topic, Carolyn. So please tell me, what did they find?
Dr. Carolyn Lam:
So, programmed ventricular stimulation significantly improved risk stratification, above and beyond the calculator predicted risk of ventricular arrhythmias, in a primary prevention cohort of patients with ARVC. And this was mainly for patients considered to be at low and intermediate risk by the clinical risk calculator. If negative, its high negative predictive value of 93% in low and intermediate risk patients, may support the decision to forego ICD use in some patients. So, programmed ventricular stimulation results may be applied to the non-invasive ARVC risk calculator, in a two step approach to facilitate personalized decision making for ICD in such patients.
Dr. Peder Myhre:
Thank you, Carolyn. That was a great summary and a great paper. So we're going to move in to see what else is in the mail bag, Carolyn.
Dr. Carolyn Lam:
You bet. There's a letter by Dr. Agirbasli regarding the article, “Coronary Artery and Cardiac Disease in Patients with Type Two Myocardial Infarction, A Prospective Cohort Study,” and this, followed by a response by Dr. Chapman.
There's an ECG Challenge by Dr. [Jingnan] Han, entitled, “Tachycardia Associated with Pacing.”
From our own Molly Robbins, we have highlights from the Circulation Family of Journals. And she covers the experience with stereotactic radio ablation and electrical storm, reported in Circulation: Arrhythmia and Electrophysiology.
The impact of accessibility to primary care on hypertension awareness and control is reported in Circulation: CV Quality and Outcomes.
There's an analysis of lifestyle factors and their impact on the risk of heart failure by background genetic risk, and that's in Circulation: Heart Failure.
There's a deep learning model of PET scans and coronary flow reserve reported in Circulation: CV Imaging.
And finally, OCT based measurement of stent expansion and associations with outcomes are presented in Circulation: CV Interventions.
A lot.
Dr. Peder Myhre:
Yeah, and there's more, Carolyn. In this issue, there is an extensive Frontiers review by the AF-SCREEN International Collaboration, entitled, “Consumer LED Screening for Atrial Fibrillation.”
There is also a Research Letter by corresponding author Qi Fu, from University of Texas Southwestern Medical Center entitled, “Neuro Cardiovascular Dysregulation During Orthostasis in Women with Posttraumatic Stress Disorder.”
And finally, a Research Letter by Pankaj Arora from University of Alabama entitled, “Mechanical Circulatory Support Devices Among Patients with Familial Dilated Cardiomyopathy, Insights from the INTERMACS.”
Dr. Carolyn Lam:
That's awesome, Peder. Thank you. Now let's go onto our feature discussion on atrial fibrillation detection and the Fitbit Heart Study, shall we?
Today's feature discussion is about the Fitbit Heart Study, and none other than the first and corresponding author Dr. Steven Lubitz, from Massachusetts General Hospital in Boston to join us today. Steve, welcome. Congratulations. Am I right to say, this is the largest study of its kind to look at the detection of atrial fibrillation using wearable devices?
Dr. Steven Lubitz:
Thanks for having me, Carolyn. And that's right, this is.
Dr. Carolyn Lam:
Oh my gosh. Okay. Tell us all about it, what you did, what you found.
Dr. Steven Lubitz:
Well, thanks, Carolyn. So as we know, undiagnosed atrial fibrillation is a potential hazard that can cause strokes. And if we can identify people who have undiagnosed atrial fibrillation early, we may be able to prevent strokes. In addition, undiagnosed atrial fibrillation may be associated with additional morbidity, which can be addressed through a number of different ways, if we can detect atrial fibrillation. Obviously, the challenge is to detect atrial fibrillation.
We also know that people are increasingly wearing devices that have sensors on them, specifically using photoplethysmography technology, which can detect the pulse rate. Software algorithms can now be developed, that can assess that pulse rate for regularity or irregularity. But they really need to be assessed and validated, to minimize the potential for false positives, which can have obviously, downstream adverse consequences of their own, if atrial fibrillation is incorrectly identified or diagnosed as a result.
As I was mentioning, we developed this novel software algorithm with frequent overlapping photoplethysmography, post tachogram sampling, which is unique. And then we tested the algorithm's positive predictive value for undiagnosed AFib in a large scale remote clinical trial, using a range of Fitbit wearable fitness trackers and smart watches.
It was a remote trial, so participants were invited. These were people who already had a Fitbit account, they were invited to participate. And in span of just a few months, in the middle of the pandemic, over 455,000 people signed up to participate in the study. And so, big thank you to all of the participants in the study.
Dr. Carolyn Lam:
Wow, that is big. And what did you find?
Dr. Steven Lubitz:
So of the 455, over 455,000 participants that enrolled, over 4,000, had an irregular heart rhythm detection and received a notification. And after inviting those participants to attend a telehealth visit, and at that telehealth visit, the telehealth provider confirmed eligibility criteria, confirmed that they didn't have preexisting atrial fibrillation, for example, and a variety of other inclusion/exclusion criteria.
They were mailed a one week ECG patch, that they applied themselves, and then returned that ECG patch. So in the end, after those exclusions, in participants that returned analyzable patches, 1057 participants were included in this ECG monitoring analytic cohort, of whom, 340 had atrial fibrillation during that ECG patch monitoring period.
The primary endpoint of the study was the positive predictive value of irregular heart rhythm detection that occurred during the ECG patch monitoring period. So a participant had to have an irregular heart rhythm detection to get notified that they were eligible to meet with a telehealth provider and receive an ECG patch monitor. And then, they had to have another irregular heart rhythm detection during ECG patch monitor wear. So the primary outcome was the positive predictive value of the first irregular heart rhythm detection for concurrent atrial fibrillation that occurred during ECG patch monitoring.
Dr. Carolyn Lam:
Okay. Cool. So many questions here, but maybe you should tell us the results first.
Dr. Steven Lubitz:
Sure. So the primary endpoint, the positive predictive value of the IHRD during ECG patch monitoring was 98.2% in the overall cohort. And it was similar between men and women, and those aged 65 or older, or those aged less than 65. And I should mention that, in this study, about 13% of participants enrolled in this study overall, were above the age of 65.
Dr. Carolyn Lam:
And you included more women than in prior similar studies. Right, Steve?
Dr. Steven Lubitz:
Yeah.
Dr. Carolyn Lam:
I was going to congratulate you for that.
Dr. Steven Lubitz:
Yeah, that's right. That's right. We're very excited to see that.
Dr. Carolyn Lam:
Okay, so that's cool. Wow. A positive predictive value of 92%. So couple of things here with-
Dr. Steven Lubitz:
98.
Dr. Carolyn Lam:
Sorry, 98%. That's right. Wow. Okay. Now with this AFib detection, it's always about duration. Right? And what do you call a positive alert? Could you maybe elaborate a bit about that here?
Dr. Steven Lubitz:
Sure. So I think this is an important point. A few points. One, the algorithm is designed. This particular algorithm requires at least 30 minutes of an irregular pulse to be detected, in order for a detection to occur. Which means that, this is unlikely to be detecting trivial amounts of atrial fibrillation. And indeed, that's what we observed. We observed that the median burden of atrial fibrillation was 7% among those who had AFib on the ECG patch monitor. We observed that the median longest episode of atrial fibrillation was seven hours. And just by way of comparison, in other studies in which ECG patch monitors have been distributed to people without this irregular pulse pre-screening, the burden is usually on the order of only a couple of percent, tops. So this, by nature, these types of algorithms, and this algorithm specifically, probably enriches for individuals who have a higher burden of atrial fibrillation. Meaning that, if these detections occur, then it's probably not detecting trivial amounts of atrial fibrillation.
Dr. Carolyn Lam:
Right. And a lot of it seems to send a very clear message that this study, and perhaps even the algorithm, is designed to be specific. Right? So that duration, as well as what you used as the outcome. How much price do you pay in terms of sensitivity? Do you know what I mean? Since we optimized for specificity, am I right to say that?
Dr. Steven Lubitz:
Sure, that's a great point. The algorithm is really optimized for specificity, as you mentioned. And although we didn't specifically calculate the sensitivity of the algorithm, in a secondary analysis, we examined the sensitivity of an IHRD during that ECG patch monitoring period, to detect any AFib that was documented on the ECG patch monitor, and it was about 67%.
So we know that we probably don't detect some atrial fibrillation. Largely, that's a function of this technology at the moment. It's very difficult to assess the pulse rate during periods of activity in motion. So a lot of these algorithms, and this algorithm in particular, doesn't operate during periods of motion. The accelerometers and the devices can tell the algorithm that motion is occurring, and then the algorithm won't operate on that information at that time. So a lot of this has to do with limitations of the technology at the moment.
Dr. Carolyn Lam:
Ah. So the detection probably occurs best at rest or at night.
Dr. Steven Lubitz:
That's exactly right. And we encourage participants to wear their devices at nighttime during the study.
Dr. Carolyn Lam:
Oh, cool. And then of course, I suppose a question you'd anticipate, I mean, we know about the Apple Heart Study, we know about the watch study, and how does this compare? How is this technology different, and the results?
Dr. Steven Lubitz:
Essentially, one of the most remarkable things about these studies is that, it appears that this pulse rhythm pre-screening really enriches substantially for people who have atrial fibrillation. So for example, in the Fitbit Heart Study, we observed that about 32% of people who had an irregular heart rhythm detection and then returned an ECG patch monitor, had AFib on it. And by comparison, in the Apple Heart Study, that number was about exactly the same, just over 30% or so.
So when we further compare this pre-screening type approach to confirming atrial fibrillation, using an ECG patch monitor, with other approaches in which say, elderly individuals were mailed ECG patch monitors to screen for atrial fibrillation, we usually only see detection in the order of four to 5% of people. So this irregular pulse based pre-screening markedly enriches for atrial fibrillation. And we also know, this is only a one week ECG patch monitor, and if we monitor people longer than one week, we're likely to detect more atrial fibrillation, since this is often paroxysmal atrial fibrillation that we're detecting.
So there are a lot of similarities, and I think the point is that, these types of consumer electronic devices are going to be great tools for identifying undiagnosed atrial fibrillation in the community. I think we have a lot of challenges ahead of us, in terms of figuring out how to integrate that information into our routine healthcare workflow, and counseling consumers and users of these types of technology on exactly what they should be doing when they do get an alert. And then also, counseling providers on how to act on these findings, what they mean and how accurate the technology is.
Dr. Carolyn Lam:
Yeah. And I appreciated a sentence in your manuscript that talks of, what are our society guidelines going to say? If you could look into a crystal ball now, Steve, based on what you found, what would you advise both patients and clinicians, if you don't mind?
Dr. Steven Lubitz:
Well, I think that, in short, if a clinician is alerted by a patient, that they received in a regular heart rhythm detection on their device, in short, I would say, don't blow it off. Take it seriously. Because the odds are, that it does represent an abnormality, and the odds are that that abnormality is atrial fibrillation. And given the potential adverse consequences of undiagnosed atrial fibrillation, there's a real opportunity to intervene, and prevent morbidity in the patient. And then, if you're a consumer who happens to have one of these devices, and you've turned on this feature, and hopefully you have, if you do have an alert, don't blow it off. Contact a provider. Because it may very well mean that you have an irregular heart rhythm that merits attention, and could be addressed to prevent downstream consequences and morbidity for you.
Dr. Carolyn Lam:
Nice. And keep your Fitbit on at night.
Dr. Steven Lubitz:
Yes. And if you do want to maximize the utility of these algorithms that use photoplethysmography, probably wearing them at nighttime will maximize the sensitivity, or utility of the devices and algorithms.
Dr. Carolyn Lam:
Aw, that's just great. What nice take home messages. Thank you so much, Steve, for publishing this really unique and important study in Circulation.
So audience, you heard it right here on Circulation on the Run. From me, Greg, and Peder, please do tune in again next week.
Speaker 4:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Kevin Roedl and Sebastian Wolfrum, as well as Associate Editor Mark Link as they discuss the article "Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the Journal and its editors. We are your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, very interesting, a randomized clinical trial of temperature control after in-hospital cardiac arrest. But before we get to that exciting study, let's grab a cup of coffee, and jump in and discuss some of the other articles in the issue. Carolyn, would you like to go first?
Dr. Carolyn Lam:
Yes. Starting with a great quiz. So Greg, which is better? How about this? It's multiple choice. Is it A; transradial, or B; transfemoral access, in terms of post-procedural mortality?
Dr. Greg Hundley:
I'm going to go with transradial. It has been, hopefully, I'm okay on this. It just seems so many fewer complications.
Dr. Carolyn Lam:
But that's exactly that we need to meta-analyze the studies that have been done. Exactly what this paper did, led by Professor Valgimigli, from USI in Lugano, Switzerland. So what they did is, they performed an individual patient data meta-analysis of 21,600 patients, enrolled in seven multi-center randomized control trials, comparing the transradial with transfemoral access, among patients undergoing coronary angiography with or without PCI. And they found that transradial access was associated with a lower incidence of the primary outcome of all-cause mortality, and the co-primary outcome of major bleeding at 30 days, compared to transfemoral access.
There was also evidence for reductions in major adverse cardiac and cerebral vascular events, net adverse clinical events, vascular complications, excess site bleeding, and blood transfusion. MI, stroke, and stent thrombosis, did not differ. And crossover was higher in the transradial access group.
At predefined subgroup analysis, the authors confirmed that the benefit observed the transradial group was generally consistent across the majority of pre-specified subgroups, except for those with significant baseline anemia. Patients with baseline anemia appear to derive a substantial mortality benefit with transradial access rather than transoral access, compared to those with mild or no anemia.
So, the authors concluded, that the meta-analysis provides evidence that transradial access should be considered the preferable access site for PCI, in patients with acute coronary syndrome, supporting most recent recommendations on the preferential use of this radial approach. So you were right, Greg.
Dr. Greg Hundley:
Very nice, Carolyn. A really important piece of science to disclose to our listeners, in that hurried state, and moving quickly door to balloon times, et cetera. And here we find another positive outcome in study result for transradial approaches.
Well Carolyn, as we know, my next paper, it's really going to come to us from the world of preclinical science. And it pertains to hypertension, which is a common cardiovascular disease, and is related to both genetic and environmental factors. But the mechanisms linking the interplay between the domains of genetics and the environment have not been well studied.
Now, DNA methylation, a classical epigenetic modification, not only regulates gene expression, but is also quite susceptible to environmental factors. Thereby, linking environmental factors to genetic modifications. So therefore, Carolyn, these authors, including Professor Jingzhou Chen, from Fuwai Hospital, National Center for Cardiovascular Diseases, and the Chinese Academy of Medical Sciences, and the Peking Union Medical College, and their colleagues, felt that screening differential genomic DNA methylation, in subjects with hypertension, would be important for investigating this genetic environment interplay in hypertension.
So this study, Carolyn, like many from the world of preclinical science and circulation, incorporated both human and animal model subjects. Methodologically differential genomic DNA methylation in hypertensive, pre-hypertensive, and healthy control individuals, was screened using the Illumina 450K BeadChip, and then verified by pyrosequencing. Plasma oviduct glycoprotein 1, or OVGP1 levels, were determined using an enzyme-linked immunosorbent assay. And OVGP1 transgenic and knockout mice were generated to analyze the function of OVGP1.
Dr. Carolyn Lam:
Wow. Nice approach, Greg. And what did the authors find?
Dr. Greg Hundley:
Right, Carolyn. These authors found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension.
Now Carolyn, in OVGP1 transgenic mice, OVGP1 over expression caused an increase in blood pressure. Also, dysfunctional vasoconstriction, and vasodilation, remodeling of the arterial walls, and increased vascular superoxide stress and inflammation. And these phenomenon were exacerbated by angiotensin II infusion.
In contrast, OVGP1 deficiency, attenuated angiotensin II induced vascular oxidase, stress, inflammation, and collagen deposition.
Now pull down, and co-immunoprecipitation assays showed that myosin heavy chain 2A, or MYH9, interacted with OVGP1. Whereas, inhibition of MYH9 attenuated OVGP1 induced hypertension and vascular remodeling.
Dr. Carolyn Lam:
So Greg, let me try to summarize, is that okay? So hypomethylation, at that specific site in the promoter region of the OVGP1 gene, is associated with hypertension, and induces its upregulation. The interaction of this OVGP1 with myosin heavy chain 2A contributes to vascular remodeling and dysfunction. And so, OVGP1 is a pro hypertensive factor, that promotes vascular remodeling by binding to this myosin heavy chain. So, really cool stuff. Thanks for teaching us.
Dr. Greg Hundley:
Very good.
Dr. Carolyn Lam:
Well thanks so much, Greg. And we go back to the clinical world now, and ask the question, what is the efficacy and safety of prophylactic full dose anticoagulation and antiplatelet therapy, in critically ill COVID-19 patients? So I'm going to tell you the results of the COVID-PACT trial. And this was a multi-center, two-by-two factorial, open label, randomized controlled trial, with blinded endpoint adjudication in 390 ICU level patients. So, severely ill patients with COVID-19, from 34 US centers. Patients were randomized to a strategy of full dose anticoagulation, or standard dose prophylactic anticoagulation. And in the absence of an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy.
Dr. Greg Hundley:
Ah, Carolyn. So what did they find?
Dr. Carolyn Lam:
Full dose anticoagulation substantially reduced the proportion of patients experiencing a venous or arterial thrombotic event, and there was no benefit from treatment with clopidogrel. Severe bleeding events were rare, but numerically increased in patients on full dose versus standard dose prophylactic anticoagulation, without any fatal bleeding events, GUSTO moderate or severe bleeding was so significantly increased with full dose anticoagulation, but with no difference in all-cause mortality.
So in summary, in a population of critically ill patients with COVID-19, a strategy of prophylaxis with full dose, versus standard dose prophylactic anticoagulation, but not the addition of clopidogrel, reduced thrombotic complications, with an increased risk of bleeding, driven primarily by transfusions in hemodynamically stable patients, with no apparent excess in mortality.
Dr. Greg Hundley:
Very nice, Carolyn. What a important piece of information, as many of us around the world are taking care of critically ill patients with COVID-19.
Well, how about we see what is in the mail bag this week? So first, Carolyn, there's a Frontiers piece by Dr. Packer, entitled, “Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 inhibitors, and Reaffirmation of the Nutrient Deprivation Signaling Autophagy Hypothesis.”
Next, there's a Research Letter, from Professor Airaksinen entitled, “Novel Troponin Fragmentation Assay to Discriminate Between Troponin Elevations in Acute Myocardial Infarction and End-stage Renal Disease.”
Carolyn, there's another Research Letter, from Professor Solomon, entitled, “Aptamer Proteomics for Biomarker Discovery in Heart Failure with Reduced Ejection Fraction.”
Also, Carolyn, [a] wonderful Cardiovascular News summary from Tracy Hampton, reviewing three articles. First, “Mechanisms Behind Cannabis Effects on Heart Health.” The second, “Exercise Inducible Metabolite Suppresses Hunger.” And then lastly, “Piezo1 Initiates the Cardiomyocyte Hypertrophic Response to Pressure Overload.”
Dr. Carolyn Lam:
Cool. There's also an exchange of letters between Doctors Jha and Borlaug on latent pulmonary vascular disease in therapeutic atrial shunt.
And finally, an On My Mind, by Dr. David Kass entitled, “What's EF Got To Do, Got To Do With It.” I love it. You must read it. It's so, so cool. All right. But now, let's go on to our feature discussion, shall we?
Dr. Greg Hundley:
You bet, Carolyn.
Welcome listeners, to our feature discussion today, and really delving into the world of in-hospital cardiac arrest, and how we manage those patients. And we have with us today, Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from University of Texas Southwestern in Dallas, Texas. Welcome gentlemen. Kevin, we're going to start with you. Can you describe for us, some of the background information that went into the construct of your study, and what was the hypothesis that you wanted to address?
Dr. Kevin Roedl:
Thank you, Greg. We thank you for the kind invitation to this podcast. We're very likened to do this podcast with you. And so, talking about the background of hypothermia in-hospital cardiac arrest, we have to go back like two decades almost, because there were two studies in New England Journal of Medicine published 2002, who introduced mild therapeutic hyperthermia to the treatment in post cardiac arrest. Primary, these two studies show the benefit of the therapy in this kind of patients. And then, 2003, it was introduced in also the international guidelines. However, these studies only addressed out-of-hospital cardiac arrest patients, and also, only shockable rhythms. And so, the question arised over the years, what about other patients like non shockable rhythms, or also in-hospital cardiac arrest?
And so, that's basically was the primary aim of our study to address this special population. Because when you see the states, the numbers, there are 290,000 in-hospital cardiac arrests a year. So it's actually, a very large population. And there's no randomized control trial to show any benefit, or maybe harm, in this group. There were some observational studies, 2016 in China published. From China, in this group, they looked at the Get With The Guidelines registry, and actually, they saw that there was probably a negative influence of hypothermia in the study. However, it was only observational. So actually, there were no randomized control trials. And that primary hypothesis was, that we wanted to know actually, does thus mild therapeutic hyperthermia work in this group of patients in the in-hospital cardiac arrest setting? And what is the outcome? Is it like in the out-of-hospital cardiac arrest setting, or not?
Dr. Greg Hundley:
Wonderful, Kevin. And so, can you describe for us then, your study population and your study design?
Dr. Kevin Roedl:
Yes, of course. We did a randomized control trial. There were over 1000 people screened, and overall, we included 242. So you see how hard it is to get people in there. And actually, in terms of hypothermic temperature control, we are 120 about, and long term at 118, and the final others of the endpoints. And when we look at the baseline characters of these patients, they were well balanced actually, about 72 years. When we look at the initial cardiac arrest rhythm, that's interesting because about 70% non-shockable rhythms, and 25% shockable rhythms. And probably also interesting, the location of the cardiac arrest. Medical boards about 50%, and ICU or ED was 22%. So that's probably summed up the baseline characteristics of our study.
Dr. Greg Hundley:
Perfect. And so Kevin, can you describe for us what was the hypothermic target for the group that was going to have their temperature recused?
Dr. Kevin Roedl:
Yes, hypodermic target was 32 degrees to 44. And so two degrees Celsius, basically the same target like in earlier trials.
Dr. Greg Hundley:
Very nice. Well listeners, now we're going to turn to our second co-author, Dr. Sebastian Wolfrum. And Sebastian, can you share with us the study results?
Dr. Sebastian Wolfrum:
Yes, Greg. Thank you very much for the opportunity to participate in this podcast. Only wanted to include unconscious patients, and therefore, we took a time and took 45 minutes after their cardiac arrest, to let the patients get away if they did so. We also excluded patients that had severe functional deficit before the cardiac arrest; since we could not really define the neurological outcome if we would've included those. And we didn't see any differences. Neither in mortality, not in the functional outcome, either when they're treated with 33 degrees Celsius, or whether normothermia was used.
The death rate after six month was in a range which is comparable to other in-hospital cardiac arrest studies, and higher than those performed in the out-of-hospital cardiac arrest studies. It was about slightly over 70% in both groups. And the number of patients with the good functional recovery after six months was 23% of the patients in the hypothermia group, and 24% of the patients in the normothermia group.
And if we look at only the survivors, we see that the ones which are worse functional outcome, were most of them dead after six months. We then also focused on the temperature curves in our patients, and to see whether we have achieved our goal. And we saw that we have reached the target temperature within four and a half hours after cardiac arrest in our hypothermia group. Which is not as fast that we had expected, but still in the range, which is comparable to other studies on this field. And we also saw that our control group was about 37 degrees, within the first 12 and 48 hours. So we truly avoided fever, which has not been done in every previous study on cardiac arrests.
Dr. Greg Hundley:
Very nice. And any differences between the hypothermia and normothermia groups, related to the age of the patient? Or, whether or not they had a shockable rhythm at the time of presentation?
Dr. Sebastian Wolfrum:
We saw as a result of our study, that age is a predictive factor for mortality. But age did not differ between our treatment groups, and therefore, did not interfere with our results. And we didn't see differences in the shockable or non-shockable rate in our patients in the different treatment groups.
Dr. Greg Hundley:
Thank you. Well listeners, now we're going to turn to our associate editor, Dr. Mark Link, one of our expert electrophysiologists at Circulation. And Mark, you have many papers come across your desk, and what attracted you to this particular paper?
Dr. Mark Link:
There were a number of things. One, it's hard to do RCTs in resuscitation, and I thought they did a very nice job with this RCT. Two, the subject of hypothermia, or therapeutic temperature management, is a very hot one in resuscitation. It's one of the few treatments in the past that have been shown to make a difference in outcome. And so, all of those trials were done in out-of-hospital arrest. So to have a trial done in in-hospital arrest was very intriguing also.
And I think we're all disappointed that it wasn't a positive trial, but we have to take the negative trials also. And I think, part of the reason it may have been a negative trial is because the normal thermic group avoided hyperthermia. And I think that's something that's coming out of a lot of these trials is avoid fever. It may not be so important to get hypothermic targets, actually, looks like it's probably not, but it looks like it's very important to avoid fever.
Dr. Greg Hundley:
Very nice. Well listeners, we're going to turn back to our expert panel here really, and start with you Kevin. Kevin, what do you think is the next study that needs to be performed in this sphere of research?
Dr. Kevin Roedl:
Thank you for this interesting question. Yeah, a bunch of studies could be performed, especially maybe in the out-of-hospital cardiac arrest study, because we don't know. This fever harmful, we have to find certain subgroups in which this treatment works. So maybe in this subgroups there is data on this and it could be a benefit. So these are, I think, the two main topics that should be done in the future.
Dr. Greg Hundley:
Thank you. Sebastian, what are your thoughts?
Dr. Sebastian Wolfrum:
As Mark said, the hypothermic treatment was, for decades, maybe the only treatment which we could give to cardiac arrest patients, which has been proven to reduce mortality. And all other studies following didn't see any be benefit of hypothermia, not even in a subgroup. Also, the TTM trials did not. So I'm questioning myself, where is the original HACA study group that benefits? Where did this hide in the other studies?
So I would think, to do another study in out-of-hospital cardiac arrest patients, whether in ventricular fibrillation that had shown in the HACA trial to reduce mortality. This should be done in a similar way to the original study, to see whether there is this subgroup. People who support the idea of hypothermia also focus very much on the fast onset of their hypothermic treatment. And they say we saw a difference in mortality in the HACA trial, and we could very fast. And I think the other studies have to show that they cool as fast as the HACA study. So the main focus should be on the time calls of hypothermia after cardiac arrest, cooling very fast to a target temperature of 33 degrees, maybe holding on for 24, maybe 48 hours.
Dr. Greg Hundley:
Very nice, Sebastian. So focusing on the speed and the timing of that cooling. And Mark, anything to add?
Dr. Mark Link:
Yeah, so if I sit here with my writing group hat on for the HA and say, "What are we going to do for the resuscitation guidelines in 2025?" I think you look at the totality of the data for targeted temperature management. And I think, the main thing you say, walking away from this, is avoid fever. Don't let your patients get hot. I'm not sure you can say much more than that right now, until we get more data.
Dr. Greg Hundley:
Very nice. Well listeners, a really interesting provocative discussion today. And we want to thank Dr. Kevin Roedl from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and our own associate editor, Dr. Mark Link from Dallas, Texas, bringing us the results of this study highlighting that hypothermic temperature control is compared with normothermia did not improve survival, nor functional outcome, at 180 days in patients presenting with coma after in-hospital cardiac arrest.
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On The Run.
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join Circulation's Associate Editor Marc Ruel and Executive Editor James de Lemos as they summarize all of the articles found in Circulation's annual Cardiovascular Surgery-Themed Issue for 2022.
Dr. James de Lemos:
Hi, welcome to Circulation on the Run. Greg and Carolyn are off today. My name is James de Lemos. I'm the executive editor for Circulation and I'm delighted to be joined today by Marc Ruel, who's the editor of our themed issue on cardiac surgery and leads the development and curation of all of the cardiac surgery content in Circulation. Marc, congratulations to you, to Mike Fischbein, to the whole Circ team on another spectacular effort to pull together this issue. Glad to have you here today.
Dr. Marc Ruel:
Well, thank you very much, James. It's really a team effort. I want to salute and thank the vision of Circulation to really give an important component to surgical science. As you often hear me say, your surgery provides the most durable and robust solution for advanced heart disease, right? So it's a very important part of the mission of Circulation as the premier cardiovascular journal. I want to thank you and also Joe Hill, our Editor-in-Chief and obviously the entire team of Circulation as well as all staff. Augie [Rivera], who is helping us on this call as well as Nick [Murphy] and many others who have made this issue possible.
Dr. James de Lemos:
Well, great. Well, let's get to this. And you recognize as well Mike Fischbein, who's the Cardiac Investor surgeon at Stanford who helps to edit the themed issue and really helps us to think about basic science into surgical specialties. Let me start, Marc, with cardiac bypass surgery. We have actually three papers in this issue that cover various aspects of CABG. The first one is one that you and I really resonated with, I know, because we talked about this. It's a paper by Ono from the SYNTAX Extended Survival study titled "Impact of Patient Reported and Pre-Procedural Physical and Mental Health on 10 year Mortality after PCI or CABG." And this is a really fascinating paper, looked at obviously patients with left main or multi vessels coronary disease, but used objective measures of physical and mental function from the SF-36 score and calculated summary physical and mental component scores.
And then used those scores to evaluate whether there were treatment interactions based on physical and mental performance metrics with regard to the benefit of CABG over PCI. And really fascinating, first that there was an interaction and that the magnitude of benefit of CABG over PCI for multi vessel disease was substantially greater among individuals that had higher physical performance as well as mental health performance. What did you think of this paper and data? I know you wrote a tremendous editorial to this. So this is something that you thought about as we were bringing the paper in, but also had to think about in terms of putting this paper in the context of this daily decision for patients with multi vessel disease.
Dr. Marc Ruel:
Thanks James. And I agree with you. I think this is a bit of a new paradigm, right, to really think of the individual patient decision. It's a form of precision medicine if you will, with regards in this case to physical functioning and mental functioning prior to something as invasive as undergoing CABG. So I want to thank you, the Circulation leadership for inviting Anne Williams who's a cardiologist and yours truly to write a tutorial on this piece because I do think you, that is really, it is something that's quite intriguing and it makes sense. I think it is intuitive. I think clinicians who send patients to CABG and see them come back and hopefully in a good state, the very vast majority of the time, do realize nevertheless that CABG is a very invasive procedure. So the patient has to be actively involved in her or his recovery.
And interestingly as you pointed out, there's quite a effect modification if you will, between the benefits of CABG over PCI in the SYNTAX trial, which many will remember as having randomized either left main or three vessel disease, coronary artery disease patients to PCI versus CABG. So there was an effect modification in those patients who had better functioning, not only physical, but interestingly, even more so mental component score of the SF-36 prior to operation. These patients would derive a greater benefit from having been randomized to CABG over PCI. So I think this is obviously logical, it makes sense and the converse will be true, but it's nice to see it formalized, to my knowledge, for the first time in the context of a rigorous randomized control trial such as SYNTAX with a long-term follow up.
Now obviously this, like any study, there are a few caveats. Not every single patient had their SF-36 at baseline, but roughly about 90 plus percent of patients did. And I think that is quite an important clinical lesson in terms of allocating PCI versus CBG... I've often said over the years as a division head and someone who performs this operation often to my more junior colleagues, "Don't perform bypass surgery if someone's not going to live five years." That might be a bit of a simplistic approach but the data and the conclusions from this paper would support that. It's probably not too farfetched to think as such.
Dr. James de Lemos:
I think that's a great point and your clinical experience is so valuable for us here. One question I have is, do you think that it would be advantageous to objectively measure these parameters or is this something that the heart team or the surgeon at the bedside can assess intuitively? Because I think that's the question, right? Is this something... It certainly fits with what we would expect intuitively, that the more complete and durable procedure works better in people that are more robust physically, mentally. But should we be measuring this preoperatively to help make that decision or should this be a intuitive decision by expert clinicians?
Dr. Marc Ruel:
It's a great question and I think it's one that's not yet answered. I mean, the data from the paper would suggest that it has to be a formalized physical component score and mental component score and then ready allocate according to turnstiles. But that being said, we all know that we can address those issues by an end of bed type of eyeball test, right? So I think you're absolutely right. It may be that a clinical expert may provide the same type of information. Unfortunately we don't have that from the paper but I think there will be several subsequent papers that will look at this.
I think we are in the era of precision medicine and one would even think, why has this not been done before considering how invasive bypass surgery is? You guys, you cardiologists and primary care physicians all know that it takes patients six to 12 months to be recover from sternal bypass surgery. Surgeons all be, I'll say that with a blink in my eye, don't always necessarily always see that, right? And think that's more like a one to three months but the data would suggest including that from randomized controlled trials such as Feedem, that it takes six to 12 months. So it's been one of my career long quest if you will, to make bypass surgery less invasive. And I think this type of paper really provides the impetus to do so.
Dr. James de Lemos:
Well, thanks. Let's shift gears from a study that makes perfect sense and fits our preconceived notions to maybe one that doesn't. And this is a research letter from a group led by Steve Goldman at University of Arizona looking at long term mortality from the VA study comparing radial arteries with saphenous vein conduits in CABG. And this looked at long term mortality from this study, which included over 700 individuals that had extended follow up beyond 10 years. At one year, the cath data had not shown differences in patency in this study, I think important to interpret, but they find absolutely no difference in mortality within similar median survival of 14 to 15 years after CABG in this study. This was controversial among the editors when we discussed it, but what are your thoughts about these data and how this informs the radial artery question in CABG?
Dr. Marc Ruel:
Absolutely. You are so right in seeing that this was controversial because there are in fact two ways to look at this paper, right? You can drain the information that's in there or you can be a naysayer. And there's credence to both approaches, in my opinion. One could say, "Well, there was no difference at one year in terms of graph patency, so why would there be one at 14-15 years?" Well, the answer to that would be the durability of the compared conduits would be potentially different, right? One to five years is what we call the "golden age of saphenous vein grafts." And beyond that time period, one could perhaps expect that the radial artery would do better and start translating into clinical benefits. But that was not seen in this long-term analysis of the VA RCT that compared the use of a saphenous vein versus a radial artery.
The other way to perhaps find why the data is discrepant versus the methodology that had been performed before showing an advantage for the radial artery, would be that this is more perhaps of a real world type of experience. It comes from VA centers. Perhaps the expertise or the level of penetrance if you will, of use of the radial artery was not the same as other centers that maybe more "academic" and more vested into using the radial. So it's possible that those could have played a difference in nullifying if you will, the results of radial artery. But I nevertheless think that it's very important data. It makes us think and it is the largest single series data available that compares the radial to saphenous vein in a randomized control setting. So one cannot ignore it, and I think it's a very important piece of information that strengthens the surgery themed dish.
Dr. James de Lemos:
Thank you, Marc. And then the last CABG related article that I'd like to talk about is the prospective piece by Mario Gaudino and Bruce Lytle discussing the right internal thoracic artery for bypass. Asking the question, did we get it wrong? And this is really a very interesting piece. I encourage our readers to look at. That attempts really to reconcile the strong promise of the RITA with the disappointing results from art and the higher than expected failure rates in other trials. And what the authors do here really resonates with, Marc some of your points about individualizing treatment.
They point out that some of the worse than expected RITA results may reflect the artery to which the RITA has been anecimosed, simply that results when an anecimosed to non-LED targets aren't as good and potentially the experience of the operators. Their final conclusion really isn't that, the reader's not a superior conduit but that perhaps more individualization, both at the patient level but also based on physician experience, maybe what's needed to achieve the optimal selection of conduits and bypass results. What did you think of this? How did their conclusions and interpretation resonate with you?
Dr. Marc Ruel:
I agree with your summary James and I think you are spot on. What's interesting in addition from this frame of reference is that it unites the opinions of two key opinion leaders, i.e Mario Gaudino, who's essentially behind much of the data favoring the radial artery over the use of the saphenous vein. And Bruce Lytle, who historically was behind really proposing the use of the right internal thoracic artery and this bilateral ITA grafting if you will, and they are really coming together and putting their thoughts in a really sensible manner with regards to the points that you raised already. I would add in my own opinion, it's twofold. One, there's nothing biologically wrong with the right internal thoracic artery. So if the LITA works, the RITA should work as well from a biologic point of view. In fact, surgeons know that it's often bigger than the left internal thoracic artery and even more suitable or suited as account with.
What might be wrong is the applicability of it and that question really goes in a couple of important manners. Let's remember surgery is a craft, right? And it's a bit different. It's something I like to repeat, and it's not always captured. It's not really a pure science, like for instance, giving atorvastatin 40 milligrams would be this much more variability. And if you allow me a ten second example, if you were to take one of the bronze tools from Rodin, a grape sculptures, and take it away from him, the sculptures would not be as good. But if you were to give that tool to all semi-professional sculptures around the globe, the United States or France for instance, you may not see any benefit from that tool. So again, the crafty example of surgery is something that we have to compose with all the time.
So the RITA is a great conduit, but it's often not onto the LED per se. And we know that LED in an average patient, which doesn't exist, it's probably about 50% of the left heart profusion. So really the LITA has an advantage from that point of view. And when we compare studies that have used the RITA on a non LED target, there are in some cases bound to fail or at least be neutral. So I think the jury's still out but really the perspective that's denoted here, as you said, is a fascinating one coming from two key opinion leaders, each in their camp of radial versus right internal thoracic artery use.
Dr. James de Lemos:
Well, fabulous discussion, Marc. I really appreciate your insights. I think as cardiologists, the decision making about conduits can often be opaque, and this is really insightful. Let's switch gears and talk about valve surgery. We have two papers on valve surgery. First, an original research article by Johan Wedin from Uppsala on bicuspid aortic stenosis demonstrating adverse ventricular remodeling and impaired cardiac function prior to surgery with a heightened risk of postoperative heart failure. This is a really interesting study that looked at 271 patients that were undergoing surgical aortic valve replacement.
About half with bicuspid valves and half with tricuspid aortic valves, and they did comprehensive preoperative echo-cardiography and then followed the patients for four to five years after followup. And despite the expected finding that the bicuspid patients for younger, they had a substantially worse LV echo parameters pre-op with greater LV wall fitness, greater LV mass, worse preoperative LV function. And that translated even after successful AVR into increased risks for postoperative heart failure hospitalizations when compared to individuals with tricuspid aortic valves. And so the authors conclude that at least in contemporary practice, perhaps individuals are undergoing surgery for bicuspid aortic valve stenosis relatively later in the natural history, and they might merit closer civilians and possibly earlier intervention. What did you think of these data and do they make you think about your timing of recommendation for surgery with bicuspid aortic stenosis?
Dr. Marc Ruel:
Absolutely, and thank you James. I think this is very much in line with the current precision medicine led trends of operating earlier on patients with aortic stenosis. I think this is another subgroup that really deserves our attention. I think there are two things at play here with regards to patients who would have a comparable degree of hemodynamic aortic stenosis, either coming from a bicuspid aortic valve phenotype versus a normal tricuspid aortic valve phenotype. And I think the two important differences are, first, often the bicuspid valves are more prone to have a mixed disease and being more calcified as well. We often see surgery, what I call these black valves, like the valve is so calcified and necrotic that it actually turns black or navy blue in color. And this is not an uncommon finding in younger patients typically than tricuspid aortic valve patients.
The second thing is that we have to remember that bicuspid aortic valve disease is a lifelong illness. So these patients often go undetected for a very long time. They may be 55 years old compared to someone who's 68 and have the same degree of hemodynamic aortic stenosis and even AI. But the disease has really, in the bicuspid aortic valve patient, has probably been there for decades, sometimes even the whole life. So I think the effects on the left ventricle are destined to be worse, and also in terms of recovery after resection and after aortic valve replacement. So I think these are humbling tidbits that come from this paper that really even allow us in this era of early TAVR and now two randomized trials that have looked... One from Europe and one from Korea that have looked at asymptomatic aortic valve replacement interventions with favorable results towards early intervention. That really tell us that we should pay even closer attention to those patients with bicuspid aortic valve phenotypes.
Dr. James de Lemos:
Thanks, Marc.
And the second valve related paper is a prospective piece by [Rebecca] Becky Hahn, Vincent Chan and David Adams, evaluating current indications for a transcatheter edged edge repair of the mitral valve for primary mitral regurgitation. I thought this was a really well done piece and one that I appreciated focus specifically on primary micro-regurgitation. The piece includes a terrific algorithm for clinicians that really helps to guide decision making through a multidisciplinary approach.
They talk about the importance of specialized valve imagers, given the complexity of evaluating even the etiology of micro-regurgitation. The importance of excellence in determining the quantitation of severe MR, valve morphology and dimensions. And then really take it a step further to drive decision makings based on risk assessment of the patient. Obviously for primary MR for adequate surgical risk patients surgery is recommended, but then it walks through the decision making for which of the patients that are not surgical candidates might be optimal candidates for transcatheter techniques. How do you think this field's moving and how did this perspective change your thinking?
Dr. Marc Ruel:
This is such an excellent piece as you denoted. I think it really comes from three experts in the field representing different school of thoughts, if you will. One, more hybrid, more catheter based and more surgery based. And I think the jury's still out on transcatheter edge to edge repair, especially for primary marginal regurgitation. It's paradoxical as we're hoping that edge to edge repair would be primarily used in secondary MR and have great results. We now know and somewhat humbling, that it works not as great as we were hoping for secondary MR and it seems to be working pretty well where we already had a fantastic surgical therapy for it, which is essentially primary MR and Fibroelastic Deficiency type of lesions. Now, as you know, these patients do extremely well with surgery. There are several series of 800, 900, a thousand patients operated either conventionally or minimal invasively with maybe one death. Still one too much I would argue, but extremely low risks.
These are the healthiest patients that a cardiac surgeon often can operate because I would argue this probably an inverse correlation with coronary artery and peripheral vascular disease in those patients. It's hard to know. There's some elements of the answer that we don't have yet. What about the very long term follow up? What about 10 years? What happens when an edge to edge repair fails and it was for primary MR in a younger patient?
And I think the authors really captured those very important caveats quite elegantly and provide a very balanced view. So like you, I'm very happy with this piece. Lastly, I'll conclude by saying there's even controversy as to sub-clinical parameters with edge to edge versus surgical mitral valve pair for primary MR. What does two plus mitral regurgitation that is post-procedure, What does that mean? Is this something that's going to impact the patient at 10 years, at 20 years and perhaps churn, what was it initially, a great therapeutic solution into one that's not so desirable? So again, as I said, the jury's still out on this and I think these really captures the main element of the answer as we know them in 2022.
Dr. James de Lemos:
Excellent points. I think really, I love your conclusion that hopefully there will be a better transcatheter solution than this for patients that aren't surgical candidates, obviously, because it doesn't, unlike TAVR, this doesn't come close to matching the surgical option. The last couple of papers in the issue focus on putting cardiac surgery in the greater context of the patient experience and the healthcare system experience and are in the health services research phase. The first one is from multi-centered team led by Amgad Mentias at Cleveland Clinic and Ambarish Pandey at UT Southwestern. And it focuses on a new performance metric that they're calling, 90 day risk standardized home time for cardiac surgery hospitals in the US.
And this group has done several studies with this new metric that basically is attempting to evaluate performance at the patient level with a very patient-centric metric of how much time they spend at home. They've published previously using data from heart failure patients and post MI patients and now are extending this to cardiac surgery and using risk adjustment of time outside the hospital in the 90 days after surgery to evaluate the variability among cardiac surgical programs. And they find that the metric correlates with mortality and readmission, that higher volume surgical centers are associated with more time spent out of the hospital.
And then when they compare it more directly with approaches that are used to currently rank performance, they see that this results in some reclassification of performance categories versus the other metrics. It's early in the life of this new metric but I'm interested to see intuitively is a cardiac surgeon, how does another tool to evaluate your performance, your team's performance and your hospital's performance resonate? And does this have any intrinsic advantages to you over the other risk standardized tools that are currently being used? Certainly in the US I don't know what's happening in Canada.
Dr. Marc Ruel:
Great points, James and I agree, this is an impressive data set. It's almost on 1 million patients from more than 1000 centers in the US. And as you said, it is a new patient based metric. It's a bit of a patient before the outcome if you will, those PROs that are so more commonly now the object of research with regards to outcomes. I would somewhat simplistically say that there are three possible outcomes to any heart surgery, patient survives and feels better. That's number one, that's what we want to achieve for everybody. Unfortunately, there are two other outcomes that can happen. Patient survives but patient is not improved by the surgery or has a complication as a result of it and quality of life does not improve. And third, obviously the one that is the obvious, highly detrimental is that patient does not make it from the surgery.
But I think really what this paper highlights is the importance of really focusing on the first one by the number of days spent at home during the first 90 days post intervention, post-surgery itself. So I think it is really a marker of how well the patient's doing. It closes the loop, if you will, with the first paper that we looked at, in an observational large data set type of way. But it again calls to, how was the patient functioning pre-op? And that data, as we know, is not available from this series. So it could be three things essentially. It could be performance and definitely it pleases the mind to think that the performance of the institution i.e, the quality of the care provided has a huge impact. But it could also be two other things.
It could be the level of functioning of the patient. The ability to get back and spend many of those first 90 days at home versus not, of the patient himself or herself, depending on the various populations that are served by those institutions. And third, it could also be a little bit of a recurrent theme of mine and I apologize for that, but it could be the degree of invasiveness that's provided if you out of surgeries offered to these patients. So I think these are interesting paradigms. They are very important. Again, they're completely in line with precision medicine and I think that this performance measure, as you alluded to, is an important point because a patient who survives but doesn't go back home really is not deriving a benefit from any operation.
Dr. James de Lemos:
Yeah, great points. And I think this discussion really leads us into our discussion, the last paper, which is another paper that attempts to put surgery in the greater context of the population and environment in which patients come. And this is led by Aditya Sengupta and her team from Boston Children's Hospital evaluating contemporary socioeconomic and childhood opportunity disparities in congenital heart surgery. This is a really next level analysis of associations between socioeconomic status and outcomes after congenital heart disease surgery in children focusing in one high volume quaternary center in Boston. And what they did is developed a novel predictor that was a US census tract based nationally normed composite metric of contemporary childhood, what they called neighborhood opportunity. And this comprised 29 indicators across three domains.
The three domains were education, health, and environment and socioeconomic domains. And they classified the patients into very low, low, moderate, high and very high neighborhood opportunity. And then they looked at evaluations across multiple outcomes. They did not see any association of neighborhood opportunity with early deaths, which I think is encouraging, but they did see that children with lower neighborhood opportunity had longer length of stay, higher healthcare costs and then significantly higher late deaths following surgery when the multiple components of long term care of these children probably have time to operationalize. I found this sobering and a complex message that excellent cardiac surgery can deliver superb outcomes across all levels of opportunity but if these issues aren't addressed, there are financial implications, but more importantly, the long term benefits of the cardiac surgical procedures aren't fully realized. Interested to hear your thoughts on this and how this might apply more broadly even to adult surgery.
Dr. Marc Ruel:
I agree, James and I too, really love this paper. As you say, it is sobering. It's a paper for physicians, but I would argue it's probably bedtime reading for Mr. Biden, any other country leaders as well. Whether it's Mr. Macron or Mr. Trudeau. Definitely something that is shows that what happens after the hospital stay, even in something as complex as congenital heart surgery, performed at Boston children, obviously a great institution. But what is shown here is that the institution with its top quality outcomes as we know them to be, is a fantastic societal and outcome equalizer, if you will. But once that passage through the tertiary or coronary institution has occurred, then reality sets in. And the childhood opportunity index that the authors had previously published in JAMA proves to be, again, a very important predictor of how these kids do later on. So this refers really to the societal contract that we're all part of as physicians. And we obviously, a big part of our mission is to improve the outcomes in hospital, but also beyond it. And I think this paper illustrates this very nicely as you so eloquently summarized.
Dr. James de Lemos:
Well, thanks. And I'll just, before I hand it over to you to conclude and wrap up, just compliment you and Mike and the entire team, as well as the authors who have submitted not just these but so many other superb papers covering the full spectrum of surgical sciences Circulation. I'm proud for us to have the opportunity to share these terrific papers with our readers and with researchers. And congratulations again to you for pulling this together.
Dr. Marc Ruel:
Well, you're very kind and thank you, James. To you and Joe, Darren and our and entire editorial leadership for the important place given to surgery within Circulation. It's something that I believe is important and resonates with surgeons but also non-surgeons who are part of the greater cardiovascular community. So it's tremendously important and we're very thankful for that opportunity.
Dr. James de Lemos:
Well, I'd like to thank all our listeners for joining us today and remind you to tune in next week when Greg and Carolyn will be back for their regularly scheduled podcast.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Sunil Rao and Guest Editor and Editorialist Gregory Lip as they discuss the article "A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction" and the editorial "Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?"
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, today's feature paper is about the factor XI inhibitor asundexian. It's the trial that we've been waiting for the PACIFIC-AMI trial. You really have to listen to it because these factor XI inhibitors are super interesting. What? We're going to tell you about the other papers in today's issue first. Aren't we, Greg? Do you want to go first?
Dr. Greg Hundley:
You bet, Carolyn. Thank you so much. Carolyn, did you ever consider the genetic underpinnings of venous thromboembolism? Well, as you know, venous thromboembolism is a complex disease with environmental and genetic determinants. And in this study, this large investigative team represented by Dr. Nicholas Smith from the University of Washington in Seattle, and their colleagues present new cross-ancestry meta-analyzed genome-wide association study results from 30 studies with replication of novel loci and their characterization through in silicone genomic interrogations.
Dr. Carolyn Lam:
Wow. Sounds like a really large effort, Greg. What did they find?
Dr. Greg Hundley:
Right, Carolyn. In the author's initial genetic discovery effort that included 55,330 participants with venous thromboembolism: 47,000 were European, 6,000 African, and a little over 1000 Hispanic ancestry. They identified 48 novel associations of which 34 are replicated after correction for multiple testing. In their combined discovery replication analysis, so that's 81,669 venous thromboembolism participants and ancestry stratified meta-analyses from the European, African and Hispanic ethnic groups. They identified another 44 novel associations, which are new candidate venous thromboembolism associated loci requiring replication. And many of the replicated loci were outside of known or currently hypothesized pathways to thrombosis. Carolyn, in summary, these findings from this very large GWAS analysis highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of anti-thrombosis treatments with reducing the risk of bleed.
Dr. Carolyn Lam:
Wow. Super interesting and very related to that feature paper that we just discuss. But nonetheless, this next paper I love as well, if I may say so myself. It deals with frailty and as we know, frailty is increasing in prevalence. And because frail patients are often perceived to have a less favorable benefit risk profile, they may be less likely to receive new pharmacological treatments. And so, we and led by Professor John McMurray from the University of Glasgow, decided to investigate the efficacy and tolerability of dapagliflozin according to frailty status in the DELIVER trial.
Dr. Greg Hundley:
The DELIVER trial. Carolyn, tell us about the DELIVER trial?
Dr. Carolyn Lam:
Sure. In deliver dapagliflozin compared to placebo, reduced the risk of worsening heart failure events or cardiovascular death and improved symptoms in more than 6,000 patients with heart failure and mildly reduced and preserved ejection fraction, so ejection fraction above 40%. Now in this pre-specified analysis, we examine the efficacy and safety of dapagliflozin according to frailty status. That was determined using the Rockwood cumulative deficit approach.
And so, what we found was that greater frailty was associated with more impairment of health status and worse clinical outcomes in patients with heart failure and ejection fraction of 40%. The beneficial effects of dapagliflozin compared to placebo on clinical outcomes were consistent regardless of frailty class. But interestingly, the improvement in symptoms, physical function and quality of life were larger in the frailest patients. Adverse events were not more common in individuals randomized to receive dapagliflozin compared to placebo irrespective of frailty class. And so, the take home message is the benefit risk balance related to frailty in patients with heart failure with mildly reduced and preserved ejection fraction is favorable for dapagliflozin. And so, these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail.
Dr. Greg Hundley:
Wow. Carolyn, really interesting. You could see with the diuretic effect in someone that's frail, the potential hesitancy, but very interesting study results in this world of frailty and the use of dapagliflozin. Well, Carolyn, this next study is very interesting and it comes to us from the world of preclinical science that takes a very interesting approach to a scientific question. Now, as you may know, RNA-binding proteins or RBPs are master orchestrators of genetic expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs, thus characterizing RBPs targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, thereby limiting our understanding of their function.
Carolyn, these investigators led by Dr. Grégoire Ruffenach from UCLA were interested in assessing pulmonary arterial hypertension and they turned to the world of cancer research. Carolyn, in cancer, the RNA-binding protein hnRNPA2B1, and we're going to abbreviate that as A2B1, promotes a pro proliferative anti-apoptotic phenotype. The same phenotype is present in pulmonary arterial smooth muscle cells and is responsible for the development of pulmonary arterial hypertension. However, the A2B1 function that's never really been investigated in pulmonary arterial hypertension.
Dr. Carolyn Lam:
Oh, Greg, that's not only fascinating, but so beautifully described. Thank you. What did they find?
Dr. Greg Hundley:
Right, Carolyn. These authors found that A2B1 expression and it's nuclear localization are increased in human pulmonary arterial hypertension, pulmonary arterial smooth muscle cells. Using bioinformatics, they identified three known motifs of A2B1 and all mRNAs carrying them and demonstrated the complimentary non-redundant function of A2B1 motifs as all motifs are implicated in different aspects of the cell cycle. In addition, they showed that pulmonary arterial smooth muscle cells and A2B1 promote the expression of its targets. Additionally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. And so, Carolyn, through the integration of computational and experimental biology, this team study revealed the role of A2B1 as a master orchestrator of pulmonary arterial smooth muscle cells in pulmonary hypertension and that phenotype and its relevance as a therapeutic target in pulmonary arterial hypertension.
Dr. Carolyn Lam:
Wow, that's super, Greg. Thanks. Shall we go through what else is in today's issue?
Dr. Greg Hundley:
You bet, Carolyn. There's a Research Letter from Professor Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium Current versus Calcium Calmodulin‐dependent Kinase II.”
Dr. Carolyn Lam:
There's also an exchange of letters between Doctors Omarjee and Diederichsen regarding vitamin K2 and D in patients with aortic valve calcification: [an] absence of evidence might not be evidence of absence? And finally, there's an On My Mind paper by me and Scott Solomon and it's entitled, “Delivering Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure.” But let's go on now to talk about the Factor XI inhibitor, shall we, Greg?
Dr. Greg Hundley:
You bet. Well, listeners, welcome to this feature discussion on October 18th at a very special article today. And we have with us the lead author, Dr. Sunil Rao from NYU in New York City and also our associate guest editor as well as editorialist, Dr. Gregory Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Sunil Rao:
Yeah, great. Thanks so much, Greg. It's a real pleasure to be here with you. The background of the PACIFIC-AMI study is really rooted in the fact that patients who have acute myocardial infarction are really at risk for recurrent thrombotic events, even after their event. And this risk continues despite the fact that we have evidence based therapies that are really around targeting the platelet as well as aspects of the coagulation cascade. There have been studies that have looked at the use of dual antiplatelet therapy plus an anticoagulant or single antiplatelet therapy plus an anticoagulant. And those studies have shown a benefit. However, their clinical use is limited because of the bleeding risk.
Factor XI is an interesting target, because factor XI is likely involved in the amplification of thrombin generation after plaque rupture. But it really doesn't play much of a role in hemostasis. And so, as a target in reducing events after acute coronary syndrome, activated factor XI is a very attractive one. And so, the hypothesis of this study was that a highly bioavailable oral, direct, selective activated factor XI inhibitor called asundexian would be safe and effective in the treatment of patients who experience acute coronary syndrome at reducing adverse events. Now, this is a phase two study, so it really wasn't powered for clinical events. It was really a dose-finding study, so it was really looking at adverse events and sort of bleeding complications.
Dr. Greg Hundley:
Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can you describe for us your study design and then maybe a little bit more about the study population, how many subjects?
Dr. Sunil Rao:
Sure. Again, this is a phase two study. It was a randomized, double-blind, parallel-group design where patients, who were admitted with acute coronary syndrome were randomized to three different doses of asundexian and or placebo in a one-to-one to one-to-one fashion. Patients who met criteria for enrollment were: patients who were admitted with a diagnosis of acute MI; if they were older than or equal to 45 years of age; they were hospitalized in acute coronary syndrome that did not occur in the context of revascularization, so it was not a type 4 event; and they were planned to be treated with dual antiplatelet therapy after hospital discharge.
Dr. Greg Hundley:
Sunil, thank you for describing this very interesting study design. Now, how many subjects did you include and could you just describe for us the study population?
Dr. Sunil Rao:
We had a total of 1,601 patients that were randomized at 157 centers in 14 countries between June 2020 and July 2021. And in order to be eligible for enrollment into the study: patients had to be admitted with a diagnosis of acute MI, they had to be greater than or equal to 45 years of age, and be hospitalized with that acute MI that did not occur in the context of revascularization, so type 4 MIs were excluded. The other inclusion criteria was that they had to be planned to be treated with dual antiplatelet therapy after hospital discharge. Now, we allowed randomization up to five days after hospital admission and randomization occurred after patients were clinically stabilized and any planned PCI was performed. We included both patients with STEMI as well as non-ST segmental elevation ACS, but we capped the number of patients with STEMI that were included to no more than 50%. Now, the main exclusion criteria were things that you would expect for a phase two trial. Obviously, hemodynamic instability at the time of randomization, active bleeding or bleeding dialysis, severe renal dysfunction, planned use of full-dose anticoagulation.
Dr. Greg Hundley:
Very nice. And so, we have several doses of this new factor XI inhibitor. Describe for us your study results?
Dr. Sunil Rao:
Again, this was a phase two trial that was really looking at safety and adverse events as you would expect. The study groups were pretty balanced across all of the dosing arms. When we looked at the pharmacokinetic and pharmacodynamic data, we found something really interesting, which was that there was a dose relationship between the dose of asundexian and the factor XIa activity. Factor XIa is activated factor XI. The higher the dose, the more suppression of factor XI activity. In fact, the highest dose nearly eliminated factor XI activity. The drug clearly works in the way that it was intended. Now again, the clinical data, it wasn't powered for clinical data. But when we look at the bleeding results, we found that there was in fact an increase in bleeding as the dose of asundexian increased. The overall rate of bleeding in the highest dose of asundexian was in 50 milligrams was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about 9.02%. Again, the efficacy outcomes, very, very low rates of overall events. Again, not powered to show a difference. Essentially, very similar across all the arms.
Dr. Greg Hundley:
And did you find the same results for the men and the women? And what about older individuals and younger individuals?
Dr. Sunil Rao:
Yeah. We did look at some subgroups. And you had to be a little bit cautious because again, the trial itself is relatively small. I mean, we didn't notice any significant patterns across these subgroups. And the overall interaction p-values were really non-significant. But I think what this does show is like a phase two trial that the drug works as in the way that it's intended. Overall, safety was as expected. And I think it really sets up data for a larger study.
Dr. Greg Hundley:
Well, listeners, what a fantastic presentation. And now, we're going to turn to our guest editor and editorialist, Dr. Gregory Lip from Liverpool. Greg, I know working for circulation, you have many papers come across your desk. What attracted you to this particular paper? And then maybe secondly, can you help us put the results of this study in the context of other studies that have been evaluating these factor XI therapies?
Dr. Gregory Lip:
Thanks, Greg. Well, I think this is an important paper, because it is a phase two trial with a novel, orally bioavailable inhibitor factor XI. And this is intriguing because factor XI efficiency in humans and experimentally in animals is associated with a reduced risk of thrombotic events like stroke or venous thromboembolism. But spontaneous bleeding is rare and also bleeding in response to trauma or surgery is much milder. Really it's the holy grail of trying to get an anticoagulant that reduces thrombosis but doesn't cause an excess of bleeding. Now, this was the quest with different anticoagulants.
And I think it was very exciting to see this particular paper in the patients who've had an acute coronary syndrome, because there was a lot of interest in the use of anticoagulants, particularly in combination with antiplatelet therapy from trials such as ATLAS and COMPASS, where there was certainly a reduction in adverse cardiovascular events. But a downside with those drugs and when using combination, was an excess of bleeding by the combination of the available anticoagulants now plus antiplatelets. The factor XIs agents offered the possibilities we might have combination therapy to reduce cardiovascular events but not causing an excess of bleeding.
Dr. Greg Hundley:
Well, listeners, what a wonderful discussion that we've had here. Let's circle back with both individuals. Sunil, we'll start with you. What do you see as the next study to really be performed in this sphere of research?
Dr. Sunil Rao:
I think that factor XI is a very attractive target in patients with acute coronary syndrome. Again, the rationale for why we did this phase two trial was to show that inhibition of activated factor XI should result in a low rate of ischemic events without a significant increase in bleeding. This phase two trial was really to try and decide which doses result in potent inhibition of factor XIa and potentially which doses should be carried forward into a larger study. What we found in the PACIFIC-AMI trial was that the doses of asundexian and the factor XIa inhibitor were very, very well tolerated with a low rate of adverse events. It resulted in a dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. I think, again, it's a very attractive target in patients with ACS and this really provides support for a larger adequately powered clinical trial in patients with acute coronary syndrome that is really looking at clinical events such as MACE as well as bleeding.
Dr. Greg Hundley:
And Greg as an editorialist, what did you see with this paper? Maybe some unanswered questions that we'd like to pursue further?
Dr. Gregory Lip:
Well, I think this does raise a lot of questions in the sense that it'll be interesting because as a phase two trial, it's a relatively moderate sized trial. It's not like a phase three large outcome trial and phase two trials also testing different doses of the novel agent. We need to see the definitive phase three trial and to look at the magnitude of benefit versus potential for bleeding if in the large phase three trial and obviously, the net clinical benefit and importantly are some of the subgroups: ST elevation, myocardial infarction, undergoing primary PCI, for example, those with renal impairment. And I think particularly intriguing would be looking at the patients in this scenario who get the new antiplatelet drugs such as ticagrelor and prasugrel. And the reason I say that is what we have with warfarin or Coumadin and from the current DOACs or NOACs, depending on the risk side upon. We refer to them, that's the direct oral anticoagulants or non-vitamin K antagonist or anticoagulants.
Well, if you give a more potent antiplatelet like prasugrel or ticagrelor, the risk of bleeding not surprisingly is higher. Hence, the guidelines recommend that if you use an anticoagulant or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as opposed to the more potent ones. If this new class of drugs, the factor XI inhibitors can work well in combination with one of the more potent antiplatelets without causing an excessive bleeding, again, this is going to be a substantial advance.
Well, with these new class of anticoagulants, will be really interesting to see the phase three trials when applied to other chronic conditions. For example, stroke prevention and atrial fibrillation. And the other category of patients would be those who've had an embolic stroke of uncertain source or ESUS or in old terminology cryptogenic stroke. With the ESUS group of patients, they're currently treated with aspirin because the trials which tried a NOAC or DOAC, they were not showing a positive result. They'll be interesting again with the factor XI inhibitors, whether we are going to see this benefit with the reduction in recurrence stroke with no excessive bleeding.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Sunil Rao from NYU in New York City and Dr. Gregory Lip from the University of Liverpool for bringing us this study highlighting that in patients with recent acute myocardial infarction, three doses of asundexian when added to aspirin plus a P2Y 12 inhibitor resulted in dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. And certainly, the data from this study support the investigation of asundexian at a dose of 50 milligrams daily in an adequately powered clinical trial of patients following acute myocardial infection.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Michelle O'Donoghue and Associate Editor Parag Joshi as they discuss the article "Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor and Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, very interesting feature this week. Evolocumab, another application for that in patients with established atherosclerotic cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other very interesting articles in this issue?
Dr. Carolyn Lam:
Oh, I'd love that. And I'd like to go first, because Craig, have you heard of hybrid debranching repair? I know, I know. I had that same look, and can I tell you about it? Because I found it so interesting.
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
Now, the management of complex aortic aneurysmal disease involving the visceral vessels is challenging due to its very high morbidity and mortality. After four decades of experience in open repair, only a few centers worldwide report laudable results. And numerous factors limit total endovascular repair, including the access to devices, experience in deploying them, and several anatomical restrictions. So, hybrid debranching procedures were introduced for those patients who are unfit for the open or endovascular excluded patients. And while these have been developed, small series have only been done and revealed a wide range of short term results. So, today's paper is very important, and it's from Dr. Oderich from UT Memorial Herman Texas Medical Center and colleagues.
It's a large multi-institutional study, which contains the five year outcomes in 200 patients offering greater clarity in the usefulness and limitations of these hybrid debranching repair procedures. What they found was that hybrid aortic debranching had a low early mortality when done in lower risk patients, but mortality remained very elevated in high risk patients. And so, this suggests that deep branching could be a good alternative in patients adequate for traditional open repair, although pulmonary complications are quite common. The bypass grafts to the visceral vessels had very good patency with a five year primary patency of 90%. Permanent spinal cord injury occurred in 6%, suggesting that deep branching in experienced centers may offer outcomes comparable to centers of excellence for open thoracoabdominal aortic aneurysm repair.
Dr. Greg Hundley:
Wow, Carolyn, very nice and so beautifully explained.
Dr. Carolyn Lam:
You know what, Greg? I'm on a roll and I'd like to tell you about one more, this time a preclinical study. First, a little bit about the background. You see, transplantation with pleuripotent stem cell derived cardiomyocytes, as we know, represents a very promising therapeutic strategy for cardiac regeneration. We even have first clinical studies in humans, but yet little is known about the mechanism of action underlying graft induced benefits. So in this paper from Dr. Weinberger from University Medical Center Hamburg in Germany and colleagues, they explored whether transplanted cardiomyocytes actually actively contribute to heart function by injecting these cardiomyocytes with an optogenetic off on switch in a Guinea pig cardiac injury model.
Dr. Greg Hundley:
Wow, Carolyn, this is so interesting. So what did they find?
Dr. Carolyn Lam:
So, light induced inhibition of endo-grafted cardiomyocyte contractility resulted in a rapid decrease in left ventricular function in about 50% of the animals that was fully reversible with the offset of photo stimulation. So in conclusion, this optogenetic approach demonstrated that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force generating myocardium can serve as a regenerative therapeutic strategy.
Dr. Greg Hundley:
Oh wow, Carolyn. That was just fascinating. Such incredible preclinical science in our journal. Well, Carolyn, this next paper comes to us from the world of myocarditis. And Carolyn, it involves a population based cohort of 336 consecutively recruited patients with acute myocarditis enrolled in both London and Maastricht. And the authors, led by Dr. Sanjay Prasad from Royal Brompton Hospital, investigated the frequency and clinical consequences of dilated cardiomyopathy and arrhythmogenic cardiomyopathy genetic variants in this population based cohorts of patients with acute myocarditis. Now, Carolyn, all participants underwent targeted DNA sequencing for well characterized cardiomyopathy associated genes and their comparison to healthy controls, of which they had 1,053 that were sequenced on the same platform. Case ascertainment of their outcomes in England was assessed against their national hospital admission data, and the primary outcome was all cause mortality.
Dr. Carolyn Lam:
So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So these authors identified for dilated cardiomyopathy or arrhythmogenic cardiomyopathy associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of desmoplakin truncating variants in those with normal LVF, and then titin truncating variants in those with a reduced LVF. So Carolyn, importantly, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing would be considered in patients with acute myocarditis to help reassure the majority of individuals that don't have one of these genes, while improving the management of those that do have one of the underlying genetic variants. Very interesting findings from the world of myocarditis.
Dr. Carolyn Lam:
Great. And a great clinical take home message. Thank you, Greg. Well, this next paper sought to investigate the influence of age on the diagnostic performance of cardiac troponins in patients presenting with suspected myocardial infarction. Dr. Atul Anand from the BHF Center for Cardiovascular Science and University of Edinburgh and colleagues did this by performing a secondary analysis of the high stakes stepped wedge cluster randomized control trial that evaluated the implementation of a high sensitivity cardiac troponin ISA in consecutive patients presenting with suspected acute coronary syndrome.
Dr. Greg Hundley:
Oh wow. Carolyn. Super interesting, and very applicable clinically. So what did they find here?
Dr. Carolyn Lam:
In older patients presenting with suspected MI, the majority of cardiac troponin elevations are explained by acute or chronic myocardial injury or type two MI. The specificity and positive predictive value of high sensitivity cardiac troponin to identify myocardial infarction decreases with age and is observed, whether applying sex specific or age adjusted 99th percentile diagnostic thresholds or a rolling threshold for the triage of patients at high probability of myocardial infarction. Serial troponin testing incorporating an absolute change in troponin concentration increased the discrimination for myocardial infarction in older adults.
Dr. Greg Hundley:
Oh wow, Carolyn. Such clinically applicable findings in this particular study, particularly when managing our aging population. Well, Carolyn, how about we discuss some of the other articles in this issue. And there's a very nice In-depth piece by our own Sami Viskin entitled “Arrhythmogenic Effects of Cardiac Memory.” And then, there's an exchange of letters by Drs. Giannitsis and Mueller regarding the article, “Unexpected Sensitivity Issue of Three High Sensitivity Cardiac Troponin I-Assays in Patients with Severe Cardiac Disease and Chronic Skeletal Muscle Diseases.”
Dr. Carolyn Lam:
Nice. There's also a Research Letter by Dr. Szendroedi on “Impaired Mitochondrial Respiration in Humans with Prediabetes: A Footprint of Prediabetic Cardiomyopathy.” And there's a CV case series by Dr. Kalra on very high cholesterol mimicking homozygous familial hypercholesterolemia. Interesting case. Well, I suppose that wraps it up. Let's go on to the feature discussion, shall we, Greg?
Dr. Greg Hundley:
You bet.
Evolocumab. Welcome listers to this feature discussion on October 11th, and we're very fortunate today. We have with us Dr. Michelle O'Donoghue from Brigham Women's Hospital and Dr. Parag Joshi from UT Southwestern, the Associate Editor for this paper. Well, Michelle, can you describe for us some of the background information that went into the preparation of your study, and then what was the hypothesis that you wanted to address?
Dr. Michelle O'Donoghue:
Sure. Happy to do so, and thank you for having me. So by way of background, the Fourier study, which was previously published in the New England Journal, compared Evolocumab to placebo in 27,000 plus patients with established atherosclerotic cardiovascular disease, and Evolocumab significantly reduced the risk of major adverse cardiovascular events. But, the follow up duration was relatively short. Median follow up was 2.2 years. So this was now an open label extension study to Fourier known as the Fourier OLE study that allowed an additional median follow up time of five years, during which time all patients were now treated with open label Evolocumab. T.
He primary hypothesis that we were testing in this extension study was primarily to look at long term safety. We had limited data to really assure us of the safety of PCSK9 inhibitors over the course of several years. And so, safety was the primary hypothesis that we were testing, but also of course of key interest, during the parent Fourier study, we know that the benefit for cardiovascular risk reduction appeared to grow over time. So this was also an opportunity to see that pattern and to see whether or not there was in fact legacy effect for patients who were treated earlier with Evolocumab versus placebo.
Dr. Greg Hundley:
Very nice, Michelle. And so, sounds like we have a substudy of the Fourier trial. Can you describe for us a little bit more, for this substudy, your study population and your study design?
Dr. Michelle O'Donoghue:
Sure. So the patients enrolled in the open label extension were a subset of those who participated in the parent study. So as I previously mentioned, more than 27,000 participated in Fourier. It was a global study. For the open label extension, it was more than 6,500 patients who participated, and those were patients who were at sites in Europe and United States. And so, those patients were then followed on average for a meeting of five years. So that means that all together, patients who had been randomized to Evolocumab in the parent study had potentially more than eight years of drug exposure for us to examine safety.
Dr. Greg Hundley:
Very nice. And so, what did you find?
Dr. Michelle O'Donoghue:
Well, first, looking at the first hypothesis of safety, we saw no evidence that there was any increased risk of any adverse events of interest when it comes to PCSK9 inhibitors as a drug class, or achieving very low levels of LDL cholesterol. So there was no uptick in terms of neurocognitive events, the risk of diabetes. We do know that there was an increased risk of injection site reactions with the PCSK9 inhibitors, but not one that appeared to persist over time. So first was the safety, but importantly, I think that the more interesting results perhaps were those for MACE, for cardiovascular risk reduction. So we saw, even though all patients were being treated with open label Evolocumab during the extension phase, the benefit that was seen during the parent study persisted.
So there was a 15% reduction in the primary outcome, a broad composite of cardiovascular events. There was also a 20% reduction in the triple composite of cardiovascular death, MI, or stroke. And then perhaps of the most interest to your listeners is that there was a 23% reduction in cardiovascular mortality, and that was not something that was seen in the parent study. It really took time for that mortality benefit to emerge.
Dr. Greg Hundley:
Very nice. Michelle. Just a couple quick clarification points. Did you see these effects in both men and women? And then was there any impact of age on those results?
Dr. Michelle O'Donoghue:
Great questions. Some of those subgroup analyses are still ongoing, but no, we did not see any evidence of effect modification at first pass. But again, we'll be continuing to dig into all potential subgroups.
Dr. Greg Hundley:
Very nice. Parag, I know you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Parag Joshi:
Yeah, thanks. And congratulations again, Michelle. It's a really phenomenal study, and the findings, as you highlighted, are just really impactful for the field. I think for our journal at circulation, this is a really high impact finding in terms of extending out, giving us a rigorous way to look at long term follow up for people on PCSK9 inhibitors and really reassure that there is safety there. And as you highlighted, a sustained reduction in LDL cholesterol, other compounds in the space, Bococizumab in particular, that there were induced antibodies against the monoclonal antibody, and that sustained response was not there. So I thought that was also really reassuring, that over the course of eight years, we see sustained LDL reduction. And with that, really reaffirming the idea that the longer you can reduce LDL, there's an associated reduction in events.
And as you highlighted, the initial Fourier, there was some question about why there wasn't a CV death mortality signal while there was in the Odyssey outcome study and slightly different patient populations of course, but just really needed more time to start to tease that out. So all of this, I think this is the first that we're seeing this kind of long-term data on this impactful class of medications that really made this a fantastic manuscript for us at Circulation.
Dr. Greg Hundley:
Wow. Boy, Parag, I don't know that you could have stated that any better. So Michelle, looking forward, what is your group thinking? And then maybe just as your comment on the field in general, what do you think is the next study or series of studies that needs to be performed in this sphere of research?
Dr. Michelle O'Donoghue:
Well, I think he started to touch upon the areas of interest to us, is that I think that there are still many opportunities to answer more questions even within this existing data set. In particular, there was a dedicated neurocognitive substudy that was built into the parent study. And we also have that now through the extension period. So, that was a sort of more rigorous assessment of neurocognitive outcomes. And so, that's another analysis that we're going to be pursuing in the near future and I think is of potential key interest. And then beyond that, I think that the PCSK9 inhibitor class in general is just so interesting. There are additional compounds that are under study, such as small interfering RNA, so different mechanisms of getting to the PCSK9 protein. And I think it'll be reassuring to see whether or not they are consistent results, regardless of how you lower PCSK9, whether it translates into similar types of clinical benefit. So I think it's an exciting field. And then stay tuned. I think there'll be more to come.
Dr. Greg Hundley:
Parag, do you have anything to add? What do you see really as the next series of studies that might be performed here in this area of research?
Dr. Parag Joshi:
Yeah, I think Michelle hit the nail on the head that seeing confirmatory evidence here would be great. And then really, what's so exciting about this space is there's so much interest in ways to address this protein, including gene editing, vaccination against it. And now you're getting the necessary evidence that, hey, you can really suppress these levels in patients for years without concerning safety signals, at least from what we've seen so far. So that's more excitement as to long term ways to address cardiovascular risk.
Dr. Greg Hundley:
Wow. Well, listeners, we've been very fortunate today to have with us Dr. Michelle O'Donaghue from Brigham and Women's Hospital, and Dr. Parag Joshi from UT Southwestern as the Associate Editor of Circulation to really bring us these exciting results, highlighting that long term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events over eight years that did not exceed those observed in the original placebo arm during the parent Fourier study, and led to further reductions in cardiovascular events compared with delayed treatment initiation.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study."
Dr. Carolyn Lam:
Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA?
Dr. Greg Hundley:
Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure.
Dr. Carolyn Lam:
Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology.
However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes.
Dr. Greg Hundley:
Oh wow, Carolyn, this sounds really informative. So what did they find?
Dr. Carolyn Lam:
Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts.
Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis.
Dr. Greg Hundley:
Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction.
So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily.
Dr. Carolyn Lam:
All right. So the Paradise MI echo substudy, what did they find?
Dr. Greg Hundley:
Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure.
Dr. Carolyn Lam:
Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial.
Dr. Greg Hundley:
Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us?
Dr. Carolyn Lam:
Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction.
Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new.
Dr. Carolyn Lam:
Wow, that's interesting. So what did this paper find?
Dr. Greg Hundley:
Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension.
So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting.
Dr. Carolyn Lam:
Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing.
Dr. Greg Hundley:
Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke?
Dr. Carolyn Lam:
Yep. In patients with EF, here we go.
Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation.
Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place?
Dr. Signild Åsberg:
Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question.
Dr. Jonas Oldgren:
My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies.
So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?"
And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment?
Dr. Carolyn Lam:
Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used?
Dr. Jonas Oldgren:
Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence.
And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study.
Dr. Carolyn Lam:
Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results?
Dr. Signild Åsberg:
Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients.
Dr. Carolyn Lam:
That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome?
Dr. Jonas Oldgren:
Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well.
So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started.
So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention.
Dr. Carolyn Lam:
Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit?
Dr. Signild Åsberg:
We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase.
Dr. Carolyn Lam:
I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds?
Dr. Signild Åsberg:
We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale.
Dr. Carolyn Lam:
Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results.
Dr. Signild Åsberg:
Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that.
We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation.
Dr. Jonas Oldgren:
And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials.
So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences.
And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients.
Dr. Carolyn Lam:
Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view?
Dr. Signild Åsberg:
Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention.
Dr. Jonas Oldgren:
I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study.
Dr. Carolyn Lam:
And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week.
Dr. Greg Hundley:
This program is Copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.
This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway.
Dr. Carolyn Lam:
Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we?
Dr. Greg Hundley:
Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom.
New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination.
Dr. Peder Myhre:
Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find?
Dr. Greg Hundley:
Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population.
Dr. Peder Myhre:
Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners.
Dr. Greg Hundley:
Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings.
Dr. Peder Myhre:
Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs.
Dr. Greg Hundley:
So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but-
Dr. Carolyn Lam:
Way to go, Peder. Way to go.
Dr. Greg Hundley:
Yeah. Well, the good news is, I can just say yes. I did know that.
Dr. Peder Myhre:
That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline.
Dr. Greg Hundley:
Oh, wow, Peder. So what did they find?
Dr. Peder Myhre:
So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59.
And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline.
Dr. Greg Hundley:
Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension.
Dr. Peder Myhre:
Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg?
Dr. Greg Hundley:
Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung.
They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag?
Dr. Peder Myhre:
So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag?
Dr. Greg Hundley:
Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.”
Dr. Peder Myhre:
And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn.
Dr. Carolyn Lam:
Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis.
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found?
Dr. Hanna-Kaisa Nordenswan:
Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis.
The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up.
Dr. Carolyn Lam:
Great. What did you find?
Dr. Hanna-Kaisa Nordenswan:
So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis.
Dr. Carolyn Lam:
Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings.
Dr. Jukka Lehtonen:
Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis.
So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients.
So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases.
Dr. Carolyn Lam:
Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk.
Dr. Mark Link:
Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid.
Dr. Carolyn Lam:
Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah?
Dr. Jukka Lehtonen:
I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well.
Dr. Carolyn Lam:
Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD?
Dr. Hanna-Kaisa Nordenswan:
Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up.
Dr. Carolyn Lam:
That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark?
Dr. Mark Link:
Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data.
Dr. Carolyn Lam:
Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first?
Dr. Jukka Lehtonen:
Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference.
I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group.
Dr. Carolyn Lam:
Thank you, Hannah?
Dr. Hanna-Kaisa Nordenswan:
Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography.
Dr. Mark Link:
Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue.
Dr. Carolyn Lam:
Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Jonathan Sterne and Associate Editor Shinya Goto as they discuss the article "Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Oh, Greg, we've got a special treat for everyone today. We have a third co-host and he is none other than Peder Myhre from Norway! Really adding to the diversity of our podcast: me from Asia, you from the US, and Peder from Europe. Welcome, Peder.
Dr. Peder Myhre:
Thank you so much, Carolyn. It's truly an honor to be here and I'm looking forward to being part of this podcast today.
Dr. Carolyn Lam:
Awesome. Well, here we go. Looks like we have a feature paper, Greg?
Dr. Greg Hundley:
Absolutely, Carolyn. Peder, welcome. So, listeners, our feature today will involve COVID-19 and its association with arterial and venous thrombotic diseases. But before we get to that, we're going to all grab a cup of coffee from all over the world and get into some of the other articles in the issue. Peder, Carolyn, how about I go first?
My first study involves a prospective cohort of 94,000 individuals from the UK Biobank, who had device-measured physical activity from 2013 to 2015 and were free from myocardial infarction and heart failure. Now, Peder and Carolyn, the study was performed because although objectively measured physical activity has been found associated with acute cardiovascular outcomes, it has not been found associated with heart failure and, of course, a syndrome that's been expanding worldwide. As such this study led by Carlos Celis-Morales from the University of Glasgow aimed to investigate the dose response relationship between device-measured physical activity and heart failure by intensity of the physical activity. Now physical activity was measured with a wrist-worn accelerometer and time spent on light, moderate, and vigorous intensity physical activity was extracted. Incidental heart failure was ascertained from linked hospital and death records.
Dr. Peder Myhre:
Wow, Greg. That sounds amazing. Tell us, what did they find?
Dr. Greg Hundley:
You bet, Peder! These investigators found that, compared with participants who undertook no moderate to vigorous intensity physical activity, those who performed 150 to 300 minutes per week of moderate intensity physical activity or 75 to 150 minutes per week of vigorous intensity physical activity were at lower risk of heart failure. Now, interestingly, the association between vigorous intensity physical activity and heart failure was a reverse J-shaped curve with a potentially lower risk reduction above 150 minutes per week.
And so, the take-home message for this first paper is that device-measured physical activity, especially moderate intensity physical activity, was associated with a lower risk of heart failure. Probably current vigorous intensity physical activity recommendations should be encouraged, but not necessarily increased. In contrast, increasing moderate intensity physical activity may be beneficial, even among those meeting current recommendations.
Dr. Peder Myhre:
Wow, Greg. That was a great summary. And the second original research article today is about high density lipoproteins. As you know, raising HDL cholesterol levels to prevent cardiovascular disease remains a hot topic. HDL plays a key role in reverse cholesterol transport and may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin cholesterol acyl transferase, LCAT, is the rate limiting enzyme in the reverse cholesterol transport and a recombinant human LCAT called MEDI6012 has previously been shown to increase HDL cholesterol. So in this study from the corresponding author, Marc Bonaca from University of Colorado School of Medicine, the investigators in the real team is 63B multicenter placebo control trial investigated whether randomized patients to, MEDI6012 or placebo would reduce the infarct size as measured by cardiac MRI, 10 to 12 weeks after the STEMI.
Dr. Greg Hundley:
Very interesting, Peder. So, MRI assessments of LV mass after PCI. So, what did they find?
Dr. Peder Myhre:
So, Greg, the authors successfully enrolled 593 patients with a median age of 62 years and 78% males. And the median time from symptom onset to randomization was 146 minutes and only 13 minutes from hospitalization to randomization. And the index MI was anterior in 70% and 65% had TIMI Flow grade 0-1. And then to the main results at 12 weeks, the infarct size did not defer between the treatment group. So that was a 9.7% infarct size for MEDI6012 versus 10.5% for placebo with a P value of 0.79. And there was also no difference in noncalcified black volume. So the authors conclude that enhanced reverse cholesterol transport with recombinant human LCAT did not reduce infarct size or late regression of noncalcified coronary REPL at 12 weeks. Okay, Greg. So tell me about the 3rd paper you have today?
Dr. Greg Hundley:
Peder, what a great description on that previous paper, beautiful job there. So Peder, this next article pertains to cardio toxicity related to the administration of anthracycline-based chemotherapy. And an example would be Doxorubicin. And this occurs in patients often with certain types of cancer. As you know, Doxorubicin is still utilized for the treatment of leukemia, lymphoma, soft tissue sarcoma and in the setting of adjuvant breast cancer treatment. And so to this end, the authors, led by Lorrie Kirshenbaum from St. Boniface Hospital abstract research, wanted to assess cytokine mediated inflammation in myocellular injury, as a result of some of the inflammation that's induced by the administration of Doxorubicin. So as a little bit of background, cytokines, such as TNF alpha, have been implicated in cardiac dysfunction and toxicity associated with Doxorubicin. Now, while TNF alpha can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart really somewhat remain cryptic.
The E3 ubiquitin ligase, TRAF2, provides a critical signaling platform for K63 length poly ubiquitin nation of rip K1, crucial for NF-kB activation by TNF alpha and survival. Whether alterations in TNF alpha, TRAF2, NF-kB activation signaling underlie the cardiotoxic effects of Doxorubicin, remains poorly understood. So herein, these authors investigated TRAF2 signaling in the pathogenesis of Doxorubicin cardio toxicity.
Dr. Peder Myhre:
Oh wow, Greg. So we're talking mitochondrial dysfunction in Doxorubicin cardiomyopathy. So please tell me, what did they find and what were the clinical implications?
Dr. Greg Hundley:
Very nice. Peder, you remind me of Carolyn, asking me the clinical implications. Okay, so first, in mouse models and in vitro measures in rats, mouse and human pluripotent stem cell derived cardiomyocytes, these investigators monitored TNF alpha levels, LDH, cardiac ultra structure and function, mitochondrial biogenics, as you just suggested, and cardiac cell viability. They found that a novel signaling axis exists that functionally connects the cardiotoxic effects of Doxorubicin to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by Doxorubicin, sensitizes cardiomyocytes to TNF alpha and BNIP3 mediated necrotic cell death. Perhaps, interventions that stabilize TRAF2, so here's the clinical implication, may prove beneficial in mitigating the cardiotoxic effects in cancer patients undergoing anthracycline-based chemotherapy.
Dr. Carolyn Lam:
So Greg, he may sound like me, but this is me going what an amazing summary and especially in something that is your specialty cardio-oncology, that's amazing. Thank you. Peder, I assume you've got one more paper?
Dr. Peder Myhre:
So Greg, now I'm going to sound like you and say that we are going to stay within the world of preclinical science. So genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease. However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. And there is evidence to suggest that the genetic influence of coronary artery disease sociability may partly act through vascular smooth muscle cells. So corresponding author, Shu Ye from University of Leicester, performed genotyping, RNA sequencing and cell behavior assays on the large bank of vascular smooth muscle cells with an N of almost 1500. And through these extensive analysis, they saw to identify genes whose expression was influenced by coronary artery disease associated variants.
Dr. Greg Hundley:
Very nice, Peder. So, more about cardiac gene expression. So, what did they find?
Dr. Peder Myhre:
Approximately 60% of the known coronary artery disease associated variants show statistically significant effects in vascular smooth muscle cells and the study identified 84 candidate causal genes whose expression quantitative trait, loci signals in vascular smooth muscle cells, significantly co-localized with reported coronary artery disease association signals, of which 38 of them are potentially druggable, so, that was the clinical implications. The authors conclude that a large percentage of coronary artery disease loci can modulate genes, gene expression in vascular smooth muscle cells and influence these cell behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. And Greg, accompanying this paper is a beautiful editorial by doctors O'Donnell and Bradner entitled "Bridging the Gap to Translating Genome-Wide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease."
Dr. Greg Hundley:
Very nicely done Peder, very nicely done. Well, as usual, we have some other items, we call it in the mail bag because we receive these wonderful research letters and also research correspondence. So I'll go first. First, Dr. Al-Khatib has a research letter entitled, "Duration of Anticoagulation Interruption before Invasive Procedures and Outcomes in Patients with Atrial Fibrillation Insights from the Aristotle Trial." And also there's a nice ECG analysis by Dr. Tsai entitled, "A Peculiar Wide-Complex Tachycardia During Flecainide Treatment."
Dr. Peder Myhre:
Nice, Greg, and there's also an exchange on letters to the editors and the response from Professors Zhao and Ding, and again, a response from Professor Zhang regarding the prior letter by Jin et al. pertaining to the previously published article "Micro RNA, 210 Controls, Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction."
Dr. Greg Hundley:
Beautifully done, Peder. Oh, wow. Welcome to this team. We're so excited to have you. And now Carolyn, I think we're going to jump over to that feature discussion and learn a little bit more about COVID-19 and arterial and venous thrombotic disease.
Dr. Carolyn Lam:
You bet! Let's go, Greg and Peder.
Now we all know that infection with COVID 19 induces a pro-thrombotic state, but the long term effects of COVID-19 on the incidence of vascular disease, both arterial and venous, remain unclear. That is until today's feature paper. We're so grateful to have corresponding author Dr. Jonathan Stern, from the University of Bristol, as well as our associate editor, Dr. Shinya Goto from Tokai University School of Medicine to join us and discuss this very important paper today. Jonathan, could you start us off on telling us why it's so important to look at this? Haven't we always known that infections, COVID or not, are associated with pro-thrombotic state? So what's so different about what you did and what you found this time?
Dr. Jonathan Stern:
So, yes, I think we already knew that serious infections, in particular infections leading to hospitalization, can result in thrombotic events, either arterial or venous. And it was also clear from January, February, March 2020, that COVID led to very serious infection and therefore was likely to lead to vascular events. The questions that we set out to address, beyond simply establishing that COVID does indeed do this, was to quantify by how much COVID multiplies the rate at which these thrombotic events occurred, to do that separately for different events, such as myocardial infarction, stroke, venous thromboembolism, pulmonary embolism. And then to importantly, because we analyzed a very large dataset, which we might want to talk about, to try to separate out the amount by which the rating events was multiplied over time and in important subgroups, for example, in hospital people who were hospitalized for their COVID, compared with people who weren't hospitalized for their COVID, by age and sex, and by other demographic characteristics.
Dr. Carolyn Lam:
I love that, you see, that really set out the novel information this added with, may I add, very important clinical implications, which we'll get to them. You've already teed me up to talk about this 48 million adults that you managed to look at. Oh my goodness! Tell us, how in the world did you do that?
Dr. Jonathan Stern:
Well, I think the first thing to say is that it's my absolute privilege to talk about this paper on behalf of a really incredible team that put the work together. And a lot of that work, or that work started with really unlocking the power of NHS data because of the COVID pandemic. So in the UK, we have a national health service, free at the point of delivery to everybody. The NHS assembled electronic health records, and there's been a long and proud history of research based on electronic health records in the UK. But for the first time, because of the pandemic, a combined data resource for the whole of England, so that's a population of about 58 million people, was established and that linked primary care data - data from family doctors, data on secondary care hospital admissions, data on COVID testing and subsequently, although it's not the subject of this paper, data on vaccination.
So those data were all linked and put into one place within what's called a trusted research environment with very strict controls on what can be output from the environment in order to protect patient privacy. And that was really done during 2020. And then the analyses for this paper took place during 2021, and it was an enormous amount of work by a large and absolutely fantastic team of people across multiple UK universities and national health service institutions.
Dr. Carolyn Lam:
Wow. Bravo! We talk about big data, we talk about using it. I trained in the NHS system. Who knew that this could come out to reveal such important results? So thank you for that as a background, but now, tell us what you found please?
Dr. Jonathan Stern:
So we found that rates of these conditions, they were primarily acute lymph infarction and ischemic stroke, which we grouped together with other conditions as arterial thrombotic events, and then deep vein thrombosis and pulmonary embolism, which we grouped together with other conditions as venous events. And we found that rates were substantially multiplied immediately after a diagnosis of COVID by up to 748 times, that the amount by which rates were multiplied diminished with time since COVID, but importantly that even six months to a year after that first diagnosis of COVID, rates of venous events were still about double in people who'd had COVID, compared to people who had COVID. And we found, it seemed quite clear that the persistence of the elevated risk was longer for venous events than for arterial events.
Dr. Carolyn Lam:
Just really fascinating results and Shinya, could I ask, what are your thoughts on this? And as you were managing this paper, the implications?
Dr. Shinya Goto:
First of all, thank you very much, Jonathan, for choosing saturation for your great paper. I'm handling quite a lot of papers, but your paper was very attractive. As Carolyn mentioned, it's huge data! 48 million, it's surprising, and also you also pick up booster rate of arterial embolism event for years, and you have also shown adjusted rate is initially increased quite a lot and then decreased gradually. And even after two months, three months still, there is a persisted higher risk. And as you mentioned, for the venous thrombo embolism, it's persisted for more than year to year. It's surprising. COVID-19's a different disease. Perhaps COVID-19 infection cuts to the vascular endarterial cell, perhaps, your research raised a lot of research questions, like endarterial damage induced by COVID-19 in the past 6 months; I would say more than half a year to one year. So that mechanistical insight is very important. And you raise a lot of any clinical questions.
Dr. Jonathan Stern:
Well, thank you very much for your kind words and you are right, I think we are left with questions about maybe in three areas. Firstly, for how long is there an elevation in risk? I should probably say, for those who haven't read the paper, that these results relate to events that occurred in England and Wales during 2020. And so that is in an era before vaccination and when we were dealing with the original variant, and to some extent, the alpha variant. So we are still waiting to see what the implications were over longer periods, and we will be doing that, we will be extending follow up. In fact, we are at the moment extending those results. I think, secondly, we are left with questions about the mechanisms, which you articulated, and thirdly, there's the question about, well, what are the implications for clinical management of patients with COVID-19? And in particular, for patients who've had severe COVID-19, for example, severe enough to be hospitalized for it?
Dr. Shinya Goto:
Yeah, you have also showed a very important point that even known hospitalization for COVID-19, the risk of thrombosis becomes high. So it's very surprising. And even non-hospitalized patients have a higher risk of thrombosis. That is probably the huge difference between other virus infections and COVID-19.
Dr. Jonathan Stern:
Yes. The good news, if you weren't hospitalized for your COVID, is that the elevation in risk declines more rapidly for people with less severe COVID who weren't hospitalized than for people with more severe COVID who were hospitalized. But nonetheless, as you say, particularly in the first week, two weeks, three weeks after COVID, there is a clear elevation in the risk of both arterial and venous events, even if you were not hospitalized for your COVID. We should probably also bear in mind that these results for 2020, when there were severe constraints for some of the time on health service resources. So you probably had to be pretty sick to get hospitalized at that time.
Dr. Carolyn Lam:
That was a very important caveat that you just highlighted. So thank you for contextualizing those findings for us, Jonathan, but then I kind of wish all podcast guests were like you, and you already asked a question, I was going to ask you. Which is, okay, so what's the clinical implication? Should we all be taking some low dose NOAC or aspirin? Whether you're hospitalized or not? Or if you were in 2020? Because, jokes aside, I know that you found some very important risk factors? Or these events which had clinical implications? Could you expand on it?
Dr. Jonathan Stern:
So maybe I'd start by saying that we didn't find that these patterns varied dramatically either by sex or by age. And in fact, when we were planning the analyses, I was convinced that we would see dramatic differences in these hazard ratios by age. And, broadly speaking, the facts on a multiplicative scale, the amount by which your rate is multiplied, looked similar across age groups and by sex. On the other hand, we did see the amount by rates of arterial and venous events were multiplied, appeared greater in people of Asian ethnicity or Black ethnicity than in people of White ethnicity. A counterintuitive finding was that the amount by which your rate was multiplied is lower, if you've had a prior event than if you hadn't. Those are the sorts of extents to which we can say something about how your own characteristics predict the consequences once you've had COVID.
In terms of management, obviously the pandemic has been tumultuous for medicine and for medical research and things have moved on greatly since the pre-vaccination era, 2020 and early 2021, to which these analyses relate. So the first thing to say is, don't get hospitalized with COVID, and the best way to not be hospitalized with COVID, is to be fully vaccinated for COVID. And that's a message that I think the whole of the medical profession has communicated loudly and clearly for a long time now.
So the second thing is, well, okay, what about if, nonetheless, you got COVID, particularly severe COVID, and we discussed this in the team extensively, and I particularly want to mention the senior clinical author, Dr. Will Whiteley from the University of Edinburgh in this regard, and I think the main message here is that risk factor management, cardiovascular risk factor management is always important, but it's probably particularly important in people who've had severe COVID to review risk factor management and make sure that existing guidelines in terms of cholesterol lowering, blood pressure lowering and so on, are being adhered to. We don't... So the most important thing is adherence to existing cardiovascular risk management guidelines. I think we don't have evidence that specific additional interventions are indicated in people who've had COVID, and COVID now in the era of Omicron and widespread vaccination is not the same as COVID during 2020.
Dr. Shinya Goto:
Jonathan, you have raised a very important issue. I strongly recommend all audiences to read this paper. We have to know persistent or higher risk of myocardial infarction, ischemic stroke, may be controlled more regularly controlled. Don't fear the COVID-19 infection to visiting the healthcare professional. In my country, some of the population stopped coming to the healthcare professional because they fear so much about infection from the hospital or clinic. But it's very important to keep that regular control like static and blood pressure control. Maybe we don't have that data about aspiring or not, but strong message your paper gave is that risk factor control after COVID-19 is very important.
Dr. Jonathan Stern:
I completely agree.
Dr. Carolyn Lam:
And I would add to that, remember the days when people were stopping their ACE inhibitors and so on for those fear? So what a great message and thank you for giving us a little bit of a peek into the future of what you're planning next with more follow up, in a population that is vaccinated from a different strain perhaps. And I think this still encourages hopefully more trials and research into this whole area of how we should be managing these patients. Well, thank you so much both of you for discussing this very, very current relevant, important paper. Thank you for publishing it in circulation with us. And to the audience, thank you for joining us today. From Greg and I, you've been listening to Circulation on the Run, and don't forget to tune in again next week.
Speaker 6:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism."
Dr. Carolyn Lam:
Welcome to Circulation On Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health Richmond, Virginia.
Dr. Carolyn Lam:
In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg?
Dr. Greg Hundley:
You bet, Carolyn. Well, how about if I go first?
Dr. Carolyn Lam:
Please.
Dr. Greg Hundley:
Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4.
Dr. Carolyn Lam:
Nice. Okay. Important question, what did they find?
Dr. Greg Hundley:
Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women.
Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome.
Dr. Carolyn Lam:
Oh, you are right. A lot of interesting data here. What's a take home message?
Dr. Greg Hundley:
Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step.
Dr. Carolyn Lam:
Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis.
Dr. Greg Hundley:
Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find?
Dr. Carolyn Lam:
Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC.
Dr. Greg Hundley:
Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight?
Dr. Carolyn Lam:
Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth?
Dr. Greg Hundley:
Yeah. Remember seven dwarfs, Sleepy.
Dr. Carolyn Lam:
Sleep.
Dr. Greg Hundley:
Very good. Great job, Carolyn.
Dr. Carolyn Lam:
Thank you.
Dr. Greg Hundley:
Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018.
Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression.
Dr. Carolyn Lam:
Okay, Greg. What did they find?
Dr. Greg Hundley:
Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years.
Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group.
Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large.
Dr. Carolyn Lam:
Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility.
Dr. Greg Hundley:
Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion?
Dr. Carolyn Lam:
Yes, let's go Greg.
Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found.
Dr. Senthil Selvaraj:
Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites.
To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment.
The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity.
Dr. Carolyn Lam:
Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati?
Dr. Svati Shah:
Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself.
To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn.
Dr. Carolyn Lam:
Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically?
Dr. Manuel Mayr:
Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress.
Dr. Carolyn Lam:
Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that?
Dr. Senthil Selvaraj:
I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space.
The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet.
Dr. Svati Shah:
Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do.
Dr. Carolyn Lam:
And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps?
Dr. Manuel Mayr:
Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis.
Dr. Senthil Selvaraj:
That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process.
Dr. Carolyn Lam:
Anything to add, Svati?
Dr. Svati Shah:
No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also.
Dr. Carolyn Lam:
Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view?
Dr. Manuel Mayr:
Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure.
Dr. Carolyn Lam:
Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Keith Channon as he discusses the article "Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Oh, Greg, today's feature paper, something that's really been discussed a lot in the press and in lay public as well, the risk of myocarditis following sequential doses of the COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Everyone's going to want to tune into that one. But before we get there, shall we go through some of the key papers in today's issue?
Dr. Greg Hundley:
You bet, Carolyn. How about if I go first?
Dr. Carolyn Lam:
Please.
Dr. Greg Hundley:
So Carolyn, this first manuscript involves the world of machine learning and ECG interpretation. And as you know, novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy detection; however, it's low prevalence, 0.5%, and resemblance to common diseases really present challenges. So Carolyn, these authors, led by Dr. Rahul Deo from Brigham and Women's Hospital, sought to develop machine learning models to detect hypertrophic cardiomyopathy and differentiate it from other cardiac conditions using EKGs and echocardiograms with a robust generalizability across multiple cohorts.
So Carolyn, what did they do? They used single-institution hypertrophic cardiomyopathy EKG models that were then trained and validated on data from three academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of hypertrophic cardiomyopathy from aortic stenosis, long-standing hypertension, and cardiac amyloidosis. And then finally, automated detection was compared to manual interpretation by three cardiologists on a data set with a realistic hypertrophic cardiomyopathy prevalence.
Dr. Carolyn Lam:
Wow, incredible. So what were the results?
Dr. Greg Hundley:
Right, Carolyn. So the authors identified 74,476 EKGs for 56,129 patients and 8,392 echocardiograms for 6,825 patients across the four academic medical centers. Now, while ECG models trained on data from each institution displayed excellent discrimination of hypertrophic cardiomyopathy on internal test data, the generalizability was limited, most notably for a model trained in Japan and then subsequently tested in the United States. Now, however, when trained in a federated manner, discrimination of hypertrophic cardiomyopathy was excellent across all institutions, including for phenotypic subgroups. The models further discriminated hypertrophic cardiomyopathy from hypertension, aortic stenosis, and cardiac amyloid. Analysis of ECG and echocardiography paired data from 11,823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists.
So Carolyn, in conclusion, federated learning improved the generalizability of models that use EKGs and echocardiograms to detect and differentiate hypertrophic cardiomyopathy from other causes of left ventricular hypertrophy compared to training within a single institution. It will be really interesting to see the future applicability of these methods.
Dr. Carolyn Lam:
Oh, I'm such a fan of this work. Awesome. Thank you, Greg. My paper, it's a preclinical paper that uncovers a novel mechanism through which GATA4 mutations can lead to heart disease.
Dr. Greg Hundley:
All right, Carolyn, no quiz this time, I'm just coming right out. I'm reversing the question on the teacher. Tell me, what is GATA4?
Dr. Carolyn Lam:
I'm glad you asked, Greg. GATA4 is a zinc finger-containing DNA binding transcription factor essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Now, in today's paper, authors led by Dr. Srivastava from Gladstone Institutes in San Francisco, California, showed that GATA4 regulated cell-type-specific splicing through direct interaction with RNA and the spliceosome in human-induced pluripotent stem cell-derived cardiac progenitors.
An unbiased search for GATA4 interacting proteins in these human iPS cells revealed interaction with many members of the spliceosome complex. GATA4 also bound to pre-messenger RNAs in a sequence-specific manner that resulted in generation of alternatively spliced isoforms in human iPS cells. Many of these GATA4-dependent isoforms had distinct functional properties illustrating the importance of the splicing regulation to cardiac function.
Dr. Greg Hundley:
Wow, Carolyn, another really interesting study from the world of preclinical science. So what's the take home message here?
Dr. Carolyn Lam:
So these results essentially uncover a previously unrecognized function for GATA4 in regulating alternative splicing through direct RNA interaction. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, thus suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.
Dr. Greg Hundley:
Very nice, Carolyn, wow. Well, my next paper comes to us from back in the world of clinical science and it's from Professor Bertrand Cariou from L'institut du Thorax in Inserm UMR1087. So Carolyn, only a few genes causally related to plasma LDL-C levels have been identified so far, and only one, ANGPTL3, has been causally related to combined hypocholesterolemia. In this study, the authors aim to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in four generations of a French family and used next generation sequencing and identified a novel dominant rare variant in the LIPC gene encoding for hepatic lipase, which co-segregates with the phenotype. They characterize the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance based lipoprotein profiling and lipids.
Dr. Carolyn Lam:
Wow, what an interesting approach to study patients and families with hypocholesterolemia for once instead of hyper. Interesting. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So the investigative team found that this unique LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase without affecting triglyceride lipase activity. And second, the hypocholesterolemic phenotype related to LIPC-E97G variant is due to an increased clearance of cholesterol within triglyceride-rich lipoprotein remnants predominantly by extrahepatic tissues.
Dr. Carolyn Lam:
Wow, so what are the implications?
Dr. Greg Hundley:
Right, Carolyn. So the novel gain of function variant in LIPC potentially represents the second cause of familial combined hypocholesterolemia after loss of function variants in ANGPTL3. And second, this study highlights an unexpected and critical role of the phospholipase activity of hepatic lipase encoded by LIPC in LDL-C metabolism and identifies it as a potential novel drug target. And then finally, Carolyn, additional data, I think, are warranted to clarify the impact of LIPC-E97G-related combined hypocholesterolemia on atherosclerosis and atherosclerotic cardiovascular disease due to the occurrence of documented coronary stenosis and evolutive carotid atherosclerosis in index cases.
Dr. Carolyn Lam:
Oh, very, very interesting. Thanks, Greg. Well, let's wrap up with the discussion of what else is in today's issue. There's an In Depth paper by Dr. Hadley on protecting cardiovascular health from wildfire smoke. There's also a Research Letter by Dr. Mevorach on myocarditis after BNT162b2 COVID-19 third booster vaccine in Israel.
Dr. Greg Hundley:
Right, Carolyn. And then I've got an exchange of letters from Professors Condello and Doenst regarding the article Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis from the REMOVE study: Results From a Multicenter Randomized Controlled Trial. Well, how about we get on to that feature discussion and learn a little bit more about COVID-19 vaccine and SARS-CoV-2 infection.
Dr. Carolyn Lam:
Let's go, Greg, thanks.
Dr. Greg Hundley:
Listeners, welcome to this September 6th feature discussion. And with us today, very interesting topic pertaining to vaccination for SARS-CoV-2 virus prevention. And we have with us Dr. Keith Channon from Oxford, England, to discuss this very interesting paper.
Well, Keith, welcome. I wanted to start by asking you, can you describe for us a little the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Keith Channon:
Thanks, Greg, for the opportunity to join you in this interesting conversation today. A group of cardiologists in the UK based at the University of Oxford, and principally at the University of Edinburgh, have been interested in the question as to whether COVID infection and/or COVID vaccination might lead to a higher incidence of myocarditis. And this is a topic that has been the subject of previous publications in the field.
And the provocation for us undertaking this study is that those previous studies have tended to be relatively small, and they've also not been able to necessarily test the details, time association, between myocarditis occurring in relation to sequential doses of vaccination. And that's important because, of course, we're now all receiving sequential doses of booster vaccines, and also those vaccines are often delivered, different vaccine types to different people in different countries. So we wanted to test whether there does appear to be a significant association between the occurrence of myocarditis and both COVID infection and the sequential different COVID vaccinations.
Dr. Greg Hundley:
Very nice. So Keith, can you describe for us, what study population did you enroll for this initiative? And then also, what was your study design?
Dr. Keith Channon:
Thank you. So, one of the really exciting things about this type of study and probably what makes it unique is that in countries with healthcare system, like that in the UK, which is the National Health Service, and universities, such as the University of Oxford and the University of Edinburgh, where there are very strong academic links between researchers and the National Health Service, we've been able to leverage an enormous data set, which is almost 43 million people in the UK who underwent vaccination against COVID-19. And rather than having to follow up 43 million people as part of a research study, we were able to take advantage of National Health Service centralized coded hospital records, number one. Number two, we took advantage of the UK's national database on COVID vaccination. And number three, we were able to look at hospital outcomes and also COVID testing.
So we were able to put together those three data sets for us to understand who developed COVID infection, who received COVID vaccination, and if so, which vaccine and when, and who then was admitted to hospital with a coded diagnosis of myocarditis. And in 43 million people, even though myocarditis is a very uncommon outcome, there were sufficient cases in that very large population to draw statistically meaningful conclusions.
I think that the UK is probably one of the few countries where this type of research can be done. And academic organizations, like our universities, the National Health Service, and also cardiovascular research funders, such as the British Heart Foundation, have put in a lot of resource and effort into giving us those capabilities to answer questions like this, and it's turned out to be a very powerful capability.
Dr. Greg Hundley:
Very nice. And so Keith, can you describe for us your study results?
Dr. Keith Channon:
So the study looked at a large 43 million people approximately over a period of time during the early to mid-phase of the COVID pandemic and looked at the likelihood that people would be diagnosed with myocarditis following either vaccination or COVID test positive. And we compared that likelihood with the likelihood of myocarditis occurring outside of those periods; because, of course, myocarditis occurs reasonably commonly in the general population. So this is another powerful aspect of the study design. It has a curated approach to look at the incidence of myocarditis in the 28 days after either vaccination or COVID infection, and it corrects, or it controls for that relative to the incidence of myocarditis outside of those sampling periods.
And what we found simply is that there is indeed, as previous studies have shown, a small but significant association between receiving a COVID-19 vaccine and being diagnosed with myocarditis in the following 28 days. However, in the population as a whole, the risk of myocarditis after vaccination is substantially lower than the risk of developing myocarditis after COVID infection, and I think that's an important finding. When we looked at subgroups, which is interesting, we found that the highest risk of developing myocarditis was in men less than age 40, so younger men, and that was one finding. And also, there did seem to be some differences in the risk of myocarditis occurring after different sequential vaccine doses.
Dr. Greg Hundley:
Keith, just a quick clarification point, what vaccines did you examine?
Dr. Keith Channon:
So in the UK, the three vaccines that have been largely used of the AstraZeneca Oxford viral vaccine, ChAdOx1, which was of course introduced very early in the UK, along with the Pfizer mRNA vaccine, and then laterally, Moderna vaccine, which of course in the UK was brought in rather later. And I think that's interesting because, as we can go on and discuss, there do appear to be some possible differences between those vaccines in terms of the likelihood of being diagnosed with myocarditis afterwards. But of course, even our experiment in 43 million people is not a perfect design because it's an observational study, and the periods in the pandemic when people were receiving principally the first two vaccines, which were by far the most numerous, was a different period in the natural history of the pandemic than when we started administering Moderna.
So it is important to recognize that it was not a prospectively controlled randomized trial of different vaccines; it was an observational study of pretty much a whole country and how it responded to the implementation of those different vaccines, which were all given to different people at different times of the pandemic. And of course, different times of the pandemic means that many different people will have already had a COVID infection and then gone on to have a booster or third vaccination. So, if you like, the immunological landscape in which these different vaccines were given in this very large population will have been different.
Dr. Greg Hundley:
Right. So I understand there are differences in timing, great point, but did you see any differences in the occurrence of myocarditis relative to either of the mRNA vaccines versus the adenovirus vaccine?
Dr. Keith Channon:
Yeah, we did. What we found is that, interestingly, there did appear to be a higher likelihood of being diagnosed with myocarditis in the 28 days after the mRNA-1273 vaccine, Moderna vaccine, and that was particularly, as I've already said, in men younger than the age of 40 years. I should say again, of course, that vaccine was given to the smallest number of people in the UK and it also tended to be rolled out later, so it was the second or third dose of the vaccine where that signal was most seen. But again, the second and third dose was by definition typically the booster vaccine later on in the pandemic. But that's what we found.
We did find these interesting differences. The incidence of myocarditis was increased after all of the vaccine doses compared with the period when people had not received a vaccine, but this was a very modest increase for most of the vaccines; but for the mRNA vaccines, particularly Moderna, it seemed to be more strikingly increased in the 28 days after the second or third dose of the vaccine. So I guess the message from that result is that there do seem to be these intriguing differences, both in the response to different COVID vaccines, either viral or mRNA or indeed even different types of mRNA vaccine, and possibly after the different dose of vaccines. In other words, after second or third sequential doses.
Dr. Greg Hundley:
And Keith, you mentioned a few minutes ago that you also had an opportunity to examine situations where maybe a patient had a vaccine and then subsequently contracted COVID, or vice versa, maybe they had had COVID and then later on had a vaccine, did you find any differences in the incidence of myocarditis in those situations as opposed to, perhaps, patients that really never had a documented episode of a COVID infection and then always had received the two vaccines and the booster dose?
Dr. Keith Channon:
Yeah, that's a harder question and is less powerfully addressed by our study, even though we were able to temporally control for that. Previous COVID infection did not preclude the risk of myocarditis after subsequent vaccine doses, but it wasn't a big enough signal to be able to give much detail over the relative risk between... Because if you think of the permutations of COVID infection plus or minus three vaccines, there's a lot of different sequential steps there, but having had COVID first doesn't prevent this small but significant signal; having a vaccine before you then get COVID infection does reduce your risk of myocarditis along with pretty much all other COVID complications.
So I think that's a really important public health message here and indeed the overarching finding of our study, which you could argue is the least exciting one but perhaps the most important, which is that you have a higher likelihood of suffering with myocarditis after COVID infection compared with after a COVID vaccination. And if you have COVID vaccination, in general, your risk of myocarditis is lower, obviously your risk of COVID infection is lower, and your risk of getting myocarditis after that COVID infection, should you still get one is also lower. So I think these are very intriguing, interesting findings that might make us think about mechanism and vaccine policy, but ultimately there are very strong endorsement of getting vaccinated to prevent the consequences of COVID-19.
Dr. Greg Hundley:
Excellent point. And then, Keith, just quickly, next study that maybe your group is considering in this space with this large database?
Dr. Keith Channon:
Yes. Well, I think there are two aspects to the study. Our group, which, as I've said, focuses mainly on large epidemiological data sets, having established this infrastructure in the UK led by universities like Oxford and Edinburgh and funded by the British Heart Foundation and others, means that we now have this infrastructure. So the surveillance and the data collection and the analysis is ongoing and we'll be able to add more cases and more power and more data, and there will be other studies that we can look at.
Second, I think there are some really quite interesting mechanistic studies that could be done based on these provocative findings to try to understand which different types of vaccines and, indeed, the immune responses which those vaccines generate. How are they linked to myocarditis and, indeed, to other cardiac and even other organ complications from COVID-19? And there are ongoing studies in the UK and elsewhere in the world that are very much focused on looking at the organ-specific consequences of COVID infection in patients who've been vaccinated or not. For example, using detailed cardiac MRI to look at the heart and look for subclinical myocarditis and to correlate any evidence of subclinical myocarditis with the immune signature, both the antibody and the cellular immune response, in the blood from those patients.
So I think what we're going to see here are enormous epidemiological studies with n=43 million, and we're also going to see more mechanistic experimental medicine immunology studies to try and tease out mechanism, and I think to understand two things. One is how to protect ourselves best against COVID-19, and what are the best vaccines and how best to use them. And second, if we can learn something about the mechanisms of myocarditis along the way, that's a really useful bonus that's come out of this pandemic.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Keith Channon for bringing us this very interesting article from Great Britain highlighting that, overall, the risk of myocarditis is greater following SARS-CoV-2 infection as opposed to a COVID-19 vaccination, and even really remains modest following sequential doses, including the booster dose of some of the mRNA vaccines.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is a copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.
This week, please join author Rod Stables and Associate Editor Nick Mills as they discuss the article "Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass through the journal and its editors. We're your co-hosts! I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, this week's feature... Very interesting. There is a lot of information about using fractional flow reserve during contrast coronary angiography. But how does that compare to just reviewing the angiograms when managing patients with coronary artery disease?
Well, we are going to hear some results from the RIPCORD 2 trial, and they may surprise you a little bit. But, before we get to that interesting feature discussion with authors and editors, how about we grab a cup of coffee and dive into some of the other articles in the issue?
Dr. Carolyn Lam:
Yeah, let's do that, Greg. Do you have a paper to share first?
Dr. Greg Hundley:
Oh, thanks Carolyn. Sure.
So Carolyn, as we know, Apolipoprotein B or apoB, provides an integrated measure of atherogenic risk. But whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndromes, beyond that provided by low density, lipoprotein cholesterol, or LDLC, that's uncertain. So Carolyn this study emanates from the Odyssey Outcomes trial, which compared the Proprotein Convertase Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite optimized statin therapy. Now the primary outcome was major adverse cardiovascular events. So MACE was coronary heart disease, death, nonfatal myocardial infarction, fatal non-fatal ischemic stroke, and hospitalization for unstable angina. And associations between baseline ApoB or ApoB at four months and MACE were assessed in adjusted Cox proportional hazards and propensity score matched models over median of 2.8 years.
Dr. Carolyn Lam:
Oh, right. So what were the results, Greg?
Dr. Greg Hundley:
Right, Carolyn so impatience with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline ApoB strata, and now evolocumab reduced MACE across all strata of baseline ApoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved ApoB was associated with lower risk of MACE, even after accounting for achieved LDLC or Non-HDLC indicating that ApoB provides incremental information. And therefore, Carolyn, if it is modified achievement of an ApoB level less than or equal to 35 milligrams per deciliter may reduce lipoprotein attributable residual risk after ACS. Isn't that interesting?
Dr. Carolyn Lam:
Yes. Very nice, Greg. Thank you. This next paper is a pre-specified analysis of the EMPEROR-Preserved trial, looking at patients with and without diabetes.
Dr. Greg Hundley:
So remind us, Carolyn, what was the EMPEROR-Preserved trial and what did it show?
Dr. Carolyn Lam:
Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor reduced risk of the composite of cardiovascular death or heart failure hospitalization, as well as first and recurrent heart failure hospitalizations and slowed renal function decline in patients with heart failure and an ejection fraction greater than 40%. So the current paper sought to determine if effects were consistent in patients with, and without diabetes, of the almost 6,000 patients enrolled, 49% had diabetes. The risk of adverse outcomes, first of all, was higher in patients with diabetes. Now the treatment effect of Empagliflozin was however, similar in that Empagliflozin reduced the rate of the primary outcome and total heart failure hospitalization, irrespective of diabetes status. The effect of Empagliflozen falls into attenuate GFR decline, however, was also present in patients with, and without diabetes, although more pronounced in patients with diabetes. Now across all these three endpoints, the effect of Empagliflozen did not differ in patients with prediabetes or normal glycemia. And importantly, there was no increased risk of hypoglycemic events in either subgroup compared with placebo. So a very nice paper there. And that was from Dr. Gerasimos Filippatos from Athens University Hospital Attikon and colleagues.
Dr. Greg Hundley:
Wow, Carolyn, just really interesting information coming out of the world of SGLT2 innovation. Well, Carolyn, my next paper comes to us from the world of preclinical science and it's from Dr. Kunhua Song from the University of Colorado Anschutz Medical campus. So Carolyn, abnormalities of calcium homeostasis are closely associated with cardiac arrhythmias and heart failure and conditions that cause death of millions of people every year. Now, Carolyn Triadin physically interacts with the Ryanodine receptor 2 and plays an important role in releasing calcium from the sarcoplasmic reticulum to increase the free intracellular calcium concentration in cardiomyocytes.
Now alternative splicing of a single Triadin gene produces multiple Triadin isoforms, the predominant cardiac Triadin isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons from one to eight. In humans, mutations in the Triadin gene that lead to a reduction in Trisk 32 levels in the heart cause cardiac dysfunction, cardiac arrhythmias and sudden death. Decreased levels of Trisk 32, in the heart, are also common in patients with heart failure. However, mechanisms that regulate alternative splicing of the Triadin gene to maintain levels of cardiac Triadin protein in the heart, remains somewhat elusive.
Dr. Carolyn Lam:
Wow. I am always learning from these cool papers. Thanks Greg. So what were the results?
Dr. Greg Hundley:
So Carolyn, the investigators found several things. First, the cardio MyoSite specific long non-encoding RNA or link RNA Triadin AS is essential for maintenance of cardiac function, exercise capacity and normal lifespan and Triadin AS knockout mice were found predisposed to cardiac arrhythmias in response to catecholamine challenge. And finally Carolyn, Triadin AS controls, levels, of cardiac Triadin isoforms, by regulating the splicing of the Triadin gene.
Dr. Carolyn Lam:
Oh, wow. All right. So could you bring it home for us, Greg? What are the clinical take home messages?
Dr. Greg Hundley:
Right, Carolyn. So cardiac explants from human heart failure patients as well as patients with cardiac arrhythmias, demonstrate reduced expression of Triadin AS and Triadin. And then next the mechanism of the Triadin AS and Triandin AS mediated alternative splicing of the Triadin gene to specifically control levels of cardiac isoforms of Triadin in the heart, provides a potential strategy for the treatment of cardiac arrhythmias and heart failure.
Dr. Carolyn Lam:
Wow. Thank you, Greg. Well, let's talk about what else is in today's issue. There's a Research Letter by Dr. Agarwal on Chlorthalidone for resistant hypertension and advanced chronic kidney disease.
Dr. Greg Hundley:
And Carolyn, I've got a perspective piece by Professor Cowie pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs. Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn, how about we get onto that feature discussion and review the utility of fractional flow reserve measurements, in patients undergoing contrast coronary angiography.
Dr. Carolyn Lam:
Great, let's go.
Dr. Greg Hundley:
Welcome listeners to this August 30th feature discussion. And we have with us this afternoon, Dr. Rod Staples from Liverpool and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. And gentlemen, welcome, Rod we'll start with you. Can you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Rod Staples:
Okay, well thanks very much for hosting today. I'm very grateful to be working circulation on this. I'm working with my co-lead investigator Professor Nick Harrison from Southampton, who's been doing an enormous amount of work on coronary physiology. He actually did the original RIPCORD study, what I suppose we'd now call RIPCORD 1, but it was called RIPCORD in the early days, an observational study that showed that systematic use of fractional flow reserve at the time of diagnostic angiography. Assessing the functional significance measured in each of the major coronary vessels, appeared in an observational study to have a dramatic effect on the subsequent management plans allocated to patients. And we decided to test this in a prospective randomized trial.
Dr. Greg Hundley:
Very nice. And so the exact hypothesis that you were going to test was what?
Dr. Rod Staples:
At the time of coronary angiography, a strategy of systematic measurement of fractional flow reserve in each and every coronary vessel, large enough to be considered for revascularization, would improve outcomes compared to a strategy based on angiographic assessments alone.
Dr. Greg Hundley:
Very nice. And so you mentioned a randomized trial. Can you describe further your study design and then which study population did you include?
Dr. Rod Staples:
Well, this is a classic multicenter randomized trial performed in the UK. We actually recruited in 17 different UK centers. We asked them to assess patients who were scheduled for invasive, currently angiography for participation against some very minimal inclusion and exclusion criteria, trying to keep the trial generalizable with good external validity. I think one important point to note is that we did allow the inclusion of both patients being assessed with elective angiography for stable symptoms, but in the end half of the population were recruited in the context of a stabilized acute coronary syndrome, a Non-ST-elevation event a day or so down the line.
Dr. Greg Hundley:
And just a quick breakdown, how many men, how many women?
Dr. Rod Staples:
Well, it's in that respect, the population is very, very typical for this type of cardiovascular trial. A 70, 30 split an age in the midsixties, a diabetic population in the high teens. So a very typical population we've seen in all this kind of trial environment.
Dr. Greg Hundley:
Very nice. And so about 1100 patients. And then what were your study results?
Dr. Rod Staples:
Well, I think there was a very good adherence to the study protocol, very, very few crossovers. And also we were pleased to see that our investigators stayed true to the protocol in that the median number of epicardial vessels assessed by FFR in that randomized arm was four. So there was a good assessment by FFR. The trial was interesting in another respect, in that we assessed an economic outcome based on all NHS hospital costs over the following year and a patient reported outcome based on quality of life using the WHOQOL, and interestingly we found no significant differences either in total subsequent hospital costs from randomization for a year, or indeed in patient reported quality of life by WHOQOL or Angina symptoms by the Canadian Cardiovascular Society classification.
Dr. Greg Hundley:
Very nice. And then, what about clinical events? Did you examine those as well?
Dr. Rod Staples:
We did. And again, just a little caveat here, the trial is again interesting in that, what is often in the UK these days called a lean efficient methodology. Whereby, rather than individually contacting individual trial participants or scouring medical records, we interrogated the central national NHS digital repository of all hospital admissions. And we examined electronically a download of every hospitalization event for every patient using algorithms based on diagnostic and procedural codes to define events. And again, we found a very credible representative rate exactly at incidents and events we would've predicted, but again, no difference between the randomized groups.
Dr. Greg Hundley:
Very nice, well listeners, now we're going to turn to our own Associate Editor, Dr. Nick Mills. And Nick, again, you see many papers come across your desk. What attracted you to this particular manuscript? And it's very interesting study results.
Dr. Nick Mills:
Thanks, Greg. Firstly, it addresses an important clinical question. Going beyond that, what appealed to me was it was investigator initiated. It was managed by independent trials unit. It recruited a target, it reported the registered outcomes and it was thoughtfully interpreted. And the fact that it didn't prove the hypothesis was irrelevant because it addresses a really important clinical question. And I think it requires some context, and that is that from the previous randomized trials The FAME series, we have been chastised as interventional cardiologists for not using FFR for relatively low use of FFR clinical practice. It's always around one in 20 patients in most series, given the evidence that FFR guided intervention improves outcomes. But actually what FFR is good at is discouraging you from stenting patients with stable Coronary Disease.
And so, I think a pragmatic trial that addresses that, the fundamental question, should we be doing more FFR more broadly in both acute and stable disease to guide revascularization with a definitive message that we shouldn't, it doesn't improve quality of life. It doesn't alter costs. Clinical outcomes are similar, but there are more complications associated with routine pressure wire use, gives us a very clear steer for the future. So this is a really important trial addressing a fairly fundamental clinical question.
Dr. Greg Hundley:
Very interesting. Well, Rod, we're going to turn back to you with Nick's comments and how we're really seeing an evolution in thought processes regarding both diagnostic angiography, and then also the use of functional testing. What do you see is the next study, really in this sphere of research that would be performed?
Dr. Rod Staples:
Well, I agree with Nick in a way that this raises important philosophical points about the use of intelligence, selective employment of tests or interventions, and that perhaps we need to reflect this in the way we conduct our future studies. I think we're all aware that fractional flow reserve and other measures of functional significance are tremendously valuable in certain clinical settings. And that value's been proven in randomized trials, but in PRECORD 2, for example, if a patient randomized to angiography only was an acute coronary syndrome patient, who had inverted their T waves in their anterior leads, had an associated troponin rise, an echocardiogram had shown some Hypokinesia in the anterior territory. Then I think the potential value of PCI in the LAD does not necessarily require FFR confirmation, and hence that patient will have an equivalent outcome in the angiography group. Similarly, high quality pre-angiography preparation in the elective population with functional testing, stress testing, other forms of imaging mean that we can reserve the use of invasive fractional flow reserve, tight indices to more selective use.
Dr. Greg Hundley:
And Nick, turning to you, what do you think is the next research study that could be informative in this space?
Dr. Nick Mills:
I think our whole philosophy by how to manage stable coronary disease is changing. In part because of some other landmark trials that the Ischemia trial and some of the key secondary analyses of the Ischemia trial that tells the Pathoma burden, low attenuation plaque, other aspects of chronic disease are vitally important in predicting major events in the future. And that leaves us with the role for FFR or CT FFR, primarily to manage symptoms. And I think we're getting increasingly good evaluating patients before they get to the Cathflow, optimizing their medical treatment. And so for me, the trial that we really need to help us, is a CT FFR trial to understand the role of Ischemia testing plus anatomical testing and how they dovetail in guiding treatment decisions before they get to the cath lab. I think we need to move this before the lab, always going to be a role for intelligent FFR testing in selected patients once we get to it. But I think that the question probably needs to be addressed before they get to the cath lab.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank, Dr. Rod Staples from Liverpool and Dr. Nick Mills from Edinburgh, Scotland for bringing us this very interesting study, highlighting that a strategy of systematic FFR assessment, when compared to angiography alone, did not result in a significant reduction in cost or improvement in quality of life.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run.
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Kory Lavine and Associate Editor Thomas Eschenhagen as they discuss the article "Donor Macrophages Modulate Rejection After Heart Transplantation."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, this week's feature, we are going to the world of preclinical science and we are going to learn about a very important new finding pertaining to heart transplant rejection, and macrophages may modulate this, but before we get to that feature, how about we grab a cup of coffee and go through some of the other articles in the issue?
Dr. Carolyn Lam:
I got mine. Would you like to go first, Greg?
Dr. Greg Hundley:
You bet, Carolyn. Well, my first study comes to us from Dr. Michael Pencino from Duke University. Carolyn, this study was performed to understand the predictive utility of a previously derived polygenic risk score for long-term risk of coronary heart disease and its additive value beyond traditional risk factors and how that might be able to inform prevention strategies. To accomplish this, data from adults aged 20 to 59 free of cardiovascular health disease from the Framingham Offspring Study and the Atherosclerosis Risk in Communities, or ARIC Study, were analyzed. Now, since the polygenic risk score was derived from people of predominantly European ancestry, individuals who self-reported white race were those that were included.
Dr. Carolyn Lam:
Oh, interesting, so what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. Somewhat surprisingly, they found that, among 9,757 participants, both the traditional risk factor score and the polygenic risk score where significantly associated with incident cardiovascular heart disease in young, early midlife, and late midlife. Now, the delta C index, when the polygenic risk score was added to the traditional risk factor, score was 0.03, 0.02, and 0.002 in the young, the early midlife, and the late-midlife participants, respectively.
Carolyn, despite a statistically significant association between the polygenic risk score and the 30-year risk of cardiovascular heart disease, the C index improved only marginally with the addition of the polygenic risk score to the traditional risk factor model among young adults and did not improve among midlife adults and, thus, Carolyn, the polygenic risk score, an immutable factor, has limited clinical utility for long-term cardiovascular heart disease prediction when added to a traditional risk factor model.
Dr. Carolyn Lam:
I really like that, Greg, because I think it also tells us that the traditional risk factors, which we can do something about, are still very important. Isn't that great? Well, the next paper is about POTS. Remember what that is? Should I give you a quiz? All right. It's okay. POTS, or Postural Orthostatic Tachycardia Syndrome, is a disorder of orthostatic intolerance that primarily affects females of childbearing age. While the underlying pathophysiology of POTS is not fully understood, it has been suggested that autoimmunity may play a role. Now, the aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between 116 POTS patients and 81 healthy controls, and they were from Calgary, Canada, and Malmo, Sweden.
Dr. Greg Hundley:
Carolyn, really interesting, so what did they find here?
Dr. Carolyn Lam:
The investigators, led by Dr. Raj from University of Calgary in Canada, found that commercially available autoantibody concentrations to G protein-coupled receptors were not increased or altered in POTS patients relative to healthy controls as assessed using ELISA. Now, while this study suggests that these G protein-coupled receptor autoantibody concentrations alone cannot explain the pathophysiology of POTS, autoantibody activity and signals not picked up by ELISA should still be explored as these results may provide more insights into the pathophysiology of POTS.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next study comes to us from the world of pulmonary arterial hypertension. Carolyn, clinical worsening is commonly used as an endpoint in pulmonary arterial hypertension trials. These authors, led by Dr. Steeve Provencher from the Institut Universitaire de Cardiologie Pneumologie de Quebec, aimed to assess the trial-level surrogacy of clinical worsening for mortality in pulmonary artery hypertension trials and whether the various clinical worsening components were similar in terms of frequency of occurrence, treatment-related relative risk reduction and importance to patients.
Dr. Carolyn Lam:
Okay, so what did they find?
Dr. Greg Hundley:
Right, Carolyn, so they searched MEDLINE, Embase and the Cochrane Library for trials evaluating the effects of pulmonary arterial hypertension on clinical worsening and, among 35 independent cohorts, so 9,450 patients, the effects of pulmonary arterial hypertension-specific therapies on clinical worsening modestly correlated with mortality. Additionally, study-level clinical worsening was not found to be a surrogate for mortality in pulmonary arterial-hypertension trials. Moreover, components of clinical worsening largely vary in frequency, response to therapy and importance to patients and, thus, are not necessarily interchangeable.
Dr. Carolyn Lam:
Thank you, Greg. Can I tell you about some other papers in today's issue? There's a Research Letter from Dr. Cosentino on cardiorenal outcomes with ertugliflozin by baseline metformin use, and this is a post hoc analysis of the VERTIS CV trial.
Dr. Greg Hundley:
Oh, very good, Carolyn. Well, I've got an exchange of letters from Professors Boriani and Steinberg regarding the article “Driving Restrictions and Early Arrhythmias in Patients Receiving a Secondary Prevention Implantable Cardioverter-Defibrillator, the DREAM-ICD-II Study.” There's also an ECG Challenge from Professor Gao entitled “Syncope in a 3-Year-Old Child During the Perioperative Period. What is the diagnosis? What Signs Point Toward Impending Life-threatening Event?”
Then, finally, there's a nice, On My Mind piece from Professor Greenland entitled “Insurance Payers Should Cover Selective Coronary Artery Calcium Testing in Intermediate Risk Primary Prevention Patients.” Well, Carolyn, how about we get on to that feature discussion and dive into the world of rejection after heart transplantation?
Dr. Carolyn Lam:
Yay. Here we go.
Dr. Greg Hundley:
Welcome, listeners, to this feature discussion on August 23rd. We have a very interesting article today to discuss with our author and associate editor pertaining to preclinical science and cardiac transplant rejection. Our author today is Dr. Kory Lavine from Washington University in St. Louis and our associate editor today is Dr. Thomas Eschenhagen from Hamburg, Germany. Welcome gentlemen.
Kory, we'll start with you. Can you describe for us some of the background information pertaining to the construct of your study and what was the hypothesis that you wanted to address?
Dr. Kory Lavine:
Well, thank you for having me. Our study focused on heart transplant rejection, which remains a major clinical challenge that limits both the survival of heart transplant recipients as well as availability of donor hearts. Current clinical practice really focuses on suppressing the immune system in a global way, and that is somewhat effective, but carries important risks that include infection and life-threatening malignancies.
Many studies have appropriately focused on immune cells that infiltrate the transplanted heart that come from the recipient to search for new ways to suppress the immune system safely. What we've understood and learned over the past several years is that the donor heart has its own immune system and its own immune cells, and the majority of those immune cells that come with the donor heart are macrophages that can be broadly divided into two distinct lineages with different functions, tissue-resident macrophages, which lack the cell surface receptors CCR2, and monocyte-derived macrophages with expressed cell surface receptors CCR2. We tested the hypothesis in this study that these macrophages that come with the donor heart remain active for a period of time after transplantation and play important roles in either suppressing or accelerating heart transplant rejection.
Dr. Greg Hundley:
What was the hypothesis that you wanted to address with your study?
Dr. Kory Lavine:
Yeah, so our prior work and others' work within this field had suggested that tissue-resident macrophages, CCR2-negative macrophages, are inflammatory, and CCR2-positive macrophages have the opposite functions being inflammatory and play roles in potentiating and initiating inflammation in the heart. In this study, we hypothesized that CCR2-negative macrophages would protect from rejection, while CCR2-positive macrophages may promote heart transplant rejection and could serve as a new therapeutic target to prevent rejection in transplant recipients.
Dr. Greg Hundley:
Excellent. Kory, can you describe for us the study design that you used to test your hypothesis?
Dr. Kory Lavine:
Yeah. The study design and approach we used involved a mouse model of heart transplantation where we transplant a donor heart into a recipient mouse that's fully mismatched at all the MHC loci, and this serves as a nice model for both cellular and antibody-mediated rejection. To facilitate tracking these donor macrophages, we used various genetic lineage tracing systems and, to study their phenotypes, we used single-cell RNA sequencing and, to understand their function, we used mouse models that allow us to specifically deplete each of the donor macrophage populations as well as genetic models to manipulate their activation and signaling.
Dr. Greg Hundley:
The outcome measures were going to be what?
Dr. Kory Lavine:
Yeah. The outcome measures for transplant rejection in this mouse model are allograph survival, so the survival of the transplanted heart. We're able to directly look at how much rejection is present by histopathology, and then we're able to observe various mechanistic features using detailed phenotyping such as single-cell RNA sequencing and T-cell activation assays.
Dr. Greg Hundley:
Very nice, Kory. Well, all, our listeners, we're very excited to hear what were your study results?
Dr. Kory Lavine:
We learned that donor macrophages are dynamic and they survive for a period of time after transplantation or eventually lost due to transplant rejection. When we phenotyped the macrophages that came from the donor heart, we learned that they remained transcriptionally distinct from immune cells that enter the heart that were derived from the recipients, and they had important and distinct functions. If we depleted the tissue-resident macrophages that were CCR2-negative, we observed reduced allograph survival and increased rejection. If we depleted CCR2-positive macrophages that came from the donor heart, we observed improved allograph survival and reduced rejection.
Mechanistically, we learned that CCR2-positive macrophages are activated through a MyD88-dependent pathway and, if we inhibited MyD88 cytokines which controls the expression of pro-inflammatory cytokines and chemokines, we could prolong the survival of the donor heart for a very significant period of time, reduce rejection and prevent the development of T-cells that would attack the donor heart. From a mechanistic aspect, what we uncovered is that this signaling pathway in CCR2-positive macrophages regulated the recruitment of an activation of antigen-presenting cells which played important roles in generating T-cells that would target the transplanted heart.
Dr. Greg Hundley:
It sounds like a really informative and leap forward in the whole sphere of transplant rejection. Well, listeners, now we're going to turn to our associate editor, Dr. Thomas Eschenhagen.
Thomas, you have many papers come across your desk. What attracted you to this particular paper and then, secondly, how do you put the results of this study really in the context of other research examining heart transplant rejection?
Dr. Thomas Eschenhagen:
Yeah, thanks for having me. I mean, first, we got attracted by this paper because it's somewhat an out-of-the-box approach. It's not the standard approach to improve the systemic immunosuppression as many studies did and with actually a lot of success over the last 30 years, survivor got much better. There had been a lot of progress in the field of transplantation medicine as we all know, but as Kory said already, we still have 30% rejection, and these immunosuppressions come at a price. Having this study which turns around somehow the argumentation and looks at the donor organ was something which really attracted us. It uses advanced methods and it applies somewhat in a practical way a concept which emerged over the last, I don't know, maybe decade this concept that macrophages are really very different kind of cells. They're all called macrophages, but they're quite different and even maybe in certain respects having opposing effect.
I think many people know about this M1/M2 concept. It's CCR2 receptor positive and negative. It's criticized by some people, but here we see that it really seems to be really important and, of course, then the third argument why we really like the story is that it has a specific, clear translation impact. I mean, looking at the heart, the donor heart, and potentially even treating the donor heart before transplanting it is something which comes immediately out of the story, and that's something which we found super attractive.
Dr. Greg Hundley:
Really interesting, so really understanding the mechanism and focusing on donor hearts. Well, listeners, let's circle back with Kory.
Kory, given that, what do you think is the next study that really needs to be performed in this sphere of research?
Dr. Kory Lavine:
I think Thomas said it exactly as we're thinking about it, so the next area that we're really excited to attack and we're hopeful that the field will focus on is ways to build methods and technologies to treat the donor heart between the time of procurement and the time of transplant, when it's being transported and potentially even being perfused for a period of time. We're really interested in finding approaches to identify small molecules and other potential biologic therapies that could be used to prevent the activation of donor CCR2-positive macrophages.
It's a really attractive approach because treating the donor heart ex vivo decreases the risk of adversely affecting other organs that may be transplanted if you're treating the donor, for instance, and it may decrease the risk of immunosuppression and infection by not having to treat the recipient and we're catching the heart in this window where the risks are much lower.
The other area that we're really excited to focus on is trying to identify the exact mediators that are generated from donor CCR2-positive macrophages that mediate the recruitment and activation of antigen-presenting cells because that would represent another potential therapeutic target.
Dr. Greg Hundley:
Very nice. Thomas, what are your thoughts about what might be the next study to be performed really in this sphere of research?
Dr. Thomas Eschenhagen:
It's obviously something rather a question to Kory than to me, but I agree to what he said. I think it is pretty obvious what are the next steps mechanistically on the one hand, but practically on the other hand. I mean, at this point, we are at the mouse level, so the question is to which extent can this concept be translated into larger animals and then finally in humans? I was wondering, given these newer methods to keep donor hearts alive for long, extended periods, I was wondering which extent you are already collaborating with the respective groups who develop this approach because that obviously would increase the window of opportunity here for drugs. I think it's really an exciting and pretty visible next steps which we see here, and I can just hope that you're going this path and that it will be successful.
Dr. Greg Hundley:
Kory, any thoughts on those collaborations that Thomas just spoke of?
Dr. Kory Lavine:
We're definitely establishing collaborations to focus on ex vivo profusion of donor hearts because that's, as Thomas mentioned, is a perfect window to manipulate the immune populations that are within the donor heart. Those studies have to be team science, they have to be collaborative and they have to have a focus on large animals and then moving into clinic. We're definitely forming those collaborations and excited to work as a group.
Dr. Greg Hundley:
Very nice. Well, listeners, what an exciting paper to discuss here as part of this feature discussion from the world of preclinical science. We want to thank Dr. Kory Lavine from Washington University in St. Louis, Missouri, and also our own associate editor, Dr. Thomas Eschenhagen from Hamburg Germany, for really bringing us this research study highlighting that distinct populations of donor and recipient macrophages coexist within the transplanted heart, and donor CCR2-positive macrophages are key mediators of allograph rejection and deletion of MyD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograph survival.
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart association, 2022. The opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Philipp Lurz and Editorialist Daniel Burkhoff as they discuss the article "Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction" and the editorial "HF?EF: The Mysterious Relationship Between Heart Failure and Ejection Fraction Continues."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
I just cannot wait to tell you about today's feature discussion, Greg. It's about heart failure with preserved ejection fraction and characteristics in the range of that ejection fraction that's above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow. How much are we going to be talking about this ejection fraction thing?" But I'm telling you, everybody has to listen to this. It's really a big stride forward in our understanding of these patients with heart failure and a higher ejection fraction. Plus it includes one of my mentors from Mayo Clinic days, and I just can't wait for everyone to hear this. But before we go there, we've got really, really cool original papers in today's issue too. Would you like to start first?
Dr. Greg Hundley:
You bet Carolyn, and I can't wait for that feature discussion, especially this is a real area of your expertise. So listeners, hold on for that feature discussion. Well, my first paper, Carolyn, really pertains to physical activity. And Carolyn, the study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan School of Public Health. And it evaluated a total of 116,000 adults from two large prospective US cohorts, the Nurse's Health Study and the Health Professional's Follow up Study that took place from 1988 to 2018. And they were examining self-reported leisure time physical activity and assessed the association between long term leisure time physical activity intensity and all cause and cause specific mortality.
Dr. Greg Hundley:
Now Carolyn, two types of physical activity were assessed. First, moderate physical activity and we're going to abbreviate that as MPA and that was 150 to 300 minutes per week, which is really recommended. Or second, vigorous physical activity for which it's really recommended that one performs 75 to 150 minutes per week. Now, Carolyn, as you know, some individuals accomplish both of these in their routine, some neither, some one or the other. And so it really remains unclear whether higher levels of long term vigorous or moderate are independently or perhaps jointly associated with lower mortality.
Dr. Carolyn Lam:
Oh, that's so interesting, Greg. Quick, quick, quick, tell us the results.
Dr. Greg Hundley:
Right Carolyn. So the nearly maximum association with lower mortality overall was achieved by performing approximately 150 to 300 minutes per week of long term leisure time vigorous physical activity or 300 to 600 minutes per week of long term leisure time moderate physical activity or an equivalent combination of both, so mixing those minutes. Also Carolyn, very interestingly, higher levels, suppose you go beyond those limits of either long term leisure time vigorous physical activity of more than 300 minutes per week or moderate physical activity of more than 600 minutes per week did not show clearly further lower all cause cardiovascular disease or non-cardiovascular disease mortality and nor did they show harm. So if you went above those thresholds, you really didn't experience greater harm.
Dr. Carolyn Lam:
Thanks, Greg. You know I'm going to be trying to apply that. That's so cool. All right. Well the next paper refers to the Cabana Trial, which I'll remind you is a trial in which catheter ablation did not significantly reduce the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest compared to drug therapy by intention to treat, but did improve quality of life and freedom from atrial fibrillation recurrence. In Cabana, the heart failure subgroup, ablation appeared to improve both survival and quality of life. The current paper led by Dr. Mark and colleagues from Duke Clinical Research Institute looked at the cost effectiveness of this ablation versus angio-rhythmic drug therapy in atrial fibrillation and which was a pre-specified Cabana secondary endpoint.
Dr. Greg Hundley:
Ah, Carolyn. So what did they find?
Dr. Carolyn Lam:
Well in this trial based economic evaluation, catheter ablation was estimated to cost $57,893 per QALY or Quality Adjusted Life Year gained compared to drug therapy in the overall cohort. And this was primarily driven by improvement in quality of life. It also cost $54,135 per QALY gained in the heart failure subgroup, driven by both gains in quality of life and survival. In summary, catheter ablation of atrial fibrillation was found to be economically attractive compared to drug therapy in the Cabana trial overall at present benchmarks of healthcare value in the US and based on projected incremental qualities, but not live years alone.
Dr. Greg Hundley:
Very nice Carolyn. Well, my next paper comes to us from the world of Preclinical Science and it's corresponding author is Dr. Swapnil Sonkusare from University of Virginia School of Medicine. So Carolyn, calcium signals in smooth muscle cells contribute to vascular resistance and control blood pressure. Now increased vascular resistance in hypertension has been attributed to impaired smooth muscle cell calcium signaling mechanisms. And in this regard, transient receptor potential vanilloid four or TRPV4 smooth muscle cell ion channels are crucial calcium entry pathways for smooth muscle cells. However, their role in blood pressure regulation has not been identified.
Dr. Carolyn Lam:
Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So these authors provide the first evidence that TRPV4 smooth muscle cell channel activity elevates resting blood pressure in normal mice. A1AR stimulation activated TRPV4 smooth muscle cell channels through protein kinase calcium signaling, which contributed significantly to vasoconstriction and blood pressure elevation.
Dr. Greg Hundley:
Surprisingly, intraluminal pressure induced TRPV4 smooth muscle cell channel activity, opposed vasoconstriction through activation of calcium sensitive potassium channels indicating functionally opposite pools of TRPV4 smooth muscle cell channels. And so Carolyn, this team identified novel smooth muscle cell calcium signaling nano domains that regulate blood pressure and demonstrate impairment in hypertension.
Dr. Carolyn Lam:
Oh wow, Greg. Thank you so much for that. Well, let's cover the other articles in today's issue. There's a primer by Dr. Jaffe on High Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. There's also Research [Letter] in there by Dr. Fordyce on the eligibility for non-invasive testing based on the 2021 American Heart Association and ACC guideline for the evaluation and diagnosis of chest pain, implications from the Promise trial.
Dr. Greg Hundley:
Great Carolyn. Well, I've also got an exchange of letters to the editor from Professors Benali and Professor Della Bella regarding a previously published article, “Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients with an Implantable Cardioverter Defibrillator, Results from the Multicenter Randomized Partita Trial.” And also there's a very nice Perspective piece from Dr. Udelson entitled “Glucose Insulin Potassium Therapy for Acute Myocardial Infarction, 50 years on and Time for a Relook.” Well, Carolyn, I can't wait to hear more of the discourse between you, the authors and editors on heart failure and preserved ejection fraction.
Dr. Carolyn Lam:
Yay. Here we go. I'm so excited about today's feature discussion. It's on my favorite topic, heart failure with preserved ejection fraction. Although thanks to one of the authors, Dr. Daniel Burkhoff of the editorial that accompanies it, I don't even know how to pronounce, it's Heart Failure question mark Ejection Fraction. I love it. How would you pronounce that?
Dr. Daniel Burkhoff:
Yeah, no, we debated how to pronounce it. HFQRef…a question mark?
Dr. Carolyn Lam:
HFQRef. Oh my goodness. What are we going to come up with next?
Dr. Daniel Burkhoff:
And we actually thought the editors would have a problem with that. Whenever we put something cute in the title, we always get knocked down. So we haven't yet got knocked down, so we'll see.
Dr. Carolyn Lam:
No, I'm not knocking you down.
Dr. Daniel Burkhoff:
But it just really emphasizes that we're in a very confusing time now as it comes to heart failure and ejection fraction, that we have to move on beyond ejection fraction. And although we have these strict buckets and upper and lower limits for each range, that maybe this is in a little bit of a way, doing us a disservice and doing the patients at disservice in terms of treatment.
Dr. Carolyn Lam:
That's really great. And everybody that was Dr. Daniel Burkhoff from the Cardiovascular Research Foundation in New York. He's the editorialist of today's feature paper. And I'm so excited that we have the corresponding author of today's feature paper as well, Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first, I mean, or second, heartfelt congratulations on this beautiful paper, Philipp. If you could start with telling us all about what you did and what you looked at and what made Dr. Daniel Burkhoff call it now, Heart Failure, QREF?
Dr. Philipp Lurz:
Yeah. So thank you so much, first of all, obviously for having me for the kind introduction and your kind words about our work. The whole thing started with the observation that in recent drug trials, the response in HFpEF patients to drugs which were before proven to be quite successful in HFrEF actually showed a quite heterogeneous response in HFpEF patients. And that there were some patterns according to the range of ejection fractions. So it seemed that those HFpEF patients with the lower ejection fractions, they respond a little bit better to HFrEF medication than those with a higher ejection fraction.
Dr. Philipp Lurz:
And HFpEF studies, they included patients within and ejection fraction or 40 and above who normally would probably would consider HFpEF to start with 50 and above. But even in those truly HFpEF patients, so from 50 and anything above to 70, there was a suggestion that there might be differences. 50 to 60 might be something else and then 60 and above. And this is where we started to look into our cohort and to group them according to ejection fraction and see whether we can see some important and clinically meaningful differences in morphology, obviously in function, but then even also in terms of our biopsy results.
Dr. Philipp Lurz:
And that also implies that we did quite a deep phenotyping of our patients. So we use imaging, echo obviously. We use magnetic resonance imaging. We were able to acquire in a larger percentage of that cohort, by the way, it was 56 patients in total, we were able to get some left ventricular biopsies. And most importantly, when it comes to the functional properties of the left ventricle, we also acquired pressure volume loops. And that has the great advantage that we obviously we can look at low dependent parameters, but more important, also low independent in disease of both systolic and diastolic function. And that's pretty much what we did.
Dr. Carolyn Lam:
Oh my goodness. I mean, as an editor at Circulation, can I just first tell you that's what really, really stood out? It's the comprehensive, careful, in-depth characterization. It may be 56 patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it was a lot, a lot that you did. Could you boil it down to what you found and maybe just to first clarify to the audience, how did you bend the ejection fraction? And then what you found?
Dr. Philipp Lurz:
We divided the cohort in two groups. One with an ejection fraction 50 to 60, and the other groups higher than 60% left ventricular ejection fraction. We ended up in lower group, 21 patients, in the higher group with 35 patients. And they were quite different. They had distinct features in terms of morphology, means that the lower injection fraction group, they had larger ventricles. That's probably what you would expect when you group them according to eject fractions. So not that surprising.
Dr. Philipp Lurz:
And at that point, and they had the same stroke volume. The low ejection fraction group, you could say that they had a certain degree of eccentric modeling, whereas those were the high ejection fraction group, that concentric modeling. When we then looked at the biopsies, the group with the low ejection fraction group, so 50 to 60, they had higher percentage of myocardial fibrosis at 15%.
Dr. Philipp Lurz:
And then on left ventricular biopsy, we saw that patients with a high ejection fraction group, they had less myocardial fibrosis, so more fibrosis in those with the lower ejection fraction group. And this is really interesting because when we then look at the real size of the pressure volume loop analysis, despite the fact that the high ejection fraction group had less fibrosis, they had the most stiff ventricles on pressure volume loop analysis. So that's already a very important point because it illustrates once again that we should not mistake fibrosis with stiffness, and also not the other way around. There are other parameters which can cause stiffness such as cellular stiffness, and it's not just the extracellular matrix.
Dr. Philipp Lurz:
So that's an important point. Those patients with high ejection fraction, they had the most stiff ventricles. They had the most relevant limitations in left ventricular filling, so the most marked diastolic dysfunction. We also looked at systolic parameters and there we found that they had a very high contractility. So this is the end systolic pressure volume relationship or also called elastics and that's a marker for contractility. So these ventricles with high ejection fraction, they can contract very well. They have high contractivity. But this is also a marker of systolic stiffness. So they stiff, both in terms of diastolic properties, but also systolic properties. And there, their most important limitation is the limitation in filling.
Dr. Philipp Lurz:
The other group, injection fraction 50 to 60, they do have some stiffness. Obviously we are talking about HFpEF. This is a disease of a diastolic dysfunction. So they have increased stiffness, but to a lesser extent. They can feel a little bit better, but what we see there is a reduction in contractility, so systolic properties. So you could argue that in some extent, that group 50 to 60, they behave a little bit more like HFrEF. Whereas those with high ejection fraction, they're completely different. Very stiff, both doing diastolically and sistolly.
Dr. Carolyn Lam:
Thank you so much. Now I really have to get the gurus insight into this. And of course by guru, I mean, Dr. Daniel Burkhoff. First, I'm going to take this opportunity to share a little private personal story that it's very hard for me to call Dr. Burkhoff, "Dan", although if you will allow me it's because I was a fellow when I first met Dr. Burkhoff. And one of my first papers was actually communicating with Dr. Burkhoff trying to draw these PV loops based on the noninvasive measurements that I was obtaining at the Mayo Clinic in the Olmsted County Cohort. And so this is just really making me smile. So Dan, if I may, what do you make of all this? And if you could give us what you think may be the clinical take home message.
Dr. Daniel Burkhoff:
Thank you so much, Carolyn. And also again, Philipp, congratulations on really a really important paper. I think as Carolyn was saying, one of the many things that impressed me was the multifaceted aspects of the thorough evaluation using multi modality characterization, which is in my mind, unprecedented, especially for this particular group of patients. And you summarized the main results very well. But to me, the thing that really struck me and that we really tried to emphasize in our editorial was the differential response to exercise, to hand grip exercise in this point.
Dr. Daniel Burkhoff:
As you already said, and I don't think this could be understated, that in the lower range, the 50 to 60, these patients were able to fill, the ventricle was able to fill more, the end diastolic pressure still went up significantly into an abnormal range, which is of course is one of the requirements for the diagnosis of HFpEF. But those patients, the end diastolic volume was able to increase and that helped them to increase their cardiac output.
Dr. Daniel Burkhoff:
In the higher EF group, the greater than 60, the end diastolic pressure went up, but the volume did not increase. So the end diastolic pressure volume relationship became higher elevated. And this of course, was reminiscent of what was identified in the early nineties by Dalane Kitzman. And really, he didn't make this distinction between the lower half and the higher half. And we had also in a paper that we did with David K and others, seen a similar finding a couple years ago. And I think this is really, to me, was the along with the apparently disparate findings on myocardial biopsies with fibrosis going the wrong way, if you will, as you already commented on. So this is at least for the higher EF group, is identifying what I would refer to as really true diastolic dysfunction.
Dr. Daniel Burkhoff:
That means that the patients can't fill, there really is some problem why the EDP can go up, but the volume does not increase. And this is obviously for future research, we have to understand what is the difference between these two groups. There are several speculations about why it might. For example, one thing that has been proposed in the literature is the pericardial restraints. If the heart is constrained in a tight pericardium, the volume is recruited from the venous system, which is another what I think is a very important part of this HFpEF phenotype, but the heart is already constrained. That would elevate both the CVP and the wedge pressure without concomitant increases in RV or LV volumes, and therefore limit the ability to increase the cardiac output.
Dr. Daniel Burkhoff:
Another alternative is delayed relaxation. That means a true abnormality of active relaxation. The tau if you will, but I believe in your study, if I remember correctly, the tau was not that abnormal and did not really change very much in either group. So it was harder to really pin it on an abnormality of active relaxation. So that was one really, I think, really important finding.
Dr. Daniel Burkhoff:
The second is now in the group 50 to 60 where they could fill, one of the limitations of the study that you pointed out was that there's no control group. So why this population, this HFpEF population, the EDP increased, but the EDV the end diastolic volume also increased, so what's different between those patients and normals? That we don't really have an answer for yet. So that would be one thing is to compliment these findings with results in a true control group that does not have HFpEF.
Dr. Daniel Burkhoff:
So we still have this mystery of why does EDP go up in this group? My perspective is not an abnormality of diastolly. It's not a diastolic dysfunction, even though it's a HFpEF. I've been trying to promote this idea for more than 20 years, that all HFpEF is not an abnormality of diastolic ventricular properties. There may be extra cardiac factors even beyond the pericardium in this group. So I think these results are just further telling us how complicated and individualized our approach to the pathophysiology of these patients should be.
Dr. Daniel Burkhoff:
And also just one final comment, making a strict cutoff at 60% or 57% as we saw from Valsartan Cuba trial, Valsartan study, is clearly also not going to do us justice. Let's say that we're dealing with anyway, patients with two different pathophysiologies. There's going to be a distribution of these different mechanisms and there's going to be an overlap of these distributions. So we need to start thinking about how we individualize and characterize the pathophysiology in individual patients. So maybe patients with EF of 55, certain patients with EF 55 will not respond to Sacubitril- Valsartan and maybe some patients with an EF of 62 will. So we need to go more deep into the clinical characterization.
Dr. Daniel Burkhoff:
And methods that you use in particular, the pressure volume loop, seem to separate, very nicely, these two different, at least two different subtypes. So I think it's very exciting, and I think people should really take notice of what you found and build on this as a foundation and understand that we need to go deeper on the clinical side to phenotype these patients.
Dr. Carolyn Lam:
Philip, what are your thoughts?
Dr. Philipp Lurz:
No, I think that the concept about stress and unstressed volume is extremely important and fascinating, but that's where it gets really complex because you could make the conclusion from our results that especially the high ejection fraction group, they are have a very high preload sensibility, which means that when we reduce pre-load too much in them, they drop the stroke volume very suddenly. So that's probably also the clinical question for the future. There are many patients, HFpEF patients in whom we should reduce stress volume and they can benefit from that.
Dr. Philipp Lurz:
But I also believe that there is a cord of patients, and those are probably more those with high ejection fraction. They actually, they could experience some harm if you reduce preload too much because of the severe filling restrictions, because of the inability to increase end diastolic volumes, especially as an adaptation to exercise. And I think if we find out ways to differentiate who will benefit from preload reduction and from decongestion and who actually might experience even harm from these interventions, then we are certainly one step further.
Dr. Carolyn Lam:
If I may, I just, I could go on forever, but I know that there's going to be this question that the audience is immediately thinking. Here we are going into the weeds, hemodynamics, we all love it. In fact, I think we're all kind of a little bit geeky about it, but then you've got, Emperor preserved, the Deliver Trial sort of being positive in heart failure with ejection fraction above 40. So, do we really need to understand the different hemodynamic? What do you think is happening that this sort of blanket benefit can occur?
Dr. Philipp Lurz:
I don't think that everyone will benefit. And I think that a better understanding of the underlying pathophysiology will help to even increase the rate of responders and dissect of those who will not respond or we need a different therapy. Obviously here we group patients according to ejection fraction. We just discussed that this is a very rough way to characterize patients. So the next step certainly would be to understand or to see distinct patterns in left ventricular functional behavior irrespective of ejection fraction. Because you might can skip ejection fraction at one day, but the conclusion is not, at least not in my opinion, that all heart failure is the same.
Dr. Carolyn Lam:
Nice. And Dan, what do you think?
Dr. Daniel Burkhoff:
Well, I think with STLT2 inhibitors, first of all, we're looking forward to actually seeing the results from Deliver what the details of it in terms of mortality versus hospitalizations and quality of life. But with regard to HSGL2 inhibitors, I don't think we know the mechanism. I mean, I've read about six papers that definitively talk about different mechanisms of action. I think we don't know. And even despite, let's say positive studies, there's still a significant residual risk that these patients have. So these are not the end of the story by any means. I think this is the beginning of the story and there's still going to be a lot to learn.
Dr. Daniel Burkhoff:
I think with SGLT2 inhibitors, I think it's difficult to identify who is or how do you define a responder on an individual patient basis? When we look at groups and you look at mortality and hospitalizations, yes, you can identify them. But that group does not overlap exactly with those who have an improvement in quality of life. So I think that we're just at the beginning,
Dr. Daniel Burkhoff:
I do think that a deeper phenotyping is going to be the way to go ultimately and I think we're going to need more therapies. Thanks again, Carolyn for inviting me to do the editorial and to participate in this. And I would really be remiss if I did not mention the extraordinary contributions for Mickey Brener and also Barry Borlaug who were equal contributors to this editorial and the evaluation of this paper. So I'm really indebted to both of them for this interpretations. And thank you again, Philipp, for just a wonderful paper.
Dr. Carolyn Lam:
Couldn't have said it better and I just want to thank you once again for providing that deeper phenotyping for opening the door. Many of us said it again and again, this is the beginning and we need more studies, frankly, in yours. I mean, I think Dr. Burkhoff wants you to send normal, healthy people for MRI biopsies, exercise, echo. I'm kidding, on PV loops, but it's true. We need that data. We need the same and the HFrEF and really just to understand the whole thing. I'm so excited about what this paper opens up.
Dr. Carolyn Lam:
I am thrilled to see your editorial, Dan. I'm sure it's going to be well received. Everyone who's listening to this, Pick up the paper, pick up the editorial. Thank you so much for joining us today. You've been listening to Circulation on the Run and from Greg and I, don't forget to tune in again next week,
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit hajournals.org.
This week, please join authors John McMurray and David Cherney, editorialist Kausik Umanath, as well as Associate Editors Ian Neeland and Brendan Everett as they discuss the original research articles "Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF" and "Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and editorial ""Dip" in eGFR: Stay the Course With SGLT-2 Inhibition."
Dr. Carolyn Lam:
Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, Associate Editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, it's the season of double features. Except this time, we're having a forum discussion of two related articles and an editorial that discusses both. What is it on? SGLT2 inhibitors. In the first paper, an analysis from the DAPA-HF trial, looking specifically at that initial dip in GFR that follows initiation of dapagliflozin in patients with HFrEF. Then we will discuss further, in a mechanistic way, the renal and vascular effects of combining SGLT2 inhibition on top of ACE inhibition. Lots and lots of good learning and insights, but let's go on first to the other papers in today's issue. Shall we?
Dr. Greg Hundley:
You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn, in this issue, wow, so many exciting original articles. In fact, there are two more articles that were going to pair together, both clinical and pertaining to TAVR procedures. In the first one, it was a group of authors led by Dr. Duk-Woo Park from the Asan Medical Center at the University of Ulsan College of Medicine. They conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy or DAPT, aspirin plus clopidogrel, in patients who had undergone successful TAVR and did not have an indication for anticoagulation. Now in this study, Carolyn, the primary endpoint was an incidence of leaflet thrombosis on four-dimensional computed tomography, CT, performed at six months after the TAVR procedure. Key secondary endpoints were the number and volume of new cerebral lesions on brain magnetic resonance imaging or MRI and the serial changes of neurological and neurocognitive function between six months and that time immediately post the TAVR procedure.
Dr. Carolyn Lam:
Oh, interesting. What did they find?
Dr. Greg Hundley:
Right, Carolyn. In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the two groups. Now because the study was underpowered, the results should be considered really as hypothesis generating, but do highlight the need for further research.
Dr. Greg Hundley:
Carolyn, there's a second paper pertaining to transcatheter aortic valve prosthesis. It's led by a group directed by Dr. Paul Sorajja from the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. Carolyn, these authors prospectively examined 565 patients with cardiac CT screening for HALT, or what we would define as hypoattenuating leaflet thickening, at 30 days following balloon-expandable and self-expanding TAVR. Now, deformation of the TAVR prosthesis, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the post-procedural CT. For descriptive purposes, an index of prosthesis deformation was calculated, with values greater than 1 representing relative midsegment underexpansion. A time-to-event model was also performed to evaluate the association of HALT with the clinical outcomes.
Dr. Carolyn Lam:
Oh, interesting. What did they find?
Dr. Greg Hundley:
Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume was related to the occurrence of HALT in patients who underwent TAVR. What's the take home here, Carolyn? These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes in these patients. Now, Carolyn, both of these articles are accompanied by an editorial from Dr. Raj Makkar from the Smidt Heart Institute at Cedars-Sinai's Medical Center. It's a very lovely piece entitled Missing Pieces of the TAVR Subclinical Leaflet Thrombosis Puzzle.
Well, how about we check what else is in this issue? My goodness, this was a packed issue. First, Carolyn, there are three letters to the editor from Professors Ennezat, Dweck, and then a response from Dr. Banovic pertaining to a follow-up from a previously published study, the AVATAR study, in evaluating valve replacement in asymptomatic aortic stenosis. There's also a Perspective piece from Dr. Wells entitled “Treatment of Chronic Hypertension in Pregnancy: Is It Time For A Change?” There's a Global Rounds piece from Professor Berwanger entitled “Cardiovascular Care in Brazil: Current Status, Challenges, and Opportunities.” Then there's also a Research Letter from Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis.”
Dr. Carolyn Lam:
There's another Research letter by Dr. Borlaug on longitudinal evolution of cardiac dysfunction in heart failure with normal natriuretic peptide levels. There's also a beautiful Cardiology News piece by Bridget Kuehn on the post-COVID return to play guidelines and how they're evolving. Well, that was a great summary of today's issue. Let's hop on to our feature forum. Shall we?
Dr. Greg Hundley:
You bet, Carolyn. Can't wait.
Dr. Carolyn Lam:
Today's feature discussion is actually a forum because we have two feature papers in today's issue. They all surround the cardiorenal interaction, should I say, of the SGLT2 inhibitors. For the first paper, discussing that initial decline or that dip in the GFR following initiation of dapagliflozin would be Dr. John McMurray, who's the corresponding author of this paper from DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now next, we have also the corresponding author of another paper, really going into the mechanistic insights of the renal and vascular effects of combined SGLT2 and ACE inhibition. Dr. David Cherney is from Toronto General Hospital, University of Toronto.
Dr. Carolyn Lam:
We have the editorial list of these two wonderful papers, Dr. Kausik Umanath from Henry Ford Health in Michigan. Finally, our beloved associate editors, Dr. Ian Neeland from Case Western Reserve and Dr. Brendan Everett from Brigham and Women's Hospital, Harvard Medical School. Thank you, gentlemen. Now with all of that, what an exciting forum we have in front of us. Could I start by asking, of course, the respective authors to talk a little bit about your papers? I think a good place to start would be with Dr. McMurray. John, please.
Dr. John McMurray:
Thanks, Carolyn. I think our paper had three key messages. The early dip in eGFR that we saw was, on average, very small in patients with heart failure, about 3 mLs/min or about 5%. Very few patients had a large reduction in the eGFR. It was around 3%. Dapagliflozin-treated patients had a 30% or greater decline compared to about 1% of placebo patients. Finally, very few of those patients had a decline in the eGFR below a critical threshold, which for cardiologists might be around 20 mLs/min. We saw that in only five patients; that's 0.2% of the dapagliflozin-treated patients. Second message was that that early decline partially reverses. The nadir in our study was about 14 days. But by 60 days, on average, eGFR had increased again. Hold your nerve if you see an early decline in eGFR.
Dr. John McMurray:
Maybe the most important message was that that decline in the eGFR is not associated with worse cardiovascular or renal outcomes. In fact, if anything, the opposite. If you look at the patients in the dapagliflozin group with a 10% or greater decline in eGFR, then compare it to patients who didn't have that decline, these individuals were about 27% less likely to experience the primary composite outcome of worsening heart failure and cardiovascular death. If you look at the placebo group, we saw exactly the opposite. Amongst those who had a greater than 10% decline in eGFR compared to those who didn't, those people with the early decline in eGFR were 45% more likely to experience the primary composite endpoint. The same is true for other cardiovascular outcomes for worsening kidney function. In the dapagliflozin group, decline in eGFR was not associated with more adverse events, not associated with more treatment discontinuation. That small decline in the eGFR is not a bad prognostic sign. If anything, it might be the opposite.
Dr. Carolyn Lam:
Thank you so much. That was really clear. David, are you going to tell us why this decline occurs?
Dr. David Cherney:
Yeah. Perhaps the paper that we published gives some insights into the mechanisms that are responsible for some of those changes in GFR that are thought to be acute hemodynamic effects. In the between trial, which is the trial that we published examining the effect of ACE inhibition followed by SGLT2 inhibition in patients with type 1 diabetes, we also saw that there was an expected effect of adding SGLT2 inhibition on top of an ACE inhibitor in people with uncomplicated type 1 diabetes. This acute dip in GFR was seen in this cohort of patients. We included only 30 patients in this small mechanistic study. At the same time, along with that dip in GFR, we also saw an increase in measures of proximal natriuresis. That proximal sodium loss is linked with changes in sodium handling in the kidney, which then causes changes in both probably afferent and efferent tone, which causes this dip in GFR primarily through natriuresis in this phenomenon called tubuloglomerular feedback. That was one major observation that gives insight into what we see in larger trials around the dip in GFR.
Dr. David Cherney:
In our mechanistic study, we also saw an additive effect on blood pressure. Blood pressure went down further with the addition of empagliflozin on top of an ACE inhibitor. In terms of the mechanisms that are responsible for the reduction in blood pressure, natriuresis certainly may be in part responsible, but we also saw a novel observation whereby there was a reduction in peripheral vascular resistance using noninvasive measures. There are likely several mechanisms that are responsible for the reduction in blood pressure. Then finally, we also saw reductions in markers of oxidative stress, which may also account for some of the effects that we see in blood pressure, as well as potentially some of the anti-inflammatory and anti-fibrotic effects that we see at least in experimental models that may have some clinical translatability to humans as well around the clinical benefits. I think the blood pressure, the renal hemodynamic effects, and some of the neurohormonal mechanisms are the major observations that we saw that may in part explain some of the really nice changes that were seen in Dr. McMurray's study.
Dr. Carolyn Lam:
Right. Thanks, David. But these were patients with type 1 diabetes and no heart failure. John, do you have any reflections or questions about how that may apply? By the way, what a beautiful study. Thank you, David.
Dr. David Cherney:
Pleasure. Thank you.
Dr. John McMurray:
Yes, David. I really enjoyed your study. In fact, I think, Carolyn, it does shed some insights perhaps to what's going on. As David pointed out, the reduction in peripheral arterial resistance, reduction in blood pressure, that may play some role in that early dip in eGFR as well as autoregulation in the kidney. Then the other interesting thing is that the distal nephron seems to adapt to that effect in the proximal tubule. Again, that may account for some of that recovery in eGFR, that reversal in the early dip that I spoke about, and which I think is very clinically important because, of course, physicians should make sure that they recheck eGFR if they see that early dip. Because they may find that few weeks later that that dip is much smaller and of much less concern.
Dr. Carolyn Lam:
Thank you, John. In fact, you're saying, stay the course, right-
Dr. John McMurray:
I have.
Dr. Carolyn Lam:
... with the SGLT2 inhibitors. I'm actually stealing the words of the title of the editorial, a beautiful editorial by Kausik. I love that. Stay the course. Kausik, please, could you frame both papers and then with an important clinical take home message for our audience?
Dr. Kausik Umanath:
Sure. I think the analysis by John and his group was really relevant with the large sample size. What's impressive? Similar to a lot of these other SGLT2 studies that have come out, both in heart failure and in kidney disease progression and so on, it's remarkable how the other analysis, like the analysis of EMPA-REG and CREDENCE and so on, of similar dips. All show more or less the same magnitude, the same relative proportions of this GFR trajectory. I think the mechanistic study only highlights that though it's working with a slightly different population of type 1 patients and much earlier in their course in terms of where their GFRs are.
Dr. Kausik Umanath:
The other piece is that ultimately we need to understand this dip and know to monitor for it and so on. But I think the general clinician should really understand that a dip of greater than 10% really occurs in less than half the population that takes these agents. That dip, if it occurs, certainly doesn't do any harm. That said, if they see a bigger dip in the 30% range, monitor more closely and consider making sure that there aren't any other renal issues out there for that patient because they are a much smaller proportion of patients in these large trials that generate that level of dip. They should be monitored.
Dr. Kausik Umanath:
The other thought that we had, and thinking through this in a practical sense, is because you expect this dip, many of our cardiologists or even the nephrologists when we titrate these drugs, they're on a suite of other drugs. It's probably best to not adjust their Lasix or their loop diuretic, or their RAAS inhibitor at the same time as you're adjusting the SGLT2 inhibitor or starting it because then you may just introduce more noise into the GFR changes that you see over the next several weeks. It may be a sequential piece or at least holding those other agents constant while this gets titrated and introduced is a prudent course of action, so you don't misattribute changes.
Dr. Carolyn Lam:
Thanks so much. What clinically relevant points. In fact, that point about the diuretic especially applies in our heart failure world. You see the dip. Well, first, make sure the patient's not overdiuresed. Remember, there's more that the patient's taking. Thank you. That was a really great point. Brendan and Ian, I have to get you guys to share your views and questions right now. But before that, can I take a pause with you and just say, aren't you just so proud to be AEs of Circulation when we see papers like these and we just realize how incredible the data are and the clinical implications are? I just really had to say that. All right. But with that, please, what are your thoughts, Brendan?
Dr. Brendan Everett:
Yeah, sure. Thank you, Carolyn. Hats off to all three of our authors today for doing some amazing science. Thank you for sending it to Circulation. I think, in particular, I handled David's paper. I'm not a nephrologist and I'm probably the furthest thing from a nephrologist. Had to do my best to try and understand these concepts that I'm not sure I ever even was exposed to in medical school many years ago. I think it shows the breadth of the interest in our readership. The fact that these changes in eGFR have become a primary focus for our cardiovascular patients and that the clinical implications are really important. I guess my question, David, is... In your paper, you talked a little bit about this hypothesis of hyperfiltration and the role that hyperfiltration plays in setting patients with diabetes up for kidney disease. Is that playing a role in John's observation or not? Again, as a non-nephrologist, I have trouble connecting the dots in terms of that hypothesis and John's observation of the clinical benefit for patients that have a reduction in eGFR as opposed to no change.
Dr. David Cherney:
Yeah. It's a great question. It's very difficult to know with certainty in a human cohort because we can't measure the critical parameter, which is intraglomerular pressure, which we think these changes in GFR are a surrogate for. But if we go along with that train of thought, along reductions in glomerular hypertension, it very much makes sense that the patients who dip are those who have the... They're taking their medication, number one. Number two, they respond physiologically in the way that you expect them to, which is that their GFR dips at least transiently and then goes back up again through some of the compensatory mechanisms that John mentioned earlier. As was mentioned not only in this paper, but also in previous analyses from CREDENCE and previous analyses from VERTIS CV and others have shown that indeed that dip in GFR is linked with longer term renal benefits, at least. That is reflected in a reduction in the loss of kidney function over time.
Dr. David Cherney:
The patients who are on an SGLT2 inhibitor and those who dip by around 10% or less, those patients tend to do the best over time in terms of preserving GFR, not losing kidney function compared to patients who are on an SGLT2 inhibitor but do not dip, or those patients who actually have an increase in GFR. That is consistent with this idea that there may be a reduction in glomerular pressure, which is protective over the long term. That ties back into your question around hyperfiltration that this may indeed be due to a reduction in glomerular pressure, which is linked with risk over the long term.
Dr. Carolyn Lam:
Ian?
Dr. Ian Neeland:
I wanted to echo Brendan's comments about the excellent science. When I read these papers, it really speaks to the existential struggle that cardiologists have between kidney function and these medications that we know have cardiovascular benefits. How do we manage that practically? It's so clinically relevant, both the observation that John's paper made about the dip in the DAPA-HF trial as well as, David, your mechanistic insights.
Dr. Ian Neeland:
I wanted to ask John potentially about the most fascinating aspect to me of this paper was that patients with a dip of 10% or more actually ended up doing better in terms of cardiovascular outcomes, specifically hospital heart failure and hospitalizations than people on placebo with a greater than 10% dip. It speaks to the fact that... Is the physiology going on here different between those individuals whose GFR went down on placebo versus those who are on SGLT2 inhibitors? All the mechanistic insight that David's paper had in terms of blood pressure and intraglomerular pressure, how does that feedback and speak to why heart failure is strongly linked to this mechanism? We see this not just with SGLT2 inhibitors, but there are other medications now coming out showing that there's a relationship between this dip in GFR and heart failure. Can you speak to why this heart failure-kidney connection is so important and becoming greater and greater in terms of our understanding?
Dr. John McMurray:
Well, thank you for asking me the hardest question and one that I truly don't think I have a good answer to. I think it's obvious to all of us that the kidney is central in heart failure and perhaps cardiologists have neglected that fact, focusing more on the other organ. But by definition, almost the fluid retention that characterizes heart failure in terms of signs, and probably is the primary cause of symptoms, that clearly is a renally-mediated phenomenon. The kidney must be central to all of this. I think David right. I think the decline in eGFR that you see with this drug is simply a marker that the drug is having its physiological effect or effects. Whatever those are, they're beneficial. Clearly, patients who have an eGFR decline on placebo are different and they reflect, again, the patients that we see all the time. As our patients with heart failure deteriorate, one of the things that we commonly see, in fact becomes one of the biggest problems that we have to deal with, is that their kidney function declines. As their symptoms get worse, as their cardiac function gets worse, their kidney function also declines.
Dr. John McMurray:
I think you're seeing two contrasting effects here. One is the background change in eGFR, which is the placebo patients, and we've always known that that's a bad thing. Then we're seeing that early within 14 days marker of the pharmacological or physiological action of the drug. I hope you don't ask me how SGLT2 inhibitors work in heart failure. That's the other most difficult question I can think of, but I think this is just a marker of the fact that they are working.
Dr. David Cherney:
Yeah. Just to add to that briefly, there is this difficulty in sorting out the mechanisms that are relevant around the acute effects in the kidney that the dip in GFR reflects natriuresis that could keep patients out of heart failure; that the reduction in glomerular pressure reduces albuminuria. Albuminuria reduction is linked with kidney protection. It's linked with heart failure and ASCVD protection. Then there's also this concept of if you dip and then you stay stable afterwards, your GFR stays stable afterwards, those patients with stable kidney function that's not declining, the dippers in other words, those patients are probably able to maintain salt and water homeostasis better than someone who's declining more rapidly. All these things probably tie together in order to reflect, of course, there's a renal protective effect, but that some of those mechanisms may also tie into the heart failure mechanisms that John was mentioning.
Dr. John McMurray:
But, David, it's hard to imagine if we don't protect the kidney, we won't protect patients with heart failure given how fundamental, as I said, the kidney is, and how fundamentally important worsening kidney function is. Not only because it is a marker of things going badly, but also because it often results in discontinuation or reduction in dose of other life-saving treatments. To Kausik's point, it was very important about the risk of changing background life-saving disease modifying therapy. Actually, we didn't see that in DAPA-HF, which was very intriguing. There was no reduction in use of renin-angiotensin system blockers or mineralocorticoid receptor antagonists.
Dr. Carolyn Lam:
Thank you so much, gentlemen. Unfortunately, we are running out of time, but I would really like to ask one last question to the guests, if possible. Where do you think the field is heading? What next? What's the next most important thing we need to know? David, do you want to start? Then John, then Kausik.
Dr. David Cherney:
I think one of the aspects that we need to know in the future is where else can we extend these therapies into novel indications and extend the boundaries of where we currently work with these therapies. People with type 1 diabetes, for example, with either heart failure or with significant kidney disease, patients with kidney transplantation, is there a renal or cardiovascular protective effect? Then another high risk cohorts who have not been included in trials, those on immunosuppressants, for example, who were excluded from the trials. I think those are some of the areas that we need to extend into now that we understand how these therapies work in even very sick patients and that we also know that they likely have at least some benefit through suppressing inflammation, and possibly reducing infectious risks. That would provide a rationale for extending into some of these new areas. I think that's certainly, hopefully on the horizon for us.
Dr. Carolyn Lam:
John?
Dr. John McMurray:
Carolyn, obviously I think looking at post myocardial infarction population, that's an obvious place to go. There are a couple of trials there. I suppose the trial that I would love to see, and which I think would address the core question that we've been discussing today, which is: Is this all about the effect in the kidney and how important is the diuretic and natriuretic action of these drugs in heart failure? I think the key study that would address this would be doing a study in patients on dialysis. Because in those patients we could, I think, separate the issue of natriuresis, diuresis, and maybe even the dip in EGR that we've been talking about. If these drugs prove to be effective in end-stage kidney disease, patients on dialysis, that would be really fascinating.
Dr. Carolyn Lam:
Kausik?
Dr. Kausik Umanath:
That is a very interesting point. I don't know that we know necessarily outcomes, but I think from working with the DAPA-CKD, we do have a little bit of the safety data because we did continue it. I was the US MLI for that study and we did continue the SGLT2 passed into renal failure. There is a little bit of safety data there. But I don't think once you've declared an outcome, you're not collecting outcomes data after that point. That's a very interesting area to look into.
Dr. Kausik Umanath:
I also think the other place where this field's heading is trying to better tier and layer the multitude of agents. I think we've been waiting for about 20 to 30 years, at least in the kidney field, for something new to affect the progression of kidney disease after the ACE/ARB trials and so on. This one we've got SGLT2 inhibitors. We've got the new MRA, finerenone, and so on, which also have very beneficial cardiovascular effects. The question becomes: How do we layer these therapies? Which sequence to go in? Some of the others that are in pipeline as well that are out there that have very beneficial cardiovascular effects that may indeed also help kidney function and diabetes control, which do you go with first and so on?
Dr. Carolyn Lam:
Wow! Thank you so much. We really could go on forever on this topic, but it has been tremendous. Thank you once again. On behalf of Brendan, Ian, Greg, thank you so much for joining us today in the audience. You've been listening to Circulation On the Run. Don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical Trials."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials.
The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we?
Dr. Greg Hundley:
You bet, Carolyn. And how about if I go first?
Dr. Carolyn Lam:
Please.
Dr. Greg Hundley:
So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control.
Dr. Carolyn Lam:
Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease.
Dr. Carolyn Lam:
Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age.
Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart.
Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls.
Dr. Greg Hundley:
Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find?
Dr. Carolyn Lam:
Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients.
Dr. Greg Hundley:
Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.”
Dr. Carolyn Lam:
There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we?
Dr. Greg Hundley:
You bet.
Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all.
And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address?
Dr. Paul Ridker:
Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts.
The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there.
In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting.
Dr. Greg Hundley:
Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design?
Dr. Paul Ridker:
We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like.
What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in.
And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated.
It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it.
Dr. Greg Hundley:
Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women.
Dr. Paul Ridker:
No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results.
Dr. Greg Hundley:
Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article?
Dr. Allan Jaffe:
Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look.
So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on.
Dr. Greg Hundley:
Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts?
Dr. Robert Harrington:
So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials?
And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results.
And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial.
Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here.
It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know.
Dr. Greg Hundley:
Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform?
Dr. Paul Ridker:
Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture?
Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with.
On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with.
Dr. Greg Hundley:
Allan, turning to you. What do you think is a next study to perform in this space?
Dr. Allan Jaffe:
Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial.
Dr. Greg Hundley:
And Bob, your thoughts.
Dr. Robert Harrington:
Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial."
But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth.
Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?"
I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this.
On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently.
Dr. Greg Hundley:
Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events.
And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures.
Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen.
And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address?
Dr. Eric Van Belle:
Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population.
And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device.
In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease.
So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure.
Dr. Greg Hundley:
Very nice. And Eric, can you describe for us, your study design, and who was your study population?
Dr. Eric Van Belle:
Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population.
And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure.
Dr. Greg Hundley:
So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find?
Dr. Eric Van Belle:
So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population.
But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population.
Dr. Greg Hundley:
Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures?
Dr. Emmanouil Brilakis:
Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation.
I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds.
Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is.
Dr. Greg Hundley:
Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research?
Dr. Eric Van Belle:
Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this.
So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome.
Dr. Greg Hundley:
And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space?
Dr. Emmanouil Brilakis:
Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient.
So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds.
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join authors Mikhail Kosiborod and Christian Schulze and Editorialist Stefan Anker as they discuss the original articles "Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial" and "Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From Antihyperglycemic Agents to All-Around Heart Failure Therapy."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
I'm so excited about the feature discussion this week. It is a paired feature along with their editorial and it's all focused on SGLT2 inhibitors. The first, results from the EMPULSE trial, Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure; and the second, the EMPAG-heart failure trial, The Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients with Acute Heart Failure. Incredibly important topics, incredibly important discussion. Wait up for it. We're just going to tell you a little bit more about two other original papers in today's issue, and I'm going to go first, Greg. Is that okay?
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
Now, really interesting topic here. We have strong evidence supporting the effective blood pressure and cardiovascular disease risk lowering properties of healthy diet such as the DASH diet, Mediterranean diet, and so on and so on. But what about the diet consumed by a fifth of the entire world's population? The Chinese cuisine. Interestingly, today's paper addresses just that. This is from authors, Dr. Wu, from Peking University Clinical Research Institute and colleagues who performed a multicenter patient and outcome assessor blind randomized feeding trial among 265 participants with baseline systolic blood pressure of 130 to 159 in four major Chinese cuisines.
And these are the Shandong, Huaiyang, Cantonese, and Szechuan cuisines, and here's how they did it. After a seven day run in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine based Chinese heart healthy diet for another 28 days. The primary outcome was systolic blood pressure. The study developed the first heart healthy Chinese diet that fits Chinese food culture and emphasizes its palatability by involving master shifts in developing the recipes.
Dr. Greg Hundley:
Oh wow. Carolyn, this is really interesting, especially one fifth of the world's population in studying a heart healthy diet. So did it work? I can't wait to hear the results.
Dr. Carolyn Lam:
Well, the change in systolic and diastolic blood pressure from baseline to the end of the study in the control group was five millimeters mercury and 2.8 millimeters mercury reduction, respectively. The net difference of change between the two groups in systolic and diastolic blood pressure were a reduction of 10 and almost four millimeters mercury, respectively. The effect size did not differ among cuisines, and so in summary, with a patient and assessor blind randomized feeding trial, this study really demonstrated that the blood pressure lowering effect of the Chinese heart health diet could indeed be substantial, and importantly, be compatible with medications while palatable and affordable in Chinese adults with high blood pressure, and so these results support the idea that food is medicine and will give many patients with high blood pressure the confidence to adopt heart healthy diets in their lifestyle treatment.
Dr. Greg Hundley:
Wow, Carolyn, that is really an interesting article. So many of these articles today could all be features in and of themselves. That was just outstanding. Well, my next paper comes to us from the world of preclinical science, and it's from Dr. Sean Wu from Stanford University School of Medicine. So Carolyn, immune checkpoint inhibitors are monoclonal antibodies that are used to activate the immune system against tumor cells. Now, despite their therapeutic benefits, immune checkpoint inhibitors have the potential to cause immune mediated adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Now histologically, patients with immune checkpoint inhibitor of myocarditis have lymphocytic infiltrates in the heart implicating T-cell mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in immune checkpoint inhibitor myocarditis are unknown.
Dr. Carolyn Lam:
Wow. So insights into the etiology of these immune checkpoint associated myocarditis cases must be very important. So what did they find?
Dr. Greg Hundley:
Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found to be significantly increased in the blood of patients with immune checkpoint inhibitor myocarditis corresponding with an analogous increase in effector cytotoxic CD8+ cells in the blood and hearts of PD-1 deficient mice with myocarditis. These expanded effector CD8+ cells had unique transcriptional changes, including upregulation of the chemokines CCL5, CCL4, and CCL4L2, and they may serve as attractive diagnostic therapeutic targets for reducing life threatening cardiac immune related adverse events in immune checkpoint inhibitor treated cancer patients, and Carolyn, just like so many of our articles, there's a very nice accompanying editorial by Professor Gianluigi Condorelli that also offers an update on current research pertaining to non-systemic steroid therapy to treat immune mediated myocarditis. Well, Carolyn, how about we jump to some of the other articles in the issue?
Dr. Carolyn Lam:
Oh, you bet, Greg. There's an exchange of letters between Drs. Madias and Knops regarding the article “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: The Analysis of All Appropriate Therapy in the PRAETORIAN Trial.”
Dr. Greg Hundley:
And also in the mail bag, Professor Mark has a Research Letter entitled “Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction, The SUGAR-DM-HF Study,” and our own Tracy Hampton has several synopses from articles published elsewhere in our piece on cardiovascular news. Well, how about we get onto that feature forum discussion, two papers, two editorialists. I can't wait.
Dr. Carolyn Lam:
Me too. Let's go, Greg.
Dr. Greg Hundley:
Welcome, listeners to this July 26th feature forum discussion. So remember, listeners, for forum discussions, we have several manuscripts that focus on a singular topic and we bring together the authors, our associate editors, and also an editorialist, and today, I want to introduce, we have with us Dr. Mikhail Kosiborod from Mid America Heart Institute in Kansas City, Missouri, Dr. Christian Shults from University Hospital Jena in Germany, Stefan Anker from Charité in Berlin, Germany, and our Associate Editors, Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, and Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentleman, and we'll start with you, Mikhail. Could you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Mikhail Kosiborod:
Well, thanks very much, Greg. The background for the study, which was the secondary analysis of the EMPULSE trial was patients that are hospitalized with acute decompensated heart failure represent a very high risk group. We know that they have high risk of death and hospitalizations, and we also know that they have very poor health status that's very high burden of symptoms, physical limitations, and poor quality of life, and so addressing those treatment goals, trying to reduce the risk of clinical events like death and hospitalizations and improve the symptoms and physical limitations in this patient population are very important treatment goals.
Now we previously demonstrated in the main results of the EMPULSE trials that using empagliflozin initiating empagliflozin SGLT2 inhibitor in this patient population as compared with placebo provided a significant total clinical benefit, which was a composite of total death, repeat hospitalizations for heart failure, or a change in a Kansas City cardiomyopathy questionnaire, which is a kind of a gold standard measure of patient's health status. What we tried to do in a much more granular fashion in this study is to understand the effects of empagliflozin as compared with placebo on this very important outcome, the Kansas City cardiomyopathy questionnaire, and we actually evaluate all of the key domains and composite symptoms, physical limitations, as well as quality of life.
Dr. Greg Hundley:
Very nice, and Mikhail, can you describe for us what study population specifically, and then what was your study design?
Dr. Mikhail Kosiborod:
Well, this was a population of patients that were hospitalized with heart failure and that EMPULSE was unique in its design because first of all, previous SGLT2 inhibitor trials mostly focused on patients with chronic heart failures that were in an outpatient setting, including prior trials of empagliflozin, and EMPULSE really focused on acutely hospitalized patient population, but it included patients regardless of ejection fraction. So as they were hospitalized with decompensated heart failure and reduced or preserved ejection fraction. They were enrolled regardless of if they had type 2 diabetes, they were enrolled essentially, regardless of kidney function, only patients with EGFR of less than 20 were excluded, and also importantly, was this study and a unique feature of the study in particular was that we enrolled patients whether they had acute de novo heart failure.
That means that was a new diagnosis of heart failure that was bad enough for them to be hospitalized or worsening chronic heart failure requiring hospitalization. So it was really an all-comer trial for patients acutely hospitalized for heart failure. So we had just over 500 patients and they were randomized in the hospital. After a brief period of stabilization, we use empagliflozin, 10 milligrams daily or placebo and treated for 90 days, and the primary outcome at 90 days was a total clinical benefit that I described that was a composite, hierarchical composite of total death hospitalizations, repeat hospitalizations for heart failure and changing KCCQ. In this study, again, we focused predominantly on KCCQ, trying to understand the effects on health status, again, symptoms, physical limitations, and quality of life.
Dr. Greg Hundley:
Excellent. And Mikhail, what were your study results?
Dr. Mikhail Kosiborod:
Well, what we observed, a couple of things. One is we first examined the effects of empagliflozin on the primary endpoint across the range of KCCQ and baseline, and what we found was that regardless of the degree of symptomatic impairment and baseline, empagliflozin was consistent in providing them total clinical benefits that I described previously, and then kind of shifting to what I think is the most interesting findings, the effects of empagliflozin versus placebo on KCCQ, what we found was that as you would imagine in this population of patients that were acutely hospitalized with heart failures, that had very poor health status, very low KCCQ at baseline, and within the first 90 days, which was observation period, both groups of patients had substantial improvements in KCCQs. As one would expect after acutely decompensated episode of heart failure and treatment in a hospital, everyone got better.
But patients treated with empagliflozin had significantly greater improvement in KCCQs than those that were treated with placebo, and that was first of all, a very substantial difference between the two groups. It was more than five points in favor of empagliflozin already at 15 days and was highly statistically significant, and it was maintained throughout the 90 day treatment period. So the fact that we saw both a clinical meaningful and statistically significant improvement in just 15 days, I think is a very important clinical message, and then finally, I guess what I will mention is these benefits of empagliflozin while main outcome we looked at was KCCQ total symptoms, we're focusing on the symptoms, but it was consistent when we looked at physical limitations as well as quality of life. So really, all key domains of KCCQ were impacted in a similar way.
Dr. Greg Hundley:
Very nice. So in acute heart failure, marked symptomatic improvement after the administration of the SGLT2 inhibitor empagliflozin at 10 milligrams per day. Well, now listeners, we're going to turn to our associate editor, Dr. Brendan Everett, and Brendan, again, you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Brendan Everett:
Well, thanks, Greg, and I think this manuscript caught my eye because of the importance of the clinical question, and Mikhail outlined why I think that was really relevant. So we understand that this class of medications or SGLT2 inhibitors have important effects on outcomes like re-hospitalization in patients with heart failure, and what was particularly striking about this paper is that it took patients rather than those with chronic heart failure, but as Mikhail mentioned, enrolled a patient population that was actually in the hospital, and I think this was an important frontier for this particular question about when to start the SGLT2 inhibitor and what kind of benefits there might be. Furthermore, I think the fact that they did not select the population based on ejection fraction was particularly striking, and of course, I think is remarkable, but now old news, they did not select on the presence or absence of diabetes as well.
And so those three components really attracted me to the paper. I also think the outcome is one that really is valuable and worth exploring, and specifically, I'm talking about how patients feel on the medication after a hospitalization for heart failure. Appropriately, we focused on re-hospitalization for heart failure and cardiovascular death in prior trials in this space, and I think we need to embellish those findings or further deepen those findings with a perspective on how patients actually feel when they get the medication, and of course, it goes without saying that what's particularly important here also is that it was a randomized placebo controlled trial, and so the results have some element of internal validity that I think is really important. So those were the things, Greg, that really attracted my attention as I read the paper for the first time.
Dr. Greg Hundley:
Thank you so much, Brendan. Well, listeners, we've got a second paper today and we're next going to hear from Dr. Christian Shults, and he also is focusing on really another aspect of the administration of empagliflozin in patients with acute heart failure and that pertains to the renal function of the patients. So Christian, could you describe for us the background pertaining to your study and what was the hypothesis that you were intending to address?
Dr. Christian Schulze:
Thanks, Greg. Well, it's great to introduce all study here in this running. So our study impacted those in acute decompensated heart failure. The impact HF trial was a study based on the hypothesis that we wanted to test, whether empagliflozin has effects in acute decompensated heart failure, and we focused on the patient population that was not addressed in EMPULSE, patients that came to the ER and needed to be treated right away, and we wanted to know and this was our main hypothesis, but are the diuretic and [inaudible 00:17:11] effects of the SGLT2 inhibitor on this case, empagliflozin, actually had an impact on diuretic regimens and kidney functions since this is one of the main end points that limits treatment, and also is one of the outcomes of patients with acute decompensated heart failure in the hospital.
Dr. Greg Hundley:
Very nice. And so Christian, what study design did you implement and who was included in your study population?
Dr. Christian Schulze:
So we also used the randomized two arm study design. We included patients with acute decompensated heart failure independent of left ventricular ejection fraction. Patients needed to have an NT-proBNP of more than 500. The average NT-proBNP in fact was 4,300 in our entire patient population, and we included patients within 12 hours of presentation. So many of these patients have been recruited in the ER, they presented two hour cardiology heart failure service, and then were immediately randomized to the trial in the two arms, and we tested not 10 milligrams of empagliflozin. We actually tested 25 milligrams of empagliflozin based on in-house data that 25 milligrams potentially had a stronger diuretic effect compared to 10 milligrams.
Dr. Greg Hundley:
And what did you find?
Dr. Christian Schulze:
So we followed patients for five days. It was a relatively short period of time. It was designed to address the in-house phase of patients with acute decompensated heart failure. The mean duration of stay was 6.3 days in the hospital so this was exactly the time that we wanted to test. We had a 30 day endpoint for safety issues, and what we could see is that patients on 25 milligrams on empagliflozin on top of standard diuretic regimens and medical care had 25% higher diuretic outputs compared to patients in the placebo group. We also found no differences in markers of renal injury dysfunction, and could in fact confirm that after 30 days, patients in the empagliflozin group had a better EGFR compared to patients in the placebo group. On top, we saw a more rapid decrease in body weight and also a more profound decrease in NT-proBNT values.
Dr. Greg Hundley:
And Christian, just for our listeners to put a little bit of this in perspective, what was the range of serum creatinine for the patients that were enrolled in your study?
Dr. Christian Schulze:
So the main EGFR in the entire population was around 60 and the creatinine values were around 107 on average in the entire cohort. So this is a very typical population. We had around 30% of the population with de Novo heart failure, around 20 to 30% of the population was pre-treated for preexisting heart failure. So very typical population of patients with heart failure presenting to the emergency room.
Dr. Greg Hundley:
And did you have any kind of lower level EGFR cutoff, I mean, for enrollment into this study?
Dr. Christian Schulze:
So when we designed the trial, we actually still had the sub classification of diabetes or impaired glucose or homeostasis as an inclusion criteria. We dropped it before we started the trial because the data came out that this is actually, in fact, not a critical issue for patients with heart failure. So diabetes was not a subgroup in our trial and the lower limit of EGFR was actually a thoroughly defined protocol.
Dr. Greg Hundley:
Very nice. Well, listeners, now we're going to turn to our second associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas, and Justin, similar to Brendan, and you see many papers come across your desk and so what attracted you to this particular paper by Christian and his colleagues?
Dr. Justin Grodin:
Well, Greg, I think first and foremost, and I think very similar to Brendan, but I think what's always striking is if I may just take a step back, decompensated heart failure in the United States is the number one cause for hospitalization among Medicare beneficiaries. So I think really, the brunt and really the truly public health message of the disease is very important in the applicability, and even though that decompensated heart failures is one of the most common things that we ever encounter when we practice, internists, cardiologists, et cetera, we have very, very little clinical trial guidance that tells us how to decongest individuals when they're hospitalized with swelling and heart failure and a lot of these individuals can be quite ill, and we have some clinical trial data, but largely, we have a lot of negative studies or inconclusive studies in this space.
So certainly, what drew me to this trial was definitely that context, and obviously, based on the mechanistic data with SGLT2 inhibitors, I think one of the natural questions, which Christian addresses, is that we know that up front, they do augment natriuresis. So I think it's very compelling to marry those two together because this is what many of us that use these medications regularly have been asking is whether or not they would have some efficacy in that regard, and then another thing that caught my eye and me as a cardiorenal investigator was, just as Christian highlighted, was we have a clinical trial that randomly assigned individuals, really that were ill and many of whom were not stabilized within 12 hours of presentation, and we're talking about patients that are coming into the hospital at all times during the day in and I think that's very remarkable that we have something with standard...
We have a study with standardized assessments where we're really trying to ask a very practical, pragmatic question, which is do these therapies lower the sodium balance in individuals with decompensated heart failure, and I think what's important is largely, we've got a lot of medications that supplement loop diuretics, which are the class of drugs that the majority of us use, and we have a lot of other therapies that we use that really have very little data or poor data that guide us such as thiazide diuretics, carbonic and hydrase inhibitors, mineralocorticoid receptor antagonists, and so here, we have a clinical trial that asks a question that's on many people's minds.
And then we do have very compelling, at least short term pragmatic and mechanistic data that does tell us that these individuals do have a greater natriuretic effect when empagliflozin is used as an adjunct to standardized loop diuretic therapy. So it's a very practical clinical question, and I think what's very important, and we could debate probably all day about the implications of GFR change and kidney function change while we're decongesting somebody with diuretics, but I think what's reassuring to all the clinicians is we really didn't see an effect on kidney function despite a greater natriuretic effect or enhanced diuretic effect, if you will, with the use of empagliflozin.
Dr. Greg Hundley:
Very nice. Well, thank you, Justin. Listeners, now we have an editorialist and as you know, editorialists really help us put the scientific presentation of an original manuscript into the perspective of really the global theme of a topic, and we have Stefan Anker from Berlin, and Stefan, can you describe for us how do we put these two manuscripts and results that we've heard about really in the context now of moving forward with the use of SGLT2 inhibitors in the management of patients with acute decompensated heart failure?
Dr. Stefan Anker:
Thank you so much. Really, I think these two papers, on the one hand, enhance our certainty about early use, and on the other hand, possibly show us that there might be even more to achieve by, on the one hand, moving even earlier with the application of SGLT2 inhibitors or possibly consider the higher dose. Now let's take one step back. These drugs were developed in type two diabetes and the first successful trial was the [inaudible 00:25:42] outcome trial. Many people have forgotten that this trial tested two doses and not only one, the 10 and the 25 milligram dose, and of course, with the success for improving kidney outcomes and heart failure hospitalization outcomes, we move forward into these two specialist areas, on the one hand, broadening it to the non-diabetic communities, but on the other end, narrowing it by focusing on the 10 milligram dose regardless of whether there is [inaudible 00:26:12].
And we basically now learn A, to use these drugs even earlier than we did in the big trials and we can now be sure to start their use in the hospital, and if you take the average change in quality of life results seen, you actually get a better result for the patient on quality of life when you start earlier than when you start late in the ambulatory studies where basically, in the chronic setting, maybe you have one and a half to two points difference. Here, you now have four and a half points in the study shown by Mikhail, and of course, it's also good to know that you can start this in any type of patient, regardless of their quality of life. The impact study from Christian, they basically moved it now even earlier, moving into the hospital space is possible based on EMPULSE. Moving it into the acute admission space is at least a consideration now based on what Christian here has shown.
And he is actually addressing the one question I hear very often in my presentations about SGLT2 inhibitors, what about this 25 milligram dose? Is there a place for this in cardiology as well, and a possible place is shown here, not only that this is a safe thing to do, but also you get urinary output. Of course, we may in the future, want to see this compared, directly compared to the 10 milligram dose, but of course, the world is not created in one day, but needs more than one and so really, I think these two studies, on the one hand, address an important issue, when to start using them. On the other hand, show us a little bit of a glimpse to the future.
Dr. Greg Hundley:
Very nice, Stefan, and listeners, we get to take advantage of having these authors, editors, and editorialists together and ask them what they see as the next study to be performed in this sort of sphere of research. So Mikhail, we'll start with you. In 30 seconds or less, what do you see as the next study to be performed in this arena of research?
Dr. Mikhail Kosiborod:
I think, Greg, what we've learned recently, including from the EMPULSE trial, we have this population of patients in a hospital with heart failure's a huge issue as Justin mentioned, and until recently, we had very little [inaudible 00:28:31] for them beyond the usual kind of decongestion with loop diuretics and trying to make them feel better, but you look at outcome data. It really was a dearth of effective therapies that have meaningful impact on important outcomes. Now that's changing, SGLT2 inhibitors is one example. There are some other recent examples in this patient population, like a firm HF and iron deficient patients with heart failure.
But the bottom line is it's no longer kind of a desert, if you will, of positive trials. We now have something we can do and I think what this proves is that we need to actually invest more, both in terms of resources and time to really do what we we're being able to do in other areas of heart failure and those patients with chronic, half and half where we can start developing pillars of therapy that can actually truly improve outcomes with this patient population and there is a lot going on that makes me optimistic that's going to be the case in the coming years.
Dr. Greg Hundley:
Very nice. And Brendan?
Dr. Brendan Everett:
Well, I think both trials mentioned today really pushed our understanding of this population forward. I think the biggest clinical question that I face when I'm caring for these patients is that we have four, at least, guideline directed therapies, right? We have beta blockers, we have ARBs, ACE inhibitors and ARNIs. We have mineral receptor antagonists and we have SGLT2 inhibitors. So which do we use in what order and how do we start them, and what kind of parameters do we use to guide us if we're limited either by renal function or by blood pressure or by some other factor.
And we often, if not always, have one of those constraints that we're dealing with and so I would say the next step for me is trying to sort out which of these therapies and what order ought to be our highest priority for patients with acute decompensated heart failure as we move quickly from the acute decongestion stage towards discharge and a chronic therapy that will then be followed as an outpatient over the ensuing days and months.
Dr. Greg Hundley:
Very nice. And Christian.
Dr. Christian Schulze:
Thank you again, and Brandon pointed out very nicely. I mean, we have good evidence now for chronic heart failure treatment. We have the four columns of heart failure medical therapy. Questions that remain open is what do we do with all these patients that are now guideline medicated, come to the hospital with an acute decompensation? Should we carry on with the medication? Should we terminate and in particular, should be carry on with full dose, 50% dose of SGLT2 inhibitors, and the next question is, what dose should we use, in fact, for SGLT2 inhibitors? Is it in group effects or is sotagliflozin comparable to empagliflozin, and then is there a role for a step by scheme that we initially have in high dose therapy that we then downgrade to 10 milligrams on the chronic heart failure treatments, and then of course, quality of life is very important. We should ask this question also in this patient population that is early on treated, do we see benefits that carry on in the outpatient setting and do we see an effect of early treatment on long term benefits?
Dr. Greg Hundley:
Justin?
Dr. Justin Grodin:
Well, I would have to agree with all of my colleagues here on this call. I think all have raised really good points, but I think one very simple, and I'll echo some of Brendan's statements, but one very simple question is we know that when we decongest people and initiate a negative salt balance in the hospital for decompensated heart failure, we cause neurohormonal activation and there are a lot of downstream untoward effects from chronic decongestive therapies, and I think one of the more compelling things is we still yet have defined what is the best way to decongest individuals with swelling or volume overload in the hospital. Here, we have compelling studies with SGLT2 inhibitors for quality of life and really, the way patients feel.
And this is really what's important to them, and then something very pragmatic to clinicians and let's make people pee more, but I think one of the compelling questions, and I don't know if it will be answered, is we have a lot of choices for supplemental therapies and different diuretic strategies when patients come in the hospital for decompensated heart failure, and I do think that these studies do move the needle with SGLT2 inhibitors. I think that's abundantly clear, but we still don't know what is the best way to dry out my patient or make my patient pee so that they feel better, but I do think that these studies do at least set the stage that there's some compelling advantages to SGLT2 inhibitors.
Dr. Greg Hundley:
And then lastly, Stefan.
Dr. Stefan Anker:
Thank you. Besides the detailed points mentioned by many, and Christian, totally support 25 versus 10 milligram, how long 25 milligram, if at all in the future. Besides this, I'm interested in the big picture question. So what about the post myocardial infarct congestion/heart failure situation, and there will be two trials in the next 18 to 24 months that report on this, and my pet kind of area is actually to treat heart failure where nobody thinks it is heart failure, and what I mean is for instance, advanced cancer patients, cardiac wasting cardiomyopathy. So the heart failure in sick cancer patients, and indeed, we are planning to do exactly that now in a study focusing on hospice care patients to really improve the quality of life, the very thing focus here on the EMPULSE trial.
Dr. Greg Hundley:
Well, listeners, we want to thank our authors, Dr. Mikhail Kosiborod from Mid America Heart Institute in University of Missouri, and Christian Shults from the University Hospital in Jena, Germany. Also, our associate editors, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, and Dr. Justin Grodin from University of Texas Southwestern in Dallas, Texas, and also, our editorialist, Dr. Stefan Anker from Charité in Berlin, Germany for bringing us these two manuscripts pertaining to two randomized clinical trials regarding the administration of the SGLT2 inhibitor, empagliflozin in acute heart failure, demonstrating first, marked improvement in heart failure symptoms and health related quality of life.
And second, in those with estimated GFRs greater than 30 mls per minute, an augmentation of natriuresis in the setting of the co-administration of diuretics without deterioration in renal function. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join Associate Editors Mercedes Carnethon and Karol Watson, as well as Guest Editor Fatima Rodriguez as they present the 2nd annual Disparities Issue. Then join Rishi Wadhera and Ashley Kyalwazi as they discuss their article "Disparities in Cardiovascular Mortality Between Black and White Adults in the United States, 1999 to 2019."
Dr. Mercedes Carnethon:
Well, good day listeners. I'm Mercedes Carnethon, and I'm joined by my fellow editors, Karol Watson, and Fatima Rodriguez, Associate Editor and Guest Editor for Circulation. And we'd like to welcome you to Circulation on the Run, for our second annual disparities issue. We have a lot of articles to discuss today, many of which we'll summarize, but we encourage you to access the issue and read the articles. First off, Fatima, I believe you have a paper to discuss.
Dr. Fatima Rodriguez:
Sure thing, Merci. My first paper is a thought provoking article by Nilay Shah, and co-authors from Northwestern University, that examine factors associated with the racial gap in premature cardiovascular disease.
Dr. Fatima Rodriguez:
This study used data from a well-known cardiac cohort, that aims to identify factors that begin in young adulthood and predict the development of future coronary artery risk. The objective of this study was to examine the relative contributions of clinical versus social factors, in explaining the persistent black/white gap in premature cardiovascular disease. After following around 5,000 black and white study participants for a median of 34 years, black men and women had a higher risk of premature cardiovascular disease. After controlling for multi-level individual and neighborhood level factors measured in young adulthood, the racial differences in premature cardiovascular disease were attenuated.
Dr. Fatima Rodriguez:
The authors found that the greater contributors to this racial disparity were not only clinical factors, but also neighborhood and socioeconomic factors. The relative explanatory power of each of these factors varied by men and women. This is really noteworthy, since we spent so much of our time in clinical medicine, focusing on identifying and managing traditional risk factors. But in reality, these structural factors and inequities are critically important to address, and contribute to differences in clinical risk factors downstream.
Dr. Mercedes Carnethon:
Thank you so much, Fatima. That was a really excellent summary. And now, I'm turning to you, Karol. I'd love to hear what you're going to be talking about today.
Dr. Karol Watson:
I'd like to discuss the paper, Association of Neighborhood Level Material Deprivation with Atrial Fibrillation Care in a Single-Payer Healthcare System Population Based Cohort Study. This is by Dr. Abdel-Qadir and colleagues.
Dr. Karol Watson:
So in this study, the author sought to determine whether there was an association between neighborhood material deprivation, by that we mean, inability to attain the basic needs of life and clinical outcomes, in individuals with atrial fibrillation. The kicker here is, they did this in an area with universal healthcare. So they wanted to see, if you took away the differences between the ability to see a physician or get your drugs paid for, if you would see any disparities.
Dr. Karol Watson:
So they performed a population based cohort study, individuals over the age of 66 years of age with atrial fibrillation, in the Canadian province of Ontario. They have universal healthcare there, and full drug coverage for anyone over 65. The primary exposure was neighborhood material deprivation. That's a metric used to estimate the inability to attain basic material needs, like healthy foods, safe housing. Neighborhoods were categorized by quintile, from the least deprived, quintile one, to the most deprived, quintile five. They find that, among about 350,000 individuals with atrial fibrillation, their mean age was 79, and about half of them were women. Those in the most deprived neighborhoods, quintile five, had a higher prevalence of cardiovascular risk factors and non-cardiovascular work comorbidity, relative to those who were in the least deprived areas.
Dr. Karol Watson:
Even after adjusting for all the confounders, they found that those in the most deprived neighborhoods had higher hazards of death, stroke, heart failure, and bleeding, relative to those in the least deprived neighborhoods. They also found that, despite having universal healthcare and drug coverage, those in the most deprived neighborhoods were less likely to visit a cardiologist, less likely to receive rhythm control intervention, such as ablation, and have worse outcomes.
Dr. Karol Watson:
And then, the accompanying editorial by Utibe Essien, he reminds us that intervening only on traditional markers of access, like health insurance and drug costs, may not be sufficient to achieve health equity. We have to address all of the structural needs that make people unable to get good help. Further, he points out that, the association between atrial fibrillation and neighborhood deprivation is very likely true with other cardiovascular conditions, as well.
Dr. Karol Watson:
So, Merci and Fatima, this just reminds us again, that addressing all the social determinants of health are necessary to achieve the best health outcomes.
Dr. Mercedes Carnethon:
Thanks so much, Karol. I really appreciate that summary of that important piece, focusing on a different domain of disparity. My first paper is an excellent piece, led by one of my favorite other associate editors at Circulation, Dr. Wendy Post, from Johns Hopkins University. And I see a familiar name on here. That's yours, Karol. You two are joined by an all-star list of authors, to describe race and ethnic differences in all-cause in cardiovascular mortality, in the multi-ethnic study of atherosclerosis.
Dr. Mercedes Carnethon:
MESA is a longitudinal cohort study that launched in 2000, and recruited just over 6,800 adults who identified as black, white, Hispanic, and Chinese. While the study participants were initially free from cardiovascular disease, over an average of 16 years of follow up, 364 participants died from cardiovascular disease. There are a number of novel findings in this paper that led our editor-in-chief to select it as his pick of the issue.
Dr. Mercedes Carnethon:
The finding that really stands out to me is, how much of an influence the social determinants of health had on black versus white disparities in cardiovascular mortality. In fact, after adjusting for socioeconomic status, the disparities were nearly eliminated. Other critically important findings are that, the oft described Hispanic paradox of lower cardiovascular mortality in Hispanics, as compared with white adults, was demonstrated in this population. And finally, we have longitudinal data on Asians living in the United States. Asian participants in MESA had similar rates of cardiovascular disease mortality as their white counterparts. There's so much to learn in this well designed cohort study, and so many hypotheses about how social determinants and structural racism influence the disparities that we see.
Dr. Mercedes Carnethon:
So Fatima, I'd like to turn to you next. What else do you have to share?
Dr. Fatima Rodriguez:
Thank you, Merci. My second paper is a research letter for my home institution of Stanford University, led by my colleague, Dr. Shoa Clarke, discussing how race and ethnicity stratification for polygenic risk course, may mask disparities among Hispanic individuals.
Dr. Fatima Rodriguez:
This study used data from the Million Veteran Program, to determine how self-identified race and ethnicity impact the performance of polygenic risk scores in predicting coronary artery disease.
Dr. Fatima Rodriguez:
The investigators found, that the current polygenic risk scores predict coronary artery disease similarly well in Hispanic and non-Hispanic white individuals. However, what I found most interesting, is that there was so much more heterogeneity among Hispanic individuals as measured by K-Means clustering, than among non-Hispanic white individuals. And this study really confirms that there is much more heterogeneity within populations than between populations. And this is particularly true as we think of the extreme diversity of Hispanic populations. Lumping Hispanic populations into one category, may mask important differences in cardiovascular risk prediction outcomes, and even the notions of the Hispanic paradox that you just discussed, Merci.
Dr. Mercedes Carnethon:
I appreciate you bringing that up again, because there are so many different nuances to the observations that we see in these studies. But I'll keep moving, because we have an embarrassment of riches in this wonderful issue. So Karol I'll turn back to you.
Dr. Karol Watson:
Thanks, Merci. The next paper I'd like to discuss, is an On My Mind piece by Peter Liu and colleagues, and they entitle it, Achieving Health Equities in the Indigenous Peoples of Canada, Learnings Adaptable for Diverse Populations. Now the author's note that, lessons learned about addressing health disparities from indigenous peoples in Canada, can offer a lot of new lessons for other populations where there are similar disparities. They begin by offering historical perspective, and they say that, most of the health to disparities for the indigenous populations originate from early colonization, in dismantling of the sociocultural economic educational and health foundations, the indigenous communities had historically.
Dr. Karol Watson:
It's true that, that is true in a number of different countries. This is data from Canada, but we can see similar things in the United States. With the recognition of the historical and ongoing social health inequities, the Canadian government initiated what they call, the Truth and Reconciliation Commission, to recommend a path towards reconciliation, to create best practices for engaging indigenous populations.
Dr. Karol Watson:
For instance, in Canada, any health research or implementation program, requires the direct engagement of indigenous communities and their elders. They have to try to develop culturally safe environment, including what they say, quote unquote, anti-racism and cultural safety education for all, both indigenous and non-indigenous populations. They want to really respect community values, customs and traditions, including the access to traditional foods, and healing practices, and the support from elders. So they really are making it a very important point, that cultural sensitivity is absolutely critical to engaging these populations. You want to jointly collect data whenever available, to track progress and outcomes. And they offer many examples of successful programs developed using these principles, such as the Diabetes and My Nation program, in British Columbia, or the mobile diabetic telehealth clinic.
Dr. Karol Watson:
They offer discussion of future initiatives as well, that can help other communities in Canada. Such as, there's an initiative addressing hypertension in the Chinese population in Canada.
Dr. Karol Watson:
So this thoughtful paper, really looks at disparities in unique populations in Canada. More importantly, it offers potential roadmaps for other populations, solutions to address longstanding legacies of racism and colonialism.
Dr. Mercedes Carnethon:
Thank you so much, Karol, for that description from our neighbors from the north.
Dr. Mercedes Carnethon:
My second paper is really relevant during this hot month of July, in much of the United States and the upper hemisphere. And that's because Sameed Khatana and colleagues from the University of Pennsylvania, discuss how extreme heat is associated with higher cardiovascular mortality. For those of us who welcome the heat of summer and the opportunity to get out from behind our desks and exposed to some vitamin D, Khatana and colleagues reviewed county level daily data on temperature, and linked those data with mortality rates.
Dr. Mercedes Carnethon:
But before I summarize the findings, I invite you to California based cardiologists to join me in Chicago, where extreme heat is really only a problem for about 30 days a year. The authors found that between 2008 and 2017, when the heat index was above 90 degrees Fahrenheit, or 32.2 degrees Celsius, there was a significantly higher monthly cardiovascular mortality rate. In total, extreme heat was associated with nearly 6,000 additional deaths from cardiovascular disease. And sadly, black adults, older adults, and men, bore the greatest burden of mortality rates from extreme heat. So, we can all take lessons from that.
Dr. Mercedes Carnethon:
But turning to you now, Fatima.
Dr. Fatima Rodriguez:
Thanks so much, Merci. I'm from Florida, so I can definitely relate to the issues of extreme heat, but I'm very happy for the perfect year round weather here in Northern California.
Dr. Fatima Rodriguez:
My third paper is led by Dr. Zubair (and Chikwe) and colleagues from Cedar Sinai, and it describes changes in outcomes by race, in children listed for heart transplantation in the United States. I won't give all the details, but this research letter really nicely summarizes how the 2016 Pediatric Heart Allocation Policy revisions may have inadvertently widened health disparities between white and non-white children. This article touches on the difference between equality and equity, even in the most well-intentioned national policies. And I invite our listeners to read the full details in this special Circulation edition.
Dr. Mercedes Carnethon:
Thanks Fatima. Karol.
Dr. Karol Watson:
The next paper I'd like to discuss, is a community based cluster randomized pilot trial, of a cardiovascular mobile health intervention, preliminary findings of the FAITH! Trial, from LaPrincess Brewer and colleagues from the Mayo Clinic.
Dr. Karol Watson:
So it's well known that African Americans have suboptimal cardiovascular health metrics, such as less regular physical activity, suboptimal blood pressure levels, suboptimal diets. So the authors of this study hypothesize, that developing a mobile health intervention, in partnership with trusted institutions, such as, African American churches, might be an effective means to promote cardiovascular health in African American patients. So using a community based participatory research approach, they develop the FAITH! trial. FAITH stands for Fostering African American Improvement in Total Cardiovascular Health. The manuscript in this issue reports, feasibility and preliminary efficacy findings from this refined community informed mobile health intervention, using the FAITH! App, developed by the investigators.
Dr. Karol Watson:
They performed a cluster randomized control trial. Participants from 16 different churches in the Rochester, Minnesota and Minneapolis St. Paul, Minnesota areas. The clusters were randomized to receive the FAITH! App, that was the intervention group, or were assigned to a delayed intervention program. The 10 week intervention feature culturally relative and sensitive information modules, focused on American Heart Association's Life's Simple 7. Primary outcomes were changes in the mean Life Simple 7 score, from baseline to six months post intervention. They enrolled 85 participants, mean age was 52, and about 71% were female.
Dr. Karol Watson:
At baseline, the mean Life Simple 7 score was 6.8, and 44% of the individuals were characterized as being in poor cardiovascular health. The mean Life Simple 7 score of the intervention group, after the end of the intervention, increased by 1.9 points. In the control comparator group, it only increased by 0.7 point. Highly statistically significant, with P value of less than 0.0001 at six months.
Dr. Karol Watson:
Now this FAITH! Trial demonstrated preliminary findings, that suggest that a culturally sensitive and mobile health lifestyle intervention could be efficacious, promoting ideal cardiovascular health among African Americans. I think what's so important about this is that, they partnered with a very trusted group, the churches, and getting buy-in to a community that has had many reasons not to trust in the past, I think is critically important.
Dr. Mercedes Carnethon:
Well, thank you so much, Karol. My third paper is an original research investigation by Anoop Shah and colleagues from the University of Edinburgh, arguing that socioeconomic deprivation is an unrecognized risk factor for cardiovascular disease.
Dr. Mercedes Carnethon:
In their study, the authors evaluated how risk scores, with and without indicators of socioeconomic deprivation, performed in a population study in Scotland, the Generation Scotland: the Scottish Family Health Study, of over 15,000 adults. Again, I won't give away all the details, so that I keep our listeners excited to read the article, but all risk scores aren't created equally. And the observed versus expected number of events varied, based on whether the risk score included socioeconomic indicators or not. Further, the performance of the risk scores varied, based on the degree of deprivation that participants were currently experiencing. It's a thought provoking piece, that may challenge us to reconsider how we identify risks for cardiovascular disease in the population.
Dr. Mercedes Carnethon:
And I'm turning to you now, Fatima.
Dr. Fatima Rodriguez:
Sure thing, Merci. My last paper is led by Dr. Anna Krawisz, and is looking at how differences in comorbidities explain racial disparities in peripheral vascular interventions. This study used Medicare fee for service data from 2016 to 2018, to examine risks of death and major amputation, one year following peripheral endovascular intervention. They found that, black Medicare beneficiaries had higher population level need for peripheral endovascular interventions, and that black race was associated with adverse events following these interventions. However, after adjusting for the higher prevalence of comorbidity, such as diabetes, hypertension, and chronic kidney disease in black populations, this observation was eliminated. Again, like a common theme in many of the articles we've discussed today, this is to suggest, that moving upstream to reduce risk factors is really critical to eliminate disparities in cardiovascular disease outcomes. And this includes the understudy disease of peripheral arterial disease. Black adults were also less likely to be treated with guideline directed medical therapies in this study.
Dr. Mercedes Carnethon:
Well, thank you so much, Karol and Fatima, for your wonderful summaries of all of the excellent pieces in this issue.
Dr. Karol Watson:
And I'd like to thank all of the fantastic investigators who submitted their really fantastic work, so that we could produce this issue. And really, keep them coming. We thank you for this.
Dr. Mercedes Carnethon:
Well, thank you. So now we'll transition to our feature discussion with Drs. Wadhera and Kyalwazi, from Beth Israel Deaconess Medical Center, and the Harvard Medical School.
Dr. Mercedes Carnethon:
Welcome to this episode of Circulation on the Run podcast. I'm really pleased to host this feature discussion. My name is Mercedes Carnethon, from the Northwestern University Feinberg School of Medicine. And I'm pleased to have with us today, Drs. Ashley Kyalwazi and Rishi Wadhera from Beth Israel Deaconess, and the Harvard Medical School. And they shared with us a really important piece of work for our disparities issue, that is describing disparities in cardiovascular mortality, between black and white adults in the United States from 1999 to 2019. First of all, I really want to thank you both for submitting your important work to circulation.
Dr. Rishi Wadhera:
Thanks so much Mercedes, and thanks for the opportunity to submit and revise our manuscript.
Ms. Ashley Kyalwazi:
Thanks so much for having us.
Dr. Mercedes Carnethon:
Wonderful. I'd like to start out with you Rishi. Tell our listeners about the objectives of your study, and what your motivation was for carrying out this work.
Dr. Rishi Wadhera:
Well, I think it's been well established that, black adults are disproportionately impacted by cardiovascular disease, and experience worse cardiovascular outcomes, due to systemic inequities and structural racism. And so, the goal of our study was really, to perform a comprehensive national evaluation of how age adjusted cardiovascular mortality rates have changed for black adults, compared with white adults, over the past two decades in the United States, with a focus on some key subgroups, like younger adults and women.
Dr. Rishi Wadhera:
In addition, because we know that the neighborhood community or environment in which you live in the US, has an immense influence on cardiovascular health, we also examine changes in cardiovascular mortality for black and white adults by geographic region, rurality, and neighborhood racial segregation. And our primary objective was really, to understand whether disparities in cardiovascular outcomes between black and white adults improved, worsened, or didn't change, from 1999 to 2019.
Dr. Rishi Wadhera:
And there are some reasons to think we might have made progress in narrowing the mortality gap between these groups over this time period. There have been substantial improvements in preventative care and treatments for cardiovascular disease over the past two decades. And the expansion of insurance coverage under the Affordable Care Act, led to increases in access to care, cardiovascular risk factor screening and treatment, particularly, for black adults. At the same time, we know that, black adults were disproportionately affected by the economic recession of 2008, and experienced worsening poverty, job loss, and wealth loss, all of which are inextricably tied to cardiovascular health, and more broadly, health. And so that was our interest in really exploring how disparities in cardiovascular mortality have changed amongst black and white adults between 1999 and 2019.
Dr. Mercedes Carnethon:
Thank you so much for that summary. It's really nice to have these sort of pieces that really outline for us a lot of data, and across a number of different domains. Because it allows us really, a chance to think about those data, and how we can use those data in order to help improve health.
Dr. Mercedes Carnethon:
So tell me a little bit, Ashley, about what your study found.
Ms. Ashley Kyalwazi:
Absolutely. Yeah. So in the United States, overall, we found that age adjusted cardiovascular mortality rates declined for both populations, so both black and white adults, by around 40% from 1999 to 2019. So encouraging declines across the country. We found that these patterns were similar for both women and men, when we stratified by gender, over the 20 year period. While mortality rates declined in all regions, we still did find disparities when we stratified by age. So between the younger and older black women, versus younger and older black men, we found that, younger black men and black women were dying at higher rates, and were at increased risk of death from cardiovascular mortality, compared to younger white women and men, respectively. But we also found that black women and men living in rural areas consistently experienced highest mortality rates. And then finally, black adults living in higher areas of residential racial segregation, and compared to those living in low to moderate areas of residential racial segregation had higher mortality rates, as well.
Dr. Mercedes Carnethon:
Wow, this is a lot. And it's really describing a lot of disparities across multiple domains that we can easily measure. Which aspects of these results in your work did you find the most surprising, Ashley?
Ms. Ashley Kyalwazi:
Yeah, I was intrigued, I think overall, by just the gaps. I was very encouraged by, I think, the declines over time. On an absolute scale, the country has made a lot of progress, in terms of reducing cardiovascular mortality rates for both groups. But still, by the end of the study period, there were notable gaps between black adults and white adults. Particularly, between black, younger women and white, younger women, we see that by the end of the study period, black, younger women still remain over two times the risk of death from cardiovascular disease than younger white women. Which I think, leaves something to be desired from a public health and health policy standpoint, with regards to how we're going to kind of decrease these disparities.
Dr. Mercedes Carnethon:
I wanted to follow up on that point. Why do you think you see such disparities between black and white younger women? I love the opportunity of the podcast to allow authors a chance to speculate, beyond what they would do in the paper.
Ms. Ashley Kyalwazi:
Absolutely. I think that, there are a lot of great efforts on a national scale right now, to kind of address the disparities between black and white women. The Association of Black Cardiologists, for example, had a whole paper out about ways to really target and provide preventative measures for black women. So for example, working with communities, where there's a high proportion of black women, to figure out what community based research looks like. Engaging with churches, different types of methods, to really understand the barriers that black women face towards obtaining preventative care.
Ms. Ashley Kyalwazi:
I think the disparities that we are seeing, could potentially parallel well known and documented disparities in maternal health outcomes. So I think, from a perspective of preventative care, really thinking about, what are the barriers to healthy cardiovascular profiles for black women pre and postnatally, to ensure that their cardiovascular health is an actionable before and after the pregnancy?
Ms. Ashley Kyalwazi:
And then I think, broadly, the challenges that black women face, mirror the challenges of black adults, plus the additions of like social stressors, things that we looked at in this study neighborhood residential racial segregation, access to healthcare, and all of those things kind of contribute to the profile that black women face, in terms of being often, the heads of their households as well, and carrying on a lot of different societal challenges.
Dr. Mercedes Carnethon:
Thank you so much for that. I really appreciate that.
Dr. Mercedes Carnethon:
As I read the paper, one of the findings that I found the most surprising, and it was challenging for me to understand, is that while the absolute difference in rates was declining, or getting smaller over time, between black and white men and women, the rate ratios remained elevated across the course of time. I think, these concepts can be a little challenging to understand, not just to me, but to others as well. That when one measure of effect is showing progress, but another is still reporting a disparity.
Dr. Mercedes Carnethon:
Rishi, could you explain for our listeners, how we can see progress on one metric, but still find a mortality rate ratio that's 1.3 times higher in black, as compared with white men, for example?
Dr. Rishi Wadhera:
Thanks for that really important question, Mercedes. Just to summarize, we presented two outcomes that compared cardiovascular deaths among black and white adults in our paper, absolute rate differences, and then separately, rate ratios. And I think, both measures provide important complementary insights. I think that, understanding the absolute rate difference in cardiovascular deaths is critically important from a public health perspective, because it characterizes excess deaths experienced by black adults, compared with white adults. The fact that the absolute rate difference in cardiovascular death has narrowed over the past two decades between these groups is positive news. In contrast, the rate ratio provides us with important insights on the relative difference, or disparity or gap, between black and white adults.
Dr. Rishi Wadhera:
So again, both are important, both provide sort of synergistic and complimentary insights. And just to sort of cement that, as an example, you were talking to Ashley earlier, about some of the patterns we noticed amongst younger black women and white women. The absolute rate difference in cardiovascular deaths between younger black women, compared to younger white women, decrease from 91 per 100,000 in 1999, to about 56 per 100,000 in 2019. And that's good progress. However, our rate ratio analysis indicated that, still in 2019, young black women were 2.3 times more likely to die of cardiovascular causes than young white women. Highlighting that, we still have a lot of work to do, to address disparities between these groups. Some of which, Ashley already talked about.
Dr. Mercedes Carnethon:
Thank you so much for that excellent explanation. I know it's certainly, I find it alarming to hear, but then I remember I'm actually not young anymore. So maybe this doesn't apply to me quite as much. But no, I appreciate the explanation.
Dr. Mercedes Carnethon:
So your report was really unique, in that you studied these disparities, as we discussed, across a number of domains, age, geography, even racial residential segregation. Whereas, the pronounced disparities have been reported in a few of the other domains that you studied. I'm really interested in hearing more about racial residential segregation. I think, a lot of people don't fully understand what the concept is, and the ways in which racial residential segregation may contribute to higher rates of cardiovascular death among blacks.
Dr. Mercedes Carnethon:
Ashley, would you mind explaining to us first, what racial residential segregation is? And then really, how it would contribute to higher rates of cardiovascular death?
Ms. Ashley Kyalwazi:
Yeah, absolutely. So in its simplest terms, racial residential segregation is just the physical separation of two or more groups by race and/or ethnicity into different neighborhoods. What gets tricky is, like the long history within the United States of how we got to this point, where you see numerous degrees of segregation across the country. Residential racial segregation in the United States dates back to policies pre World War II, that resulted in kind of discriminatory banking practices and policies. For example, reverse red lining and gentrification, much of which the extent still exists today. And that's what we see kind of, I think, in our results when we looked at high versus low to moderate areas of residential racial segregation, and how those kind of track onto the trends that we see in cardiovascular mortality over time.
Ms. Ashley Kyalwazi:
The residential racial segregation impacts almost every aspect of life. You can imagine where you live, we know definitely impact, for example, your zip code can impact health outcomes. We've seen individual's cardiovascular health kind of trend with something as simple as your zip code. Where you live really does impact your, for example, access to affordable housing, health insurance, where your primary care physician is, whether or not you even have one. What that trip looks like to see your primary care physician, is it hours on end, and unrealistic to get to, or is it just around the corner?
Ms. Ashley Kyalwazi:
Educational opportunities, which leads to income, which we know is linked to cardiovascular disease employment in all of these aspects. Even access to green space. In some metropolitan areas that are more segregated, we see that, black adults, for example, have less access to green space, and numerous studies have shown that, that does impact overall health, but then also, from a cardiovascular disease perspective as well. So I think that, given that we know that lack of access to all of these key determinants can adversely affect cardiovascular mortality, and just general cardiovascular health, I think is very interesting that we found that, there was this link between high residential racial segregation and cardiovascular mortality. That we definitely can look into more, and understand kind of in more detail, that the mechanisms at play and ways to intervene.
Dr. Rishi Wadhera:
And just to layer onto and reinforce Ashley's really excellent answer to that question. We know that black adults are more likely to live in disadvantaged neighborhoods, because of the intentionally racist policies that were put in place many decades ago, that Ashley described so well. And black communities and segregated communities, as Ashley mentioned, are less likely to have access to primary care, high quality hospital care, and green spaces, but also, pharmacies and healthy foods. And we also know, there's a lot of empirical work that's shown that black communities, disproportionately experience psychosocial stressors, trauma.
Dr. Rishi Wadhera:
Also, these communities are disproportionately exposed to climate change, such as extreme heat. There was a recent paper that extreme heat has been linked to increases in cardiovascular mortality, and disproportionately affects black communities. These communities are also disproportionately exposed to pollution. All of these things we know are linked to cardiovascular health, and represent the effects of again, intentionally racist policies that were put into place many decades ago, the effects of which still persists today. Which will require equally intentional policies that aim to dismantle these longstanding effects, if we hope to make progress in advancing health equity, and specifically, cardiovascular health equity.
Dr. Mercedes Carnethon:
I appreciate the facility with which the two of you address the multiple complex contributors to cardiovascular health. It's even more impressive coming from two clinicians. So I really appreciate you taking the time to explain this. And this is where I really like the opportunity to open up and say, what more do you want your clinical peers to know about? For example, how does this affect the day to day encounters that you have in clinic with black patients, and other patients who've been traditionally underrepresented? How do you hope your clinical peers will use this information to promote cardiovascular health equity? And I'll open it up to either of you to respond.
Ms. Ashley Kyalwazi:
Yeah, I can get on that one. I think that, the disparities that our paper highlights, really requires a multisystem level approach to tackling, from public health to public policy. But I think at a provider level, to your question, Mercedes, physicians must be able to, I think at first, read the data and understand that these disparities exist.
Ms. Ashley Kyalwazi:
If there's no insight with regards to the risk profiles, that simply black women and black men have, because of systemic racism, because of these inequities, then I think, we're already kind of steps behind where we need to be. So recognizing disparities in cardiovascular disease burden for black men and women, prioritizing education on cardiovascular risk. A lot of the conditions are preventable with appropriate access to care and education around these topics. And so, providing education about the signs and symptoms of heart disease and treatment options for black men and women. Recognizing the history of medical mistreatment for black adults in this country. And really, tailoring the approach towards the individual who comes into the office, who might have very valid reasons for hesitating to take a medication, or a lot of questions that need time and consideration.
Ms. Ashley Kyalwazi:
At a research level, I think, more data and resources should be spent on studying risk prevention and treatment for cardiovascular disease in black adults, and really, developing more community based models, that really get at the specific interventions that work within black communities, that are culturally specific, that are targeted and relevant, for the populations that we're talking about.
Ms. Ashley Kyalwazi:
I think finally, and I'll let Rishi chime in, I think, this is shockingly low level of racial and ethnic representation in the field of cardiology as a whole. And we know that, diversity in healthcare can improve health outcomes. So from a cardiology perspective, I think, training the next generation of black young men and women to take up their seats at the table, and really advocate for some of these issues, alongside individuals who are already doing great work, would be essential towards reducing disparities that we see. And so all of the above, I think, I would encourage for my colleagues.
Dr. Mercedes Carnethon:
Thank you so much. Rishi, any final thoughts?
Dr. Rishi Wadhera:
No, I'll just add onto Ashley's again, really outstanding response that, this is a tension we face when we see patients in cardiology clinic all the time. I think, awareness about disparities, and the multiple factors that contribute to disparities in cardiovascular health, particularly, as it relates to race and ethnicity, are increasingly being recognized as they should be.
Dr. Rishi Wadhera:
And one of the challenges, how much can clinicians do within the bounds of hospital walls? We can make sure that we get patients the treatments they need. We can make sure we screen patients appropriately. But we know, as we've discussed, that so many factors beyond hospital walls, like widening income inequality, that's disproportionately affected black adults, and has been worsening over the last several decades. Widening educational inequality, that again, disproportionately affects black adults, and has been worsening over decades, also affect how. So I think, thinking about how clinicians, researchers, and policy makers, can work together to address some of these challenges, issues, and broader social determinants of health, that also exist outside our clinical practice, or hospital walls, will be really, really important, if we are serious about advancing health equity in this country.
Dr. Rishi Wadhera:
I don't think, we can operate in silos anymore. In the clinical world, in the research world, in the policy making world, we need more researchers and clinicians to have a seat at the table when it comes to policy making, individuals who understand how all of these complex factors are inextricably tied to one another, so that we can seek and implement solutions that advance cardiovascular health.
Dr. Mercedes Carnethon:
Thank you so much. The insights that we've gotten, from not only your written work, but even more importantly, this opportunity to speak with you today, and share with our readership, have just been invaluable. And I really appreciate the amount of time that you spent, in preparing the manuscript, and really contextualizing the findings with us today, as well as in writing. So thank you so much for contributing this really important work to our annual disparities issue.
Dr. Rishi Wadhera:
Thank you so much, Mercedes. We really appreciate all the time you and the Circulation team took to make the manuscript stronger.
Ms. Ashley Kyalwazi:
Thank you so much for having us. It was truly an honor to have this conversation and to submit our work.
Dr. Mercedes Carnethon:
Well, thank you.
Dr. Mercedes Carnethon:
That wraps up our feature discussion for this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, from Northwestern University, Associate Editor and guest editor of the disparities issues. So thank you so much.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit hajournals.org.
This week, please join author Ambarish Pandey and Editorialist Linda Peterson as they discuss the article "Frailty Status Modifies the Efficacy of Exercise Training Among Patients with Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the HF-ACTION Trial" and the editorial "Heart Failure With Reduced Ejection Fraction (HFrEF): ‘The Importance of Being Frail.’"
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article, Heart Failure Reduced Ejection Fraction in Evaluating the Efficacy of Exercise Training. But guess what? It appears it may be more efficacious in those that have high Frailty Index scores, as opposed to those that may not. But before we get to our feature discussion, let's grab a cup of coffee and go through some of the other articles in the issue. Would you like to go first?
Dr. Carolyn Lam:
I would love to, and this first paper is one that defines epigenetic biomarkers of lifelong cardiovascular health exposure and really contributes to our understanding of their roles in cardiovascular disease development. First though, a little quiz for Greg. So, Greg, what does DNA methylation mean to you?
Dr. Greg Hundley:
Well, Carolyn, DNA methylation. So, what I understand is these methyl groups get involved with our DNA and actually affect change over time that leads to phenotypic expression of, maybe, new traits. But I don't know. Maybe I'm not quite up to date.
Dr. Carolyn Lam:
Oh, you're perfect. Indeed, DNA methylation is a widely characterized epigenetic modification, which means exactly as you said. It's a regulatory modification to our DNA induced by environmental exposures and can affect gene expression. And this is the topic of today's paper by Doctors Zheng, Hou, and Lloyd-Jones from Northwestern University Feinberg School of Medicine and their colleagues. So, what they did is they studied blood DNA methylation at over 840,000 methylation markers measured twice over five years in participants of the CARDIA study. Epigenome-wide association analyses on a clinical cumulative cardiovascular health score were then performed in both CARDIA and compared in the Framingham Heart Study.
Dr. Carolyn Lam:
The authors identified 45 midlife DNA methylation markers associated with clinical cardiovascular health metrics, such as body mass index, blood pressure, blood glucose, and total cholesterol longitudinally measured since young adulthood. The methylation markers were located in genes involved in lipid metabolism, insulin secretion, and cytokine production, which could not be fully attributed to genetic factors. So, they proposed and validated in summary a methylation-based risk score to promote a personalized cardiovascular disease risk evaluation beyond traditional cardiovascular risk factors.
Dr. Greg Hundley:
Oh, wow, Carolyn. Interesting, a methylation-based risk score to promote personalized cardiovascular disease risk evaluation. Wow! That's really exciting.
Dr. Greg Hundley:
Well, I'm going to go to the world of preclinical science, and just like last week where we had a really nice article on myocardial regeneration, this week, we've got another. And so, Carolyn, early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a very short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than one week after birth.
Dr. Carolyn Lam:
Interesting. Now, I see that these investigators worked with possums. Could you tell me why they did that, and what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So, this work was led by Dr. Wataru Kimura from the RIKEN Center for Biosystems Dynamic Research and their colleagues. The reason they studied possums, so the marsupial possum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least two weeks after birth. Remember we stated before, all the other mammalian species, it's only one week after birth. So, this appears to be the longest postnatal duration of such a capacity among mammals examined to date, and AMP kinase signaling was implicated as an evolutionary conserved regulator of mammalian postnatal cardiomyocyte proliferation.
Dr. Greg Hundley:
And they additionally found that in a separate mouse experiment, the authors noted that the pharmacological inhibition of AMP kinase signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in neonatal mice, so really exciting work in the area of cardiomyocyte regeneration.
Dr. Carolyn Lam:
Wow, indeed! And I've learned now about possums. Thank you, Greg.
Dr. Carolyn Lam:
So, Greg, have you ever asked yourself, what is the frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated gene variants in the general population? Well, guess what? This next paper addresses just that in more than 18,600 UK Biobank participants who had undergone whole-genome sequencing, ECG, and cardiovascular magnetic resonance imaging.
Dr. Greg Hundley:
Wow, Carolyn, another really interesting study from the UK Biobank. So, what did they find?
Dr. Carolyn Lam:
So, this study is from Dr. Chahal from the Center for Inherited Cardiovascular Diseases Wellspan Health in Lancaster, Pennsylvania and colleagues, and they found that approximately one in six of adults with putative pathogenic variants in dilated cardiomyopathy genes exhibited early dilated cardiomyopathy features potentially associated with the genotype. And it's most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.
Dr. Carolyn Lam:
Among individuals with putative pathogenic dilated cardiomyopathy gene variants, ECG or CMR-detected early features were nearly four times more common than clinically manifest dilated cardiomyopathy or early features. Over 90% of subjects with these gene variants in dilated cardiomyopathy-associated genes did not have a prior history of dilated cardiomyopathy, and the overall clinical or subclinical penetrance of dilated cardiomyopathy-associated single pathogenic variants was highly variable between genes ranging from zero to 67%. And so, in conclusion, a genotype-first screening approach for dilated cardiomyopathy using a large genetic panel is currently not suitable in the general population due to incomplete understanding of the genetic architecture and reduced penetrance of the associated genes.
Dr. Greg Hundley:
Very nicely said, Carolyn. Wow! Well, let's take a look and see what's in the mailbag. And first, there's a Research Letter from Professor Huguenard entitled, “Frequency of Screening Detected Intracranial Aneurysms in Patients With Loeys-Dietz Syndrome.” And our own Bridget Kuehn has a really nice piece on Cardiology News.
Dr. Carolyn Lam:
Nice. There's also an On My Mind paper by Dr. Sattar, McGuire, and Gill entitled, “High-Circulating Triglycerides Are Most Commonly a Marker of Ectopic Fat Accumulation: Connecting the Clues to Advanced Lifestyle Interventions,” and an exchange of letters between Dr. Groothof and myself, Dr. Lam, regarding my article on “Efpeglenatide and Clinical Outcomes With and Without Concomitant SGLT-2 Inhibition in Type 2 Diabetes: An Exploratory Analysis of the AMPLITUDE-O Trial.”
Dr. Carolyn Lam:
Ah, that was awesome. Well, thanks, Greg. I am so excited to get to the future discussion that you queued us on so well, frailty in heart failure with reduced ejection fraction. Here we go.
Dr. Greg Hundley:
You bet.
Dr. Greg Hundley:
Welcome, listeners, to this July 12th, 2022 feature discussion. And we have with us today, Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and Dr. Linda Peterson, an editorialist for this article from Washington University in St. Louis. Welcome to you both. Well, Ambarish, We're going to start with you. Could you describe for us basically the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Ambarish Pandey:
Thanks, Greg, for having me on this, and thanks to Circulation for publishing our article. Yeah, I think the premise for this study stems from the longstanding known benefit of exercise training in patients with heart failure with reduced ejection fraction. Now, that was shown in the HF-ACTION trial, where individuals with chronic stable heart failure with reduced ejection fraction underwent exercise training, and there was demonstrated benefit in quality of life and adjusted analyses. There was a protocol-specified adjusted analysis that did demonstrate improvement in some of the key primary endpoint.
Dr. Ambarish Pandey:
Based on these results, CMS has approved exercise training and cardiac rehabilitation in patients with chronic stable heart failure with reduced ejection fraction. However, despite this mandate from CMS and generally well-accepted benefits of exercise training in heart failure with reduced ejection fraction, the uptake of exercise training has been pretty low, and there's a lot of heterogeneity in the improvement in outcomes that is associated with exercise training.
Dr. Ambarish Pandey:
So, we wanted to see whether frailty, which is a well-characterized syndrome of reduced physiologic reserve and impaired homeostatic tolerance to stressors and is common in patients with HFrEF, we wanted to see how frailty modifies the beneficial effects of exercise training in HFrEF. And based on the existing literature and some of the prior works we have done, we hypothesized that individuals who are frail and who have more functional impairments are going to have more targets for improvement in their functional status and thus would be more likely to benefit from exercise training. And we looked at this in the HF-ACTION trial itself and using the Rockwood Frailty Index and the difference in primary outcome and treatment effect of exercise among frail and non-frail individuals.
Dr. Greg Hundley:
Very interesting, so really sort of a look back in HF-ACTION data. Describe a little bit more for us that study design, and then specifically, what was the study population that you used to test your hypothesis?
Dr. Ambarish Pandey:
Right. So HF-ACTION was a randomized control trial multi-centered that was sponsored by NHLBI and was conducted in the early 2000s and basically focused on chronic stable patients with heart failure with reduced ejection fraction who have not had a hospitalization in the past six weeks and have ejection fraction less than 35% and class II to IV. And these participants were randomized in one-to-one fashion to getting aerobic exercise training followed by some home-based exercise versus the usual care.
Dr. Ambarish Pandey:
And in our study, what we looked at was we looked at the effect modification by baseline frailty status on the treatment effect of exercise training. So, we calculated the frailty index, which is a well-established measure of frailty using a Rockwood Index Model, and we stratified patients by frail versus non-frail status based on a Frailty Index cut-off of 0.21, such that higher index identifies more frail participants. And then, we looked at how the treatment benefit of exercise training on different outcomes was differential across the frail and non-frail strata. We looked at qualitative interaction, and we also looked at the Frailty Index, so the continuous variable to assess the benefits of exercise across the spectrum of frailty in the study population.
Dr. Greg Hundley:
And so, before we get to your study results, how many patients were in your study? Give us an idea of what was the range in age, and then also the composition of sex? How many men? How many women?
Dr. Ambarish Pandey:
Right, so this is really important because that's addressed to the generalizability of the study. So, the study included around a little over 2,100 participants. The mean age was 59 years. 28% were women, and 32% were self-reported black individuals with chronic stable heart failure. That was the demographic distribution. The age was slightly younger than what you've commonly see in observational studies with heart failure, and that is largely because the study recruited patients who were able to do exercise training and were able to do exercise tests with peak VO2 and peak VO2 peak excess capacity assessment at baseline and follow-up. So, that kind of selected for a slightly younger population.
Dr. Greg Hundley:
Very nice. And so, what were your study results?
Dr. Ambarish Pandey:
So our study results are, indeed, pretty interesting. We identified that around 60% of patients with chronic stable heart failure with reduced ejection fraction who were in the trial were actually frail based on the Rockwood Frailty Index Model. And we observed that among the study participants, the exercise training was associated with significant improvement in the primary composite endpoint of all-cause hospitalization or death in frail participants, but not in the non-frail or less fail participants. And there was a significant treatment interaction, such that baseline frailty modified the treatment effect of exercise training for the primary composite endpoint.
Dr. Ambarish Pandey:
Now, this was largely driven by a significant reduction in all-cause hospitalization among frail individuals who underwent exercise training, and not so much by an effect on mortality. And we did not see a significant difference in the mortality component of the primary composite endpoint across frail versus non-frail status participants. So, in a nutshell, baseline frailty did modify the treatment effect, largely driven by substantial reduction in the risk of all-cause hospitalization among frail participants more than non-frail participants.
Dr. Greg Hundley:
And before we get to Linda in her interpretation of your study, Ambarish, did you see the same effects in frail men, in frail women? And also, what about in individuals that might be a little older versus those that were perhaps younger?
Dr. Ambarish Pandey:
That's a really important question, and we were a little bit limited to do further subgroups because we are dealing with around, I think, 2,000 participants and we had frail, non-frail, and we did not do a further subgroup stratification by sex or by age. The age range was rather narrow. It's 58 years plus/minus 13 years, so we didn't really have a lot of older individuals above 75, something like what REHAB-HF Trial has shown in the news, a recent trial.
Dr. Ambarish Pandey:
We couldn't address the question of whether the effect modification was further modified by sex or age, so I think that's the two-level interaction. But I think that is something that would be interesting to test perhaps in a pool analysis of multiple exercise training studies, which is something we are considering.
Dr. Greg Hundley:
Thank you. Well, listeners, now we're going to turn to our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, and, Linda, very provocative results here, heart failure reduced ejection fraction. And certainly, we like to go to things like cardiac rehab, but we're hearing this it seemed to make a difference if you were frail versus not frail.
Dr. Linda Peterson:
Right, I think that's an important distinction here in this article as Ambarish has so eloquently put forth, and it's especially important because other articles have shown in looking at the PARADIGM-HF Study and ATMOSPHERE it appears that one out of two patients with HFrEF are actually frail. And so, the magnitude of these findings and the importance of these findings is highlighted by that study. And this frequency of frailty is roughly double that of community-dwelling adults who are over age 90, so we're thinking of frailty usually as much older adults, but in HF-ACTION, actually, the patients' average age was 60 in the patients with HFrEF.
Dr. Linda Peterson:
So, there's almost an accelerated aging phenotype we're seeing here in a large proportion of the patients who have HFrEF. I think this has an enormous impact on a lot of the patients that we're seeing with HFrEF, and we should be alerted to looking for frailty and potentially screening for frailty. And I think another highlight of this study is that it points out the importance of frailty because frail patients have a 50% higher risk of hospitalization and death, according to some other studies, particularly one by Faray and their group and also by Yang and their group.
Dr. Linda Peterson:
And so, it highlights the importance of getting patients who are frail with HFrEF into cardiac rehab or getting them some sort of aerobic exercise training. But paradoxically, frailty is also associated with a lower likelihood of those particular patients on getting into cardiac rehab and also getting on goal-directed medical therapy. And that was shown by Phil Ades and his group. So, I think the importance of these findings by Ambarish and his group are to be commended, and they're very important for a large proportion of our patients with HFrEF.
Dr. Greg Hundley:
Very nice. Well, let's turn back to Ambarish, and then follow up with Linda. Ambarish, what do you see as the next study that should be performed in follow-up to your study?
Dr. Ambarish Pandey:
I think that's a great question. And I think we are just beginning to realize the magnitude of impact that frailty has in the care of patients with heart failure. And this goes across the spectrum of ejection fraction, both HFpEF or heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Indeed, the burden of frailty is higher in patients with heart failure with preserved ejection fraction, and they are more of the accelerated aging phenotype.
Dr. Ambarish Pandey:
And I think the next study basically should look at a targeted approach to exercise training or category of intervention among patients who are most likely to benefit from it, which would be patients who have a high frailty burden or patients who have HFpEF. I think they go hand in hand when it comes to frailty and HFpEF. So, I think that's the next study to do is to see to what extent we can actually identify and target exercise training in the highest risk individuals who are most likely to benefit from it because that subset of highest modifiable risk is indeed identified by frailty and when you look at other subtypes by HFpEF which has a lot of high frailty burden.
Dr. Greg Hundley:
And, Linda, from your perspective, what do you see as the next study to be performed in this sphere of research?
Dr. Linda Peterson:
Yeah, I think this study really provides a springboard for future studies in HFrEF, in particular. One, what hospital interventions can be done in patients to get them moving more, and really assess is there a possibility of different types of exercises to get patients less frail even while they're in the hospital when they're enroute to going home? And then also, how do we have different mechanisms by which we can get more patients into cardiac rehab? Clearly, our national average of getting patients who qualify for cardiac rehab, which is a class I indication is 20% at best, and the aim from the AHA is 70%.
Dr. Linda Peterson:
There's a big gap there, so interventions looking at implementation and getting patients to cardiac rehab or looking at other types of aerobic exercise training, such as home-based cardiac rehab for patients who don't have a cardiac rehab center next to them, I think the field is wide open for different studies to springboard off of these findings.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, for bringing us this research study, highlighting that among patients with chronic stable heart failure and reduced ejection fraction, that baseline frailty modified the treatment effect of aerobic exercise training with a greater reduction in the risk of all-cause hospitalization.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.
Speaker 5:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Fabian Eichelmann and Associate Editor Svati Shah as they discuss the article "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we are going to get into the world of lipidomics and understand how some lipid metabolites may be more predictive of cardiovascular events above and beyond the conventional serum lipoproteins, like HDL and LDL. But before we get to that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
Sure thing. This first paper is about the basilar artery. Have you ever heard the analogy that the basilar artery is the neurologists' equivalent of our cardiologists' left main coronary artery? Well put, isn't it? Well, that's from the editorial that accompanies this paper, but basically, occlusion of either artery can be fatal without rapid re-perfusion. So that's why the basal artery is the neurologists' left main coronary artery. Re-perfusion therapies for acute basilar artery occlusion include thrombolysis or mechanical endovascular thrombectomy.
Dr. Carolyn Lam:
In today's issue, Professor Hu from University of Science and Technology of China, and Professor Nogueira from University of Pittsburgh School of Medicine in the US, these are the co-corresponding authors, and their colleagues, reported the outcome of the attention registry of more than 2000 patients with acute basilar artery occlusion who enrolled prospectively and consecutively at 48 sites in China from 2017 to 2021, and followed for the primary outcome of a favorable neurological functional outcome defined as a modified Rankin score of zero to three at 90 days.
Dr. Greg Hundley:
Wow, Carolyn, I love that analogy. So the basilar artery is kind of similar in the brain to the left main coronary artery in the heart. Whoa, what did they find here?
Dr. Carolyn Lam:
So, in this nationally representative observational study, the authors found a significant association between endovascular thrombectomy and better functional outcomes and survival at 90 days in patients with acute basilar artery occlusion, and this was compared to chemical thrombolysis. Now, notably, this relationship was modified by the baseline NIH stroke scale. Specifically, patients with baseline NIH stroke scale of 10 or more had an increased rate of favorable outcome when treated with endovascular thrombectomy, whereas no significant beneficial effect was seen in patients with baseline NIH stroke scores of less than 10. Now, all this is discussed in a beautiful editorial by Dr. Hankey, entitled, "Endovascular therapy for acute basilar artery occlusion."
Dr. Greg Hundley:
Oh, beautifully stated, Carolyn. What a great article. But guess what, Carolyn? I've got a quiz for you.
Dr. Carolyn Lam:
Uh-oh.
Dr. Greg Hundley:
This one's open answer, so it's not multiple choice. Can you name a unique feature of zebra fish pertinent to the study of cardiovascular disease?
Dr. Carolyn Lam:
Okay. Watch me hedge there because, first of all, I'm a daughter of a zoologist. So my dad would have a heart attack if I couldn't say something about the zebra fish. So, what I do know is the zebra fish is an excellent animal model for genetic studies of heart generation, basically development. So, there must be something really cool there about how we can observe that.
Dr. Greg Hundley:
Excellent, Carolyn. So very well done. As you know, and your dad knows, certain non-mammalian species like zebra fish, have an elevated capacity for innate heart regeneration. Now, understanding how heart regeneration occurs in these contexts can help illuminate cellular molecular events that can be targets for heart failure prevention or treatment, your area of expertise. The epicardium, the mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebra fish, and these authors, led by Dr. Jinhu Wang from Emory University performed single cell RNA sequencing and identified seven epicardial cell clusters in adult zebra fish, three of which displayed enhanced cell numbers during regeneration.
Dr. Carolyn Lam:
Oh, interesting, Greg. So did these cell clusters provide some clues that could be applied clinically?
Dr. Greg Hundley:
Yes. Carolyn. So these authors identified that these subsets of epicardial cells emerge in post embryonic, zebra fish and sponsor regions of active cardio myogenesis during cardiac growth and regeneration. And as the heart achieves its mature structure, these cells facilitate extracellular matrix hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. These cells associate with the function of the hyaluron and proteoglycan link protein 1 or HAPLN1 paralogue in production and organization of hyaluronic acid containing matrix in cardiac injury sites and thereby enable normal cardiomyocyte proliferation and muscle generation. And so Carolyn, potentially in the future targeting hyaluronic acid regulation by manipulation of HAPLN1 in human epicardial cells could potentially modulate cardiac repair after myocardial infarction.
Dr. Carolyn Lam:
Well, thanks, Greg. That was awesome. Well, the next paper I want to tell you about is one in which a novel ECG based machine learning approach was used to determine and predict multiple structural heart conditions. So the authors led by Dr. Chen from Department of Translational Data Science and Informatics at the Geisinger Health System in Danville, Pennsylvania. So these colleagues hypothesized that a composite model would yield higher prevalence and positive predictive value to facilitate meaningful recommendations for echocardiography.
Dr. Greg Hundley:
Oh wow, Carolyn. Machine learning, it's just emerging everywhere these days. So don't we need a large data set to do this?
Dr. Carolyn Lam:
Absolutely, and listen to how large this is. So using more than 2.2 million ECGs linked to electronic health records and echocardiography reports from almost 500,000 adults between 1984 and 2021, the authors trained machine learning models to predict the presence or absence of any of seven echo confirmed diseases within a year, and the composite model and the composite label that they used included moderate or severe valve disease and reduced ejection fraction. So their composite recommend model where reco is E-C-H-O we used age, sex ECG traces, and had an area under the receive operating curve of 0.91 and a positive predictive value of 42% at 90% sensitivity with a composite label prevalence of 17.9%. Whereas the individual disease models had area under curve ranging from 0.86 to 0.93 and lower positive predictive values from about 1% to 31%.
Dr. Carolyn Lam:
So in summary, they showed that an ECG based machine learning model using a composite endpoint can identify a high risk population for having undiagnosed clinically significant structural heart disease while outperforming the single disease models and improving practical utility with higher positive predictive values. So this approach may facilitate targeted screening with echo to improve under diagnosis of structural heart disease.
Dr. Greg Hundley:
Wow, Carolyn, really great article from the world of machine learning. Well, how about we jump to some of the other articles in the issue and I can go first. There are two Research Letters. The first Research Letter comes from Professor Adlam entitled "Pregnancy and Spontaneous Coronary Artery Dissection Lessons from Survivors and Nonsurvivors." And our own Dr. Joe Hill, our Editor-in-Chief also has a Research Letter entitled “Impaired AMP Kinase Signaling in HFpEF Associated Atrial Fibrillation.”
Dr. Carolyn Lam:
Wow, what an issue filled with great stuff. There's an AHA update by Dr. Churchwell on promoting nutrition security through policies and programs. And there are highlights from the circulation family of journals by our own Molly Klemarczyk, now known as Molly Robbins. I'd love to tell you a little bit about it. The association of new onset AF with cardiovascular outcomes in patients hospitalized with COVID-19 are described in Circ Arrhythmia, and EP. Rates of cardiovascular and cerebral vascular disease mortality among Asian subgroups are presented in Circ CV, Quality and Outcomes. Blood pressure and glycemic control are presented in patients with heart failure in Circ Heart failure. The associations of atrial update with technetium 99 pyrophosphate scans for transthyretin amyloid cardiomyopathy with incident atrial fibrillation and possibly earlier diagnosis of amyloid is presented in Circ Cardiovascular Imaging.
Dr. Carolyn Lam:
And finally the outcomes associated with larger burdens of residual thrombus after aspiration thrombectomy for STEMI are presented in Circ CV Interventions. Isn't that cool? And finally, we've got an On My Mind paper by Dr. Arany on “It’s Time to Offer Genetic Testing to Women with Peripartum Cardiopathy”. So that wraps it up, Greg. Let's go to our feature discussion, shall we?
Dr. Greg Hundley:
You bet.
Dr. Greg Hundley:
Welcome listeners to this feature discussion on July 5th, and we are very fortunate today. We have with us Dr. Fabian Eichelmann from the German Institute of Human Nutrition in Potsdam, Germany, and our own associate editor, Dr. Svati Shah from Duke University in Durham, North Carolina. Welcome to you both. Fabian, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?
Dr. Fabian Eichelmann :
Yeah, sure. So first of all, thanks for the invitation to speak here. So this project was basically comes from a collaboration between us and a group in Redding, UK and we are part of a consortium called FAME, which is short for fatty acid metabolism. And there, we are interested in the health effects of fatty acid metabolism in general. And in this paper that we did, this was particularly cardiometabolic diseases. And I think this is no surprise that we look at lipid metabolism in this context, because there's so many really now also causal factors, lipoproteins, total triglycerides for specific cardiometabolic outcomes. So this is the reason why we wanted to look at it. And through this collaboration, we were also able to harness the potential from two different study designs that I probably will go into later, but which really gave us an opportunity to really generate I think, quite interesting insights.
Dr. Greg Hundley:
Very nice. And so what was that hypothesis?
Dr. Fabian Eichelmann:
So the hypothesis was that since the lipid metabolism has formally only been mostly in the clinic, at least been measured by lipoproteins and total triglycerides, for example, but the lipidome of plasma, for example, is really rich. It's really heterogeneous and it contains many different lipid classes and different fatty acids. And through novel technologies and in this case, lipidomics, you can really dive in really deeply and look at this in a specific manner. And then the idea was to really look at this and potentially identify lipids that would be associated or could surface as biomarkers for cardiometabolic diseases and at the same time, if those lipids were also sensitive to a dietary intervention that really tried to modulate the dietary intake of a fat.
Dr. Greg Hundley:
Very nice. And so how did you set this up? What was your study design and what was your study population?
Dr. Fabian Eichelmann:
So we had two different study populations for this. So the first one was the EPIC-Potsdam, which is a cohort study, a large scale cohort study here in Potsdam, which started in the nineties. And there, we basically associated baseline concentrations of these lipid measurements with later on occurring incident cardio metabolic outcomes. And in this case, this was type two diabetes and primary CVD and CVD in our case meant myocardial infarction and stroke. And we did that we checked which lipids would be statistically significantly associated after multiple testing with at least one of these outcomes. And then we took those lipids further into intervention trial, which is called the DIVAS trial in Redding, as I said, UK. And there, they had basically a dietary intervention trial that really wanted to assess if the change in the fatty acid proportions in the diet affects the lipids. So there we had the lipidomics measurements at baseline and after four months, and then we compared three different trials to each other.
Dr. Greg Hundley:
Very nice. And so how many patients did you include and who were these patients? Men and women? And did they have, for example, prior cardiovascular disease?
Dr. Fabian Eichelmann:
So in EPIC-Potsdam, that's a population based cohort study. All of the participants were drawn from the registries and invited. So these were apparently healthy people. And in those we did these association analyses and those we used the design, which is a case cohort design, which is a sub sample of the whole cohort, which is a really effective way and efficient way of analyzing biomarker projects. And there we had in total 1,262 control participants, and then later on additionally, a 775 type two diabetics and 551 CVD cases. In the DIVAS trial, that was a trial where participants also men and women, which was also the case in EPIC-Potsdam were invited, and they were at a higher risk of at the higher cardiovascular disease risk, which was measured by score, but they didn't have any prior cardiovascular diseases. And those were 113 participants that were randomized to one of these diets.
Dr. Greg Hundley:
Right. So it sounds like two studies. One, a large case control study and looking at different plasma lipid concentrations in two separate groups. And then the second was a randomized trial, a smaller trial of 113 individuals looking at a dietary intervention. So with that established, tell us your study results.
Dr. Fabian Eichelmann:
Yeah. So in the first step, as I said, where we associated lip concentrations to later occurring disease, we found from the 282 lipids that we looked at, 69 were really associated to at least one of these outcomes. And interesting here we saw that only eight were associated to both outcomes and 49 were specific to cardiovascular disease and 12 for specific to type two diabetes. And from those 69, we found 19 were also sensitive to the dietary intervention, and what was really striking here was that of these 19, 17 were perfectly in agreement with a suggested beneficial effect, meaning that those lipids that were associated in the EPIC-Potsdam studies on the cohort study with a higher disease risk were reduced by these diets or in the opposite direction, we saw those lipids that were associated with lower risk were increased by these diets. So this was quite a striking observation there.
Dr. Greg Hundley:
So it sounds like from the lipidomics analysis, there was a construct of certain blood lipid markers that were associated with cardiovascular events, and then in your randomized trial, you were able to modify those by different dietary interventions?
Dr. Fabian Eichelmann:
Exactly.
Dr. Greg Hundley:
So listeners, now we're going to turn to our own associate editor, Dr. Svati Shah. And Svati, you see many papers come across your desk. What attracted you to this particular paper and how do we put this study's results in the context with other studies that have been published in really the sphere of lipidomics research?
Dr. Svati Shah:
Yeah. Thank you, Greg. I just want to point out that this is a really elegant translational study. I think these papers can be very complicated to understand, and I think the authors did a fantastic job of really laying out how you can combine cutting edge what we call omics, using these cutting edge technologies, but applying them to human cohorts with a very strong clinical lens. So it's not just what do we learn about biology, but also what do we learn about biomarkers that might be relevant to how we take care of patients? And that's really one of the biggest things I loved about this study is sort of, you get to have your cake and eat it too. You get to learn about biology, but with a very strong clinical lens towards identifying clinically relevant biomarkers. I think another really important strength of this study, which differentiates it is this sort of use of really cutting edge lipidomics.
Dr. Svati Shah:
So this is a subset of omics where we're really looking at these granular lipid classes. And some of the clinicians might say, well, we measure cholesterol, why is this different? And you know, Greg, really what lipidomics allows us is a much more granular snapshot of these complex lipid species that are only grossly captured by the cholesterol levels that we would measure normally if we were seeing a patient in clinic. So to be able to get this really granular snapshot of what is happening to lipid biology and how it might relate to cardiovascular events, diabetes, I think is really important. And finally, I think the coolest part about this study is, in other studies we always have a little bit of a hard time with what we call confounders. And what does that mean? That means there may be other things for why you're seeing these biomarkers associated with your disease and those might be uncaptured things, things that you didn't measure in this study. And we call that residual confounding.
Dr. Svati Shah:
And I think the authors in this study, not only statistically adjusted for those potential confounders, but also importantly, the DIVAS study, where they took the biomarkers that they found from EPIC-Potsdam and said, do they change with the dietary intervention? And in fact, they did find that many of these lipid, these granular lipid species improved, meaning they went in the proper direction in terms of your health with a diet that was higher in unsaturated fats. So really proving not only the potential biology of the benefit of diets enriched in unsaturated fats, but also that these particular biomarkers are modifiable, so they're able to be changed even in this case within 16 weeks with just a dietary intervention. So to me that really was just a beautifully laid out study that highlights really what translational omics and these biomarker studies can do as we think about the clinical care of patients.
Dr. Greg Hundley:
Very nice. And so it sounds like listeners, moving beyond the lipoproteins, LDL, maybe total cholesterol and these granular lipid species cholesterol esters, free fatty acids, fingo-lipids, glycerophospholipid, et cetera, that's what we were studying in this particular manuscript. So, well, let's turn back to Fabian. And Fabian, what do you see is the next study to really be performed in this sphere of research?
Dr. Fabian Eichelmann:
I think what would be really interesting and what would really kind of prove what we saw is if you could find a way that an intervention, be it like a drug intervention and not diet because we looked at dietary intervention, that kind of shows the same as we saw, but also that really specifically only alters these lipids and how obviously not really feasible, but if that would be going on for a long enough period, if you also saw these effects that we now saw after four months would also affect the health outcomes instead of just only these proxies.
Dr. Greg Hundley:
Very nice. And Svati, how about you? What do you see as the next study that might be informative in this sphere of research?
Dr. Svati Shah:
Yeah. Great question, Greg. I mean, to me, I really think about this gap that we have in actually translating these findings in how we take care of patients. So again, really provocative results here. We have really significant P values, strong effect sizes, biomarkers that are modifiable, but in the paper they show that it adds on top of a clinical model, so what we might use as clinicians in the clinic that these biomarkers may help on top of what we already know about patients. But we really need to implement these findings and study that implementation for how this might in a real world setting actually change outcomes in patients and how we can actually help explain to clinicians how these results might be beneficial for clinical care.
Dr. Svati Shah:
So on top of what Fabian already said, I think really implementation science is a huge gap in how we take these translational omics discoveries and use them in support of improving patient care. We have lots to learn about these lipid biomarkers and lots more discovery science that can be done. As Fabian said, can we find drugs that might beneficially modified these lipid subspecies? But again, I think this gap in implementation science is really important.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Fabian Eichelmann from the German Institute of Human Nutrition in Potsdam, Germany, and our own associate editor, Dr. Svati Shah from Duke University in Durham, North Carolina for bringing us these really provocative results, highlighting the identification of several lipids and their association with cardiometabolic disease risk. And then also nested within the same paper, a subset of individuals undergoing a randomized clinical trial demonstrating benefit by a dietary fat intervention, and there possibly supporting the substitution of dietary saturated fatty acids with unsaturated fatty acids perhaps as a potential tool for primary disease prevention.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week's special podcast features the CardioNerds. Join Maryjane Farr, Vanessa Blumer, and M. Trejeeve (Tre) Martyn as they interview Amit Goyal and Daniel Ambinder, who started the Cardio Nerds podcast, website, and learning resources.
Dr. Maryjane Farr:
Welcome, everybody, to Circulation on the Run. My name is Maryjane Farr from UT Southwestern, and here we have an opportunity to take a week from Circulation on the Run and let our social media editors take over and do an interview of their choice. To welcome both two of our social media editors, first, Vanessa Blumer, who is going to be doing her postgraduate year seven in Cleveland Clinic, in advanced heart failure, and Trey Martin, who is a newly-minted faculty member in heart failure and amyloidosis and population health at the Cleveland Clinic. And they've chosen to interview Dan Ambinder and Amit Goyal of CardioNerds.
Dr. M. Trejeeve (Tre) Martyn:
So, thanks to Vanessa and to Dr. Farr for setting this up, and thanks for Amit and Dan for being here. Really excited to talk to you guys. The first thing I want to start off with is to get a little bit of an origin story about CardioNerds. And if you could tell us how you got started and how this all came to be, I think the listeners would be interested to hear that.
Dr. Daniel Ambinder:
Thank you so much, Trey, and it is really great to be here and nice to meet you. This is Dan. So, the origins of CardioNerds actually began early 2019. One of our mentors put us together, Dr. Reza Manesh, who's one of the co-founders of Clinical Problem Solvers, and thought that we should be thinking about potentially starting a podcast. And that definitely lit the spark and is it going to be something that's worthwhile pursuing?
Dr. Daniel Ambinder:
And so, we said to ourselves, at rounds we could teach five people at Noon conference, maybe we could reach out to 20 and to 40 people, but maybe with a podcast, we could reach 500 people at a time and that would be something that would be really worthwhile. So let's just sit down, create a script and start from there. And we created the first episode, aortic stenosis, and we did the recording and we just loved that process. And after that, we said, "This is worth it." So we made a couple more episodes-
Dr. Amit Goyal:
Hey, I'm just going to chime in here real quick. This is Amit. And I'll start off by saying, thank you so much for this invitation and what a joy it is to be doing this with two people who we respect so much, Vanessa and Trey. The process of creating this podcast and education, we learned so much. And it was so much fun that we decided why don't we just give it a shot and trial it by creating maybe three, maybe four episodes and seeing how it goes from there. So that was a backstory.
Dr. M. Trejeeve (Tre) Martyn:
I was curious how you guys thought about initially getting traction. Because that, I think, is the really challenging part and how you thought about getting listenership for your podcast and expanding. And was it focusing on the product, obviously? But I was curious how you, because now you have, you guys have this gravitational pull of prominent faculty and trainees that want to work with you, but how did you get there, and what was the strategy in doing that?
Dr. Amit Goyal:
I'll say that, initially, like Dan said, that we went out with the idea of just giving it a shot, seeing if it fit with our schedules, seeing if we enjoy the process and if there was enough of a need and a desire for this. And so, we said, why don't we create a short number of episodes? And if we could get 500 listeners, that would be the biggest audience that we have individually reached. And before you knew it, the 500 per episode turned into 5,000 per episode.
Dr. Amit Goyal:
And we realized that, even without actively and very deliberately trying to promote this, there was already a need and a desire for this. There was a niche that we were filling that we hadn't realized. The value of asynchronous medical education for people within or people who are interested in the care of patients with cardiovascular illness. So I think that's one. I think that's one takeaway, that there is value for open access, asynchronous education that is high quality.
Dr. Amit Goyal:
I think from there, our next big major pivot was well into COVID-19 when ACGME and the bodies decided that we should have virtual recruitment. This is when, enter Dr. Nosheen Reza, who was the chair of ACC FIT section at the time. And she messaged us on Twitter early afternoon, one day, saying, hey, is there maybe a way we could potentially use social media and the growth that cardio nurses has already had up until that point to maybe help connect residents with programs, ACGME accredited cardiology program, to have their fellows present a case, use one of their experts to provide an editorial expert commentary and then had the program director have a message for the applicants.
Dr. Amit Goyal:
And in discussing the case, the fellows would also talk about the program. And what that did was, I think, internally for us, it helps us realize that this just made it so much, the quality of the content and the breadth of the content, the depth of content just skyrocketed, right? I mean, we had fellows bring us cases of preeclampsia and bicuspid aortic valve, aortic stenosis with pregnancy. I mean, it was just, it was incredible that CardioNerds wasn't just about what we wanted, it was very rapidly turning into a communal entity that other people could take pride of. And so, that became really important to us.
Dr. Daniel Ambinder:
Yes. And I'll just add, again, as Amit's explained is, it happened sequentially. But it was actually a pivotal moment, right before the CardioNerds case report series was launched, where things were feeling stale. We definitely love to teach, there's no doubt about it, and that is a huge part of this. But there was a certain point where we were teaching and we just felt like there needs to be something more.
Dr. Vanessa Blumer:
Thank you so much, Dan and Amit. I mean, I think everything that you do, this is Vanessa. I think everything that you guys do, it's so inspiring for, I think, all generations, right? I think it's inspiring for future generations, but I think you guys inspire people at all levels. When you think about CardioNerds, what is your purpose? What drives you? What is your motivation? What do you think is your ultimate, why?
Dr. Daniel Ambinder:
While we had this passion to educate, that is not necessarily the why. And all of a sudden, as soon as we took off, there was multiple opportunities and multiple things dragging us in different directions. And we immediately sought out our mentor, Dr. Sanjay Desai, who is our program director at the Osler Medical Residency, and he said, "You got to find out your why right away." So, now our why includes to create and disseminate education, promote diversity, equity, inclusion, foster wellness, and humanity in the field of cardiology and in life, and provide mentorship and sponsorship and invigorating a love of cardiovascular medicine and science. Choices were easy. We can just say, "Does this fit the rubric of our mission? Is this an opportunity that we want to pursue? Is this something that's going to enhance this mission?"
Dr. Amit Goyal:
Putting words to a mission was extremely helpful for us. And actually, part of that conversation we're having at that time was around diversity and inclusion, because that's when Sanjay was saying you have to define what your organization stands for and what is a mission, and who are the people that are going to represent these cardiology fellowship training programs, in the eyes of residents who are thinking about a field in cardiology, and how deliberate we want to be about asking program directors to be cognizant about representing diversity in the fellows that they have representing the programs. And so, around these discussions, that's when Sanjay said, okay, there are a lot of things that you can do with CardioNerds, but before you do that, figure out what is your goal and how every action fits into that goal.
Dr. M. Trejeeve (Tre) Martyn:
Thanks, Amit. So, keeping that mission that you described in mind, what do you think is the ultimate goal of CardioNerds? Or, I guess I should say, where do you see CardioNerds being in five to 10 years? I know that's far out and some of the days you're just trying to get through the day you have in front of you. But if you could envision a future and, in the structure or the mission, keeping that in mind, where do you see CardioNerds in five years, let's say?
Dr. Amit Goyal:
Yeah, thanks, Trey. That is such an important question and a very difficult question to answer. I will say that things have evolved so quickly. And so, I think our one challenge that we talk about that we don't know how to resolve just yet is how to build CardioNerds in a way that's scalable, that outlives us. How do we make CardioNerds go beyond us? And that's Dan and I, but also everyone else within CardioNerds, a generation later. How do you maintain CardioNerds?
Dr. Amit Goyal:
And I think the logistic part of that is probably not that hard to figure out, right? You need admin support, you need resources, you need to delegate, you need leadership structure, but how do you grow it and have it outlive you in a way that still continues within the ethos of how you started it, within that mission, within the goals that you set it out to? And I think that's really something that we have to figure out, but that's going to be probably a deliberate way of how we grow it and how people grow into a leadership structure within it, how we design the programs. So I think that that part of the growth depends on the actions and the decisions we make today.
Dr. Daniel Ambinder:
Yeah. I definitely agree with all of that. And just to be brief, I just reiterate, CardioNerds is really for the people and what people want changes. And so, we're always listening and we're getting tons of feedback. And as the network grows, people are coming to us with projects and ideas, and we always try to find people that are just really passionate about what they want to do and give them a space to do it and try to give them as many resources and mentorship and sponsorship as we can, and then get out of the way. And so, that has already been a great recipe for a lot of different outpouchings and outgrowths of CardioNerds that really, again, goes back to the entire mission. And so, it's almost really hard to predict what will happen in five to 10 years, but we are ready and listening and looking to see what we can help the community with and vice versa.
Dr. Vanessa Blumer:
Thank you so much, Dan. And I mean, these answers have been fascinating, honestly. This interview, in general, has just been so enlightening. Dan, I think you touched on the point of democratizing cardiovascular education, which I think is, or should be, one of the highlights of this interview. Can you maybe touch a little bit more on this? And we talked about the why, can you talk about the how and see how you see this moving forward?
Dr. Daniel Ambinder:
Yeah. Thanks so much, Vanessa. We agree, democratization of cardiovascular education, what does that even mean? But what we mean by that is that why should somebody, somewhere off in a distant country, not have the ability to take care of their patients in the most topnotch way, because they may not have had the exposure to a particular part of cardiovascular education? Breaking down some of the formal barriers between levels of trainees, so, for example, CardioNerds' journal club really encompasses that.
Dr. Daniel Ambinder:
Once a month, our CardioNerds Academy, which you haven't talked about, puts on an amazing show. It's really a way where journal club hits Twitter in a traditional format, same process of discussing the article, but in the Twitter format. So it allows for this amazing group of, usually hundreds of people, honestly, to come together and discuss. And what's so amazing is that the scientific community has really gotten on board. So we often have authors of the papers that we're discussing join the actual Twitter club.
Dr. Daniel Ambinder:
And then we have medical students that are asking questions of the authors and this amazing engagement between multi-levels of education coming together. There are certainly ways that some, I wouldn't say the barriers, there are certain ways that these things can be helpful, like traditional learning and formats like that, but sometimes not. And so, we aim to be constructively destructive in terms of that way. And that's what we've done with democratization of cardiovascular education.
Dr. Amit Goyal:
If I might just add, then when we think about democratizing cardiovascular education, it's both for the learner, in terms of making high-quality education available and accessible, but also for the educators, right? I had a conversation with a mentee when he was a resident, and he called me and said, "Amit, I want to be an interventional cardiologist, but I also want to be a medical educator. How does that work?". And the fact that he was asking that is, for me, a problem, right?
Dr. Amit Goyal:
I've had this conversation with Dr. Katie Berlacher, who was also a medical educator, but is a cardiologist. Why does there seem to be strain between becoming a medical educator and becoming a cardiologist, right? That's not there for hospitalist medicine and other fields. So that's part of the reason we really enjoy having all sorts of trainees and faculty come on and teach on the show and be deliberate about how they want to teach on the show.
Dr. M. Trejeeve (Tre) Martyn:
Thanks a lot, Amit and Dan. In some ways, it sounds like you guys have been able to democratize another area other than education, which is clinical trials. And I wanted to get your perspective and hear a little bit more about the CardioNerds Clinical Trials Network. It really seems like an amazing program you guys have set up.
Dr. Amit Goyal:
It all goes back to the mission, but the origins of that is, Dr. Starling, he was a pretty early adopter for CardioNerds. He was a part of our very early heart failure series back in early 2020. And he was such a great supporter and source of encouragement and mentorship for so long. And Trey, I know you understand this, and Vanessa, you too, but he, for one reason or another, he brought up CardioNerds at a meeting about PARAGLIDE-HF. And I think present were Dr. Eugene Braunwald, who's part of the steering committee and Dr. Robert Mentz, who is the lead principal investigator, began recruiting around the time of COVID-19, affecting recruitment for a lot of trials. Lot of challenge there that I think we can all understand at this point.
Dr. Amit Goyal:
And we said, "Okay, well, not sure. We haven't thought about clinical trials, but why don't we think about it and get back to you?" So then, we said, okay, well, what's the core strength of CardioNerds? It's the people, right? After we did the CNCI recruitment series, hosting fellowship training programs, we realized that that worked out really well, because brilliant fellows from all these different programs came and elevated the education. So we established the Healy Honor Roll, after Dr. Bernadine Healy, of training programs who are part of the honor roll by nominating a FIT ambassador, a fellow and training ambassador, who's interested in education.
Dr. Amit Goyal:
We said, okay, well, why don't we just extrapolate that to a clinical trial? Instead of fellowship training programs, it would be trial sites that have training programs affiliated with them. Instead of a program director nominating a FIT ambassador for education, it would be the site PI nominating a FIT trialist for recruitment. But how would that fit as part of the mission? Well, with the Healy Honor Roll, with the academy, with everything else, hosting people on the podcast, it's always been, how do we pair content creation with personal and professional development?
Dr. Amit Goyal:
So, with a clinical trials network, the question was, how do we pair equitable trial enrollment with FIT personal and professional development? How do we meaningfully engage the fellows in the conduct of clinical trials, but also meaningfully help develop their interest in clinical trials and academic careers? How do we equip them with important skills and knowledge in the space? So we created a curriculum that's related to career development and equitable enrollment. And then, also, how do we make sure that they have, and deliberately, they have networking and mentorship as part of this?
Dr. Amit Goyal:
Since then, after we got all the fellows involved, the impact has been absolutely amazing. Because there are two goals here, right? There's equitable recruitment and there's fellow development. And just by having these meetings, by having the curriculum, the fellows are already engaged. So at the very minimum, half the mission is working out really well. But what about the other half, and that's equitable recruitment. So I will say from the time of the first FIT-recruited patient up until June 2nd, okay? So, that's February 8 to June 2nd, we account for 16% of all trial sites, but 49% of patients enrolled.
Dr. Amit Goyal:
Of the patients that we have enrolled, 54% are women compared to 47% for the non-CardioNerds sites. And 80% are BIPOC, or Black, Indigenous and people of color populations, compared to 19% for patients not enrolled by CardioNerds fellows. So, the impact there is, I think it's flooring, honestly. It is earth shattering and we are all amazed by it. And part of the question has been, can this be consistent, right? Is this a fluke? But since, when we had 30 patients enrolled, then we had 35 patients enrolled, we had 40 patients enrolled, these numbers had stayed relatively consistent.
Dr. Amit Goyal:
The question now is why? How is it that we've been so effective in disproportionately recruiting patients who had been historically underrepresented? And that's a very important question that we are really excited to dive deep into the data and try to understand. So our plans with Rob Mentz and the rest of the people who really made this possible is to really look at the numbers in terms of recruitment.
Dr. M. Trejeeve (Tre) Martyn:
That's really amazing, guys. And I have to applaud you on the vision to do that, and then to think about how to meet your mission, and then also to meet an unmet need that is... Because clinical trial enrollment, when you go through it, it's always slower than you hope. And this is such a great way to light that, to one, ignite a new generation into how to do clinical trials on the ground floor, but then also to increase the diversity of enrollment is amazing and you guys should be applauded for that.
Dr. Vanessa Blumer:
I also want to congratulate the both of you. Thank you. You guys are trailblazers and definitely are changing the world for all of us and making it a better place. So, we're so proud of you. We have to wrap up, so maybe just one last question before we go. So, maybe a two-part question, or you can choose to answer one or the other. But what do you guys feel most proud of? And what do you guys think has been the most important lesson that you have learned in the CardioNerds journey so far?
Dr. Daniel Ambinder:
Thanks, Vanessa. It definitely always helps to emphasize this. We really started this right before COVID. We had no idea COVID-19 would hit. And, really, the whole world was lurched into this virtual space. And there was always the hashtag, in real life? Is this even real life? And there was a sense that maybe it wasn't. And when we went to ACC and we met our people in person, and relationships were, not like they were just starting, but they had been ongoing for years. We really, really felt that this is something so real, and that is the lesson of CardioNerds. The lesson of CardioNerds is that the cardiovascular community is a real cohesive, beautiful community, and there's a lot of CardioNerds out there that embrace their nerdom when it comes to cardiology.
Dr. Amit Goyal:
I think in terms of what I'm taking away from this journey and what I'm going to keep relying on, the lessons I'm going to keep relying on, are one, is just find something you love and lean in. Right? I mean, when we first started telling people, "Oh, we're going to make a podcast and, hey, by the way, we're going to call the CardioNerds," the reactions we were getting from people, people we deeply respect and look to for advice and for role models, there were a lot of people who said, "Oh, that's great. It's so nice to have a hobby, but what are you going to do during your research block?" Right. That's great.
Dr. Amit Goyal:
But I think the reason why we've been able to stick with it is because we found something that we genuinely love to do. And so, I think that's really, whatever it is for you, that's really important. I think the second thing that's been extremely important for us is to surround yourself by people who inspire you, who push you, who will advise you, who make you want to be better. And that's people who are senior to you, people who are your peers, people who are junior to you, right? Because you can get as much inspiration from somebody who's 10 years your junior as you can from somebody who's 10 years your senior.
Dr. Amit Goyal:
I know I've taken a lot of inspiration from Vanessa and Trey and have relied on both of you for advice. I remember Vanessa, I think I had a very, a specific conversation about the clinical trials program when it was just a burgeoning idea way back when. And if number two is to take inspiration, take advice, take mentorship, number three is give. To flip that around and try to just give yourself and make yourself available to as many people around you, because that's how you build a community and that's how you give back and thank the people who give to you.
Dr. Maryjane Farr:
Okay, great. So, thank you. Thanks all of you. Four contemporaries who are leading the way into the future of cardiovascular medicine, science, and education. So, on behalf of Circulation on the Run, we have been so delighted and honored for you to spend some time with us, have a podcast about the podcasters. But you're not just podcasters, this is a real and amazing and innovative platform, and we are so excited to see where you go next. Any final, last words from Trey and Vanessa or Amit and Dan?
Dr. Vanessa Blumer:
Thank you so much to Circulation on the Run and Dr. Farr for this opportunity. Amit, Dan, like always, it's such a pleasure. I learn so much from you every single time that I get the opportunity to interact with the both of you and you are an inspiration to all of us. So thank you so much for this platform.
Dr. M. Trejeeve (Tre) Martyn:
Thanks to Dr. Farr for Circulation on the Run, for this platform, Amit and Dan for taking the time out of their evening to be here, Vanessa, for joining me in Cleveland. And I would say that you guys, the CardioNerds founders, you're an inspiration that you don't necessarily have to wait to make an impact.
Dr. Amit Goyal:
Yes. Thank you so much. I don't even know what to say. I'm speechless. I'll say that, for Dan and I, we're still just a couple of nerds. I do my recordings in my attic, Dan's in his home office. I think if you, we're still besides ourselves with disbelief that we are a topic of conversation for a platform like Circulation on the Run. It is absolutely a privilege and an honor for us. And so, I think all I can do is just say thank you so much, and then to Dr. Farr for the invitation to have this conversation for Circulation, and Dr. Hill for giving us this platform. I think this is just such a... Again, we are speechless. Thank you. Thank you so much.
Dr. Daniel Ambinder:
I'm equally as speechless and this podcast, Circ on the Run, really reminds me of my earlier roots, reaching out of my own institution, because it was a Circ social media team that first gave me a great glimpse at what happens outside of the institution that I had been training at for many, many years. And to see how the sausage is made, in terms of how research is vetted and undergoes a strict peer review, was really amazing. And I had the opportunity of meeting Dr. Hill and also being part of the team as COVID was revving up and Circulation had to... We're getting bombarded with all these COVID-related articles. And there was just a very important understanding that what gets published is going to be really, really important.
Dr. Daniel Ambinder:
So, watching that from the sidelines, under the mentorship of Dr. Amit Kara, just seeing how that happened, gave me such an important understanding that what you put out into the world, whether you're Circulation or writing a personal tweet or putting something out on CardioNerds is just really important and treat it as if it's something that's going to be there forever. And I learned so much about collaboration and I also learned so much about podcasting, because of Circ on the Run, it was actually the first podcast I was on and I don't like to listen to that very often. So thank you so much. This is such an honor to bring this full circle and come back and join you all.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Roderick Tung, editorialist William Stevenson, and Associate Editor Sami Viskin as they discuss the article "First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial" and the editorial "Can Early Ablation of Ventricular Tachycardia Improve Survival?"
Dr. Greg Hundley:
Welcome listeners to this June 21st, 2022 issue of Circulation on the Run. And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Listeners, what a very interesting forum that we're going to have in this session today with Dr. Rod Tung, bringing us an article from first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy with concurrent defibrillator implantation. Some results from the Pause sudden cardiac death randomized clinical trial.
This article is really interesting because it is collecting data from multiple centers from multiple countries in Asia. But before we get to that article, why don't we grab a cup of coffee and go through some of the other articles in the issue? Well, the first is entitled cardiovascular magnetic resonance for rejection surveillance after cardiac transplantation. And it comes to us from Dr. Jim Pouliopoulos from the Victor Chang Cardiac Research Institute. In this study, CMR based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between cardiovascular magnetic resonance and endomyocardially based measures of cardiac rejection and determine the CMR cutoff values between various cardiac rejection grades.
Then after that, a prospective randomized noninferiority pilot study was undertaken in adult orthotopic heart transplant recipients who were randomized at four weeks post orthotopic heart transplant to either CMR or endomyocardially based rejection surveillance. And clinical endpoints were also assessed at 52 weeks. And so listeners, what did this investigative team find? Well, despite similarities in immunosuppression requirements, kidney function and mortality between the groups, the rates of hospitalization and the rates of infection were lower in the CMR group.
On 15 occasions, patients that were randomized to the CMR arm underwent endomyocardial biopsy for clarification or logistic reasons, representing a 94% reduction in the requirement for endomyocardially based surveillance. And so listeners, a noninvasive CMR based surveillance strategy for evidence of rejection in the first year after orthotopic heart transplantation is feasible. And interesting, listeners, these results really suggest the possibility for further studies to confirm whether CMR and perhaps in combination with other modalities could be used to survey orthotopic heart transplant patients for acute rejection without necessarily having to undergo endomycardial biopsy. There's an excellent editorial by Dr. Jim Fang from the University of Utah who also reviewed this paper.
Well, listeners, let's next turn to the world of preclinical science. And this paper comes to us from professor Simon Sedej from Medical University of Graz. It involves the insulin and insulin growth factor one or IGF-1 pathway. And that is known as a key regulator of cellular metabolism and aging. Now, although its inhibition promotes longevity across species, the effect of attenuated IGF-1 signaling on cardiac imaging really remains controversial. So what did the authors find? Well, they found that cardiomyocyte IGF-1R over expression in mice resulted in physiological hypertrophy and superior cardiac function in early life, but led to accelerated cardiac aging, heart failure and reduced lifespan in late life. Mechanistically, increased cardiomyocyte IGF-1R signaling accentuated cardiac dysfunction by reducing autophagy and mitochondrial oxidative capacity at old age, and therefore clinically pharmacologic inhibition of cardiac IGF-1R signaling in late life could suppress the age related deterioration of cardiac performance and perhaps increase lifespan. And therefore age should be considered as a major outcome determinant in future clinical trials, testing IGF-1R P13K inhibitors for cardiac benefits.
Well listeners, what is our next study? And this study is somewhat related to our feature discussion, which we'll get to in a few minutes. It's from Dr. Paolo Della Bella from San Rafael Hospital, and it is a two phase prospective multicenter randomized clinical trial that was performed to evaluate the benefit of ablation after first implantable cardiovert defibrillator, or ICD shock. And patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock. And that was phase A of the study. Then afterwards, they were re-consented and patients were randomly assigned in a one-to-one fashion in the second phase or phase B to immediate ablation. That's within two months from shock delivery or continuation of standard therapy.
And the primary endpoint of the study was a composite of death from any cause or hospitalization for worsening heart failure. And amiodarone intake was not allowed except for documented atrial tac-arrhythmias. So listeners, what were the results from this trial? Well, ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined endpoint of death or worsening heart failure for hospitalization, lower mortality and fewer ICD shocks. And these findings therefore provide support for considering ventricular tachycardia ablation after the first ICD shock.
Now this study and the feature which will be coming up in a few minutes is nicely reviewed in an editorial from Bill Stevenson at Vanderbilt University. Well listeners, what other articles are in this issue? Well, from the mail bag, we have a research letter from Professor Solomon entitled Health Status Trajectories Before and after hospitalization for Heart Failure. Also, there is a second research letter from Professor Eikelboom entitled Rivaroxaban 2.5 Milligrams Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients with Chronic Atherosclerosis. And then next there's an ECG challenge from Professor Rosenfeld entitled Around and Around, a Wide Complex Tachycardia.
Well listeners, what a great series of articles. And now we're going to get on and visit with Rod Tung, Sami Biskin and Bill Stevenson to evaluate first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy, concurrent with defibrillator implantation.
Well, listeners, welcome to this June 21st feature discussion. And we're very fortunate today to have with us Dr. Roderick Tung from the University of Arizona in Phoenix. We also have our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee. Welcome gentlemen. Well, Roderick, we're going to start with you. Rod, can you describe for us some of the background information that went into the construct of your study and what was the hypothesis that you wanted to address?
Dr. Roderick Tung:
Well, thank you, Greg, Pause is really the culmination of a lot of personal academic and cultural exchanges between many Asian centers and particularly in China. In terms of exchanges, where we would go across overseas, do a lot of different VT cases. And this all started in about 2013. And at that point in time, I was struck by a lot of differences that we were seeing, particularly whenever they wanted us to do a case, it tended to be a nonischemic etiology patient, and they always wanted to see some sort of epicardial procedure. And these are the ones that are enriched for epicardial substrates. As many listeners know, the ischemics tend to have more endocardially based scars. And that's why epicardial BT ablation is typically reserved for those that either have failed endocardial or those ARVC patients or non-ischemic cardiomyopathy.
So that was the first thing, is there's a paucity of ischemic cardiomyopathy in Asia, which is still inexplicable. The second thing that was really interesting in my observations going to Asia was that the defibrillator penetration and adoption is not widespread like it is in America. And in a very Amero-centric view, we always think that, oh, well, everything else is a departure from a standard of care. Well, when you look at 1.4 billion people, that's a really significant population at risk for sudden death that's not being treated the same way that we typically see it in a lot of Western cultures. So I felt like it was a perfect fertile grounds for clinical exploration. And that's really where Pause was born, is to be able to look at the impact of catheter ablation and ICD therapies on the risk of sudden death. And that's really how the trial began.
Dr. Greg Hundley:
And what was the hypothesis, Rod, that you wanted to address?
Dr. Roderick Tung:
Well, when we started designing Pause in 2014, 2015, there had only been two prior trials that were published and that was Smashed VT in New England Journal. And then there was VTAC by Karlheinz Cook in Lancet. So really the hypothesis was to be able to assess whether preemptive or first line catheter ablation at the time of defibrillator implantation, which is not what we do in the US, we usually wait till there's therapies, if that decreases the composite endpoint of recurrent VT cardiovascular hospitalization mortality.
Dr. Greg Hundley:
Very nice. And so describe for us, Rod, your study population, and then the design that you use to address the hypothesis.
Dr. Roderick Tung:
So this was a randomized controlled trial, multicenter across 11 centers in China, Korea, Japan, Taiwan. These were really well respected and regarded academic centers. I do want to give a shout out to many of them, Kyoko Sojima, who trained with Bill Stevenson, wrote so many seminal papers in VT. In Japan, Akid Nogogami who really was charged with and responsible for opacity some of the mechanisms of particular VT, then there's Yao Yin in Beijing who's done great work in atrial fibrillation, cardiac neuroablation. Ming Long Chen, Chan Yang Jeng. So some really great names, and it was done over 11 centers, one to one randomization between control, which was just ICD, and the active arm was ICD with catheter ablation within 90 days of the ICD implantation.
Dr. Greg Hundley:
And how many patients, and then what were your study results?
Dr. Roderick Tung:
So we ended up with 121 patients that were randomized, 61 versus 60, 180 were eligible and screened. And what was really also different about this trial compared to others is that we involved a non-randomized registry. Those were patients that refused to be randomized, and most typically didn't want to have a defibrillator. And that's where the cultural differences of ICD acceptance are different. For two reasons. Number one, physicians actually don't truly believe a lot of the defibrillator data is relevant to non ischemics in Asia and the Asian population. So there's actually a little bit of an academic barrier of generalizing historical ICD data to Asia, which I observed with a lot of the physicians.
And number two, patients sometimes don't want that technology in there, and they have different ideas of sudden death. So these patients were actually put into a registry and followed prospectively with catheter ablation alone without background ICD therapy. And that's very unique because the amount of data that has been prospectively followed for ablation sans ICD therapy is very few. So that was 47 in the registry. And there was 121 that was one to one randomized.
Dr. Greg Hundley:
And what did you find?
Dr. Roderick Tung:
Well, we found that those that underwent concomitant ablation with their ICD implantation that presented with monomorphic VT had a lower rate of the composite triple endpoint of VT recurrence, cardiovascular hospitalization, and death. This was largely driven by a nearly 20% absolute risk reduction in VT recurrence. There was a 4% absolute risk reduction in cardiovascular hospitalization, but this is not significant. And mortality rates were low. It was seven and 8% in those arms. So one of the things that we were hoping to get to was actually looking at mortality, but I think this is challenging with background ICD therapy there. And number two, it's challenging because mortality rates are lower in non-ischemic cardiomyopathy. And that's because they don't have the concomitant comorbidities of peripheral vascular disease, coronary artery disease, older age, cetera. So we actually had a pretty low rate of mortality, which we were hoping to get to, but that wasn't able to be assessed in this because of the low rates.
Dr. Greg Hundley:
Very nice. Well, now listeners, we're going to turn to our own associate editor, Dr. Sami Biskin. And Sami, many papers come across your desk. What attracted you to this particular study?
Dr. Sami Viskin:
Well, we need to better define what is the optimal timing for VT ablation in patients with the organic heart disease. As we have seen many patients that are referred too late for ablation, where they already have an arrhythmic storm and recurrent shocks. And on the other hand, we have seen studies like the Berlin Study from Cook that fail to show any benefit on endpoints like heart failure or mortality. So the study by Tung arrived shortly after the different study by Paolo Della Bella, the PARTITA study, that was also studying patients at an earlier stage. So in the Partita study, they were studying patients at the time of the first ICD shock. And then Rod came with this study where he studied patients at the time of ICD implantation.
Now, usually authors ask to get an executive review of their article. In this occasion, we as the editors, we saw the opportunity and asked Rod to submit his paper as fast as possible and made the correction as soon as possible so we could get the two papers dealing with early VT ablation in the same issue with an invited editorial by Dr. Stevenson so we could put everything in context.
Dr. Greg Hundley:
Very nice. Well, Bill, Sami has set you up very nicely here. And as the editorialist, help us put these results from Rod into the context of what we know already today in this sphere of investigation pertaining to VT shocks, defibrillator implantation.
Dr. William Stevenson:
Yeah. So first I want to congratulate Rod on a very important study. It has been so difficult to conduct randomized trials of VT ablation and intervention, and to be able to bring this to fruition and internationally in Asia is really quite an accomplishment. We definitely need more information that guides us as to when VT ablation should be performed in people who have defibrillators and are having spontaneous episodes of VT. And we know that in patients with ischemic heart disease, with coronary artery disease, post infarct VTs, that catheter ablation can reduce the episodes of recurrent VT and reduce shocks from VT. And this is a very important quality of life issue for patients with defibrillators. But we haven't really had good data, certainly not randomized multicenter data in other patient populations. And we still are grappling with, does a reduction in VT episodes improve other outcome measures?
Does it really improve quality of life? Does it reduce hospitalizations? Does it translate to a reduction in mortality? And so Rod's study, one of the strengths of it being in Asia is that there were a lot of patients who had non-ischemic causes of heart disease. And more than a third of patients had arrhythmogenic right ventricular cardiomyopathy, and his study makes it clear that those patients really benefit substantially with a reduction in VT episodes. And that overall, VT episodes are reduced in all three of the subgroups of different diseases, the ARVC and the ischemics and the non ischemics that were included in the trial. But I think it's worth digging in a little more to the non-ischemics, because they did not seem to receive the benefit that the arrhythmogenic right ventricular cardiomyopathy and the ischemic cardiomyopathy patients received. So that the efficacy was largely driven by the benefit in the ischemics and the ARVC patients.
So one of the important considerations I think is when you're in your office with a patient who has a defibrillator and has had episodes of VT, and you're considering does this patient need a VT ablation? I think that if they've got ischemic cardiomyopathy, this data strongly supports that approach. If they've got arrhythmogenic right ventricular cardiomyopathy, again, ablation is very likely to reduce their episodes of VT/ for the non-ischemic group, which is about a third of the patient population that Rod studied, the data are less convincing in that group. And we know that's a harder group to achieve success with, with ablation. So we'll definitely want more data in that group. And I'm looking forward to some of the more detailed and sub-study sorts of analyses that I'm sure Rod is planning.
Dr. Greg Hundley:
Very nice, Bill. Well, listeners, and Bill you've teed it up nicely to really sort of circle back through each of you and ask, what is the next study to be performed in this space? So we'll start with Rod and then Sami, and then finish up with you, Bill. So Rod, what is the next study that you see needs to be performed really in follow up to yours?
Dr. Roderick Tung:
Well, we're thinking Pause too might be a nice just ARVC study alone, because again, inexplicably, there's a very high incidence of ARVC in Asia, and I was always taught that this was a disease from the Veneto region of Italy. And that might not be the case, or there's a lot of sarcoid mimicking of it as ARVC and undiagnosed. But we're thinking about a Pause too being an ARVC study, maybe without background I,CD therapy with background ICD therapy, this might provide justification for that. Because again, those in the registry did quite well, but that's because they were younger and had ARVC and normal LV function. So that might be a nice area to explore worldwide. And then lastly, just to put things in perspective for the Circ listeners, you need 8,400 patients in paradigm to show benefit mortality and heart failure hospitalization for an ARNI. Right? For IRNESTO.
We're talking about 120 patient studies when we talk about VT ablation, with these very complex ablation trials. So I think we just need larger trials. And the hard thing for us as VT ablation centers is we often will get patients that have had recurrent VT after a failed procedure. So it's hard to come by these that are very early, but I think we need 500 patient studies, a thousand patient studies. And also for the listeners, it's very hard to show mortality reduction with a background ICD therapy. And that's the problem, is that ICD is so effective as an abortive treatment that it's very hard to show reduction and mortality. You'd have to show it in terms of heart failure.
Dr. Greg Hundley:
Very nice, Rod. And Sami, what would you like to add?
Dr. Sami Viskin:
Oh, obviously the last word on the optimal timing of VT ablation is not out there. And we need more studies to really define when is the appropriate time for the VT ablation. That's what we need.
Dr. Greg Hundley:
Very good. And Bill?
Dr. William Stevenson:
Yeah, I agree with Sami. And with rod, we need larger studies to assess the benefit, to really help guide our clinical decision making that can get at quality of life issues as well as the mortality and cardiovascular hospitalization issues in even more detail. But this is a wonderful first initial step into the ischemic, non-ischemic and ARVC populations.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Rod Tung from university of Arizona, Phoenix, Dr. Sami Viskin from the Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee, for bringing us this study that highlighting among patients, particularly with ARVC in an ischemic cardiomyopathy from Asia across multiple centers in different countries that early catheter ablation performed at the time of ICD implantation really reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. And these findings were really nicely driven by a reduction in the ICD therapies. Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week, on the run.
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Christan Mueller, editorialist Christopher deFilippi, and Associate Editor Torbjørn Omland as they discuss the research article "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T" and the editorial "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T."
Dr. Greg Hundley:
Welcome, listeners, to this June 14, 2022, version of Circulation on the Run. I am Dr. Greg Hundley, associate editor and director of Poly Heart Center at VCU Health in Richmond, Virginia. This week I don't have my good friend Carolyn with me, but we will grab a cup of coffee and work through several of the articles in the issue.
Dr. Greg Hundley:
Well, first, I want to tell you about the feature discussion today, and we're going to interview with Christian Mueller and talk about the utility of cardiac troponin T and its association with an elevation in those individuals with skeletal muscle disorders, but, before we get to that, let's go through some of the other articles in this issue.
Dr. Greg Hundley:
Listeners, the first study comes to us from Professor Haidong Kan from Fudan university. These investigators conducted a time stratified, case crossover study among 1,292,000 acute coronary syndrome patients from 2,239 hospitals across 318 Chinese cities between January 1 of 2015 and September 30 of 2020 to determine the associations between sub-daily or hourly levels of criteria air pollutants with the onset of an acute coronary syndrome.
Dr. Greg Hundley:
Now, hourly concentrations of fine particulate matter, coarse particular matter, nitrogen dioxide, sulfur dioxide, carbon monoxide and ozone were collected, and the hourly onset data of acute coronary syndrome and its subtypes including ST segment elevation myocardial infarction, non-ST segment elevation myocardial infarction and unstable angina were obtained.
Dr. Greg Hundley:
Listeners, what did the investigators find? Well, their results indicated that transient exposure to the air pollutants of fine particulate matter, nitrogen dioxide, sulfur dioxide, and carbon monoxide, but not coarse particular matter or ozone may trigger the onset of acute coronary syndrome even at concentrations below the World Health Organization Air Quality Guidelines. Now, greater magnitude of associations were observed among patients that were older than 65 years in age or those without a history of smoking or chronic cardiorespiratory diseases and those in the cold seasons.
Dr. Greg Hundley:
Listeners, next, we're going to move from the study of air pollution to the world of preclinical science. Listeners, this study comes to us from Dr. Ming-Hui Zou from Georgia State University. Indoleamine 2,3-dioxygenase 1 or IDO1 is the rate limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis, and vascular smooth muscle cells with an osteogenic phenotype promote calcification and features of plaque instability, but it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes vascular smooth muscle cell osteogenic reprogramming and arterial calcification.
Dr. Greg Hundley:
Listeners, what did this study find? Well, this investigative team and their results revealed the previously unrecognized protective role of IDO1 in arterial calcification in that vascular smooth muscle cells defective of IDO1 result in enhanced runt-related transcription factor 2 and ectopic calcium deposition in plaques. In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression.
Dr. Greg Hundley:
Also, listeners, the authors found that patients with coronary artery calcification have abnormal tryptophan metabolism, and serum IDO1 activity was inversely associated with calcification development in clinical settings, so, listeners, what are the clinical implications here? Well, this work reveals a protective role for IDO1 in mitigating arterial intimal calcification through kynurenine production and then, secondly, developing interventions toward the IDO1 kynurenine RUNX2 access may prevent the pathogenesis of arteriosclerotic complications.
Dr. Greg Hundley:
Well, listeners, a really interesting article, and now let's turn our attention to some of the other articles in the issue. Well, first, there's a Research Letter from Professor Modarai entitled “A Higher Incidence of Chromosomal Aberrations in Operators Performing a Large Volume of Endovascular Procedures,” and then, also, there is an AHA Update from our exiting AHA president who addresses “What Does the American Heart Association Do (and How Can You Help)?” Well, now, listeners, let's turn now to our feature related to a discussion of the utility of troponin T as well as troponin I in those with skeletal muscle disorders that may also present with acute coronary syndromes.
Dr. Greg Hundley:
Welcome, listeners, to this June 14 issue, and we're very excited today. We have with us Dr. Christian Mueller from the University Heart Center at Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and Dr. Chris deFilippi from Inova Heart and Vascular Institute in Falls Church, Virginia.
Dr. Greg Hundley:
Welcome, gentlemen, and, Christian, we'll start with you. Could you describe for us some of the background information that went into your study, and what was the hypothesis that you wanted to address?
Dr. Christian Mueller:
Thank you very much for giving me the opportunity in this podcast to discuss our study with you and together with Torbjorn and Chris, who both contributed so enormously to the field with their own research. It's about cardiac troponin, cardiac troponin, an essential pillar in our early diagnosis of myocardial infarction. In this specific study, we tried to address possible non-cardiac causes of cardiac troponin T. In our clinical practice, we use and guidelines recommend both cardiac troponin T and I more or less as equivalent in providing identical information and, when going back from the clinical practice to biology, we have learned that, the troponin complex, that it is composed of three isoforms, T, I, and C.
Dr. Christian Mueller:
While they are very similar in their function, they are distinct regarding amino acid sequence in configuration in cardiac and skeletal muscle. As the cardiac form, of course, is the one that we are interested in, cardiac-specific assays have been developed both for cardiac troponin T and cardiac troponin I. As with any other tests in medicine, they are very good, but they may have limitations, and the specific questions that we had set for this study is whether skeletal muscle disease might be non-cardiac source for cardiac troponin T as measured in blood, therefore, with the possible harm of having false positive increases that could lead to a misdiagnosis of acute myocardial infarction.
Dr. Greg Hundley:
Very nice. We're trying to understand the utility of cardiac troponin T measures in those individuals that may have concomitant skeletal muscle disorders. Christian, what was your study population, and describe for us your study design?
Dr. Christian Mueller:
Our study had two components, a clinical component and a translational component. The clinical component included 211 consecutive patients that presented with active and chronic muscle symptoms to a workup either with a rheumatologist or a neurologist or internal medicine specialist, so more or less elective workup for muscle, skeletal muscle symptoms, to have a population that is broad and reflects all possible skeletal muscle disorders, their possible impact on cardiac troponin T concentration.
Dr. Christian Mueller:
In this population, we quantified cardiac involvement as this is common in some of these musculoskeletal disorders to be either major, minor or are not. They're according to patient history, according to … ECG and cardiac imaging, and we did the measurement of high sensitivity cardiac troponin using the high sensitivity cardiac troponin T assays used all over the world and three high sensitivity cardiac troponin I assays to look for mismatches, the percentage of patients that might have elevated T concentration, but not I as a possible sign that the T might be from the muscle, not the heart, particularly in those patients that didn't have any imaging evidence of cardiac involvement, and then we correlated the amount of high sensitivity cardiac troponin T with the amount of muscle injury as quantified by CK.
Dr. Christian Mueller:
In the translational part, those patients who have received a skeletal muscle biopsy with quantified by differential gene expression, the MRNA of the cardiac isoform of cardiac troponin T as well as of I in those patients who had the biopsy and matched it and compared it to controls to see whether the cardiac isoform would be upregulated in those with the cases of skeletal muscle disease.
Dr. Greg Hundley:
Very nice, and so, Christian, was this one single measurement at one point in time or did you have a series of measures over time?
Dr. Christian Mueller:
In fact, this is a large, ongoing project where patients will receive followup appointments. The current study reports the first phase versus single measurement at a single time point was performed.
Dr. Greg Hundley:
Very good. Christian, what did you find?
Dr. Christian Mueller:
We first found that even in those patients with active skeletal muscle disease, cardiac troponin T still reflected the presence of cardiac disease. Those patients with severe cardiac disease did have significantly higher concentration than those patients with mild or with no cardiac disease. That was the good thing. However, the more challenging one for this biomarker in this setting is that high sensitivity cardiac troponin T was significantly higher in these patients as compared to controls. We had the chance to have a couple of thousand controls from another study that presented with non-cardiac chest and no skeletal muscle disease and, while high sensitivity troponin I concentrations were similar, cardiac troponin T was elevated, resulting in a much higher prevalence of elevated T concentration versus elevated I concentration and corresponding mismatches in these patients.
Dr. Christian Mueller:
In the second part, we were able to show that there was a significant correlation between high sensitively cardiac troponin T with CK quantifying somehow muscle damage while this was not seen in the correlation with high sensitivity I, and that signaled that some of the systemic cardiac troponin T concentration seems to be derived from the muscle. It was confirmed in the translational part of the study in which the differential gene expression showed an eightfold over-expression of cardiac troponin T in skeletal muscle biopsies of those patients with disease, so with active skeletal muscle disease. This … expression correlated with disease activity, a pathological score that quantifies the extent of damage in the skeletal muscle history and correlated with the high sensitivity cardiac troponin T plasma concentration measured with the immunoassay.
Dr. Greg Hundley:
Very nice. Listeners, it sounds as if, in patients with skeletal muscle disorders, Christian's team observed an elevation in cardiac troponin T, but not necessarily cardiac troponin I, and you've got mechanistic understanding from the biopsies where you see this cardiac troponin T expression in the damaged skeletal muscles. Well, Torbjorn, you have many papers come across your desk. What attracted you to this particular paper?
Torbjorn Omland:
Thank you, Greg. I think, in general, when I receive papers from circulation, there are three main criteria I consider. The first is whether this is an interesting research question and then, second, whether the study is well-designed and the third is whether they're in themselves are novel, robust and interesting with potential clinical implications.
Torbjorn Omland:
For this specific papers, I must say it seemed to me to fulfill all these criteria and that it would be able to bring this field forward. The study of re-expression of troponin T in skeletal muscle is not entirely novel because it has been done in small samples, but mainly with rare and neuromuscular diseases previously, but this study broadened that or generalized that to a much more clinically relevant population. The clinical implications also seemed to be much greater than what has been reported by previous papers.
Dr. Greg Hundley:
Very nice. Listeners, we have in addition to Dr. Omland, we have another expert with us today, Dr. Chris deFilippi, really in the area of biomarkers particularly as they pertain to cardiac injury.
Dr. Greg Hundley:
Chris, now turning to you, how do we put the context of the results today really with the broader scope of what we have learned about cardiac troponin I and cardiac troponin T and then their use in diagnosing acute ischemic syndromes or even forecasting future cardiovascular events down the road?
Dr. Christopher deFilippi:
Thank you, Greg, and thank you Circulation for inviting me to participate in this podcast and to write this editorial. First, Christian, this was a terrific paper and one that was probably great to review during the pandemic because, as I spent a good Sunday peeling back layers of the onion and reiterating what Torbjorn said, this paper makes a tremendous contribution where there already was some knowledge to maybe the expression of the cardiac specific troponin T and skeletal muscle, but there's something there for everyone just to get the takeaway message, but for those who really want to delve in, there are supplemental tables that contribute a huge amount of nuance and detail that I think will help guide researchers in the future in maybe how to optimally use cardiac troponin T and troponin I both in the evaluation for acute myocardial infarction and then in a variety of chronic conditions, so first putting this in context of how you would evaluate patients with acute myocardial infarction, and that's the predominant indication for measuring a high sensitivity troponin T or troponin I.
Dr. Christopher deFilippi:
As Christian in an earlier study has shown and others have shown, actually, the correlation between a high sensitive troponin I by a variety of commercial assays. Troponin T is really pretty good. I think in one study from Christian's group, it was measured at 0.89. Now, the issue that's relevant is more around the edges. People who come in with just a low elevation and, as Christian pointed out and colleagues pointed out in the paper, using the ESC algorithm, a number of those patients would have qualified for myocardial infarction with the skeletal myopathies particularly the myositis or the non-inflammatory myopathy. If there is an index of suspicion for these disorders I think particularly around the cutoff for troponin T, one has to be cautious. Whether one can actually look at serial changes and try to differentiate that way I think is an open question. It may be.
Dr. Christopher deFilippi:
I think the other thing that gets quite interesting for me in an area that we've delved in over the past decade is the use of high sensitive troponin T or troponin I as a measure of chronic injury that's been codified in the fourth universal definition of MI published four years ago to identify individuals at risk. These can be individuals who are living in the community without known cardiovascular disease or actually without, perhaps, a lot of other comorbidities other than advanced age, for example, who an elevated troponin I or troponin I can be indicative of an increased risk for incident heart failure over the next five to 10 years. It can be patients with other chronic comorbidities.
Dr. Christopher deFilippi:
Actually, what drew me to this paper and thinking along these lines was a paper that Torbjorn had published back in 2013 where, using the key study which are individuals who have chronic ischemic heart disease without heart failure, he measured both troponin I and troponin T and found there was quite a discordance. There, we're looking at … value of about 0.4 and found that troponin I was a great predictor for the risk of coronary heart disease event and an acute myocardial infarction in the future, but T was not, but both T and I were good predictors of incident heart failure in the future.
Dr. Christopher deFilippi:
Other investigators, the … investigators, investigators from Scotland have also found this discordance between I and T in chronic ambulatory populations with or without comorbidities, and so it opens an interesting question in individuals with maybe conditions of pre-frailty or frailty or some element of sarcopenia, subclinical skeletal muscle disease. Does this cause this discordance? Ultimately, we know particularly with heart failure, with preserved ejection fraction, it is a systemic disorder, and measures of skeletal muscle disease may be relevant in ultimately determining who's going to have symptomatic heart failure.
Dr. Christopher deFilippi:
I think it really opens things wide open potentially to further investigation. Is this modifiable? Is it through intervention simply like physical activity? Could you see changes in cardiac troponin T that may be reflecting cardiovascular changes and skeletal muscle changes, but maybe not so much with I, and does this have relevant prognostic implications? I think I was really excited about it based on the defined pragmatic findings with respect to evaluating patients for myocardial infarction who have these underlying skeletal muscle diseases, but also implications, what this might mean in chronic disease populations as well.
Dr. Greg Hundley:
Very nice. Well, Chris, you've led us really to our next series of questions, and maybe we'll circle back with each of you, first, Christian. What do you see, Christian, as the next study to be performed in this space?
Dr. Christian Mueller:
I think the next study should address two aspects. The first one is I think we already, with the current population have found that skeletal muscle disease includes various pathologies, and as indicated by Torbjorn, the cardiac troponin T re-expression seems to be at least of our current understanding limited to the two groups of myositis and the muscular dystrophies, whereas the other skeletal muscular disorders at least in those that we have currently investigated did not seem affected. However, we were limited by the number of patients in this subgroup, and so for sure need a larger population to cover all aspects or all classifications of skeletal muscle disease in more detail.
Dr. Christian Mueller:
The second point that I'd like to highlight is the followup and to look for cardiac events and to look for cardiac changes, functional or anatomical changes in cardiac imaging, because it still may be that some of the T that is more commonly seen in this patient, that the majority of this is derived from the heart, so it's not a black and white, it's only from the muscle or only from the heart. It's still possible that some of the higher concentration of T found in these patients, as in many of the skeletal muscle systemic disorders, they have cardiac involvement which may not be identifiable by current imaging techniques at the first visit. This may become apparent during followup, and so these studies will help us to get a better quantitative understanding, so ideally to understand is it just a tiny amount, I don't know, 10, 20% of the systemic T concentration that is derived from the muscle? Then it would have a very different clinical implication as compared to if, I don't know, more than 50% of the systemic concentration would be derived from the skeletal muscle rather than the heart.
Dr. Greg Hundley:
Very nice. Torbjorn, I would like to turn to you. What do you see as the next study to be performed in this space?
Torbjorn Omland:
Oh, I agree with Christian that the serial assessment of changes of disease activity versus troponin changes would be very interesting to study in more detail and also correlate that to changes, for instance, by cardiac MRI if you can see whether there are actually correlations there. Long-term prognostic implications of skeletal muscle derived cardio troponin is another subject, and then, finally, I think that we do need to know even more accurately what is the impact of these alterations on the diagnostic workup in the acute coronary syndrome setting. Is it really a clinically important confounder? I think studies that could address that will be important.
Dr. Greg Hundley:
Very nice, and then finally Chris, and, Chris, I want to add just another question. Just from my listening to this, if I'm trying to identify someone with an acute ischemic syndrome and then they may also have an underlying skeletal muscle disorder, both Christian was talking about inflammation, but you brought in frailty and things of that nature. Should we really then turn clinically to measuring cardiac troponin I in this setting when we're trying to rule out, for example, acute myocardial infarction?
Dr. Christopher deFilippi:
Yeah. I don't want to overstate that. I mean, Christian's work and others have shown actually a high sensitive troponin T and a variety of different high sensitive troponin Is in a very heterogeneous chest pain population have been equivalent, looking at receiver operator curves area under the curbs, and so they're probably our people at the margins where this will make a difference, but it should be. Listeners should be reassured at this point because troponin T is a very common assay that it's still quite efficacious and accurate for the diagnosis of acute myocardial infarction from what we know, and a lot of Christian's work has identified this.
Dr. Christopher deFilippi:
Again, moving into the more chronic disease population outside the evaluation of acute myocardial infarction, maybe where we can use it as a differentiator, it could be helpful in some instances to look at interventions. Earlier work has shown in just small numbers of patients have been published, but patients with hypothyroidism, patients with statin-induced skeletal myopathies, the treatment of these has actually led to a decrease in high sensitive troponin I corresponding with decreases in CK, so there may be opportunities for lifestyle interventions like physical activity, and you could see that response and whether that has prognostic implications. This could be of interest for future research.
Dr. Greg Hundley:
Very nice. Well, listeners, what an incredible discussion today. We want to thank Dr. Christian Mueller from University Heart Center in Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and also Dr. Chris deFilippi from the Inova Heart and Vascular Institute in Falls Church, Virginia, for really helping us understand that in patients... from this research, that in patients with active chronic skeletal muscle disorders, elevations in cardiac troponin T are common and may not be related to cardiac disease. These elevations were not observed in those with assessment of cardiac troponin I and, coming back to in the case of cardiac troponin T based on this wonderful biopsy work, the elevations of the troponin T appear related to re-expression of troponin T and skeletal muscle.
Dr. Greg Hundley:
Well, listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit aha journals.org.
This week, please join author Ratika Parkash and Editorialist Sean D. Pokorney as they discuss the article "Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial" and the editorial "The Evidence Builds for Catheter Ablation for Atrial Fibrillation and Heart Failure."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Centre and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature discussion, oh, so exciting. We enter the month of June, and it pertains to heart failure and atrial fibrillation. And we are going to learn a little bit more from the RAFT-AF trial, involving randomizing patients to ablation and rhythm control, as opposed to just settling for rate control for patients with AFib. But before we do that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I absolutely would. And I will start by asking everyone a question. Could a single high-sensitivity cardiac troponin T level, below the limit of detection of six nanograms per liter, exclude an acute myocardial infarction? Well, you are going to find out because, remember that data for excluding AMI with a single high-sensitivity cardiac troponin level relies largely on the limit of detection, which is really a threshold of five nanograms per liter, which cannot be reported in the United States, per the FDA, because there, only the lowest reportable concentration is allowed, which is the limit of quantitation of six nanograms per liter.
Dr. Carolyn Lam:
So, today's authors Dr. Sandoval from Mayo Clinic and colleagues, very cleverly sought to determine whether a single high-sensitivity cardiac troponin T level below the limit of quantitation of six nanograms per liter could indeed identify patients at low risk for AMI.
Dr. Greg Hundley:
Very interesting, Carolyn. So we have the limit of quantitation and then the limit of detection. This is really intriguing. And of course, cardiac troponin T, as cardiologists, we receive a lot of requests for consults on this. So, what did this study find, Carolyn?
Dr. Carolyn Lam:
A total of over 85,000 patients were first evaluated in the CV data marked biomarker cohort, amongst which 29% had a baseline high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter. Among 11,962 patients with this baseline high-sensitivity cardiac troponin below six nanogram per liter and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% and a sensitivity of 99.6%.
Dr. Carolyn Lam:
In an adjudicated cohort, among those with a non-ischemic electrocardiogram, only 0.2% had myocardial infarction or death at 30 days. So in summary, Greg, this is the largest study evaluating a single high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter to identify patients at low risk for AMI.
Dr. Carolyn Lam:
And indeed, the present study demonstrates that a single high-sensitivity cardiac troponin level below six nanogram per litter is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.
Dr. Greg Hundley:
Oh wow, Carolyn, really informative study. Well, Carolyn, my next study comes from the world of preclinical science. And Carolyn, vascular smooth muscle cell phenotypic switching contributes to cardiovascular diseases. And epigenetic regulation is emerging as a key regulatory mechanism with the methylcytosine dioxygenase Tet2, acting as a master regulator of the smooth muscle cell phenotype.
Dr. Greg Hundley:
The histone acetyltransferases, HATs p300, and CBP are highly homologous and often considered to be interchangeable. And their roles in smooth muscle cell phenotypic regulation are not known. So Carolyn, these authors led by Dr. Kathleen Martin from Yale University School of Medicine assessed the roles of p300 and CBP in human vascular smooth muscle cells with knockdown in inducible, smooth muscle specific knockout mice, and in samples of human intimal hyperplasia.
Dr. Carolyn Lam:
Cool, Greg. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So, they found that p300 and CBP serve non-redundant and opposing function in vascular smooth muscle cell phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with Tet2 or HDACs. And Carolyn, targeting specific histone acetyltransferases therefore may hold therapeutic promise for future cardiovascular disease interventions.
Dr. Carolyn Lam:
Oh, that's great, Greg. Well, to round it all up, there are some other papers in today's issue. There's a Research Letter from Professor Zhang, entitled “Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time-Window of Cardiomyocyte Proliferation and Myocardial Regeneration.” There's also a Research Letter from Dr. Vaduganathan, entitled “Estimating the Benefits of Combination Medical Therapy in Heart Failure with Mildly Reduced and Preserved Ejection Fraction.” Ah, that's such a cool issue. Now, let's go on to our feature discussion. Shall we, Greg?
Dr. Greg Hundley:
You bet, and learn a little bit more about rhythm versus rate control in patients with heart failure and atrial fibrillation.
Dr. Carolyn Lam:
Our feature discussion today is about the long-awaited results of the RAFT-AF trial, and that is the randomized ablation-based rhythm control versus rate control trial in patients with heart failure and atrial fibrillation. Thank you so much, Dr. Ratika Parkash for joining us today as the first and corresponding author from Queen Elizabeth II Health Sciences Center in Canada, as well as Dr. Sean Pokorney, the editorialist from Duke University.
Dr. Carolyn Lam:
I am so, so excited to be discussing this paper. I really meant it. You know, as a heart failure cardiologist, we've been waiting for these results and trying to understand everything in context. So maybe, Ratika, could you please start off by telling us about the RAFT-AF trial and what you found?
Dr. Ratika Parkash:
Thank you, Carolyn. I'm happy to be able to talk about this study on behalf of the RAFT-AF investigators and my co-PI, Dr. Anthony Tang. So the trial... First of all, the rationale for the study, I think many of us, as heart failure or heart rhythm specialists, understand that in the past, we've done many trials looking at rate versus rhythm control, the AFFIRM trial being the largest, and then of course, specifically in heart failure patients, the AF-CHF trial, both of which were negative in reducing cardiovascular events and mortality in patients with or without heart failure, in terms of a rate to rhythm control.
Dr. Ratika Parkash:
One of the issues with those trials is that the form of rhythm control was antiarrhythmic drugs. So we have learned that catheter ablation is superior to antiarrhythmic drugs in maintaining sinus rhythm. And based on that premise, we decided to go forward with the RAFT-AF study.
Dr. Carolyn Lam:
That's great, Ratika, so thanks. And what were the results?
Dr. Ratika Parkash:
The main finding, so the primary outcome of the study was mortality and heart failure events. Heart failure events was defined as a heart failure hospitalization or any escalation of heart failure therapy that was done in the outpatient settings, including the use of intravenous Lasix in an emergency department setting.
Dr. Ratika Parkash:
So the main findings were that ablation-based rhythm control was not statistically significant in reducing mortality and heart failure events over rate control in patients with atrial fibrillation and heart failure. The study included patients both with preserved ejection fraction, as well as reduced eject fraction. And we did stratify based on ejection fraction at the entry point into the trial. The hazard ratio was 0.71 and the 95% confidence interval just crossed unity, ranging from 0.49 to 1.03 with a P value of 0.066.
Dr. Carolyn Lam:
Oh, ouch. So, thank you. And again, truly, congratulations on a very, very important trial. Sean, I said it before, I'll say it again, really, really loved your editorial. Could you put these findings in the context of... Maybe, start with even the most recent guidelines, the 2022 ACC/AHA/HFSA heart failure guidelines, which I believe gives catheter ablation a class 2A recommendation. Maybe, start from there, and how does this fall in place?
Dr. Sean Pokorney:
Yeah, no, absolutely. I think, first of all, it's a really important trial and it's great to have this additional data. I do think, as you said, that it's important to understand the context. We now have several recent guidelines that have commented on the role of catheter ablation in patients with heart failure.
Dr. Sean Pokorney:
You mentioned the most recent heart failure guidelines. We also have additional AFib guidelines and we have the 2019 AHA/ACC/HRS guidelines for atrial fibrillation that give catheter ablation a 2B recommendation in patients who have heart failure, to potentially lower mortality and reduce hospitalization. And it has a 2A indication in the 2020 ESC guidelines. And we're currently undergoing some revisions of the guidelines for atrial fibrillation, and there'll be new guidelines around atrial fibrillation coming out from AHA/ACC/HRS in the coming years. And so that will also be helpful, I think, to incorporate some of this additional data.
Sean Pokorney:
When you really look at the guidelines and see what's driving the guidelines, there are several trials now that are really driving the guidelines. And so I think, looking back on the data, we have the AATAC trial, which was a trial of 203 patients that looked at ablation versus amiodarone. And we have the CASTLE-AF trial, which had 363 patients in it and was looking at atrial fibrillation in patients with heart failure with reduced ejection fraction and defibrillators.
Dr. Sean Pokorney:
And when you put that data into context, the AATAC trial did find lower rates of death and hospitalization as a secondary outcome, and CASTLE-AF did identify a reduction in heart failure hospitalizations and death. At the three year follow-up, there was a statistically significant reduction, although the event number was lower than the previously sort of calculated target sample size.
Dr. Sean Pokorney:
And so in aggregate, these trials do show a modest evidence of benefit for clinical outcomes in this population. And that's where adding more data is really critical.
Dr. Carolyn Lam:
That's so true. And actually, Ratika, is there any plan for some meta-analysis or sort of adding the data? And if you could, also speak to, the trial was interrupted at some point, so how that may have impacted things as well.
Dr. Ratika Parkash:
Those are important questions. So, first of all, there is a planned longer term follow-up for the study, to look at whether or not following these patients out beyond our meeting follow-up of 37 months, it will actually produce a different result than what we observed in the current findings.
Dr. Ratika Parkash:
I think a meta-analysis is obviously going to show benefit for ablation-based rhythm control, based on the data that Sean had just described. One of the things that we'd need to keep in mind is that this trial, the RAFT-AF study really enrolled patients who were suitable for either ablation-based rhythm control or rate control. So it wasn't a study that looked at rhythm control only.
Dr. Ratika Parkash:
So, the CASTLE-AF trial had essentially two rhythm control arms. The medical therapy arm was, was amiodarone in that trial, versus catheter ablation. So patients could get rhythm control in both. And so, the types of patients that would've gotten into CASTLE-AF were different than the patients in our trial, even when you look at the reduced ejection fraction patients.
Dr. Ratika Parkash:
Having said that, our curves, when you look at the reduced ejection fraction group in our study does mirror what was observed in CASTLE-AF. So, even if a patient is not deteriorating initially with rate control, it appears that over time they begin to deteriorate. And that's what all of these trials have shown, is that patients do better with ablation-based rhythm control, the best form of sinus rhythm maintenance that we have.
Dr. Ratika Parkash:
And it takes time for them to deteriorate and it takes time to accrue those events. And this is evident in all trials of atrial fibrillation. You either need a very large sample size, like 15,000 patients, to look at heart failure in a short period of time, or you follow them longer, so that you can accrue those events.
Dr. Ratika Parkash:
In terms of the stopping of the trial, certainly, had we reached the sample size of 600, which was the intended sample size after recalculation during the study from 1000 down to 600, I believe we would have reached a positive outcome. But again, we hope that our longer term follow-up might shed some light on that. The interruption of the study was based on the DSMC decision and certainly could have affected the power of the study.
Dr. Ratika Parkash:
We have to remember that the other possibilities are that ablation-based rhythm control is not superior to rate control. And as someone who is pro-ablation, it's difficult to say that, but we see hints of benefit and we have to recognize that.
Dr. Ratika Parkash:
The other issue is that the secondary endpoints in our trial were all significant, as overall, it doesn't matter which group you looked at, NT-proBNP, six-minute walk test, quality of life, both for heart failure and atrial fibrillation, as well as ejection fraction, were all improved. And for many of the studies that have been done previously, those were the primary endpoints of those studies.
Dr. Ratika Parkash:
The idea of whether ablation-based rhythm control reduces heart failure per se, is from our study, purely from our study, we can't be a hundred percent certain. There's definitely a hint of clinical benefit there. From all the secondary endpoints, which are the current guidelines, is what they indicate ablation should be done for, is to improve quality of life. Our study was certainly supportive of that.
Dr. Carolyn Lam:
You know, Sean, I especially appreciated your discussion of these issues, the early stopping of the trial, the secondary endpoints. Could you know, share some of those thoughts?
Dr. Sean Pokorney:
I think it's really an important topic. I think that, again, as Ratika said, part of why this trial is so important is that many of the previous trials that have been published and many of the data sets have really looked at rhythm control versus rhythm control in this population, even including the analysis from CABANA, which included almost 780 patients from CABANA that had heart failure. And in that population, they did show a reduction in the composite primary endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. And again, CABANA was, as well, a study of rhythm control with ablation versus medical therapy, most patients getting rhythm control in that medical therapy arm.
Dr. Sean Pokorney:
And so this data really is additive. I think that one of the challenges is always, how do we make sure to get the most information out of a clinical trial once we commit patients to that scientific process? And I think here, at least in retrospect, it's obviously unfortunate that the trial was stopped early. I think that more data would certainly be helpful.
Dr. Sean Pokorney:
I appreciate the fact that longer term data may help solve that gap and close that gap a little bit. I think that, I guess, it'd be interesting to hear from Ratika a little bit more about the process that was involved with interaction with the DSMC and stopping the trial.
Dr. Ratika Parkash:
Yeah. Thanks, Sean. That also is a very good question. The DSMC really evaluated the data, evaluated the progress of the trial, back in 2017. It had been six years since we'd started the study. The data they had, in fact, did not show any benefit to ablation-based rhythm control over rate control at the time. So the follow-up period at the time was around two years.
Dr. Ratika Parkash:
And again, if you look at our Kaplan-Meier curves, you can understand why they would have made that decision at the time, based on 363 patients for the data that was available to them. They had a futility index that they looked at. it was calculated. The cutoff for stopping of the study was 0.8, and it was 0.81. So, there was a 19% chance that the study was going to show any benefit. And based on that, plus the progress of the trial, they made a decision to stop the study.
Dr. Sean Pokorney:
Yeah. I think it's really important when we look at these decisions, that there was example when we talk about this in the editorial as well with the ISIS-2 trial, where early on in the data, ISIS-2 was a trial looking at aspirin versus placebo. And basically in that trial, when you looked early on at the events that were accumulating, there was really roughly no difference between aspirin and placebo. And ultimately, that trial became positive and was a really critical trial. And if it had been stopped at that point for futility, we wouldn't have had some really critical data.
Dr. Sean Pokorney:
So, it's always a challenging decision. And obviously, the decisions are trying to be made in the best interest of the patients. Here, it just shows how important this additional follow-up data is for this trial, for RAFT in particular. And ultimately, it'll be interesting to see, as you mentioned, as we add additional long-term follow-up, how that will affect the results.
Dr. Ratika Parkash:
Absolutely. So, we hope that our additional follow-up is of benefit to clarifying our results. The unfortunate issue, I agree, was the stopping of the study, but we do trust our DSMCs. We have them for a reason and they perform an important function. So, we have to pay attention of course, to how they see things and evaluate the... at the time.
Dr. Ratika Parkash:
The other thing we should keep in context is that ablation for those, that time period, is not the same as it is today. Our safety has improved. You may have noticed that there were some adverse events in the study with ablation, and we would expect it to actually be lower, but in this day and age, but at the time, contact force wasn't available.
Dr. Ratika Parkash:
There were some tools and techniques that we now have at our disposal, improved mapping systems and so on, that allow us to do a safer and more efficacious job. But even in the context of that, our sinus rhythm maintenance was almost 80 to 90% for patients that you wouldn't normally expect to have that much sinus rhythm.
Dr. Sean Pokorney:
Yeah. I think that's a really critical point. You made a lot of really important points there, actually. Obviously, the vision of the field of electrophysiology is shifting, as you mentioned. And with data from EAST-AFNET 4, we're really shifting towards earlier rhythm control, as well as additional ablation trials attest, stop AFib or stop AF.
Dr. Sean Pokorney:
So again, there have been several studies that have shown the benefits of earlier rhythm control, EAST-AFNET 4, I think, being obviously one of the most relevant, looking at addressing atrial fibrillation of population of patients who've been diagnosed within the last year, and showing that there was a benefit to rhythm control, although the majority of rhythm control in that study was antiarrhythmic medications.
Dr. Sean Pokorney:
I think in the heart failure population, the challenge with rhythm control is that we're a lot more limited in terms of the medical therapies that are available for these patients. And I think that's where ablation really plays in a more important role, because not only have you shown that it seems to be efficacious in this patient population, with a really high rate of rhythm control, but in a lot of these patients, it's often a safer alternative than antiarrhythmic therapy.
Dr. Ratika Parkash:
Absolutely. And we've already shown that amiodarone is ineffective in this population, in AF-CHF. So, using that drug does not seem to be, in a population that could go for an ablation, the appropriate approach.
Dr. Sean Pokorney:
Yeah. And as well, I think that's important. And when you look back at data from SCD-HeFT as well, there were some concerns with safety signals of amiodarone in patients with heart failure as well, from that study, again, likely related to the side effects of the medication itself.
Dr. Sean Pokorney:
So again, it is a complex patient population in terms of decision-making and management. And I do think, again, we talked a lot about the trial being stopped earlier than we would've ideally liked. I still think that the data that you guys produced is really important and critical and additive. Again, we're consistently seeing these modest treatment effects across multiple studies. And the fact that all the studies are pointing in the same direction is very reassuring.
Dr. Ratika Parkash:
Yeah. I was just going to comment on some of the points that Sean had raised, with respect to early rhythm control and the concept of atrial substrate, and how advanced atrial substrate with a negative remodeling effect in patients with heart failure or prolonged atrial fibrillation may not necessarily be in our patient's benefits to then try to intervene, and trying to get these patients early would be useful.
Dr. Ratika Parkash:
So in RAFT-AF, patients did not have to fail an antiarrhythmic drug in order to get into the study. So that, again, critical, very much along the lines of EAST-AFNET and EARLY-AF, which was also published, demonstrating benefit for early intervention.
Dr. Carolyn Lam:
Wow. Just, thank you so much, both of you. That was such a rich discussion, really, really unpacking very, very important elements of the trial, not just the trial results, but also the implications of what happens with trial conduct and execution and so on.
Dr. Carolyn Lam:
Again, thank you so much Ratika, for publishing this very important paper in circulation, Sean, for your beautiful editorial that put it all in context, the audience for listening today. From Greg and I, you've been listening to circulation on the run. Thank you for joining us today, and don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAJournals.org.
This week, please join author Ronald Goldberg, Editorialist Hertzel Gerstein, and Guest Editor Rury Holman as we discuss the article "Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study" and the editorial "Shouldn't Preventing Type 2 Diabetes Also Prevent Its Long-Term Consequences?"
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Today. Oh, this feature discussion involves the glance of diabetes. Truly this interview, I felt like I was sitting among gurus and just learning so much about diabetes, the history and the whole topic is about long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its outcome study. Now, way more than that, we discussed. You have to have to listen. But okay, before that, let's summarize today's issue for our listeners. Shall we, Greg?
Dr. Greg Hundley:
You bet Carolyn. So the first paper that I've got to discuss today really comes to us from the world of interventional cardiology and it's led by Dr. William Fearon from Stanford University Medical Center. Well, Carolyn previous studies have shown quality of life improves after coronary artery revascularization, more so after coronary artery bypass grafting than after PCI. Now this study aimed to evaluate the impact of fractional flow reserve guidance, and current generation zotarolimus drug-eluting stents on quality of life after PCI compared with CABG.
Dr. Greg Hundley:
Now the study emanates from fractional flow reserve versus angiography for multi vessel evaluation or the fame three trial. And Carolyn, that's a multicenter international trial that included 1500 patients with three vessel coronary artery disease who were randomly assigned to either CABG or FFR guided PCI. Now, what did they assess? So quality of life was measured using the European Quality of life Five Dimensions. And we're going to abbreviate that EQ-5D questionnaire baseline, one, and then 12 months following the procedure. Also, Canadian cardiovascular class angina grade and working status were assessed at the same time points, and then also an additional time point in six months. And the primary objective was to compare the EQ-5D summary index at 12 months, and secondary endpoints included angina grade and work status.
Dr. Carolyn Lam:
Ooh, interesting Greg. So quality of life in the theme three trial. All right. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So the EQ-5D, so that... European Quality of life Five Dimensions summary index at 12 months did not differ between the PCI and CABG groups, but the trajectory over the 12 months at the one month time interval between PCI and CABG did differ. Now, the proportion of patients with the Canadian cardiovascular class or CCS2 or greater angina 12 months was 6.2% versus 3.1% respectively in the PCI group compared with the CABG group. Additionally, a greater percentage of younger patients, so those less than 65 years old were working at 12 months in the PCI group compared with the CABG group. So in summary, Carolyn, in the fame three trial, quality of life after fractional flow reserve guided PCI with current generation DS compared with CABG was similar in one year. And the rate of significant angina was low in both groups and not significantly different. However, the trajectory of improvement in quality of life was significantly better with PCI as was working status in those less than 65 years old.
Dr. Carolyn Lam:
Wow. Thanks Greg. Hey, guess what? It's time for Greg quiz. The next paper is about the Chocolate Touch Study. So, Greg, is this about, A, the benefits of eating chocolate? B, the benefits of chocolate mud baths? Or C, the benefits of a second generation drug coated balloon?
Dr. Greg Hundley:
So, Carolyn, I just have one question. Where in the world do we get the benefits of chocolate mud bath? I don't think that's right. I do love eating chocolate, but I am going to go with the benefits of the second generation drug coated balloon.
Dr. Carolyn Lam:
Yeah, yeah, yeah. I made it easy for you. All right. So first generation drug coated balloons have significantly reduced the rate of restenosis compared to balloon angioplasty alone. However, high rates of bailout stenting and dissections persist. The chocolate touch drug coated balloon is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis, so you were right, Greg. In today's study led by Dr. Shishehbor, from University Hospital's Harrington Heart and Vascular Institute at Cleveland, Ohio. They studied 313 patients with claudication or ischemic rest pain, and superficial femoral or popliteal disease. And randomized them one to one to the chocolate touch or Lutonix Drug Coated Balloon at 34 sites in the United States, Europe and New Zealand. The primary efficacy endpoint was drug coated balloon success defined as primary patency at 12 months. The primary safety endpoint was freedom from major adverse events at 12 months. A composite of target limb related death, major amputations, or reintervention. Both primary endpoints was assessed for non-inferiority and have met sequential superiority testing for efficacy was pre-specified.
Dr. Greg Hundley:
Interesting, Carolyn. So this nitinol constrained balloon designed to reduce acute vessel trauma. So, what were the results of this study?
Dr. Carolyn Lam:
So in this trial, the second generation chocolate touch drug coated balloon met both non-inferiority endpoints for efficacy and safety. And was more effective than the Lutonix Drug Coated Balloon at 12 months for the treatment of femoral popliteal disease. Cool, huh?
Dr. Greg Hundley:
Very interesting. Great summary, Carolyn. So Carolyn, my next paper comes to us from the world of preclinical science. And the impact of three dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human dilated cardiomyopathy remains elusive. And so these authors led by Professor Lei Jiang from Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Science, generated a compendium of 3D epigenome and transcriptome maps from 101 biobank human dilated cardiomyopathy, and non-filing heart tissues and mouse models to further interrogate the key transcription factor implicated in 3D chromatin organization, and transcriptional regulation in dilated cardiomyopathy pathogenesis.
Dr. Carolyn Lam:
Oh, wow. Sounds like a lot of work. What did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So they found that enhancer promoter connectomes are extensively rewired in human dilated cardiomyopathy, which reside in pre accessible chromatin size and also hand one drives the rewiring of enhancer promoter connectome to induce dilated cardiomyopathy pathogenesis.
Dr. Carolyn Lam:
Okay, Greg. So what are the clinical implications?
Dr. Greg Hundley:
Right, Carolyn. So first, dilated cardiomyopathy enriched enhancer promoter loops identified in this study could be developed as novel 3D genomic biomarkers for dilated cardiomyopathy. And then second Carolyn, targeting hand one might be used as a novel approach for therapeutic intervention in patients with dilated cardiomyopathy.
Dr. Carolyn Lam:
Oh, nice. Greg. Well, also in today's issue, there's an On My Mind paper by Dr. Brook, entitled, “The Doctor is Out, New Tactics and Soldiers For our Losing Battle against Hypertension.” In another paper, we have Molly Klemarczyk bringing us highlights from the Circulation Family of Journals.
Dr. Greg Hundley:
Right, Carolyn. And also from the mailbag, there's a Research Letter from Professor Baggish, entitled, “Cardiovascular Outcomes in Collegiate Athletes, Following SARS-CoV-2 Infection: The 1-Year Follow Up From the Outcomes Registry for Cardiac Condition in Athletes.” Well, Carolyn, how about now we get onto that feature discussion and learn a little bit more about the long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program.
Dr. Carolyn Lam:
Hold on to your seats, everyone. Here we go. We know that lifestyle intervention and metformin have been shown to prevent diabetes. However, what is their efficacy in preventing the cardiovascular disease associated with diabetes development? Well, guess what? We're going to have data on that through today's feature paper and what a star crowd I'm talking to today. We have Dr. Ron Goldberg and he's a first end corresponding author from the University of Miami Diabetes Research Institute. We have the editorialist Dr. Hertzel Gerstein from McMaster University Population Health Research Institute. And a guest editor for this paper, Dr. Rury Holman from University of Oxford. I have to admit I'm starstruck. You gentlemen have totally defined the field. I cannot wait to learn more, but shall we start with you, Dr. Goldberg? Could you tell us a little bit more about your paper, what you did, what'd you found?
Dr. Ronald Goldberg:
So the background is that the Diabetes Prevention Program started in 1996 was a Diabetes Prevention Program to test the effects of intensive lifestyle intervention versus metformin, versus placebo on the prevention of diabetes in over 3000 individuals with impaired glucose tolerance, a form of prediabetes. And after demonstrating the efficacy of those interventions over about three years, we went on to do a follow up study in which the metformin group continued to receive it. Everybody got lifestyle because it worked so effectively. And we are now reporting after a further 18 years of follow up on the question of whether these interventions, now 21 years later, had any effect on cardiovascular outcomes. The background to that of course, is that people with prediabetes have a somewhat increased risk for heart disease and that rate increases as diabetes develops, particularly with severity of hyperglycemia and duration of diabetes. So, that was the study and we're now reporting on whether these interventions had a significant effect on the major cardiovascular.
Dr. Carolyn Lam:
Well, first Dr. Goldberg, congratulations on the foresight to get the informed consent and to plan ahead to be able to get these valuable data. But because I know this is going to be a critical point later. Could you tell us a little bit about the completeness of follow up and perhaps surveillance for outcomes before you share the results?
Dr. Ronald Goldberg:
Absolutely. So, 86% of the original randomized group of participants agreed to continue with a follow up study, so there was a loss at that point. And then of course, over 18 years of follow up, there's going to be a further loss. Some due to death and some due to loss to follow up. But despite that, I would say the group that entered the follow up study, we were able to maintain follow up in 85%.
Dr. Carolyn Lam:
Fantastic. And the results?
Dr. Ronald Goldberg:
The findings were that we found no significant effect of either of the two active interventions on our primary cardiovascular outcome, which was nonfatal myocardial infarction, stroke and fatal cardiovascular disease. We also had an extended outcome with more events in it, and similarly found no significant benefit or harm from either of those two intervention.
Dr. Carolyn Lam:
Oh, I love that paper. What a great, great, perhaps surprising conclusion that Dr. Gerstein loved the title of your editorial, you crystallize it. Shouldn't preventing type two diabetes also prevent long term consequences? So please tell us what was your thoughts when you saw this paper and how you frame it?
Dr. Hertzel Gerstein:
Thanks very much, Carolyn. And first of all, I was very impressed by the extensive amount of work and analysis done by Dr. Goldberg and his team. I thought that it's wonderful to see this sort of long term follow up. I've had the privilege in the past of speaking together with the DPP team on their trial and in their long term follow up. And I continue to be impressed by the extensive amounts of work and data collected and a rigor and academic value of the analysis. So, that was my very first impression and obviously it's a pleasure to write on this. I think the findings are clearly important and they both highlight the importance of long-term follow up as well as highlight the difficulties of long-term follow up in a study like this.
Dr. Hertzel Gerstein:
So this was a study done in a trial, originally done in a fairly young cohort of individuals who had very low risk for cardiovascular events. And over their 18 year follow up that Dr. Goldberg Ron described, the actual annual event rate for the primary outcome was 0.6% per year in that ballpark. Now, anybody... I've had the privilege as Ron Avery of doing many cardiovascular trials and we all know that we would never start a trial recruiting people with an event rate of 0.5% per year, 0.6% per year, because we would have to recruit 30,000 people and follow them for seven years in order to accrue enough events to be able to detect a clinically relevant benefit of the therapy. So because of this low event rate, the advantage was the long term follow up, the 26th year, I think it was in the end follow up. No, it was a 21 year median follow up period, because of the long follow up, you get a little bit away from the advantage of the low event rate.
Dr. Hertzel Gerstein:
But even then, over the course of the 21 years, there were only about 310 first cardiovascular events and most cardiovascular outcomes trials, for instance, we need close to at least a 1000, 500 to a 1000 is what we like to see. So that being said, it's perhaps not surprising that we didn't see a benefit of diabetes prevention because even if diabetes reduces the risk of a cardiovascular event by a quarter, by 25%, there would've only been a 50, 50 chance of detecting that with this particular cohort of people.
Dr. Hertzel Gerstein:
So I would say that the most conservative assumption is that diabetes prevention doesn't reduce the event rate by 25% or less or 30, but it's certainly... pardon me, by 25% or more, it could reduce it by 20%, 15% we would not have detected at all, or Ron would not have detected and his team would not have detected it with this thing. So I think that to me is the most important caveat in interpreting this does not mean that diabetes prevention has no effect on cardiovascular outcomes.
Dr. Hertzel Gerstein:
It means that diabetes prevention doesn't have a moderate or smaller effect. So, that's I think the most important message to take and as is even mentioned in the paper by Ron and the team is that there has been at least one diabetes prevention trial conducted in China many, many years ago that showed clearly that people who were randomly assigned to the diabetes prevention arm, 26 years later did have lower cardiovascular events and even death than people who were in the control arm. So, I think this adds to the story but it's clearly like everything, not the final word in this, but it certainly adds a lot of important data.
Dr. Carolyn Lam:
Oh, I would love to hear Dr. Goldberg's response to that. But before that, Dr. Holman, could I ask you to weigh in as well?
Dr. Rury Holman:
Yes. Sure. So, I agree with Hertzel that this is underpowered, but this is a question I've long wanted to see the answer to. And I congratulate Ron and his team for actually doing the work. All major studies should have long term follow up. People should be consented for life so that we can answer these questions. And Hertzel even though the power is perhaps minimal, we still need to do this analysis.
Dr. Rury Holman:
And if there had been a dramatic result, then we'd have all been very excited. I think one of the issues... one, if I could just bring it up, you mentioned the look ahead study in your discussion as being a negative dietary intervention. But I have a slightly different take on that. When you look at that paper in detail, what you see is that the people in the usual care group forgot quite a lot more risk factor reduction medications, and that's because their usual care physicians spotted the fact that their risk factor levels were higher than in the intensive care group, of course it was blinded at that point. But there's a whole point here is, in your paper you show an increase in the statin proportion, which is higher in the placebo group compared with the metformin and your intensive lifestyle, significantly so for the lifestyle one. So I'm just wondering whether even the low power was further blunted by the drop in effects of these other medications.
Dr. Ronald Goldberg:
Thanks very much for those comments guys, I think they're spot on. Let me first respond Hertzel with my thoughts on this, and then go over to your point, Rury. I think it's really interesting to look back over time and realize how much medical management has changed. And that goes right to your point, Rury, that doing a clinical trial like this where the primary care physicians are informed about what we're doing, what... communicated with on a regular basis, particularly when their patients develop diabetes, it just heightens the entire level of medical management. And I think you're absolutely right, but it's interesting to see what's happened to cardiovascular disease over the last 25 years, both in the general population and in the prediabetic population, the risk of cardiovascular disease has gone down. And then on top of that, we've got this very intensive cardio prevention intervention by primary care physicians, with high rates of statin usage, high rates of any hypertensive treatment, even the placebo group to your question, really lost weight.
Dr. Ronald Goldberg:
And they knew full well what was... and this was a very hands on type of study where our participants were really followed now for all these years, really became integrated with the research team. And so everybody knew what everybody else was doing. And so I'm sure the placebo effect was very strong, but I think nevertheless... Oh, and the last point I wanted to make was of course, the severity of the diabetes, even though 60% are developed diabetes, the severity of the diabetes was relatively mild. Even in those who developed diabetes, we know their average A1C was only about 6.7. And so I think that has a lot to do with blunting the acceleration effect of diabetes on cardiovascular disease. So, I think all of these factors contributed together to produce a negative result. But I think an important message, nevertheless.
Dr. Hertzel Gerstein:
I can highlight that point, that Ron was saying is that if diabetes prevention is going to prevent cardiovascular outcomes, it's going to do that because of a difference in glycemic exposure. The diabetes is by definition a disease of an elevated blood sugar. So if diabetes prevention prevents cardio, it means that the blood sugar's going to be lower than it would otherwise be. So if there's very little difference over the long term follow up in blood sugar because of co-intervention and therapy of all the treatment groups, then that would eliminate a lot of the benefits of diabetes prevention, because these are patients who are in this trial, who are being scrutinized even more than they would be if they were out there free range without being involved in any follow up. So, that's a spot on point. Rury, you wanted to comment.
Dr. Rury Holman:
Yeah. So, Hertzel just to expand on that. Obviously the glycemic impact on macrovascular disease is relatively modest compared to the impact on microvascular disease, which of course is what we all saw originally with type 2 diabetes. In fact, in KPDS35, when we looked or calculated what 1% reduction in A1C would do, it would only reduce stroke or MI by about 12 to 14%. So it's quite a shallow slope if you like. And your point is spot on is if that glucose levels are kept low by good treatment and good management role tell us about the great team they have. Then there was no room for a glycemic impact in this particular study. It's another question, whether you think metformin acts by different mechanisms to reduce cardiovascular disease, that's another question I had for Ron that he might like to address, is if there was a magic effect of metformin, why didn't we see that?
Dr. Ronald Goldberg:
And that's a really interesting question, Rury, because you may be aware that we published a paper a few years ago on our assessment of coronary calcification in a subgroup, in about 60% of the population who agreed to do this and who were eligible. And interestingly found that metformin did was accompanied by a reduction in the prevalence of coronary calcium in men, not women.
Dr. Ron Goldberg:
And the effect was actually when we did subgroup analysis, we found it was particularly strong in young men. And actually that gave us some sense of optimism that we might see something when we came to actual events. And of course, as you all know, metformin has beneficial effects on several cardiovascular risk factors. And so the question is whether there is some effect of metformin that might yet be identified, a coronary calcium after all is a surrogate of events and may take time, or it may be that... And we are really interested in the idea that both prediabetes and diabetes are heterogeneous. There's more and more interest in looking at subgroups of individuals who may be more predisposed. And it may be that metformin might have beneficial effects in some of those subgroups.
Dr. Hertzel Gerstein:
But also remember on the other hand, there was a lot of co-intervention with metformin in all groups after the trial was over. So all groups were offered metformin, et cetera. So even if metformin had an effect, it could have easily been washed out by the exposure of all the other groups to metformin during follow up. But Ron, you also touched on both the hope and the frustration too, because if we start thinking about subgroups, we can always think of subgroups. Yeah. But then the problem with subgroups is you have a study, let's say you have a cohort study with 7,000 or 10,000 people and it followed for five years and, oh, well the effect isn't in all 10,000, it's only in 20% of them. So now you have a study of 2000 people, that's not enough to detect an effect in a subgroup.
Dr. Hertzel Gerstein:
So, subgroups just eat away at power in an exponential, not a linear way, so that you just rapidly lose any ability to detect anything. And so, yes, this is going to work in people with these three snips on this gene, in this subpopulation. Good luck, that's the difficulty and the challenge of... We need to find sometimes better or more efficient ways of identifying outcome protective therapies, because we can't keep drilling into some groups because we just don't have the resources to find it really. I don't know what other people feel about that, but.
Dr. Carolyn Lam:
I'm personally so enjoying this conversation as I know the audience is and we covered a lot. I'm sure everyone wants to pick up the paper and the editorial. Now, we talked about being underpowered for the number of studies. We talked about profitable dilution of things like statins, antihypertensive agents, even the crossover of potential treatment in the placebo arm and so on. And then we started talking about, or is it the how you got there and the drug that was used. And here, please don't shoot me, but I just know I have the answers on behalf of everyone else's thinking it. What do you say of people who go, "Well, it's because it's metformin. What if it was an SGLT2 inhibitor? What if it was a GLP-1 receptor agonist?" And as you know, a lot of people say those would in spite of the effect on glucose.
Dr. Hertzel Gerstein:
I can quickly jump in. It's very clear. We've learned this in the last 10 years, is that there are glucose lowering drugs and there are glucose lowering drugs with benefits. And the GLP-1 receptor agonist and the SGLT2 inhibitors are glucose lowering drugs with benefits. They lower glucose, but they seem to have a separate cardioprotective effect. And with the SGLT2 inhibitors that cardioprotective effect does not seem to be related to the glucose lowering. There are a few meta regression analyses that suggest that with the GLP-1 receptor agonist, part of the cardioprotective effect is related to glucose lowering and part is not. And clearly mediation analysis with some of the trials have shown the same thing with the GLP-1 receptor agonist, not really with the SGLT2 inhibitors. So, maybe, that's my spin on this.
Dr. Carolyn Lam:
Dr. Holman.
Dr. Rury Holman:
Yeah. I was going to echo what Hertzel said in that regard, these other agents do have multiple effects. They change weight, they change blood pressure. And so other risk factors are brought into play other than glucose lowerings. We've already agreed, glucose lowering impact on cardiovascular disease is quite modest. I'd rather have it than not, but it wouldn't be my primary way to treat cardiovascular disease. And coming back to Ron's study, which is crucial today, the issue here is whether we could untangle an impact particularly of metformin, which has been foundation drug for type 2 diabetes for so long.
Dr. Rury Holman:
But clearly within the dataset we have here, underpowered it is. There are no clear messages in that respect, which is disappointing, but it doesn't mean that there isn't an effect. With longer follow up, with more data than you might see it. When the study... I'm coming for you Hertzel, was stopped for futility then the hazard ratio has changed, that often the way, not for the right way, but it's often what happens when you stop studies. I wondered if you wanted to comment on that aspect, because I know it's something that you've talked a lot about.
Dr. Carolyn Lam:
Dr. Gerstein. Did you want to?
Dr. Hertzel Gerstein:
I agree with what Rury said. I think the point you're making Rury goes back to power, and the ability to have enough people and enough events to detect and effect and that's clearly true, so...
Dr. Carolyn Lam:
Well, I hate to be the one to break the party up, but we have gone over time and intentionally so, there's just so much learning here. But Dr. Goldberg, could I give you the last say please? What do you think is the important clinical take home message of your paper?
Dr. Ron Goldberg:
Well, I think that the fact that we demonstrated that our study has been able to maintain really low levels of cardiovascular risk factors, low levels of A1C, even though that likely contributed to the negative finding still leaves the physician where the recognition that it is important to identify individuals with prediabetes to Institute Diabetes Prevention Programs, because I think it's entirely possible as I said earlier, and we've begun to identify them, subgroups of individuals who do progress more rapidly and who do warrant a more effective treatment, which would come from an early intervention program.
Dr. Carolyn Lam:
Wow. Thank you so, so much for that. Thank you so much. All three gentlemen for this amazing discussion. Well, audience, you heard it right here on Circulation on the Run from Greg and I thank you for joining us today and don't forget to tune in again next week.
Speaker 6:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Sanjiv Shah, Editorialist Evangelos Michelakis, and Associate Editor Justin Ezekowitz as they discuss the article "Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure" and Editorial "Atrial Shunt Devices in Patients with Heart Failure and Preserved or Mildly Reduced Ejection Fraction and the Pulmonary Circulation: Promises and Concerns."
Dr. Carolyn Lam:
Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I love today's featured article. It's all about heart failure with mildly reduced and preserved ejection fraction, talking about device therapy and the response to therapeutic atrial shunt device. Now, this is a very interesting discussion of how specifically selecting patients based on latent pulmonary vascular disease may hold some answers, but we're going to keep everyone hanging here. You've got to, got to listen to the discussion. But first, we'd like to tell you about some of the papers in today's issue. And I think Greg, you've got one to start us with, right?
Dr. Greg Hundley:
Absolutely. Carolyn, thank you so much. Well, this first paper comes from Dr. Eliot Peyster from the University of Pennsylvania. And Carolyn, the aim of this study was to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies, to develop a precision medicine tool for predicting cardiac allograft vasculopathy, years before overt clinical presentation.
Dr. Carolyn Lam:
Ooh, interesting. Again, precision tools. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So there was a clinical predictive model that achieved modest performance on the independent test set, with area under the receiver operating curve of 0.7. But interestingly, a histopath- predictive model for predicting cardiac allograft rejection achieved good performance, with an area under the receiver operating curve of 0.8. Most importantly, however, a model, incorporating both clinical and histopathologic features, achieved excellent predictive performance, with an area under the receiver operating curve of 0.93.
Dr. Greg Hundley:
So in summary, Carolyn, these authors found that prediction of future cardiac allograft vasculopathy development is greatly improved by incorporation of computationally extracted histologic features. Their results suggest morphologic details, contained within regularly obtained biopsy tissue, have the potential to enhance precision and personalization of treatment plans for post heart transplant patients.
Dr. Carolyn Lam:
Aw, that's cool. Makes so much sense, but yet so novel. Thanks.
Dr. Carolyn Lam:
Well, for the paper I want to talk about, we are going to talk about dapagliflozin. Now we know the SGLT-2 inhibitor, dapagliflozin, improved heart failure and kidney outcomes in patients with Type two diabetes with or at high risk for cardiovascular disease, in the DECLARE–TIMI 58 trial. In the current paper, authors, led by Dr. Wiviott from the TIMI study group, aimed to analyze the efficacy and safety of dapagliflozin stratified, according to baseline systolic blood pressure.
Dr. Greg Hundley:
Ah, so an interesting question, since SGLT-2 inhibitors are known to reduce blood pressure. And given the concerns regarding the safety of SGLT-2 inhibitors, in patients with low to normal systolic blood pressure. So Carolyn, what did they find?
Dr. Carolyn Lam:
Nicely put Greg. So in patients with type two diabetes with, or at high risk of, atherosclerotic cardiovascular disease, dapagliflozin reduced the risk for heart failure hospitalizations and renal outcomes, regardless of baseline systolic blood pressure, with no difference in benefit for reduction in heart failure or renal outcomes, among patients with blood pressure from the normal range, all the way to severe hypertension. Moreover, there appeared to be no difference in adverse events of volume depletion, acute kidney injury, or amputations, across the levels of baseline blood pressure. So these results indicate that dapagliflozin provides important cardiorenal benefits in patients with Type two diabetes at high risk, the independent of baseline blood pressure.
Dr. Greg Hundley:
Oh, very nice, Carolyn. Well, my next paper comes to us from the world of preclinical science, and it's from professor Jeffrey Towbin and colleagues, at Le Bonheur Children's Hospital. So Carolyn, as we know, arrhythmogenic cardiomyopathy is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 has been reported to be the most common disease causing gene when mutation is positive. Now in the early concealed phase, the arrhythmogenic cardiomyopathy heart is at high risk of sudden cardiac death before cardiac remodeling occurs, due to mis-targeted ion channels and altered calcium handling. However, the results of pathogenic plakophilin-2 variants on myocyte contraction in arrhythmogenic cardiomyopathy pathogenesis, really remains unknown. So Carolyn, these authors studied the outcomes of a human truncating variant of plakophilin-2 on myocyte contraction, using a novel knock-in mouse model, as well as evaluation of human subjects.
Dr. Carolyn Lam:
Oh, interesting. So what were the results from this plakophilin-2 knock-in mouse model?
Dr. Greg Hundley:
Right, Carolyn. So serial echocardiography, a plakophilin-2 heterozygous mice revealed progressive failure of the right ventricle, but not the left ventricle, in animals older than three months of age. Now next, adrenergic stimulation enhanced the susceptibility of plakophilin-2 heterozygous hearts to tachyarrhythmia and sudden cardiac death. Contractility assessment of isolated myocytes demonstrated progressively reduced plakophilin-2 heterozygous RV cardiomyocyte function, consistent with right ventricular failure, measured by echocardiography.
Dr. Greg Hundley:
And the next, Western blotting of plakophilin-2 right ventricular homogenates revealed a 40% decrease in actin. In contrast, plakophilin-2 heterozygous left ventricular myocytes had normal contraction and actin expression.
Dr. Greg Hundley:
And finally, Carolyn, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in the right ventricles of end stage arrhythmogenic cardiomyopathy patients. So in conclusion, Carolyn, during the early concealed phase of arrhythmogenic cardiomyopathy, reduced actin expression drives loss of RV myocyte contraction, and that contributes to progressive RV dysfunction.
Dr. Carolyn Lam:
Wow. Thanks, Greg. Well, also in today's issue, there's an exchange of letters among Drs. Whitman, Ibrahim, and Løfgren, regarding physics at the heart of the matter, referring to the article, “Anterior–Lateral Versus Anterior–Posterior Electrode Position for Cardioverting Atrial Fibrillation.”
Dr. Greg Hundley:
Right Carolyn. And also in the mail bag, there's an On My Mind piece, from Professor Taegtmeyer, entitled, “The 2022 Beijing Winter Olympics, The Spotlight On Cardiac Metabolism.”
Dr. Greg Hundley:
Well, how about we get onto that feature article, and learn a little bit more about atrial shunts, and how they may be helpful in heart failure with preserved ejection fraction?
Dr. Carolyn Lam:
Ooh, can't wait.
Dr. Greg Hundley:
Well, listeners, we have a very interesting feature discussion today related to hemodynamics pertaining to interatrial shunt devices, in those with and without pulmonary hypertension. And we have, gosh, a repertoire of speakers today. We have Dr. Sanjiv Shah, from Northwestern University in Chicago, Dr. Evangelos Michelakis, from Edmonton Alberta, and our own associate editor, Dr. Justin Ezekowitz, also from Edmonton Alberta.
Dr. Greg Hundley:
Well, Sanjiv, we're going to start with you. Describe for us, some of the background pertaining to your study, and what was the hypothesis that you wanted to address?
Dr. Sanjiv Shah:
Great. Thanks, Greg. Thanks for having me today. Well, the background of our study is that, it was a subgroup analysis, or a secondary analysis, of the REDUCE LAP-HF II trial. Now this trial has been in the making for over 12 years, almost 13 years. It started out as an idea that was David Celermajer. David is a pediatric cardiologist in Australia, who had this idea that, in mitral stenosis patients, it's well known that, if there's a concomitant secundum ASD, a congenital secundum ASD, in these patients with mitral stenosis do better. They have a way to unload the left atrium, and distribute that blood to the systemic veins and the right atrium, the right side of the heart. And so could this be helpful in quote, diastolic, heart failure or HFpEF?
Dr. Sanjiv Shah:
And so, I started working with him about 12 years ago. This started out as a concept. It was studied in animal models, and then in humans, in open label studies, and then, in a first randomized controlled trial. Where we showed, that an intraatrial shunt device, an iatrogenic ASD, so to speak, put in humans with heart failure with risk preserved EF, results in a lowering of exercise pulmonary capillary wedge pressure. And so based on that data, we designed a pivotal trial, a Phase III trial, the largest trial of its kind, of heart failure with preserved and mildly reduced ejection fraction, to see if interatrial shunt device would improve outcomes. And we published that trial earlier this year in the Lancet. Unfortunately, it was a totally neutral trial. And when you have a neutral trial in any condition, but as we see often in HFpEF, the question is, was it neutral overall? Or was there a subgroup that benefited? And what we found in that trial was that, there were three predefined subgroups that came out that seemed like there was a difference.
Dr. Sanjiv Shah:
First, there was a sex difference. Women did better. Men did worse with the device. Then, there was right atrial volume. Those with bigger right atrial volumes did worse. If you had a smaller right atrial volume, you did better. But the most significant interaction and subgroup was exercise pulmonary artery systolic pressure.
Dr. Sanjiv Shah:
If the pulmonary artery systolic pressure was greater than 70 at 20 Watts of exercise, so just with a little bit of exercise, those patients did worse. And if PA pressure stayed low, the patients did better. And so we sought to further explore this to say, "Okay, what's exactly going on?" In a post hoc analysis, what's going on with the pulmonary vasculature during exercise, and how does that differentiate how patients potentially respond to the device? And that's what we hope to figure out.
Dr. Sanjiv Shah:
We hypothesize, that if exercise pulmonary vasculature resistance is lower, then the shunt can actually work, and blood can flow from the left to the right, into the lungs, and the right heart doesn't get too overloaded. And we know, that the normal response of the pulmonary vasculature is to vasodilate with exercise. And so, if patients had retained that response, the ability to do that, that they may benefit. And so, we sought to figure that out with this subgroup analysis.
Dr. Greg Hundley:
Sanjiv, it sounds like a really elegant, well thought out hypothesis. So what was your study design? And describe your study population.
Dr. Sanjiv Shah:
Yeah. This was a randomized controlled trial. And so this was 626 patients enrolled at 89 centers across the world. And it was really, heart failure with mildly reduced, so an EF of greater than 40, or preserved EF, and 93% of them had HFpEF. And what was unique about this trial is that we, this is the first trial really, that confirmed that these patients actually had heart failure, with mildly reduced or preserved ejection fraction. Most trials say, well, you have to have an elevated BNP, and you have to have some sign of structural heart disease, and maybe, a history of heart failure hospitalization. In this trial, every single patient had to undergo rigorous noninvasive echocardiography. And then, on top of that, they had to undergo exercise invasive hemodynamic testing. And people thought that it wasn't possible for 626 patients, but we did it. And every single patient had had an exercise pulmonary capillary wedge pressure greater than, or equal to, 25. And so this really was HFpEF. So it's a randomized trial.
Dr. Sanjiv Shah:
And then, beyond that, we did a subgroup analysis. So we looked on various subgroups, focusing on exercise PVR, and we really looked to see the effect on three outcomes. Number one, a hierarchical endpoint, a combination of cardiovascular death, ischemic nonfatal stroke, recurrent heart failure hospitalizations, and the KCCQ. And then the other two outcomes were just the individual recurrent heart failure hospitalizations, and the KCCQ. We looked at all of these, and tried to figure out if there are certain subgroups that benefit.
Dr. Greg Hundley:
Great detail. So Sanjiv, what did you find?
Dr. Sanjiv Shah:
Well, we found that, there's this group of patients, that during exercise, the pulmonary vascular resistance at peak exercise stays above 1.74 Wood units. Now that seems like an arbitrary number, but in fact, in older individuals that are healthy, when you exercise them, the PVR upper limit, the exercise PVR upper limit, is about 1.8. So we're right about the upper limit of where the PVR should be. And if it was above that, the patients actually did worse with the shunt device. They had a lot more heart failure hospitalizations. Their KCCQ got worse, didn't benefit. And if they were below that threshold, meaning they were, sort of compliant pulmonary vasculature, and it stayed compliant, or they vasodilated effectively with exercise, then they benefited from the device. And what we call this concept of exercise-induced pulmonary vasoconstriction, or inability to vasodilate, is latent pulmonary vascular disease.
Dr. Sanjiv Shah:
And so, if you have that latent pulmonary vascular disease, your win ratio is 0.6. That means you do worse. And if you don't have this pulmonary, this latent pulmonary vascular disease, your win ratio is 1.31. And that means, you do better with the device. And we saw very similar findings with the KCCQ. We saw similar findings with the recurrent heart failure hospitalizations.
Dr. Sanjiv Shah:
And the final thing is, we found that, we looked at various other subgroups, and it turned out that if there was no latent pulmonary vascular disease and no history of pacemaker, which we found was kind of associated with sex and right atrial volume, those patients, for about 50% of the group, actually did the best. And that was what we called, the responder subgroup.
Dr. Greg Hundley:
Thank you, Sanjiv. Well, listeners, we're going to turn now to our associate editor, Justin Ezekowitz. And Justin, you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Justin Ezekowitz:
So Greg, this paper kind of stood out for a number of different reasons, as I sent you. You're to be congratulated for a variety of reasons. But the number one is, pursuing the data from a neutral trial overall, to understand who might benefit and who might be harmed from a pretty novel device and way to treat patients in such a scale, that's not being done like this before. So it stands out by just the magnitude of number of right heart catheterizations, number of patients enrolled, number of procedures done. And all of those things really lead to us to be able to understand the area much better than I think we can in a human population.
Dr. Justin Ezekowitz:
Where this sits with other devices that are very similar, is hard to really know, if all devices are going to be the same or different, but your population is quite unique is if they're not all end stage, but they're sick enough to get into your trials. So there's this population we treat actively. And I wondered if you could touch on that continuous nature. And so for readers, there's this beautiful figure, which shows a continuous nature of exercise PVR. And I wonder if you could touch on that. Is this mid group, the group that we should target for our future therapies like this, or this needs further study?
Dr. Sanjiv Shah:
Well, I think it needs further study. I think the listeners should be aware that this is a post hoc analysis. We did pre-specify exercise PA pressure. This is one trial. But it makes a lot of sense, pathophysiologically. What we're doing here is we're shunting this excessive LA, overloaded LA, shunting the blood from the LA to the RA and into the pulmonary vasculature. Well, if that pulmonary vasculature can't accept that increased flow, the patient's not going to do well. And how can we simulate that? Well, we can simulate it with exercise. As the patient's pedaling on the bike, on the cath lab table, there's increasing blood flow to the pulmonary vasculature, and we're seeing what happens with the pulmonary vasculature. Does it vasodilate, does it not? And so, I think that's why we were excited about this finding.
Dr. Sanjiv Shah:
I do think that, there are at least seven other companies making shunt devices, interatrial shunt devices or therapies. And I do think, they need to pay attention to this and really look at this. Not all trials are doing exercise and basic hemodynamics, that needs to be done, I think. So it'll be really interesting to see.
Dr. Sanjiv Shah:
Now, one thing I will say is that, and I've written about this, this is a really interesting trial. Because the BNPs were lower, and so you would think, okay, these are patients that are less sick. And yet, their heart failure hospitalization rate was at least one and a half times higher than pharma Phase III trials. KCCQ was way lower, like 30 points lower. So there are these patients out there that are really sick, and they're the ones that I think, are where their life, their sort of quality of life, their outcomes, are being driven by the HFpEF. And that's what we found in this trial.
Dr. Greg Hundley:
Very nice. Well, listeners, let's turn now to our editorialist, Dr. Evangelos Michelakis. And Evangelos, two questions. How do we put the results of this substudy, really in the context of the main trial? And then secondly, do you have any, with your expertise in endothelial function, and understanding the mechanisms of pulmonary hypertension, can you describe what you think might be operative as a mechanism here, and why Sanjiv observed these positive results in some patients?
Dr. Evangelos Michelakis:
Thank you. So the first point is that, I have to also repeat, that it was a remarkable achievement to do all this right heart catheterization on a treadmill in the cath lab. It's a very complex procedure. And it is, they have to be congratulated, the authors, for actually doing this. There is no question that, like Sanjiv said, ongoing trials for future trials will need to include the hemodynamics in the trials, before and after the procedure.
Dr. Evangelos Michelakis:
So another important thing is that, the authors brought up this, they called it latent pulmonary hypertension, we could call it latent pulmonary hypertension, or probably, early pulmonary hypertension, as an entity. Now that entity, it's newer in the heart failure field. It's not that old in the PIH, the pulmonary interior hypertension field, since it used to be in the guidelines for this disease, that exercise pulmonary hypertension was a diagnostic criterion for that. Because the idea is that, exercise pulmonary hypertension reflects early pulmonary hypertension. So you needed to intervene with therapies early.
Dr. Evangelos Michelakis:
Now, I'm not sure that this is a fact. But it is very likely that these patients, in Sanjiv's trial, that had the early, that had the sort of enhanced response with exercise, did have at least, endothelial dysfunction in the pulmonary arteries. Not only because this population has a number of endothelial risk factors, diabetes, smoking, you name it. But also, there are newer problems like SNPs polymorphism mutations, that will recognize more into the pulmonary arterial hypertension field, to be more unique to the pulmonary circulation.
Dr. Evangelos Michelakis:
But the reason I say that is that, the reason that you dilate with exercise, is mostly because of your pulmonary arterial endothelial cells, secreting vasodilatory factors. And also, allowing previously closed capillaries to open up with increased flow. However, the problem is that, if you have pulmonary arterial endothelial cells in vitro, and you expose them to high flow, like in this case, you can actually change their identity. Turn them into cells that are not endothelial cells anymore, are proliferative pro-inflammatory, and they can actually cause structural pulmonary circulation damage.
Dr. Evangelos Michelakis:
Also, there are animal models and people working in PAH and ASD, where they've shown that, if you have, if you're given endothelial toxin in animals, and then, you do an aortocaval shunt, then you get really severe pulmonary hypertension with structural disease, that is not even reversible if you remove the shunt.
Dr. Evangelos Michelakis:
So from this trial, the conclusion that patients with pulmonary hypertension should not get the device, is very clear. And probably, the ones with exercise pulmonary hypertension. My theoretical concern is, for those that don't have exercise pulmonary hypertension, or those that do have it, could they get worse after a number of years, and have structural pulmonary vascular disease? And unfortunately, we didn't have a follow up right heart catheterization to prove that, whether this is right or wrong. Which is a thing, is the most important thing to do in the future. So mimic the protocol for this trial from now on, but also add a follow up right heart catheterization, perhaps not just in a year, but longer. In other words, enough time to allow the structural pulmonary remodeling get established, but also, affect the right ventricle, these things don't. So maybe in a few years. It's a very demanding thing for these protocols, but I think, that's what needs to be done before we say this device can actually be beneficial for those patients, or for some patients, or not hurt others.
Dr. Greg Hundley:
Very nice. And so, a great segue, Evangelos, into what we think the next studies may need to be performed in this particular sphere of research.
Dr. Greg Hundley:
So Sanjiv, in just 30 seconds, could you share your thoughts first, and then we'll circulate back to Justin, and then finish up with Evangelos. Sanjiv?
Dr. Sanjiv Shah:
Yeah. I think the key thing is, to do a confirmatory trial. And that's what we're aiming for, is to do a confirmatory randomized sham-controlled trial, but focus in on these patients with an exercise peak PVR of less than 1.75, around there. And I think, that'll help answer the question. The Qp/Qs we get with this device is 1.2 to 1.3. So I don't think it's a high flow. And we actually have open label studies, where we've gone out to three years, with repeat invasive hemodynamic testing, echocardiograms, and we've had patients who've been implanted for seven years. We're not seeing, at least at that point, any sort of worsening of pulmonary vascular disease, or RV function, or anything like that. And so, it remains to be seen.
Dr. Sanjiv Shah:
The last thing I'll say, which I think is provocative, in the field of HFpEF, all pulmonary vasodilator drugs have failed. And though, we only measure pulmonary vascular resistance at rest. And what we saw in this trial, is that some patients have a high PVR and it comes down. Some people have a PVR that stays low, and is low and stays low. Some people have a low PVR and it goes up. You know? So I think what we need to think about in the field of PH‐HFpEF, is more exercise genotyping, to determine what's the dynamic exercise PVR? And maybe, those with exercise elevation of pulmonary vascular resistance are the ones that respond to pulmonary vasodilators. So that's another thing that I think we can think about taking away from this trial.
Dr. Greg Hundley:
Thank you, Sanjiv. Justin.
Dr. Justin Ezekowitz:
Yeah. So my thoughts are mimicking Sanjiv's. But one of the things that we desperately need is, ways in which we can noninvasively assess the exercise PVR, so that we can think about the large scale interventions that might come down the road, if interventions such as this work well. Because the noninvasive scans will really help us look at broader populations. Those are, that don't make it into trials, and those that aren't traditionally in our studies of HFpEF. So I think, that's another area where we can really grow the field, and then, grow our knowledge.
Dr. Greg Hundley:
Very nice. And Evangelos.
Dr. Evangelos Michelakis:
So, yes. Of course, like everybody said, we need trials that will have a follow up right heart catheterization, at least address, if not both, like the investigators did. But because the big question is, are these patients having an earlier stage pulmonary hypertension or not? These patients that the authors called, latent pulmonary hypertension, we need to phenotype more their endothelial cells, or their disease. And in the absence of biopsies, the only way we could do that, is perhaps, with molecular imaging, or at least, in some small populations. Or with analyzing pulmonary arterial endothelial cells in the blood, and their molecular phenotype, to see if they are a distinct group, which I suspect they may be. So further genotyping of this exercise induced pulmonary hypertension in this population, will be important as well.
Dr. Greg Hundley:
Thank you. Well, listeners, we've had a great discussion today, from Dr. Sanjiv Shah, from Northwestern University in Chicago, our editorialist, Dr. Evangelos Michelakis, from Edmonton, Alberta, and our own associate editor, Dr. Justin Ezekowitz from Edmonton, who brought us this study, demonstrating that in patients with heart failure and preserved ejection fraction, or heart failure and mildly reduced ejection fraction, the presence of pulmonary vascular disease, uncovered by invasive hemodynamic exercise testing, identifies patients who may worsen with atrial shunt therapy. Whereas, those without pulmonary vascular disease may, at least in the short term, benefit. And of course, as Evangelos has pointed out, the long term findings really warrant further study.
Dr. Greg Hundley:
Well listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Andrew Stokes as he and Greg Hundley discuss the Research Letter "E-Cigarette Use and Risk of Cardiovascular Disease: A Longitudinal Analysis of the PATH Study (2013–2019)."
Dr. Greg Hundley:
Well, listeners, welcome to this May 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, associate editor, director of the poly heart center at VCU Health in Richmond, Virginia. And this week, Carolyn is away out on vacation and we are going to go through the summaries together. We have a great feature today on e-cigarette use and the risk of cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And the first one comes to us from the world of clinical science and Dr. Jiaqi Huang from the National Cancer Institute. Listeners, the objective of this study was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption through the prospective analysis of 27,000 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC Study, and also a systematic review and meta-analysis of several other cohort studies.
Dr. Greg Hundley:
So, what did the investigators find? Well, first, based on 482,000 person-years of follow-up, the authors identified 22,000 deaths, including 9,110 deaths from cardiovascular disease. Now, greater dietary cholesterol and egg consumption were associated with increased risk of overall and cardiovascular disease mortality. Now, second, from the meta-analysis component of the study, overall consumption of one additional 50-gram egg per day was associated with an increased cardiovascular disease risk with a pooled relative risk of 1.04 with a higher risk of cardiovascular disease among those from us cohorts where their pooled relative risk ratio was 1.88, a borderline higher cardiovascular disease risk in European cohorts with a pooled relative risk of 1.05, but not an increased cardiovascular disease risk in the Asian cohorts. So, the results from this study, which includes an updated meta-analysis, suggest that there is support for restricted consumption of dietary cholesterol as really a means to improve long-term health and longevity.
Dr. Greg Hundley:
Well, let's go to our next article. So, in this next study, we are going to move from cholesterol risk now to salt substitution. And this article comes to us from Professor Maoyi Tian from the Harbin Medical University. Listeners, the Salt Substitute and Stroke Study, or SSaSS is a five-year cluster randomized controlled trial and demonstrated that replacing regular salt with a reduced sodium added or potassium salt substitute reduced the risk of stroke, major cardiovascular events, and premature death among individuals with prior stroke or uncontrolled high blood pressure that lived in rural China. So, this particular study, a substudy, assessed the cost-effectiveness profile of this particular intervention.
Dr. Greg Hundley:
So, listeners, what did the study find? Well, there was a mean follow-up of 20,995 participants that was conducted a little over four years, and over the period, replacing regular salt with salt substitute reduced the risk of stroke by 14% and the salt substitute group had on average 0.054 more quality-adjusted life years per person. The average costs were lower in the salt substitute group, and this intervention was dominant. That is better outcomes at a lower cost for prevention of stroke as well as for quality-adjusted life-years gained. Now, interestingly sensitivity analyses showed that these conclusions were robust except when the price of the salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95% probability of being cost-saving and a greater than 99.9% probability of being cost-effective. A really interesting article.
Dr. Greg Hundley:
Well, now, let's turn our attention to the world of population science. And in this study, these authors led by Dr. Steven Lubitz from Massachusetts General Hospital performed a Genome-Wide Association Study or GWAS of the QT corrected interval among 84,630 United Kingdom Biobank participants. And they created a polygenic risk score. Now, among 26,976 participants with whole-genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine or TOPMed program, they identified 160 carriers of punitive pathogenic, rare variants in 10 genes known to be associated with the QT interval.
Dr. Greg Hundley:
So, the authors here examined the QTC corrected associations with the polygenic risk score and with rare variants from the TOPMed cohort. So, what did they find? They found 54 independent loci by GWAS in the UK Biobank. 21 loci were novel of which 12 were replicated in TOPMed. The polygenic risk score comprising over a million common variants was significantly associated with the QTC in TOPMed, and carriers of punitive pathogenic rare variants had longer QTC intervals than non-carriers. Now, 23.7% of individuals with a QT corrected of greater than 480 milliseconds carried either a monogenic rare variant or had a polygenic risk score in the top decile. 3.4% for monogenic and 21% for the top decile of the polygenic risk score.
Dr. Greg Hundley:
So, listeners, the findings of this study indicate that the QTC duration in the population is influenced by both rare variants in genes, underlying cardiac repolarization and polygenic risk, with a sizeable additional contribution from polygenic risk. And therefore, comprehensive assessment of the genetic determinants of QTC prolongation should include incorporation of both polygenic and monogenic risk.
Dr. Greg Hundley:
Well, listeners, let's turn our attention to the world of preclinical science. And this next article comes to us from Professor Junbo Ge from the Department of Cardiology in Zhongshan Hospital in Fudan University. Well, listeners, after myocardial infarction, cardiac resident macrophages, which are self-maintaining in that they originate from embryonic hematopoiesis are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes. And that process is called efferocytosis. Now, efferocytosis is required for inflammation resolution and tissue repair. However, the underlying molecular mechanisms of this process really remain unknown.
Dr. Greg Hundley:
So, as such, listeners, these authors sought to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Well, what did Dr. Ge and colleagues find? Several things. First, they identified legumine as a gene specifically expressed by cardiac resident macrophages, and legumine deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in-vivo efferocytosis in the border area of infarcts. Furthermore, the formation of LC3 to dependent phagosome around secondary encountered apoptotic cardiomyocytes was disabled. In addition, legumine deficiency increased infiltration of MHC to high CCR2+ macrophages, and the enhancement of recruitment of MHC to low CCR2+ monocytes with downregulation of anti-inflammatory mediators, such as IL10 and TGF-beta, and upregulation of pro-inflammatory mediators, including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6, and IFN-gamma.
Dr. Greg Hundley:
So, listeners, in summary, the results of this study directly link efferocytosis to wound healing in the heart and identify legumine as a significant link between acute inflammation resolution and cardiac function after infarction. Well, listeners, also in this issue, we have a wonderful On My Mind feature from Professor Camlet entitled “A Role for the Vascular Endothelium in Post-Acute COVID-19.” Well, next, we're going to head to our feature article on e-cigarette use and the risk of cardiovascular disease.
Dr. Greg Hundley:
Well, listeners, welcome to our feature discussion today. A very interesting topic. E-cigarette use and the risk of cardiovascular disease. And we have with us today the senior author of this particular manuscript, Dr. Andrew Stokes from the Boston University School of Public Health in Boston, Massachusetts. Welcome, Andrew. Andrew, to get started, can you describe some of the background information pertaining to your study and what was the hypothesis that you wanted to address?
Dr. Andrew Stokes:
Absolutely, and thank you for having me on the podcast. Despite the increasing popularity of electronic cigarettes, the long-term health effects of habitual e-cigarette use remain unclear. Most of the studies that have been conducted to date are either cross-sectional or they pertain to small clinical samples. The goal of the present study was to develop a longitudinal design to see if e-cigarette use at a point in time was linked to cardiovascular events over a multi-year follow-up period.
Dr. Greg Hundley:
Very nice. So, your specific hypothesis really pertained to e-cigarette use, correct?
Dr. Andrew Stokes:
That's right. As a novel product, information on e-cigarette use and its health effects is lacking, and so our goal was to see if e-cigarette use was associated with the incidence of clinical events.
Dr. Greg Hundley:
And so, can you describe for us your study population and your study design?
Dr. Andrew Stokes:
Absolutely. Data come from the Population Assessment of Tobacco and Health Study or the PATH Study, which is a nationally representative cohort study of the non-institutionalized population containing five annual waves of self-reported data collected between 2013 and 2019. The initial sample included over 30,000 US adults ages 18 years and older with oversampling of tobacco users. We excluded respondents who were lost to follow-up or who had a previous diagnosis of CVD or were missing baseline exposure information. Ultimately, we ended up with a sample of just over 20,000 individuals.
Dr. Greg Hundley:
Very nice. And so, what were your study results?
Dr. Andrew Stokes:
So, we had several key findings. One key finding was that, compared to people who only smoke cigarettes, people who smoke both traditional cigarettes and used e-cigarettes had no significant reduction in risk for heart attack, heart failure, or stroke, nor any cardiovascular disease outcome. This is significant because many e-cigarette users use both e-cigarettes and cigarettes in combination. Very few move to exclusive e-cigarette use. Additionally, we found that those who do move to e-cigarette use exclusively though, representing a very small fraction of the cohort, had some evidence of reduction in cardiovascular harm. However, these results for exclusive e-cigarette users were not statistically significant, indicating that additional studies with longer follow-up will be required before we can make any definitive conclusions about this group.
Dr. Greg Hundley:
Very nice. And did you notice any discrepancy in your results between either men versus women or between individuals that were younger in age versus those that may say be 50 years or older?
Dr. Andrew Stokes:
I think both sources of effect modification will be valuable directions for future research. Unfortunately, samples of e-cigarette users are quite small and incident events over follow-up are quite limited. Therefore, the present study did not pursue or explore these types of stratifications.
Dr. Greg Hundley:
Very good. So, sounds like more research to come forward. Well, Andrew, how do we put your results really in the context with other studies evaluating the harmful effects of e-cigarettes?
Dr. Andrew Stokes:
Of course. So, we know from toxicological studies that there are many constituents of e-cigarette aerosols that are concerning and have substantial toxicity. We know that the inhalation of e-cigarette aerosols among young healthy adults induce inflammation and oxidative stress. Population-based studies from cross-sectional data sources also suggest evidence of harm. What's needed are more longitudinal studies with longer follow-up periods and more incidence events so we can really parse this risk and identify the magnitude of these harms. Finally, we also need to understand better whether there's any harm reduction potential associated with e-cigarette use. E-cigarettes are currently not an FDA-approved cessation product. Therefore, we do not recommend their use despite preliminary evidence of potential harm reduction. We'll need further evidence before we can make any such conclusions.
Dr. Greg Hundley:
And Andrew, describe for us, and you've started to already, what series of studies are needed next to be performed in this sphere of research?
Dr. Andrew Stokes:
Right. So, it's difficult to really identify definitively the effects of e-cigarette use in the absence of randomized control trials. However, we can use observational data with target trial approaches to emulate the clinical trial that we would like to do if we were able to. So, the next step is really to look at transitions across products between cigarette and e-cigarette use and to associate those who switch products, such as from e-cigarettes to cigarettes or vice versa, to see if those switches are associated with any harm or harm reduction.
Dr. Greg Hundley:
Very good. Any specific racial or ethnic groups or even social determinants of health that may need to be targeted with some of these future studies?
Dr. Andrew Stokes:
That's a great question. So, what we know so far from preliminary research is that some groups are more likely to switch to e-cigarettes than other groups. Particularly among current combustible cigarette users, the rates of switching do vary by race and ethnicity. Thus, we need further research to understand why these patterns differ across subgroups and what their implications may be for health.
Dr. Greg Hundley:
Do you foresee any difficulty in trying to enroll participants from those other groups as you plan these studies moving forward?
Dr. Andrew Stokes:
The advantage of the current research design is that we're using a large secondary data set of survey participants who are enrolled in the Population Assessment of Tobacco and Health study. Therefore, we are not enrolling patients ourselves and the response rates are quite high in these surveys.
Dr. Greg Hundley:
Well, Andrew, we hear that some of the inhalants that are mixed with the inhaled nicotine can be flavors and perhaps have been approved by the FDA for consumption in the GI tract where, whatever these additives are, you would think might be broken down by the digestive system. But if they're inhaled and get into the lung tissue and the parenchyma, the alveoli, et cetera, do they perhaps have harmful effects that maybe we're not aware of?
Dr. Andrew Stokes:
Absolutely. E-cigarettes come in thousands of characterizing flavors including sweet flavors, tobacco flavors, and many other miscellaneous flavors. As we saw with the outbreak of lung injury associated with the use of e-cigarettes in 2019, inhaling flavors can have health effects that are unanticipated based on research in the GI tract, and therefore, as a next step in this research, we really need more work to investigate how different flavors are associated with the incidence of clinical events, whether cardiovascular or pulmonary conditions.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Andrew Stokes from the Boston University School of Health for bringing us this data from the PATH study, suggesting that combining smoking with e-cigarette use does not reduce cardiovascular events and that quitting both products is needed to ensure overall cardiovascular disease risk reduction.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join Guest Host Mercedes Carnethon and Author Brendon Neuen as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data from Randomized, Controlled Trials."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, this week's feature paper is on one of my favorite topics, SGLT2 inhibitors. And this time, looking at their association with the risk of hyperkalemia in people with type-two diabetes. Now this is something we've all been waiting to look at. It's a meta-analysis of individual participant data from randomized controlled trials, so a very important, clinically applicable discussion coming right up. But first, I'm actually going to talk to you about text messages.
Dr. Greg Hundley:
Wow, Carolyn. I can't wait to hear about this article.
Dr. Carolyn Lam:
Well, specifically the TEXTMEDS randomized clinical trial, which is our first paper today. It is a trial that examined the effectiveness of text-message delivered cardiac education and support on medication adherence following an acute coronary syndrome.
Dr. Carolyn Lam:
This is from Dr. Clara Chow from University of Sydney and her colleagues, who performed a single blind multi-center randomized controlled trial of post-ACS patients across 18 rural and urban centers and three time zones in Australia. The control group received usual care, and the intervention group additionally received multiple motivational and supportive weekly text messages on medications, and healthy lifestyle, with the opportunity for two-way communication.
Dr. Greg Hundley:
Wow, Carolyn. So text messaging to facilitate medication adherence. I can't wait to hear. So what did they find?
Dr. Carolyn Lam:
I think the design, it's such a neat study. However, the study found no significant impact on the primary outcome of medication adherence at six and 12 months, nor on LDL cholesterol or blood pressure.
Dr. Carolyn Lam:
However, intervention participants were more likely to achieve a normal body mass index and to eat guideline-recommended servings of fruit and vegetables. Qualitative analysis demonstrated a high level of acceptability, utility in being a unified source of information, high program engagement, and emotional support, especially during times of uncertainty.
Dr. Greg Hundley:
Interesting, Carolyn. Sounds like an impact on diet, so what did we learn from this study?
Dr. Carolyn Lam:
Well, customized and personalized text message-based prevention programs are indeed a scalable and low-cost means of delivering consistent education and support to patients following hospitalization for ACS. So this study shows it's feasible. The lack of impact, however, on medical adherence, though with better adherence to healthy lifestyle practices, suggests that maybe external factors, such as cost, may strongly influence medical adherence. These need to be addressed, in addition to education programs, to improve medical adherence. But all of this is discussed in a beautiful editorial entitled, "Opportunities and Challenges of Mobile Health Tools to Promote Health Behaviors" by Drs. Sharma and Avram.
Dr. Greg Hundley:
Very nice. Carolyn, what a great summary. Well, my paper comes to us from Professor Mario Delmar from New York University School of Medicine, and Carolyn, exercise training as well as catecholaminergic stimulation increases the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy or ARVC, and this correlates with plakophilin-2 mutations. Now, Carolyn, separate data show that reduced abundance of plakophilin-2 leads to dysregulation of intracellular calcium homeostasis, and Carolyn, these authors studied the relation between exercise and or catecholaminergic stimulation, intracellular calcium homeostasis, and arrhythmogenesis in plakophilin-2 deficient murine hearts.
Dr. Carolyn Lam:
Ooh. So what were the effects?
Dr. Greg Hundley:
Right, Carolyn. For training, the mice underwent 75 minutes of treadmill running once per day, five days each week, for six weeks. And the authors observed that exercise disproportionately affected calcium intracellular homeostasis in plakifilin-2 deficient hearts, in a manner facilitated by stimulation of intracellular, beta-adrenergic receptors or hyper-phosphorylation of phospholamban.
Dr. Greg Hundley:
Now these cellular changes created a pro-arrhythmogenic state that can be mitigated by plakophilin receptor blockade. Additionally, Carolyn, these authors' data unveiled an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of a deficit in plakophilin-2. They suggest that membrane-permeable beta blockers are potentially more efficient for ARVC patients.
Dr. Greg Hundley:
And also they highlight the potential for ryanodine-receptor channel blockers as treatment for the control of heart rhythm in this population at risk, and propose that plakophilin dependent and phospholamban-dependent, ARVC-related arrhythmias have a common mechanism.
Dr. Carolyn Lam:
Wow, thanks again, Greg. That was really, really a nice explanation. Well, for this next original paper, it looks at the question of the association between major bleeding and non-major clinically relevant bleeding, with subsequent mortality in hospitalized patients, and authors did this by exploring this relationship in the MAGELLAN and MARINER trials of extended thrombo-prophylaxis in hospitalized medical patients.
Dr. Greg Hundley:
Wow. Carolyn. I can't quite remember, and maybe for our listeners, remind us of the design of the MAGELLAN and the MARINER trials.
Dr. Carolyn Lam:
These trials evaluated, whether rivaroxaban compared with enoxaparin or placebo, could prevent venous thromboembolism without increased bleeding. The authors, led by Dr. Spyropoulos from the Feinstein Institute of Medical Research in New York, hypothesized that patients with major bleeding, but not those with non-major clinically relevant bleeding, would be at an increased risk of all-cause mortality. So Greg, would you like to guess what they found?
Dr. Greg Hundley:
Oh, Carolyn, you've put me on the spot here. I'm not sure.
Dr. Carolyn Lam:
Maybe just, did the authors get it right or wrong? Just....
Dr. Greg Hundley:
I'm saying, they got it right.
Dr. Carolyn Lam:
Oh, always clever. They found that compared to patients with no bleeding, the risk of all-cause mortality for patient with non-major clinically relevant bleeding was not increased in MARINER, but was increased in MAGELLAN. Major bleeding, however, was associated with a higher incidence of all-cause mortality in both studies, while trivial bleeding was not associated with mortality in either study. These results really inform the risk benefit calculus of extended thromboprophylaxis in medically ill patients.
Dr. Greg Hundley:
Wow. Carolyn, great presentation. We've got some other articles in this issue. And let me tell you about two that I have. First is a Research Letter from Professor Frankel entitled "Trends in Opioid Use after Cardiac-Implantable Electronic Device Procedures in the United States, between the years of 2004 and 2020." And Tracy Hampton, from the National Association of Science Writers, presents some very recent news in the world of cardiology.
Dr. Carolyn Lam:
Nice. Well, there's an exchange of letters as well between Drs. Yang and Nagareddy regarding the article "Retention of NLP3 Inflammasome-Primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-Induced Granulopoiesis." And finally, in the Editor’s Page, a nice piece from Drs. Joe Hill, Darren McGuire, and James de Lemos on “Circulation: Best Papers, 2021.” Gosh, really, really nice issue. Now let's go on, though, to the feature discussion, yeah?
Dr. Greg Hundley:
You bet.
Dr. Mercedes Carnethon:
Welcome to this episode of Circulation on the Run podcast. My name is Mercedes Carnethon, one of the associate editors, and I'm a professor of preventive medicine at the Northwestern University Feinberg school of Medicine. I'm really excited today to have a guest with us. Dr. Brendon Neuen, who has shared with us his really outstanding research on SGLT2 inhibitors and the risk of hyperkalemia in people with type-two diabetes, a meta-analysis. So welcome to our podcast today, Brendon.
Dr. Brendon Neuen:
Thanks very much for having me Mercedes. It's a real pleasure to be here.
Dr. Mercedes Carnethon:
Well, thank you for joining us. We're really pleased that you chose Circulation to share with us your really important findings. Can you tell us a little bit about the rationale for your study and how you carried out your work?
Dr. Brendon Neuen:
Yeah, absolutely. So we know that in people with diabetes and people with CKD, hyperkalemia is a common occurrence, and it's a problem for two reasons as you'd be aware. Firstly, it is associated with cardiac dysrhythmias and secondly, perhaps at least as importantly, it limits the optimal use of treatments that reduce kidney disease progression and heart failure events. So that is, agents that block the renin angiotensin aldosterone system.
Dr. Brendon Neuen:
We now know, and we've got robust evidence from large outcome trials, that SGLT2 inhibitors reduce the risk of heart failure and kidney disease progression in people with and without diabetes, but we haven't really, up and until now, systematically evaluated their effect on potassium outcomes, particularly hyperkalemia. And so we set out to assess whether these agents affect serum potassium levels and alter the risk of hyperkalemia as well as hypokalemia.
Dr. Mercedes Carnethon:
Thank you. That sounds like a really excellent and well needed study, given how much we've heard within the field about the benefits of SGLT2 inhibitors. It's nice to see a careful evaluation of what some of the considerations are in their use. So tell us a little bit about how you carried out this study and what you ultimately found.
Dr. Brendon Neuen:
What we did was, we identified clinical trials that enrolled people with type two diabetes at high cardiovascular risk or with chronic kidney disease. And what we did is, we approached the investigators of each of these trials and asked them to collaborate on a large meta-analysis using individual participant data.
Dr. Brendon Neuen:
What that allowed us to do was, then, standardize across all of the trials of different outcome definitions, and allowed us to assess the effective SGLT2 inhibitors on a primary outcome of time to first serum potassium greater than or equal to six, defined as serious hyperkalemia, as well as hypokalemia, investigator-reported hyperkalemia events, and a range of other potassium-related outcomes in a broad population, including people with chronic kidney disease, people with heart failure, and people using different concomitant medications, such as diuretics and MRAs in the background.
Dr. Mercedes Carnethon:
So thank you, Brendon, for the explanation of the use of the meta-analytic design and the entry criteria of type-two diabetes and chronic kidney disease. Can you tell us, what were the outcomes across these studies?
Dr. Brendon Neuen:
The primary outcome we evaluated was time to first serious hyperkalemia, defined as a serum potassium greater than or equal to six, as well as a range of other potassium-related outcomes, including investigator reported hyperkalemia, change in potassium over time, as well as hypokalemia, defined as a serum potassium less than 3.5.
Dr. Brendon Neuen:
What we found was that overall SGLT2 inhibitors reduce the risk of serious hyperkalemia by about 16%. And that effect was consistent across the agents within the class, and across different subpopulations and trials. This effect was supported by a 20% risk reduction in investigator-reported hyperemia events and importantly, there was no difference in risk of hypokalemia, that is a serum potassium less than 3.5, between SGLT2-treated and placebo-treated participants.
Dr. Mercedes Carnethon:
Thank you for that summary. You know, one of the very impressive aspects of this clinical trial is certainly the size and the number of participants. Brendon, I was really struck by your description of the consistency of findings across the subgroups. And in particular, when I reviewed the findings in the paper, I noticed that serious hyperkalemia was higher in those with poorer kidney function. Did you find that surprising?
Dr. Brendon Neuen:
From clinical practice, we know that one of the major determinants of hyperkalemia risk is kidney function. It's a major problem that we run into in people with more advanced CKD. And what that means is that for people with more advanced chronic kidney disease, who are at high risk of hyperkalemia, the absolute benefits of SGLT2 inhibition on hyperkalemia risk are likely greater in these individuals, because they're at high risk of this outcome.
Dr. Brendon Neuen:
Other patients who might be at increased risk of hyperkalemia include those with heart failure or those taking mineralocorticoid receptor antagonists at baseline. And so you'd expect that if the relative effects are consistent across many subgroups, then the absolute risk reductions are likely to be larger in people taking MRAs or people with more advanced CKD.
Dr. Mercedes Carnethon:
Thank you so much for summarizing the importance of these findings and what they mean for our clinical audience. It's wonderful to have this sort of information from a meta-analysis because it allows us large sample sizes, where we can do things like you describe, such as describing subgroup effects.
Dr. Mercedes Carnethon:
It also presents us with very robust evidence that can be taken into clinical practice for our clinical audience to use. Based on what you found, how do you anticipate that these findings can be used by our clinicians?
Dr. Brendon Neuen:
Well, thanks, Mercedes. I think the reduction in risk of hyperkalemia that is observed in these data suggests that SGLT2 inhibitors might enable better use of other proven therapies that reduce cardio-renal risk in people with chronic kidney disease and people with heart failure. We all know that in treating these high risk patients, hyperkalemia is a problem. And by reducing the risk of hyperkalemia with SGLT2 inhibitors, it might enable better use of renin angiotensin system blockade and mineralocorticoid receptor antagonists in people with chronic kidney disease and heart failure.
Dr. Mercedes Carnethon:
So you've provided a really excellent overall summary of the impact of these finding for clinical practice and the possible next steps. I wanted to end on a note of asking you what surprised you about these findings that might lead to further future investigations.
Dr. Brendon Neuen:
Thanks, Mercedes. I think that's a really interesting question. What was somewhat surprising, but also reassuring, was the consistency of the treatment effect on hyperkalemia, regardless of how we defined it, whether that was defined based on investigator-reported hyperkalemia events or central laboratory-measured serum, potassium levels, the treatment effect was very consistent. And I think that gives us some confidence about the robustness of these findings and their application to clinical practice.
Dr. Mercedes Carnethon:
Well, thank you so much, Brendon. I have really enjoyed this discussion with you today and this really important paper that is describing an important safety outcome for SGLT2 inhibitors in patients with type two diabetes. And again, I really want to thank you for sharing your excellent work with us here at Circulation. I anticipate that our readership, when they leave this podcast and pick up their journals, will be thrilled to read about all of the details about the excellent work that you and your team have carried out. So thank you very much for joining us today.
Dr. Brendon Neuen:
Thanks very much for having me, Mercedes. It was a real pleasure.
Dr. Mercedes Carnethon:
Thank you, and thank you again to our audience for joining us for this episode of Circulation on the Run.
Speaker 5:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Guest Host Mercedes Carnethon, Author Brian Bergmark, and Associate Editor Parag Joshi as they discuss the article “Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.”
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this week's feature, non-high density lipoprotein cholesterol levels in statin treated patients with elevated cholesterol. We're going to hear from the TRANSLATE-TIMI 70 study. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I would. And by the way, that feature is going to be all exciting. It was discussed at the American College of Cardiology. But okay, how about from cholesterol to vitamins? Let's start with the Greg quiz. Greg, which vitamins have been associated with arterial calcification? Is it A, B, C, D, E?
Dr. Greg Hundley:
I'm going to pick E and K.
Dr. Carolyn Lam:
You’re smart. Indeed. Vitamin K2, also known as menaquinone-7 is the most effective co-factor for the carboxylation of proteins involved in the inhibition of arterial calcification. Furthermore, combined low vitamin K and low vitamin D have been associated with increased all-cause mortality risk. And so, today's paper is from Dr. Diederichsen from Odense University Hospital in Denmark and colleagues really present the first double-blind, randomized controlled trial to test whether vitamin K2, a drug-targeting processes of calcification in addition to vitamin D, could slow the progression of aortic valve calcification and stenosis. So, in a randomized double-blind multicenter trial, men from the community with an aortic valve calcium score above 300 arbitrary units on cardiac non-contrast CT were randomized to daily treatment with 720 micrograms of vitamin K2 plus 25 micrograms of vitamin D or matching placebo for 24 months. And the primary outcome was the change in aortic valve calcium score.
Dr. Greg Hundley:
Carolyn, so menaquinone-7 and aortic valve score. So, what were the results?
Dr. Carolyn Lam:
Menaquinone-7 had no major effect on the progression of aortic valve calcification as assessed by CT or echo. High-dose menaquinone-7 was, however, safe and well tolerated. Now, some limitations is that this external validity is limited to men aged 65 to 74 with aortic valve calcification scores of greater or equals to 300 arbitrary units. Thus, caution is needed if we extrapolate these findings and other pathways need to be explored in order to identify an effective therapy for this unmet clinical need.
Dr. Greg Hundley:
Wow, very nice Carolyn. Well, my first article comes to us from Dr. Michael Laflamme from the University Health Network. And Carolyn, human pluripotent stem cell-derived cardiomyocytes or hPSC-CMs exhibit promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. So Carolyn, this research team hypothesized that large scale manufacturing of mature hPSC-CMs could be achieved via culture on polydimethylsiloxane, and we're going to call that PDMS, lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes then with conventional immature hPSC-CMs populations.
Dr. Carolyn Lam:
Oh, that's neat, Greg. So, what did they find?
Dr. Greg Hundley:
Right, Carolyn. So, these authors demonstrated the economic generation of greater than one times 10 to the eighth mature hPSC-CMs per PDMS line roller bottle. And compared to their counterparts, PDMS matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More importantly, intracardiac graphs formed with PDMS matured myocytes showed greatly enhanced structured alignment, better host graft electromechanical integration, less pro arrhythmic behavior, and greater beneficial effects on contractile function. So in summary, Carolyn, this team describes practical methods for the scale generation of mature human pluripotent stem cell-derived cardiomyocytes and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo. And there's a wonderful editorial by Professor Murray entitled Flexing Their Muscles: Maturation of Stems Cell-Derived Cardiomyocytes on Elastomeric Substrates to Enhance Cardiac Repair.
Dr. Carolyn Lam:
Wow! That's really significant. Thank you, Greg. Well, the next paper is the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals. And this is from Dr. Xia Chen from Fudan University and Dr. James Wilson from University of Edinburgh in UK, and their colleagues. And guess what, it focuses on severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID 19. And we know that that enters human cells using the ACE2 protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems.
Dr. Greg Hundley:
Wow, Carolyn. ACE2, and also a very important topic here with SARS-COVID-2. So, what did they find?
Dr. Carolyn Lam:
First, the overall heritability of ACE2 level is 16% of which 30% can be explained by 10 protein quantitative trait loci identified in this study. ACE2 level is genetically correlated with both COVID-19 and cardiovascular. Elevated ACE2 levels show a causal relationship with COVID-19 severity, hospitalization and infection as shown by Mendelian randomization analyses. ACE2 regulatory variants are enriched on DNA methylation sites in immune cells.
Dr. Greg Hundley:
Wow, Carolyn. So, elevated ACE2 and a causal relationship with COVID-19 severity. So tell us, what are the clinical applications of this really nice study?
Dr. Carolyn Lam:
The causal evidence of ACE2 suggests that pharmacological inhibition of circulating ACE2 may be a promising approach for treating COVID-19 or its comorbidities. Transcription factors that play essential roles in ACE2 generation could provide alternative paths to pharmacological modulation of ACE2 plasma levels. The genetic correlations between ACE2 and both COVID-19 and cardiovascular disease imply that the cardiovascular complications seen in COVID-19 patients may be intrinsic to the disease and mechanically or/and mechanistically-driven by ACE2. Isn't that neat?
Dr. Greg Hundley:
You bet, Carolyn. Boy, what an exciting issue. And we've got other articles in this issue.
Dr. Carolyn Lam:
Yeah. Now, let me start this time. There's an exchange of letters between Drs. Duan and Chang regarding the article “Therapeutic Exon Skipping Through a CRISPR-Guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy in Vivo.” There's a Perspective piece by Dr. Morris, “The Updated Heart Failure Guidelines: Time for a Refresh.” Love that piece! There's an AHA Update piece (AHA President’s Page) by Dr. Elkin on The Road to Equity in Brain Health, and ECG challenge by Dr. Kolominsky, Electrical Extremists in a Critically ill Patient, and an On My Mind Paper by Dr. Paulus entitled “Border Disputes Between Heart Failure Phenotypes.”
Dr. Greg Hundley:
Wow, Carolyn. And I've got two Research Letters. The first from Professor Groeneveld entitled “Prevalence of Short-Coupled Ventricular Fibrillation in a Large Cohort of Dutch Idiopathic Ventricular Fibrillation Patients.” And then a second Research Letter from Professor Yamashita entitled “Single Cell RNA Sequence Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome.” Well Carolyn, now, we get to go onto our feature, vupanorsen on non-high-density lipoprotein cholesterol levels and catching up with TIMI 70.
Dr. Carolyn Lam:
Let's go.
Dr. Mercedes Carnethon:
So, good morning listeners. I'm really pleased to invite you to this episode of our Circulation on the Run podcast. For those of you who don't hear me often, I'm stepping in as a guest host today. My name is Mercedes Carnahan from the Northwestern University Feinberg School of Medicine. And I'm really excited to be joined today by Dr. Brian Bergmark, and associate editor, Dr. Parag Joshi. And we will have today Dr. Bergmark discussing his new article published with us on the effects of vupanorsen on non-HDL cholesterol levels in the TRANSLATE-TIMI 70 trial. We're really thrilled to have you with us here today, Brian, to talk about the really important findings coming from this trial. So to start us off, just tell us, what did you find?
Dr. Brian Bergmark:
Great. Thank you so much. It's really a pleasure to be here and I'm grateful for the opportunity. So, in the big picture, despite numerous agents to reduce lipid-mediated cardiovascular risk, obviously, residual risk remains and there are novel targets to address that risk. One of them is angiopoietin-like 3, which is a protein made in the liver. Angiopoietin-like 3 or ANGPTL3 inhibits lipoprotein lipases among other lipases, and thereby interferes with metabolism of triglyceride-rich lipoproteins. And so, the idea here was that if ANGPTL3 could be inhibited that LPL or lipoprotein lipase function could be augmented and metabolism of these lipoproteins could be augmented. And so, what we did is we took patients with an elevated non-HDL cholesterol, at least 100 milligrams per deciliter, and elevated triglycerides, 150 to 500 milligrams per deciliter, and randomized them to placebo or one of seven doses of vupanorsen, which is an antisense oligonucleotide, which inhibits the synthesis of ANGPTL3 in the liver. We then follow them to see what the impact was on their non-HDL cholesterol, as well as other lipid parameters through 24 weeks.
Dr. Mercedes Carnethon:
Thank you so much. It's a wonderful design, and I'm really excited to hear a little bit more about what you found.
Dr. Brian Bergmark:
Great. So, the primary endpoint was the change in non-HDL cholesterol from baseline to 24 weeks. And we did find that all vupanorsen regimens reduced non-HDL cholesterol in a statistically significant manner. The magnitude of that effect was up to 27.7% in one of the dose arms or about 28%. We also saw a statistically significant reductions in the target ANGPTL3 up to about a 95% reduction in the highest dose arm, as well as statistically significant reductions in triglycerides at all of the dose regimens. The effect on LDL cholesterol and on apolipoprotein B or apo B was variable across regimens and only statistically significant in a few of the dose arms. We also found several safety signals. One, there appeared to be higher rates of injection site reactions in the skin at higher total monthly doses. We also found higher rates of elevation in liver enzymes, AST and ALT at higher total monthly doses. And we also found significant increases in hepatic fat fraction or the fat content of the liver at higher total monthly doses.
Dr. Brian Bergmark:
In the end, we found that while statistically significant, the magnitude of the reduction in non-HDL cholesterol was modest as was the reduction in apo B. And so, the goal here was to find a dose that might have a reduction of a magnitude that would be clinically meaningful for cardiovascular risk reduction. We were underwhelmed by the magnitude of that reduction, and then it was paired with these safety signals, which if there's interest, we could get into more detail in our thinking about why those occurred, what the implications are, but suffice it to say that there were medically meaningful safety concerns paired with a modest reduction in non-HDL cholesterol.
Dr. Mercedes Carnethon:
Thank you for that excellent summary. Before I turn it over to the associate editor, I read this with great interest, and in particular, looking at one of the first figures in the paper, which is demonstrating the adjusted change at 24 weeks across different doses and based on how frequently the doses were given the four week as compared with the two week. And one thing that really stood out to me was the clear dose response with the four week regimens with the higher doses appearing to demonstrate the greatest reductions but a less clear signal with the two week regimens. Do you have any hypotheses about why these patterns appeared so different?
Dr. Brian Bergmark:
Yeah. It's a great question. So, the responsiveness of this is something of interest here I think. So, if you look at the effect of the drug on its target, ANGPTL3, there is a very clear dose response, so there's no doubt that higher doses were impacting the target ANGPTL3 to a greater extent. So, one of the most direct effects would be on triglycerides, one of the most direct lipid effects, and that appears pretty close to a dose response relationship within each of these frequencies of administration. But once you start getting to non-HDL cholesterol, it starts to break down a bit. And is it simply because of random chance or is there actually something distinct going on with how the lipids are being metabolized?
Dr. Brian Bergmark:
That is something we are diving into. So, the hope would be that we actually reduce apo B, the number of these actually circulating lipoproteins as has been demonstrated with the monoclonal antibody. It's possible that with this other different mechanism in the antibody, this antisense oligonucleotide, perhaps, we're simply shifting the content of these lipoprotein molecules and decreasing the triglyceride content but not actually meaningfully modifying the amount of apo B, LDL cholesterol. And that might be part of what we're seeing with the more muted relationship between dose and the effect on non-HDL cholesterol. I don't know for certain we are diving into this a bit more with other lipid fractions, et cetera.
Dr. Mercedes Carnethon:
Oh, well, thank you so much for that explanation. I know that a number of people, this was extremely well received when shared at the recent American College of Cardiology meetings, and so I was really thrilled to find that this was appearing in the journal circulation. So Parag, I'm really interested in hearing your perspectives on why we knew that this was certainly a priority paper for us.
Dr. Parag Joshi:
Yeah. Let me first start, Brian, congratulations. Fantastic work. And we were excited to receive the paper. I think really hard to pull off trials right now or in the last couple years, so kudos to you. And I echo the sentiments from Mercedes. This is great work. Really important space, the residual risk space I think is very important of course and is critical to moving forward with improving cardiovascular health. So, one of the big picture questions and as we get to this triglyceride-rich lipoprotein lowering space, certainly, there's strong associations with residual risk, but can we impact that risk? And here, we're starting to explore that. And I think when you think of the lipoprotein space, many of us are interested in what is the effect on these lipoproteins as opposed to the cholesterol content or the triglyceride content. And non-HDL cholesterol or apo B, clearly, the better, stronger markers for that risk, so we were really excited to see this paper.
Dr. Parag Joshi:
And as Brian mentioned, unfortunately, not the strongest impact here on those measures. And I want to dive into that a little more because I think that carries significant implications for the space, and I'd love to hear your thoughts on that. But overall, really fantastic work. I think my first question really is around the apo B aspect of this and the less than anticipated lowering of those levels. You hinted at this in terms of, is this shuffling cholesterol and triglycerides across particles, or do you think this could be the mechanism by which this happens through ANGPTL3? You do inhibit the levels quite a bit. Did we just miss that... Is this not the right target? What do you think?
Dr. Brian Bergmark:
Yeah, it's a great question. I do think the target itself holds great promise. Obviously, a monoclonal antibody against this same target results in major reductions in apo B, LDL cholesterol, and the latter through a mechanism that is not really known but is not dependent on the LDL receptor, and therefore has real clinical utility that's approved for people with familial homozygous hypercholesterolemia. Beyond that, of course, in genetic studies, there's a clear association with loss of function in the ANGPTL3 gene and lower levels of all of these lipids, lower rates of coronary artery disease, et cetera.
Dr. Brian Bergmark:
So, I think it's not that this pathway is not promising and actually already being taken advantage of, I think it's that this particular agent acting through this mechanism was not able to achieve a necessary efficacy with reasonable safety. Some genetic data suggests that there is not actually a dose response between a reduction or loss of function in ANGPTL3 and reduction in apo B or lower levels of apo B and non-HDL cholesterol, but it really requires your complete elimination of ANGPTL3 function, which is probably, likely achieved with the monoclonal antibody. And so, even though we had quite large reductions with the antisense oligonucleotide, perhaps, we just didn't cross that threshold that's needed to modify the lipid panel in the way that would've been clinically meaningful.
Dr. Parag Joshi:
Yeah. I think that's fantastic as you allude to with evolocumab and the impact that has on apo B levels. I didn't think of it as a threshold effect, but that makes a lot of sense as maybe that just getting to that tipping point is where the issue is here. In terms of the liver signal, what were your thoughts on that? And is that something that we should expect to see in ASOs or do you think it's specific to this compound?
Dr. Brian Bergmark:
Yeah, I don't know. That was unexpected. Right, there are two liver signals and it's unclear how related they are. One is the inflammation of the liver as indicated by the elevation in enzymes, and then the other is the fat accumulation. So with respect to the fact, if anything, genetic data suggests perhaps loss of function in ANGPTL3 might result in lower rates of hepatic steatosis. In animal models, the antisense oligonucleotide reduces liver fat, and so there's, there was promise going into this that this could actually be beneficial for non-alcoholic fatty liver disease. And additionally, there's not data to suggest that the monoclonal antibody increases liver fat. So, there's not a lot to support this as being an on-target effect that by inhibiting ANGPTL3, by that pathway, the liver fat was increased. So, I think a reasonable person might wonder whether this was an off-target effect of the drug.
Dr. Brian Bergmark:
By what mechanism that occurred, I don't know, what the implications would be for other related agents, I don't know. And then similarly, the liver enzyme elevations, is that related to this? I'm not exactly sure, but also unexpected and I think off-target. But that sort of intrinsic to this mechanism of hepatic targeting, is this something we need to be worried about for other agents in this class or not? I don't know. Obviously, we can't answer that from this single study. We are going to dive into it a bit more to try to overlay patients with hepatic fat accumulation, liver enzymes, et cetera. Of course, both of those happen more at higher doses. How much we can really parse this? I'm not sure yet.
Dr. Parag Joshi:
Yeah. That's really fascinating. I think the appeal of this paper to the circulation audience is that you have a really exciting novel target and pathway to explore here but somewhat divergent results from what's existing in this space. And I think that raises a lot of questions, really interesting questions going forward for this space. For the ANGPTL3 pathway, what do you see there coming down the line or what are your thoughts on that going forward for this target and ways to approach risk related to it?
Dr. Brian Bergmark:
Yeah. Great. Thank you. Yeah. No, so I agree. I think moving into this other end of the spectrum of triglyceride-rich lipoproteins, et cetera, I think this is where we're headed and this is why we do the trial. We weren't expecting these things that's why you do this experiment, and this is what we found. So now, where do we go from here? So there are, of course, other ways beyond the monoclonal antibody of targeting ANGPTL3 specifically. There's siRNA, there is gene therapy being investigated. So, I think all of them hold an great promise. And of course, we will need to see as those therapies move along what the actual trials show. And then there are, of course, other pathways that are of interest, APOC3, for instance. So, I think there's a lot more in this space that's coming down the line.
Dr. Parag Joshi:
Yeah, absolutely. I think it's a really exciting space, and we're really happy to get this paper as one piece of that whole puzzle. So, thank you.
Dr. Mercedes Carnethon:
Yes. And I echo that as well. And as a methodologist myself, I'm always really pleased to see such well-designed studies. I think this was sophisticated in many aspects in testing different dosing and different timing of the dosing. And also, I'm really impressed by your inclusion criteria, particularly when I noted that 44% of the participants were female, and that you reported those stratum-specific effects. I just had a final question as we wrap up. You acknowledge a nominally significant interaction by sex and I see, for example, that it appears that the magnitude is larger possibly in the relatively smaller subset of females as compared with males. Is this something to pay attention to or do you think this is just some type of an artifact related to greater variability because the group is smaller?
Dr. Brian Bergmark:
Yeah, it's a good question. So, this is the burning question. We had no a priority reason to suspect that biologically and we are not adjusting for multiple testing in the key value of 0.04. So just to put my money down, I would say, I would guess it's random chance. We found it. It's worthy of looking into a bit more. There were, of course, the important implications for other drugs, et cetera. So, I think it's worth diving into as we will, but are we likely to uncover some biological difference? I doubt it. I wouldn't guess. There are other subgroups where I think at least upfront, you might expect there could be a difference. So, there are thoughts about insulin's effect on LPL. Could diabetes status have an interaction with the drug? I think though not statistically significant, it's also something worth looking into that group and the subfractions of the lipid panel and all of that stuff. So, I think it's all worth looking into but cautiously with the constraints.
Dr. Mercedes Carnethon:
Well, thank you so much for that explanation. And I've really enjoyed this discussion with you today, Brian, and you, Parag. I've certainly learned a lot and I'm really excited to see this excellent work coming out in the journal circulation. So, thank you very much for your time this morning and thank you to our listeners. Wrapping up this episode of Circulation on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Vasan Ramachandran and Associate Editor Mercedes Carnethon as they discuss the article "Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I'm so excited about today's feature paper. You see, I trained at the Framingham Heart Study and today's feature paper talks about the temporal trends in the remaining lifetime risk of cardiovascular disease among middle aged adults across six decades in the Framingham Heart Study. Truly a landmark study and a discussion nobody wants to miss. But first, let's talk about the other papers in today's issue, and I understand that you've got one ready.
Dr. Greg Hundley:
You bet Carolyn. I'll get started first. Thank you. So my first paper comes from Dr. Daniel Mark from Duke University and it refers to the ISCHEMIA trial.
Dr. Carolyn Lam:
Ooh, could you please first remind us what is the ISCHEMIA trial and are you presenting a substudy, is that correct?
Dr. Greg Hundley:
Right, Carolyn. So the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, or ISCHEMIA, compared an initial invasive strategy with an initial conservative strategy in 5,179 participants with chronic coronary disease and moderate or severe ischemia. And this sub study of the ischemia research program included a comprehensive quality of life analysis.
Dr. Carolyn Lam:
So very interesting. What did they find Greg?
Dr. Greg Hundley:
Right, Carolyn. So this study included 1,819 participants. 907 in the invasive, 912 in the conservative. And collected a battery of disease specific and generic quality of life instruments by structured interviews at baseline. And then at three, 12, 24 and 36 months post randomization, and then finally at study closeout. Now Carolyn, these assessments included an angina related quality of life assessment from the 19 item Seattle Angina Questionnaire, a generic health status assessment, an assessment of depressive symptoms, and for North American patients, cardiac functional status from the Duke Activity Status Index, or DASI. In this study, Carolyn, in terms of results, the median age was 67 years and about 20% were women and about 16% were nonwhite. So Carolyn, getting to the results. The estimated mean difference for the SAQ 19 summary score favored invasive therapy. And remember the SAQ 19 was the Seattle Angina Questionnaire.
Dr. Greg Hundley:
Next, no differences were observed in patients with rare or absent baseline angina. Next, among patients with more frequent angina baseline, those randomized to invasive had a mean point higher score on the SAQ 19 summary score than the conservative approach, with consistent effects across all of the SAQ subscales including physical limitations, angina frequency and quality of life health perceptions. For the DASI, and remember DASI refers to the Duke Activity Status Index, no difference was estimated overall by treatment. But in patients with baseline marked angina, DASI scores were higher for the interventional arm. Whereas patients with rare or absent baseline angina showed really no treatment related differences.
Dr. Carolyn Lam:
Oh, okay. So a lot of results. What's the take-home message, Greg?
Dr. Greg Hundley:
Right, Carolyn. Glad you asked. So in the ISCHEMIA comprehensive quality of life substudy, patients with more frequent baseline angina reported greater improvements in the symptom physical functioning and psychological wellbeing dimensions of quality of life when treated with an invasive strategy. Whereas patients who had rare or absent angina baseline reported no consistent treatment related quality of life differences.
Dr. Carolyn Lam:
Wow. Thank you, Greg. Very interesting indeed. Now from angina to now cholesterol. Now, cholesterol guidelines typically prioritize primary prevention statin therapy based on 10 year risk of cardiovascular disease. Now the advent of generic pricing may in fact justify expansion of statin eligibility. Moreover, 10 year risk may not be the optimal approach for statin prioritization. So these issues were looked at in this next paper by authors led by Dr. Kohli Lynch from Northwestern University and colleagues who estimated the cost effectiveness of expanding preventive statin eligibility, and evaluated novel approaches to prioritization from a Scottish health sector perspective. A computer simulation model predicted long term health and cost outcomes in Scottish adults, age 40 years or more.
Dr. Greg Hundley:
So Carolyn, what did they find?
Dr. Carolyn Lam:
The advent of generic pricing has rendered preventive statin therapy cost effective for many adults. Absolute risk reduction guided statin therapy, which is based on 10 year cardiovascular disease risk and non HDL cholesterol levels, is cost effective and would improve population health. Whereas age stratified risk thresholds were more expensive and less effective than alternative approaches to statin prioritization. So guidelines committees may need to expand statin eligibility and consider new ways to allocate statins based on absolute risk reduction rather than 10 year risk thresholds.
Dr. Greg Hundley:
Very nice Carolyn. Always important, new information regarding statin therapy. Well Carolyn, my next paper comes to us from the world of preclinical science. And Carolyn, as you know, the regenerative capacity of the heart after myocardial infarction is limited. And these authors led by Dr. Tamer Mohamed from University of Louisville previously showed that ectopic introduction of Cdk1, CyclinB1 and Cdk4, CyclinD1 complexes and we'll refer to those now as 4F, promoted cardiomyocyte proliferation in 15 to 20% of infected cardiomyocytes in vitro and in vivo and improved cardiac function after MI in mice. So Carolyn, in this study using temporal single cell RNA sequencing, the investigative team aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. And also using rat and pig models of ischemic heart failure, they aim to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia induced heart failure.
Dr. Carolyn Lam:
Oh, wow Greg. So what did they find?
Dr. Greg Hundley:
Several things, Carolyn. First, temporal bulk and single cell RNA sequencing and further biochemical validations of mature HIPS cardiomyocytes treated with either LAcZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours post-infection with 4F. Which was mainly associated with sarcomere disassembly and metabolic reprogramming. Second Carolyn, transient overexpression of 4F specifically in cardiomyocytes was achieved using a polycistronic non-integrating lentivirus encoding the 4F with each driven by a TNNT2 promoter entitled TNNT2-4F polycistronic-NIL. Now this TNNT2-4F polycistronic-NIL or control virus was injected intra myocardial one week after MI in rats, so 10 per group, and pigs, six to seven per group.
Dr. Greg Hundley:
And four weeks post-injection the TNNT2-4F polycistronic-NIL treated animals showed significant improvement in left ventricular injection fraction and scar size compared with the control virus treated animals. And four months after treatment, the rats that received TNNT2-4F polycistronic-NIL still showed a sustained improvement in cardiac function without obvious development of cardiac arrhythmias or systemic tumorigenesis. And so Carolyn this study advances concepts related to myocellular regeneration by providing mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell factors, thanks to the use of a novel transient and cardiomyocyte specific viral construct.
Dr. Carolyn Lam:
Wow. What a rich study. Thanks so much, Greg.
Dr. Greg Hundley:
Well, Carolyn, how about if we see what else and what other articles are in this issue. And maybe I'll go first. So there's a research letter from Dr. Wu entitled Modeling Effects of Immunosuppressive Drugs on Human Hearts Using IPSC Derived Cardiac Organoids and Single Cell RNA Sequencing. Carolyn, there's an EKG challenge from Dr. Yarmohammadi, entitled “Fast and Furious, A Case of Group Beating in Cardiomyopathy.” And then finally from Dr. Tulloch, a really nice Perspective entitled “The Social Robots are Coming, Preparing For a New Wave of Virtual Care in Cardiovascular Medicine.
Dr. Carolyn Lam:
Oh, how interesting. Well, also in the mail back is an exchange of letters of among Drs. Lakkireddy, Dhruva, Natale, and Price regarding Amplatzer Amulet Left Atrial Appendage Occluder versus Watchman Device for stroke prophylaxis, a randomized control trial. All right. Thank you so much, Greg. Shall we go on to our feature discussion now?
Dr. Greg Hundley:
You bey. Welcome listeners to our feature discussion today. And we're so fortunate we have with us today, Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. Welcome to you both. And Vasan, let's start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address?
Dr. Vasan Ramachandran:
Thank you, Greg, first of all for having me. So we know two facts. One is that heart disease and stroke disease death rates and incidents are declining over the last six decades in the United States. Juxtapose against that is also the observation that there is rising incidence of obesity and overweight, and also a rising burden of diabetes. There are a lot of advances in our ability to treat high blood pressure, high cholesterol, as well as high blood sugar. So we wanted to ask the question, given the historic trends in control awareness of risk factors and their control, interrupted by this escalating burden of obesity, overweight, and diabetes, what is the lived experiences of people over time in terms of the risk of developing heart disease or stroke using a metric we call as the remaining lifetime risk of developing heart disease or stroke.
Dr. Greg Hundley:
The hypothesis you wanted to address?
Dr. Vasan Ramachandran:
The hypothesis we wanted to address was that perhaps the decline in the incidence of heart disease and stroke may have decreased over time given the escalating burden of overweight, obesity and diabetes.
Dr. Greg Hundley:
Very nice. And can you describe for us your study population and your study design?
Dr. Vasan Ramachandran:
Thank you, Greg. So the Framingham Heart Study is one of the oldest running epidemiological studies in the world. We have multiple cohorts. The study began in 1948 with the original cohort, the offspring cohort enrolled in 1971, third generation cohort in 2002, and two minoritized cohorts in the 1990s and 2002. So we have an observation period of different cohorts over a six decade period. So we asked the question, if you were a participant in the Framingham study between 1960 and 1979 and then 1980 to 1999, and then 2000 to 2018, what was your lifetime risk of experiencing a heart disease or stroke in the three different time periods? Is it going down, is it steady or is it going up?
Dr. Greg Hundley:
Very nice. And so, Vasan, describe your study results.
Dr. Vasan Ramachandran:
Look, what we found was if you look at the first, the 20 year period from 1960 to 1979, and compare that with the latest, which is 2000 to 2018, in the initial time period, the lifetime risk of developing heart disease or stroke in a man was pretty high. It was about one in two. And that for a woman was about one in three. So when you come to the latest epoch, what we find that the risk of one in two men had dropped to about one in three men in the latest decade. For women, the risk declined from what was one in three in the earlier epoch to one in four. So approximately there was about a 36% reduction in the lifetime probability of developing heart disease or stroke across the six decade period of observation.
Dr. Greg Hundley:
Very nice. And so help us a little bit, put the context of your results into what that might mean for us today as we are managing patients with atherosclerotic disease.
Dr. Vasan Ramachandran:
Yes, Greg. What it means is that the permeation of the advances in science in terms of the screening of risk factors, awareness of risk factors, medications to lower these risk factors effectively, the clinical trials that have given us these new medications, they may have translated into a reduction in risk over time. That the lived experience of people in the later decades is better in terms of having a lower risk of heart disease or stroke as the consequence of multiple advances that have happened in heart disease and stroke.
Dr. Greg Hundley:
Well, thank you so much Vasan. Well listeners, now we're going to turn to our Associate Editor, Mercy Carnethon. And Mercy, you have many papers come across your desk. What attracted you to this particular paper and how do you put these results really in the context of other science pertaining to risk associated with populations that may have atherosclerotic cardiovascular disease?
Dr. Mercedes Carnethon:
Thanks so much for that question, Greg. And again, Vasan, I really thank you and your team for bringing forth such outstanding research. You know, as cardiovascular disease epidemiologists, we were all raised and taught that what we know about risk factors for cardiovascular disease are based on the Framingham cohort. And so I was really excited to see this very comprehensive piece of work that characterized what the Framingham study has identified and also leverages the unique characteristics of a study that started in 1948.
Dr. Mercedes Carnethon:
So, you know, we're almost 75 years in and actually has the ability that cross sectional studies don't have to look over longer periods of time at risk. And you know, when we think about papers that excite us, that we really want to feature in circulation, they are papers that teach us something new. And I will say there were aspects of this work that confirmed what I had heard but had not seen using empirical data. Namely that the remaining lifetime risks for developing cardiovascular disease were going down over time, and they were going down secondary to better management and recognition of the risk factors that the Framingham cohort study had really been instrumental in identifying in the first place.
Dr. Mercedes Carnethon:
There were surprising elements of the paper. The surprising elements being that I think as you brought up earlier, we were concerned that risk factors that were on the rise, such as obesity, were threatening these increases in life expectancy. And it was really nice to see that the findings held, even in the face of rising risk factors. And just to summarize, what I really like about this piece when we situate it within circulation, where we are addressing clinical treatment factors, where we're also featuring clinical trials and even other epidemiologic studies, is that your work identifies for us the overall context in which the clinicians who read the journal are thinking about managing patients and where we're going. It highlights our successes, but it also really brings up what we need to do next. And I look forward to hearing from you about where you think this may be headed.
Dr. Greg Hundley:
Well, Mercy, you're teeing us up for that next question. Vasan, what do you think is the next study or studies that need to be performed in this space?
Dr. Vasan Ramachandran:
Thank you, Greg and Mercy, for your kind comments. Like I shared, this is a success story for a predominantly white population in the Northeast. We are very much aware about the heterogeneity and the geographic variation in heart disease burden in our country. So one of the success stories interpretation might be this represents the upper bound. What can happen to a population that is compliant with screening of risk factors, awareness of risk factors, treatment and healthcare access. I think the next set of studies should broaden the study population to bring in additional populations that are more diverse, that are also followed up over a period of time to assess and put the current observations in the appropriate context. Do we see similar findings longitudinally in other cohorts with non-white participants? Is it different, is their lived experience different? If so, why? And that could inform us how we can reach the success story and replicate it across the entirety of our country.
Dr. Greg Hundley:
And Mercy, do you have anything to add?
Dr. Mercedes Carnethon:
I do. You know, I really like that focus on broadening to whom these results are applicable. We've undergone a lot of shifts within our country and also around the world. You know, circulation, we have a worldwide readership. I would love to see this sort of work replicated across different countries to the extent that we have the data to do so, recognizing that limitation. But I'd love to see work focus on comparing how these things change in low income countries, middle income and high income countries, so that we can really think about resource allocation and find strategies to try to replicate the successes that we are seeing based on the data from the Framingham heart and offspring studies.
Dr. Greg Hundley:
Excellent. Well listeners, we really appreciate the opportunity to get together today with Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. And really appreciate them for bringing us these epidemiologic data from the Framingham cohort, indicating that over the past decades, mean life expectancy increased and the remaining lifetime risk of atherosclerotic cardiovascular disease decreased across individuals in the cohort, even after accounting for increasing incidences of other cardiovascular risk factors like obesity and smoking. Well on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Andrew Chapman and Guest Editor Harvey White as they discuss the article "Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Greg Hundley:
Well, Carolyn, this week's feature on April 19th refers to coronary artery and cardiac disease in patients with type two myocardial infarction. And we will have more to learn about that, but how about we grab a cup of coffee and get started with some of the other articles in the issues.
Dr. Carolyn Lam:
Please? You first.
Dr. Greg Hundley:
Thanks Carolyn. So Carolyn, this team investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity based proteomic assays to estimate their association with incident heart failure. And so to accomplish this, the team, led by Dr. Thomas Lumbers from University College of London, utilized a fixed effect meta-analysis of four population-based studies comprising a total of 3,000 plus participants with 732 heart failure events. Now, the causal effects of heart failure associated proteins were then investigated by Mendelian randomization using CIS protein, quantitative loci, genetic instruments identified from genome-wide association studies or GWAS and over 30,000 individuals.
Dr. Carolyn Lam:
Wow! Big study, important stuff. So what did they find?
Dr. Greg Hundley:
Right Carolyn, several things. So 44 of 90 proteins were positively associated with the risk of incident heart failure. Now, among these eight proteins had evidence of a causal association with heart failure that was robust to multiverse sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney injury molecule one were positively associated with the risk of heart failure, whereas higher adrenomedullin chitinase-3 like-protein-1, cathepsin L1, and fibroblast growth factor 23, and matrix metalloproteinase 12 were protective. And so Carolyn in summary, the team identified 44 circulating proteins that were associated with incident heart failure of which eight showed evidence of a causal relationship, and seven were identified as being drugable, including adrenomedullin, which represents a particularly promising drug target.
Dr. Greg Hundley:
Additionally, Carolyn, this is a really interesting study as the teams approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.
Dr Carolyn Lam:
Wow! Super cool. Yeah, indeed the methodology is significant there too. Thanks Greg. Well, this next paper deals with hypertrophic cardiomyopathy and we know that familial hypertrophic cardiomyopathy is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. But how exactly is the dysregulated sarcomeric force production sensed and how does that lead to pathological remodeling?
Dr. Carolyn Lam:
Well, today's authors and they are Dr. Qyang from Yale University School of Medicine and colleagues gained insights from a severe phenotype of an individual with hypertrophic cardiomyopathy and a second genetic alteration in a sarcomeric mechanosensing protein. They derived cardiomyocytes from patient specific induced pluripotent stem cells and developed robust, engineered heart tissues to study human cardiac mechanobiology at both cellular and tissue levels. They further used computational modeling for muscle contraction and rescue of disease phenotype via gene editing and pharmacological interventions to identify a new mechanotransduction pathway in hypertrophic cardiomyopathy.
Dr. Greg Hundley:
Wow, Carolyn! Tell us more about this new pathway.
Dr. Carolyn Lam:
The study presents a novel biomechanical mechanism by which enhanced myofilament contractile force generation due to sarcomeric mutations, destabilize the muscle limb protein Z-disc mechanosensory complex, and this leads to disinhibition of calcineurin nuclear factor of activated T-cells or NFAT signaling and consequently leads to hypertrophy. Normalization of hypercontractile force in proband cardiomyocytes either with gene editing approaches or with ectomyosin crossbridge inhibitor mavacamten, resulted in an increase in Muscle Lim Protein levels, a decrease in that calcineurin and fat activity and a rescue from the hypertrophic cardiomyopathy defects.
Dr. Carolyn Lam:
The authors provided evidence that the common Muscle Lim Protein W4R variant is an important modifier that worsens the disease severity of hypertrophic cardiomyopathy, but alone does not appear sufficient to cause disease. All in all, these data established a foundation for developing innovative mechanism-based treatments for hypertrophic cardiomyopathy that stabilize the Z-disc Muscle Lim Protein mechanosensory complex.
Dr. Greg Hundley:
Oh, wow Carolyn! What a really nice mechanistic study and important new information too. Well, Carolyn, my next paper comes to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital at the Harvard Medical School and Carolyn the LV myocardium increases in mass in response to pathological as well as physiological stimuli. The former or pathologic hypertrophy, often proceeds cardiomyocyte loss and heart failure. The latter or physiologic, paradoxically protects the heart enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Now, while long non-encoding RNAs are important in cardiac development and disease associated with pathologic hypertrophy, less is known about their roles in physiologic hypertrophy or cardiomyogenesis.
Dr Carolyn Lam:
Oh, interesting! So what did these authors find about link RNAs and physiologic hypertrophy?
Dr Greg Hundley:
Right, Carolyn. So in this study of mice, the authors identified exercise regulated cardiac link RNAs termed lncExACT and lncExACT1 was evolutionarily conserved and decreased in exercised hearts, but increased in experimental heart failure. Cardiac lncExACT1 over expression caused pathological hypertrophy and heart failure while lncExACT1 inhibition induced physiologic hypertrophy and cardiomyogenesis protecting against cardiac fibrosis and dysfunction.
Dr. Greg Hundley:
Now, lncExACT1 functioned by regulating microRNA 222 calcineurine signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCH2 over expression in zebra fish induced pathological hypertrophy and impaired cardiac regeneration promoting scarring after this injury. In contrast mirroring DCH2 deletion, induced physiological hypertrophy and promoted cardiomyogenesis.
Dr. Carolyn Lam:
Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take home message?
Dr. Greg Hundley:
You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch, toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the benefits of exercise.
Dr Carolyn Lam:
Oh, thank you, Greg. Well, also in this issue is an In-Depth paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro Exhale Flow Pump Support in Cardiology.” There's a Research Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.”
Dr. Greg Hundley:
Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter to the Editor from Dr. Gronda entitled “The Failing Heart and SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in Business?” We also have from Dr. Viskin, an ECG challenge entitled “Sinus Node Dysfunction with a Nice Twist.” And finally, Carolyn, there's a Perspective piece from Dr. Schulman entitled “The Price and Quality of the Generic Pharmaceutical Market.” Well, how about at Carolyn we get on our feature discussion involving type two myocardial infarction.
Dr. Carolyn Lam:
Yay! Let's go.
Dr. Greg Hundley:
Well, listeners, welcome to our feature discussion on this April 19th and we have with us today, Dr. Andrew Chapman from Edinburg, Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome gentlemen. And we'll start with you, Andrew. First, could you describe for us some of the background information that went into the preparation of your study?
Dr Andrew Chapman:
Good morning and good evening and thank you very much for the invitation. So type two myocardial infarction is an interesting diagnosis. It was first introduced in around 2007 in recognition that patients could have heart injury when they were in hospital with other problems that led to an imbalance in myocardial oxygen supply, or an unmet need in myocardial oxygen demand, without the presence of atherothrombotic coronary artery disease. We don't know a great deal about these patients.
Dr. Andrew Chapman:
There have been a number of observational cohort studies, including from ourselves in Scotland, which have demonstrated the outcomes for this patient group are poor. We know only around one-third of patients with type two MI, survive to five years after diagnosis. And we also know, and previously demonstrated from patients in Scotland that those with underlying coronary artery disease actually had the worst outcomes and were at increased risk of future myocardial infarction events due to plaque rupture. So we hypothesized that patients with type two myocardial infarction may have failed a physiological stress test due to another illness and we wanted to investigate what the prevalence of underlying coronary artery disease and/or structural heart disease was, using a panel of different imaging modalities.
Dr. Greg Hundley:
And so Andrew tell us the hypothesis that you wanted to address?
Dr. Andrew Chapman:
So we believed that observational evidence suggested that coronary artery disease was important in patients with type two myocardial infarction and we felt that this was increasing their susceptibility to these events. Our primary hypothesis was that the majority of patients with type two myocardial infarction would have underlying coronary artery disease, which was previously quiescent undetected.
Dr. Greg Hundley:
Tell us a little bit about the study design and the study population that you use to answer this question.
Dr. Andrew Chapman:
Demand MI is to our knowledge, the first prospective observational cohort study in which patients who were in hospital with evidence of myocardial injury, so a raised cardiac troponin, were screened for the presence of supplier demand imbalance and the clinical diagnosis of type two MI. Now, in those patients that we were able to recruit, we did obviously have important exclusion criteria, but we designed a series of different investigations depending on individual patient risk factors and the appropriateness of such, but the primary goal was to undertake coronary angiography, ideally using an invasive coronary angiogram, which would allow us to undertake additional testing, such as plaque imaging and pressure wire study, to look for the functional consequences of stenosis. In those not fit for an invasive angiogram, we undertook CT coronary angiography. And in all patients we undertook structural imaging and we aimed to do cardiac MRI in all. Due to the coronavirus pandemic and for other reasons, we used echocardiography where MRI was not available.
Dr. Greg Hundley:
And so the total number of subjects here was how many?
Dr. Andrew Chapman:
We recruited 100 patients with a clinical diagnosis of type two myocardial infarction.
Dr. Greg Hundley:
Very good. And so now, Andrew, what were your results?
Dr. Andrew Chapman:
It's a really fascinating study, obviously, in my opinion. So we recruited 100 patients with a clinical diagnosis of type two myocardial infarction who had evidence of supplier demand and balance, a raised cardiac troponin concentration and evidence of symptoms and/or signs of myocardial ischemia. So in line with the universal definition criteria. Of 100 patients after undertaking coronary imaging, we reclassified the diagnosis in seven.
Dr. Andrew Chapman:
In five patients, we found that there was evidence of either plaque rupture or a stent thrombosis. And in two patients, we found evidence of myocarditis and stress cardiomyopathy respectively. The first principle finding is that actually despite careful characterization and really detailed screening, we were correct in 93 of 100 patients and we got the diagnosis wrong in seven. The principle hypothesis related to the prevalence of coronary artery disease and this was, as alluded to, undertaking with invasive and noninvasive imaging. But overall, the prevalence of coronary artery disease was 68% of those with type two myocardial infarction and this was obstructive in 30%.
Dr. Andrew Chapman:
We also undertook structural imaging as mentioned. We observed evidence of left ventricular systolic dysfunction in 34% of patients, of around a third, and perhaps most surprisingly, although we had a clear diagnosis of myocardial infarction in these patients, we only found imaging evidence of in part pattern late gadolinium enhancement, which is considered the gold standard for its diagnosis of myocardial infarction. We only observed that in 42%, which raises some interesting questions.
Dr. Andrew Chapman:
One of the principle clinical findings of the study is that these underlying conditions of coronary artery disease and left ventricular impairment, both of which are readily treatable with secondary prevention. These conditions were previously unrecognized in 60% of patients and only one-third were on appropriate evidence-based treatment, which gives me some cause for optimism, that there may be a role here for targeted treatment, which could plausibly, plausibly impact on outcomes.
Dr. Greg Hundley:
And Andrew, just a clarification point, maybe a subgroup analysis, any differences in your findings in regarding men versus women?
Dr. Andrew Chapman:
Excellent question. And in most studies of type two myocardial infarction, it's thought that this condition is more prevalent in women than men, but undoubtedly in all observational cohorts, there is selection bias as you will only diagnose a type two myocardial infarction if a clinician requests to test troponin in the first place. In our study, interestingly, we recruited more men than women. We had 56% men and we did not find any differences by sex in our analysis.
Dr. Greg Hundley:
Well listeners, what an excellent description from Dr. Chapman. A very interesting study. And we now want to turn to one of our editors, guest editors, Dr. Harvey White, and Harvey, we want to thank you for your work here with us at the American Heart Association and Circulation, and you receive many articles to review. What attracted you to this particular article and how do we put in context, these results with others that have been published pertaining to type two myocardial infarction?
Dr. Harvey White:
Thanks, Greg, it's a pleasure to work for Circulation. This paper is very close to my heart because I introduced the typing system in 2007 and it had minimal support and people said, "Why do we need a typing system? We've got killer class and Canadian class and you've done a troponin release system as well". And people stood up and then I laid out the type one plaque rupture. We know the pathophysiology and we know the treatment. Type two, I'd worked on beta blockers, supply and demand and I thought we should define the pathophysiology and define the treatment. That's 2007, which is 15, 16 years ago. And Andrew's paper is really lovely. As I said, it's close to my heart and he inches things forward. I've written an editorial, which I call "Zooming in on the enigmas of type two MI" and enigma means mystery or it's unclear, uncertain.
Dr. Harvey White:
And that's for sure we don't have full support for the diagnosis. It's become very practical, used in clinical trials and clinically, but we don't know how to manage it and we don't know how to define the groups. Andrew and colleague study is very nice. It's prospective and it has set out to define the coronary artery disease. I've tried for about 10 years to subdivide type two and to those without coronary disease and those with coronary disease. And you could also have a type C, which hasn't been investigated or unknown. And Andrew has answered one of the enigmas and it's really interesting. Large proportion, normal coronary arteries, diagnosis was changed a little bit based on the finding of thrombus. We're challenged with that finding because all MIs have thrombus at PM and really type one should be ruptured plaque. But Andrew changed the diagnosis in a few where one was an OTC, a marvelous case with marvelous pictures, changed the diagnosis. So I like the study and I like the findings. Thanks.
Dr. Greg Hundley:
Very nice. Well, Andrew, what a perspective and listeners getting just to listen to Dr. White is really quite exciting for me. Andrew, what do you see as the next study to be performed in this sphere of research?
Dr. Andrew Chapman:
I think we've gone some way to provide some insights into the underlying pathophysiology of this condition and these coexistent conditions of coronary artery disease and left ventricular impairment, which might increase an individual's susceptibility to a type two myocardial infarction. The question is what can we do about it and does targeted treatment with secondary prevention therapies for coronary disease and treatment for heart failure left ventricular impairment, does that improve outcomes?
Dr. Andrew Chapman:
The next study for me is clear. The next study for me, needs to be a randomized controlled trial, whereby patients with type two myocardial infarction are randomized to current best practice or risk stratification by a cardiologist with an interest in this condition, followed by targeted investigation for coronary disease and LV impairment and thereafter treatment as appropriate. This will be a trial of a complex intervention. I'm very grateful that we've received funding in Scotland already for this pilot phase of this trial, which we've called Targets Type Two and we'll begin recruitment for that trial in August of this year.
Dr. Andrew Chapman:
I must acknowledge colleagues in this area are looking at coronary disease and type two myocardial infraction. Professor Derek Chew is leading a study called Act Two, which is already recruiting and that will also provide invaluable information as to the prevalence of coronary disease and the potential benefits of treatment of that coronary disease in patients with this condition.
Dr. Greg Hundley:
And Harvey. How about your, what is your perspective in terms of the next series of studies perhaps that need to be performed in this space?
Dr. Harvey White:
There's a number and I like very much, Andrew's suggestion. The study that we're doing is randomizing to angiography or not angiography working with Derek Chew. I think all patients with MI should have coronary angiography. It's simple, it takes about 10 minutes. There's obviously some contraindications, but the information as Andrew has pointed out is really so useful. He found dissection, he found an embolus. Normal coronary arteries that in my view changes the management. Whether you should do an angiogram is very important. Randomization to various treatments. That's important. I would like to get more information about the objective evidence of type two MI, the criteria for low hemoglobin, shortness of breath, low blood pressure, high blood pressure, and so forth. There's a lot to do. As Andrew pointed out, the outcome may be worse than type one that's becoming more common and I think these studies will be very, very important.
Dr. Greg Hundley:
Very nice well listeners. We want to thank Dr Andrew Chapman as lead investigator and Dr Harvey White as guest editor for bringing us this study using advanced imaging of patients with type two myocardial infarction, which identified coronary artery disease in two-thirds and left ventricular dysfunction in one-third, and also highlighting that unrecognized and untreated coronary or cardiac disease occurs in many patients with type two MI and gives us pause for thought on a series of studies that may be performed in the future.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.
This week, please join author Enrico Ammirati and Guest Editor Stephane Heymans as they discuss the article "Prevalence, Characteristics, and Outcomes of COVID-19–Associated Acute Myocarditis."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature on this April 12, we are going to review COVID-19–associated acute myocarditis, looking at the prevalence and the outcomes. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other articles in the issue, and maybe there could be a quiz in there somewhere.
Dr. Carolyn Lam:
Oh, yikes.
Dr. Greg Hundley:
But before we get to that quiz, Carolyn, would you like to go first?
Dr. Carolyn Lam:
I would, and we're starting with a topic that we rarely talk about, it's about neurodevelopmental impairment. We know that it's common in children with congenital heart disease, yet postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedence for neuro development disabilities might begin in utero, these authors, led by Dr. Rollins from Boston Children's Hospital and Harvard Medical School, analyzed whether fetal brain volume predicted subsequent neuro development outcome in children with congenital heart disease. To do this, the authors studied fetuses with isolated congenital heart disease and social demographically comparable healthy controlled fetuses, all undergoing fetal brain MRI and two year neurodevelopmental evaluation.
Dr. Greg Hundley:
Ah, Carolyn, wonderful, interesting article that we're taking on here in Circulation. What did this group find?
Dr. Carolyn Lam:
In children with congenital heart disease, a smaller total brain volume on fetal MRI correlated with worse neurodevelopmental outcome at two years of age, across all domains of development and adaptive function. A predictive model, including total brain volume, along with sociodemographic and medical data, accounted for up to 45% of the variance in neurodevelopmental outcome within the congenital heart disease group. Fetal brain volume was the most consistent predictor of outcomes across neurodevelopmental domains compared with other sociodemographic and medical or surgical variables.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my first paper comes to us from the world of preclinical science. Okay, Carolyn, we're going to start it with the infamous Carolyn's quiz. Here we go.
Dr. Carolyn Lam:
Wait a minute, we should put a rule here, no quizzes on preclinical basic science, especially stuff we can't pronounce.
Dr. Greg Hundley:
Ah, yes, but seems to me, there's a heart failure expert on the team. Always remember, you can phone a friend because we have our wonderful Augie Rivera, our production manager, who is available and you can call on him at any time. Okay, here's the quiz, is Cam Kinase II helpful to cure or harmful to exacerbate heart disease?
Dr. Carolyn Lam:
Oh goodness, Greg. Okay. Cam Kinase II, I know it's Calcium-calmodulin Kinase II. I know there are different isoforms, and I'm cheating here a bit because last week we talked about targeting CaM Kinase II in heart disease. I'm going to guess harmful, I'm going to guess dealing with something with calcium overload, but I'm sure there's more to the story.
Dr. Greg Hundley:
Carolyn, getting onto to the article, cardiac ischemia-reperfusion injury really has emerged as an important therapeutic target for ischemic heart disease, the leading cause, as we know, of morbidity and mortality worldwide. Currently, there is no effective therapy for reducing ischemia-reperfusion injury. Calcium II Calmodulin dependent Kinase II, or CaM Kinase II plays, a pivotal role in the pathogenesis of severe heart conditions, including ischemia-reperfusion injury. Therefore, pharmacological inhibition of CaM Kinase II could be an important strategy in the protection against myocardial damage and cardiac diseases. But to date, however, there is no drug targeting CaM Kinase II for the clinical therapy of heart disease. Furthermore, currently, there is no selective inhibitor of CaM Kinase II Delta, the major CaM Kinase II isoform, in the heart.
Dr. Carolyn Lam:
Wow. What did the authors do?
Dr. Greg Hundley:
Okay, Carolyn. A small molecule kinase inhibitor library, and a high throughput screening system for kinase activity of CaM Kinase II Delta9, the most abundant CaM Kinase II Delta splice variant in the human heart, were used to screen for CaM Kinase II Delta inhibitors. Using cultured neonatal rat ventricular myocytes and human embryonic stem cell derived cardiomyocytes, as well as in vivo mouse models, in conjunction with myocardial injury induced by ischemia-reperfusion or hypoxia-reoxygenation and CaM Kinase II Delta9 over expression, this team, led by Professor Yan Zhang, from Peking University, sought to investigate the protection of Hesperidin against cardiomyocyte death and cardiac diseases.
Dr. Carolyn Lam:
Oh, wow. Please tell us, so what happened?
Dr. Greg Hundley:
Right, Carolyn. Several important findings. First, Hesperidin, the Aurora B kinase inhibitor, with antitumor activity in vitro directly bound to CaM Kinase II Delta and specifically blocked its activation in an ATP competitive manner. Second, Carolyn, functionally, Hesperidin ameliorated both ischemia-reperfusion and over express CaM Kinase II Delta9 induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell derived cardiomyocytes. And then, finally, Carolyn, in an in vivo BALB/C nude mouse model, with xenografted tumors of human cancer cells, Hesperidin delayed tumor growth without inducing cardiomyocyte death or cardiac injury.
Dr. Carolyn Lam:
Wow. Goodness, Greg, that's impressive. Okay, what's the take home message?
Dr. Greg Hundley:
Well, Carolyn, these results suggest that Hesperidin is a specific small molecule inhibitor of CaM Kinase II Delta with dual functions of cardioprotective and antitumor effects. These findings not only suggests that Hesperidin is a promising leading compound for clinical therapy of cardiac ischemia-reperfusion injury, and heart failure, but also could provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anti-cancer treatment.
Dr. Carolyn Lam:
Wow, Greg, that is an amazing summary. Thank you. Well, for my last paper, I'd like to tell you about a study in which authors led by Dr. Lubo Zhang from Loma Linda University in California, and the colleagues, tested the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion injury by controlling mitochondrial bio energetics and reactive oxygen species flux. Myocardial infarction in an acute setting of ischemia-reperfusion was examined via comparing loss versus gain of function experiments in microRNA-210 deficient and wall type mice.
Dr. Greg Hundley:
Ah, Carolyn, another really interesting paper from the world of preclinical science. What were the results here?
Dr. Carolyn Lam:
MicroRNA-210 deficiency induced an ischemic sensitive phenotype and exaggerated acute myocardial infarction and cardiac dysfunction after MI in males in a gender dependent pattern in a murine model of myocardial infarction. The study identified a novel mechanism of MicroRNA-210 targeting mitochondrial glycerol-3-phosphate dehydrogenase in controlling mitochondrial energy metabolism, and reactive oxygen species flux, and improving cardiac function in the setting of acute ischemic-reperfusion injury. Thus, the present findings reveal new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.
Dr. Greg Hundley:
Oh, beautiful descriptions, Carolyn. Well, my next papers come from the mail bag, and there is a great Research Letter from Professor Downing entitled “Critical Illness Among Patients Hospitalized With Acute COVID-19 With and Without Congenital Heart Defects.” Carolyn, there's a second Research Letter from Professor Zhao entitled “Dual Genetic Lineage Tracing Reveals Capillary to Artery Formation in the Adult Heart.”
Dr. Carolyn Lam:
Nice. There's also an On My Mind paper by Dr. Mintz on “Prioritizing Quad Therapy and the Path Forward in Guideline-Directed Medical Therapy for Patients with Heart Failure with Reduced Ejection Fraction.” Cool, Greg, thank you. Now, let's go to our feature discussion, shall we?
Dr. Greg Hundley:
You bet. To learn more about the prevalence and outcomes in COVID-19–associated acute myocarditis.
Dr. Carolyn Lam:
Acute myocarditis is thought to be a rare cardiovascular complication of COVID-19, or is it? Well, we have minimal data available in case reports, but really not a large scale study until today's issue and today's feature paper, which really aims to look at the prevalence, baseline characteristics, in hospital management and outcomes for patients with COVID-19–associated acute myocarditis.
Dr. Carolyn Lam:
I'm so pleased to have the first author with us, Dr. Enrico Ammirati from Niguarda Hospital in Milano, Italy, as well as our guest editor, Dr. Stephane Heymans from Maastricht University Medical Center in The Netherlands. Welcome, gentlemen. Enrico, thank you, thank you, thank you for this very important study. Could you please tell us what you did and what you found?
Dr. Enrico Ammirati:
Carolyn, it's a pleasure to be here with you and Stephane. We performed, let's say, large study on myocarditis associated with the COVID-19. That is a multicenter study, including 23 centers in the United States and in Europe. The senior author is Professor Marco [Metra], from Brasia, and the co first author is Dr. Laura Lupi, again, from Brasia. What we have done was to better characterize the prevalence of in-hospital myocarditis among the patients hospitalized with the COVID-19 diagnosis.
Dr. Enrico Ammirati:
And then, we tried to describe the outcome and the clinical characteristic at presentation. First of all, we define the myocarditis as a definitive or probable. That was based on the presence of cardiac magnetic resonance imaging consistent with myocarditis plus increase in troponin plus presence of symptoms that are compatible with an acute myocarditis. Alternatively, the patients must have a positive endomyocardial biopsy.
Dr. Enrico Ammirati:
The first result was that among more than 56,000 patients hospitalized in these hospitals, the rough prevalence of myocarditis was around 2.4 among 1000 hospitalized patients. The second main message was that the prognosis, we divided the population, we spitted the population in two groups. Patients with an ongoing and concurrent pneumonia and patient with myocarditis, but without evidence on CT of pneumonia. What we have found it was that among 57% of cases of COVID patients, you can have a myocarditis without pneumonia. So this is an interesting and new finding, and we compare the clinical characteristic of this patient comparing with the patient with the pneumonia. And we found that generally patient with pneumonia were older comparing with the patient with the isolated myocarditis and the prognosis of patients was worse comparing with the patient with just myocarditis.
Dr. Enrico Ammirati:
The outcome was around, overall, the outcome of this population that had median age of 38 year was an incidence of 6% of death. And if we look at the patient with the concurrent pneumonia, the outcome was worse. Then we have other findings that are of potential interest. And that is, for instance, that in 55% of patients, corticosteroids were used, and that is consistent with the idea that corticosteroids can work in this setting. We have also data on the presence of such Coronavirus, two in the heart, in patient that undergo vital search. And it was just in 21% of cases that underwent genome research in the myocardium. So I would say that these are the main findings of this research.
Dr. Carolyn Lam:
Oh, wow. First of all, heartfelt congratulations more than fifth, almost 57,000 hospitalized patients with COVID-19 and 23 hospitals across us and Europe. Stefan, you really appreciate that you served as guest editor here. Could you tell us some of your initial reactions, put the findings in context, perhaps?
Dr. Stephane Heymans:
Yes, yes. For sure. Enrico, indeed, I would like to concur with this congratulations on this beautiful study. It's a lot of work to collect this data and also to try to distinguish myocarditis from all other possible cause of cardiac injury. When I first saw this data, I think, oh, how difficult should be to make a diagnosis of myocarditis. And, of course, increased troponins are often seen in those COVID-19 hospitalized patients. Cardiac MRI is quite a specific for any non-ischemic myopathy. Yeah, I was wondering, so are these cardiac MRI images suggestive of acute myocarditis, but a really specific, sensitive enough to make a definite accurate diagnosis of COVID 19 related myocarditis, or could also be severe illness related to COVID-19 sepsis of pneumonia, give similar images on cardiac MRI?
Dr. Enrico Ammirati:
Stephane, this is a very good point. We haven't studied so in detail the cardiac injury in patients with the viral pneumonia, with the other viruses, so we cannot say that this kind of cardiac involvement is specific for such Coronavirus too. But what I can say is that this population is a population of highly likely acute myocarditis because if you look at simple clinical characteristics, and you can find that the median age is 38 years. This is the first reassuring a clinical characteristic because if we compare with the age of the population, of the laboratory registry of acute myocarditis we published in 2018 in Circulation, the media age was 36.
Dr. Enrico Ammirati:
Then, another point in support of our finding is that in the end, we have both present of edema and positive LG in patients with consistent myocarditis on magnetic resonance imaging. So, I know that probably edema can be associated with either other form of myocardial injury that are not necessary so specific for myocarditis. But if you look at troponin increase in this population, the median increase was 55 folds above the upper reference limit, so it was not just a small increase. It was a huge increase in troponin.
Dr. Enrico Ammirati:
Specifically, in patients that were above 45 years, we have a confirmation that was no coronary artery disease associated, to assure the readers that likely these are myocarditis. But as you said, we cannot be 100% sure about that. And you mentioned an important point, we cannot say that, also, in other form of viral disease, we can have a myocardial injury that can be very similar to myocarditis.
Dr. Stephane Heymans:
Yes. Thank you so much for your clear answer. It just underscores how sick a COVID-19 can make you because the numbers you're getting is two [in] 1000, you would say, okay, that's a small number, but still, there's so many more patients with a cardiac injury related to COVID-19. Indeed, to put it into context, so common viral myocarditis occurs in one to 10, 100,000, so the COVID-19 related myocarditis is up to 100 times more with your numbers. And of course, the common viral myocarditis, it's at the same age, similar age around 36, means a young, relatively young age.
Dr. Stephane Heymans:
Indeed, this COVID-19 is probably a trigger in immune and maybe genetic susceptible, young persons had to get myocarditis upon COVID-19 disease. Whereas, the COVID-19 vaccination related myocarditis, which is getting much more media attention, at least, previous months, only occurs in one to five in 100,000 people. And those patients are completely recover and transplant free. Survival is over 99%. To put it in context, it's still quite severe at this COVID-19 related myocarditis.
Dr. Carolyn Lam:
Thank you so much. Stephane.
Dr. Enrico Ammirati:
Can I add some comments? First of all, we have to say that these patients that died with myocarditis associated with the COVID-19, died to complication related to ECMO. For instance, we had a patient with a brain hemorrhage, and we had one patient who had a complication related septic shock. So, myocarditis can be something on top of a severe disease. We have a condition that is as background that is quite severe, and we a further complication related to myocarditis, so what we have seen is that, generally, even comparing with the previous Lombardy Registry I referred before the outcome of this patient was worse. Of course, it's very difficult to compare studies that have been performed in different centers during a different time period. But, of course, if you think that most of viral myocarditis are secondary to cold or flu, so the background condition is really mild.
Dr. Enrico Ammirati:
The main focus is the myocarditis. While in this patient, we have a subpopulation where you have in a great proportion of them, a severe myocarditis associated with a pneumonia. So you have the double component and that can explain why this patient had a worse outcome. Referring to them, vaccination, my thought is that for the first time we have a large vaccine campaign in this range of age, between 15 and 30 years or 35 years, that is the population at higher risk for myocarditis, where we do not generally perform large campaign for vaccination.
Dr. Enrico Ammirati:
In the end, it can be that we have seen more myocarditis related to vaccination because it was the first time that we vaccinate this kind of population. We have seen something similar with a smallpox vaccination in the military population. And that's the case because for other reason, that are not really related to the health reason, we vaccinated a high-risk population for myocarditis by itself. And we found that smallpox is more associated with myocarditis. Probably, there are, as you said, genetics per count that can explain in some patients an increase risk of myocarditis, but that can be possible that is there is also hormonal or epigenetics phenomena that can explain the higher risk in this population for myocarditis, both for COVID related or for vaccine related.
Dr. Stephane Heymans:
Ah, yeah. Enrico, could you remind me, was this incident of prevalence of COVID-19 myocarditis more prevalent in male patients compared to female when correcting for the background numbers?
Dr. Enrico Ammirati:
In our population, the main population was exactly was about 60%. There was just a slight increase in the number of cases in the male population, but it was not such a large prevalence as you expect in, let's say, uncomplicated myocarditis, where you can find an 80% of male prevalence or in vaccine.
Dr. Stephane Heymans:
Indeed. In the common or the vaccine related myocarditis, it's mainly young male, hetero sex, hormonal factors are being involved, so probably, as you say, these COVID-19 patients have a change in their immune background. And some of those, might some of those also have already background cardiomyopathy or myocarditis, maybe cardiomyopathy, that was not known yet. And then with the COVID-19 might have developed a clinical myocarditis/cardiomyopathy.
Dr. Enrico Ammirati:
When we look at the endostolic diameter of the left ventricle, I can say that the diameter was in the normal range, so that can support the idea that generate this patient did not have a previous dilated cardiomyopathy, but I cannot say that this patient had a known dilated cardiomyopathy before this event.
Dr. Carolyn Lam:
You know, once in a while, Augie, I get to do some of these interviews, and it just takes off on its own. And I love it. And there's nothing I need to do except to sit and listen, and to be grateful that you are publishing this and having such a lovely discussion on this podcast. Thank you, both of you. And, if I could, just very quickly, do you have any take home clinical messages now, from what you've seen, for someone who may be managing one of these COVID-19 patients and suspecting anything?
Dr. Enrico Ammirati:
Can I add that, in the end, what I can, say based on this research, is that likely myocarditis associated with COVID-19 is worse compared with myocarditis associated to vaccine. So even if we see that probably the prevalence is, again, high year with COVID-19, but the most important point is that it's even worse with myocarditis is associated with COVID-19 comparing with the vaccine, so please get the vaccination.
Dr. Carolyn Lam:
Thank you. And you've been listening to Circulation on the Run. From Greg and I, thank you for joining us today. I'm sure you're so grateful, and have learned so much, as I have. And don't forget to tune in again, next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, please join author Zdenka Pausova and Associate Editor Svati Shah as they discuss the article "Circulating Metabolome and White Matter Hyperintensities in Women and Men."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, have you ever wondered what white matter hyperintensities in a brain are made of? Well, guess what? The feature discussion is going to give us a little clue. Believe it or not from the circulating metabolome, interesting, huh? Well, I'm going to keep you in suspense, as we first discuss other papers in the issue. And I want to go first, may I?
Dr. Greg Hundley:
Absolutely, but let's all grab a cup of coffee.
Dr. Carolyn Lam:
All right. You got yours. And here goes. This first paper reviews the results of endovascular aneurysm repair in patients from the Japanese Committee for Stent Graft Management registry, to determine the significance of persistent type II endoleak and the risk of late adverse events, including aneurysm sac enlargement.
Dr. Greg Hundley:
Ah, Carolyn, a very clinically relevant question. So what did this study show?
Dr. Carolyn Lam:
Of more than 17,000 patients who underwent endovascular aneurysm repair for abdominal aortic aneurysm from 2006 to 2015, 29% had persistent type II endoleak. The cumulative incidence rates of abdominal aortic aneurysm related mortality, rupture, sac enlargement, and reintervention were higher in patients with persistent type II endoleak. Specifically, the cumulative incidence rates of rupture and abdominal aortic aneurysm related mortality increased to 2% at 10 year follow up, which is dissimilar to the previously reported frequency of only about 1%. Cox regression analysis revealed older age, female sex, proximal neck diameter, and chronic kidney disease as independent, positive correlates of sac enlargement.
Dr. Carolyn Lam:
So these wonderful results are from Dr. Hitoshi Matsuda and colleagues from the National Cerebral and Cardiovascular Center in Osaka Japan, and really suggests that persistent type II endoleaks are not always benign.
Dr. Greg Hundley:
Beautiful summary, Carolyn. Well, my paper comes from the world of pre-clinical science. And Carolyn, in most eukaryotic cells, the mitochondrial DNA is uniparenterally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mitochondrial DNA. All copies are therefore, nearly identical or, as we would call homoplasmic.
Dr. Greg Hundley:
Now Carolyn, the presence of more than one mitochondrial DNA variant in the same cytoplasm can arise naturally or as a result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH.
Dr. Greg Hundley:
Now Carolyn, these investigators led by Professor Jose Enriquez from the Centro Nacional de Investigaciones Cardiovasculares hypothesized that DNPH is maladaptive and usually prevented by the cell.
Dr. Carolyn Lam:
Wow, that's really interesting, investigations from the world of preclinical science. What did the investigators find?
Dr. Greg Hundley:
Right, Carolyn. So, the investigative team engineered and characterized divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, as we've talked about before, mice throughout their lifespan. The authors found that DNPH impair mitochondrial function with profound consequences in critical tissues that did not resolve heteroplasmy, particularly within cardiac and skeletal muscle. Progressive metabolic stress in these tissues led to severe pathology results, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. And finally, Carolyn, symptom severity was strongly modulated by the nuclear context.
Dr. Greg Hundley:
So in conclusion, Carolyn, these findings suggest that medical interventions that could generate divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, so to address potential incompatibility between donor and recipient mitochondrial DNA.
Dr. Carolyn Lam:
Oh wow. That is fascinating. Well guess what? My next paper is also about mitochondria, but this time looking at the role of the mitochondrial calcium uniporter. So we know that calcium is a key regulator of energy metabolism and impaired calcium homostasis damages mitochondria, resulting in cardiomyocyte death, pathological hypertrophy, and heart failure.
Dr. Carolyn Lam:
This study by Dr. Wang from University of Washington and colleagues investigated the regulation and the role of the mitochondrial calcium uniporter in chronic stress induced pathological cardiac remodeling. In a series of elegant experiments in the mitochondrial calcium uniporter knockout or transgenic mice infused with isoproteronol, the authors found that the mitochondrial calcium uniporter is up regulated in the stressed heart to orchestrate mitochondria sarcoplasmic reticulum, and cytosolic calcium handling, preventing cytosolic calcium overload induced cardiomyocyte death.
Dr. Carolyn Lam:
Lack of mitochondrial calcium uniporter mediated mitochondrial calcium uptake is detrimental. Whereas, transgenic over expression is beneficial to the heart during chronic beta adrenergic stimulation. The nuclear translocation of calcium/ calmodulin kinase II delta beta via calcineurin mediated dephosphorylation of serine 332 activates CAMP response element binding protein to promote mitochondrial calcium uniporter gene expression in adult cardiomyocytes.
Dr. Greg Hundley:
Well, Carolyn, what's the take home here? What are the clinical implications?
Dr. Carolyn Lam:
Ah, thought you might ask. Well, this study indicates that enhancing mitochondrial calcium uptake could be a new approach to prevent chronic beta adrenergic stimulation induced heart remodeling. Targeting this cam kinase two delta beta KREB mitochondrial calcium uniporter pathway could be a therapeutic option for pathologic cardiac remodeling associated with chronic adrenergic stress.
Dr. Greg Hundley:
Excellent description, Carolyn, and thank you for walking us through that wonderful paper. Well, we've got some other papers in the issue and from the mail bag, Professor Lusis has a Research Letter entitled Identification of DNA Damage Repair Enzyme, ASK II as Causal for Heart Failure with Preserved Ejection Fraction. And Carolyn there's a cardiovascular case series from Professor Barrett entitled, “The Unrepairable Infant Mitral Valve, an Unexpected Case of Decompensated Heart Failure.”
Dr. Carolyn Lam:
Interesting. There's an exchange of letters between Doctors Matrougui and Wang regarding the article, “Integrated Stress Response Couples Mitochondrial Protein Translation with Oxidative Stress Control” and a Perspective piece by Dr. Fatkin on “Fishing for Links between Omega-3 Fatty Acids and Atrial Fibrillation.” Wow. Super cool. Greg, let's go on now to a feature discussion, shall we?
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
For our feature discussion today, we are talking about white matter hyperintensities. Now that's the most common brain imaging marker of small vessel disease. That may be known, but there's a lot more to it. For example, what are they made of? Well, you're going to so enjoy today's feature paper, and I'm so proud to have the corresponding author with us, Dr. Zdenka Pausova from Hospital for Sick Kids in Toronto, Canada, as well as our associate editor, Dr. Svati Shah from Duke University. So welcome ladies. And Zdenka, if I could start with, could you explain the rationale for your study and what you did?
Dr. Zdenka Pausova:
Yeah. Thank you. Thank you for having me. Well, we were thinking that it is important to know what the metabolic variables that associate with white matter hyperintensities might be, simply because we know that there are other studies that have shown that whatever circulates in blood is in some way related to brain health. For example, different lipids associated with Alzheimer Disease, cognitive functioning and with structural properties of the brain. So we were wondering what the metabolics that are associated with white matter hyperintensities might be, simply because we would like to know a little bit more about the pathogenesis of the disease, because that's what metabolomic profiling can provide. And also if one can identify biomarkers that potentially could be used in the clinical setting.
Dr. Carolyn Lam:
Wow. Thank you. And Zdenka, this may be a very basic question, but we hear a lot about the metabolome and sometimes it's not very clear what metabolome profiling actually is. And could you just say a little bit about the technique and your study population and then your findings? Thanks.
Dr. Zdenka Pausova:
Yes. Sure. So we actually studied over 9,000 individuals from eight different population based studies and all of those individuals had metabolomic assays done with two main platforms. It's mass spectrometry and nuclear magnetic spectroscopy. Mostly these platforms are actually commercially available and altogether across all platforms, there were over 2,200 different metabolites. And from those we could study about 1200 that we had at least in two populations. And what the metabolites are, these are different metabolites of lipids, sugar, proteins, amino acids that people put on those platforms or that designers put on the platforms, in order to test some of their hypotheses, that they were actually these metabolites of interest for different sorts of diseases, including cardiovascular and cerebrovascular disease.
Dr. Carolyn Lam:
Wow. So this is really large scale, massive, big data, if I may, and if I'm not wrong, it's the first large scale study to identify circulating metabolomic measures associated with white matter hyperintensities. So could you please summarize the main findings?
Dr. Zdenka Pausova:
Well, overall we actually found that there were 416 metabolites that were nominally associated with white matter hyperintensities, but as it is in epidemiology, you have to correct for multiple comparisons. So when we did DR correction, there were only 30 variables associated with white matter hyperintensities. And when we wanted to check whether those associations are independent of the risk factors for white matter hyperintensities, such as hypertension, type two diabetes, smoking, obesity, we actually ended up with seven markers, seven metabolites that were significantly associated in the fully adjust model.
Dr. Zdenka Pausova:
And the main one was actually a derivative of amino acid hydroxyphenol that probably is a marker of ischemia in the brain. And what actually I am coming to is, and one of the main findings was, that many of those metabolites were associated with white matter hyperintensities in a sex specific manner. That is that they were detected in the pool sample, but essentially the signal came from only one of the sexes. And so this one that was the most significant was detected only in males essentially, and not really in females.
Dr. Zdenka Pausova:
And that I think is an interesting, one of the most interesting findings that we can expect that there are really sex specific pathways, biochemical pathways, that accompany white matter hyperintensities.
Dr. Carolyn Lam:
Wow. Zdenka, thank you so much. I have to bring Svati in right now to share some perspective, Svati, especially to put these findings into context, please.
Dr. Svati Shah:
Yes. Dr. Pausova, really wonderful paper. This is an incredible study, if you think about it. The largest scale study that really is trying to understand metabolic by biomarkers, but the biomarkers actually tell us about the potential biology of what's going on with these white matter hyperintensities. We know that these hyperintensities in the brain are associated with increased risk of stroke, increased risk of cognitive decline, but we don't really understand stand what the risk factors are. There's been some studies suggesting that there's genetic risk factors, but this is really the first large scale study to say, "Hey, what's in the blood that we can measure?" And just to be clear, these technologies are measuring these biomarkers that are very, very, very low levels in the blood, really granular snapshot of what's going on with the human being.
Dr. Svati Shah:
And by looking at these blood markers that the authors were able to find biomarkers that are associated with these brain abnormalities, but really highlighting some of the important biology as Dr. Pausova started to talk about. So I think what it gets us to is we get to have our cake and eat it too. We get to learn about biomarkers that might have clinical utility, but we also have discovered, they've discovered new biology that could lead to new therapies, for example, and a better understanding of the mechanisms of why some people develop these hyperintensities as they age. And some people do not.
Dr. Carolyn Lam:
Wow, Svati, you put that so eloquently and just to put it out there for everyone, that significant metabolite hydroxyphenol pyruvate explain 14% of the variants of white matter hyperintensity volumes in males. Whereas, the proportion of variants explained by hypertension is only 1% or type two diabetes is only 1 to 3%, or smoking is even less than 0.1%. So this is, as you said, Svati, it's a significant discovery as well. Zdenka, though, how do we apply this clinically?
Dr. Zdenka Pausova:
Well, it could be a marker that is measured in circulation and it is a marker that can be measured in blood and can indicate early stages of white matter hyperintensities. But I think before we get there, it would be of high value to actually carry out some longitudinal studies, because it would be really interesting to know if it is an early marker before the white matter hyperintensities extent is enlarged. And so that would one thing. But other than that, I think if that would be the case, we can just measure it in blood and see how predictable it is.
Dr. Carolyn Lam:
Can I ask what about the women? Did anything predict it in women?
Dr. Zdenka Pausova:
That's a good question. There was only actually one variable. To our surprise, only one variable that was significantly associated with white matter hyperintensities in women. And it is really surprising because the sample size was the same. The extent, the volume of white matter hyperintensities was quite similar. They were of similar age, similar adiposity. So there were no huge differences, yet we could not actually detect too many metabolized associated with white matter hyperintensities in women. Really surprising. And I don't have a good answer for it now.
Dr. Carolyn Lam:
Wow. Thank you. Svati, did you have further thoughts on the clinical applications and implications of these tremendous data?
Dr. Svati Shah:
Yeah. I think the ability to have a biomarker as Dr. Pausova nicely articulated that would potentially prevent people from having to get an MRI. And we would be able to identify people hopefully at an earlier stage in the process. In this lovely study, they were looking at biomarkers in people who already had the hyperintensities. I think the next step as Dr. Pausova outlined to be able to identify whether these predict high risk people who will develop them in the future and then try to target therapies. A potential advance in precision medicine in the neurologic space, that we could use this biomarker to say, "You need this particular medication."
Dr. Svati Shah:
Some of the biomarkers that Dr. Pausova's group discovered were actually just cholesterol measures. So maybe we need to be instituting more aggressive cholesterol therapies in these patients who are at high risk. I'm not saying we can do that yet, but these provocative results suggest that this could lead to a more personalized approach to high risk individuals who may have consequences and develop these white matter hyperintensities.
Dr. Carolyn Lam:
And Zdenka, did you have anything to add to that?
Dr. Zdenka Pausova:
Perhaps one interesting aspect of the study that I actually was nicely surprised at the end of the study that the markers, one could the different lipids or the different derivatives of amino acids, the literature provided actually a possible pathways, how those could be involved in the development of white matter hyperintensities. Some of them actually, we could possibly link to impairment of myelination of a neuronal axons, or actually the axons themselves could be the metabolized could reflect damage of those axons.
Dr. Zdenka Pausova:
And also, one suspicious pathway or one pathway that is suspected to be big part of the development of white matter hyperintensities is the disruption of blood brain barrier and some of the markers could be actually linked to that vascular dysfunction.
Dr. Carolyn Lam:
Aw, that's wonderful. Thank you so much, Zdenka, for publishing this beautiful work with us in Circulation. And thank you, Svati, for taking this paper through and inviting this beautiful editorial. In fact, it quite summarizes our discussion. It's entitled, What Turns White Matter White? Metabolic Clues to the Origin of Age-Related White Matter Hyperintensities and it's by Dr. Eric Smith from University of Calgary and I invite everyone to read this.
Dr. Carolyn Lam:
So thank you once again for joining us today on Circulation on the Run. From Greg and I, it's been wonderful having you. Don't forget to join us again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, join authors Steven Lubitz and Associate Editor Mark Link as they discuss the article "Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Huntley, Associate Editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Well, guess what we have for the featured discussion today, Greg. It's about screening for atrial fibrillation in older adults at primary care visits. Very, very important topic. And what we'll be looking at is the vital AF randomized control trial. Ooh, we're going to keep everyone in suspense here as we carry on and discuss today's papers. Can I start?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
Alright. This first paper is about infective endocarditis. Now, we know that cardiac surgery often represents the only treatment option in patients with infective endocarditis. However, infective endocarditis surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. So, authors Dr. Doesnst from Friedrich Schiller University of Jena in Germany, and colleagues, decided to investigate the impact of hemo absorption during infective endocarditis surgery on post-operative organ dysfunction.
This multicenter, randomized, non-blinded controlled trial assigned 288 patients undergoing cardiac surgery for infective endocarditis to hemo absorption, which is integration of cytosorb to the cardiopulmonary bypass or control. The primary outcome was defined as the difference between the mean total postoperative sequential organ failure assessment score, calculated maximally to the ninth postoperative day, and the difference with the basal score. Secondary outcomes were 30 day mortality, durations of mechanical ventilation, basal presser and renal replacement therapy. Cytokines were also measured in the first 50 patients.
Dr. Greg Hundley:
Interesting study, Carolyn. Wow. So, what are the results?
Dr. Carolyn Lam:
Yes, this trial involved a lot of work and results showed, however, that there was a failure to demonstrate a reduction in postoperative organ dysfunction, 30 day mortality, or any of the clinically relevant secondary outcomes through intraoperative hemo absorption. Although hemo absorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcomes.
Dr. Greg Hundley:
Great description, Carolyn. Well, my first paper comes to us from the world of preclinical science. And Carolyn, the ascending thoracic aorta, site of aneurysm formation, is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field, or the cardiac neural crest. Second heart field derives cells, populate areas that coincide with the spatial specificity of thoracic aortopathies that are often associated with aneurysms. And so, this study, led by Dr. Alan Daugherty, from the University of Kentucky. Its purpose was to determine whether and how second heart field derived cells contribute to as sending aortopathies.
Dr. Carolyn Lam:
Wow, an important topic, Greg. What did the authors find?
Dr. Greg Hundley:
Okay. So, Carolyn, first, ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin 2 infused mice. And so, the investigators found several things. First, second heart field derived smooth muscle cells and fibroblasts associate with angiotensin 2 induced aortic pathologies. Second, angiotensin 2 induced a distinct fibroblast sub-cluster that was less abundant for messenger RNAs related to major extracellular components and TGF beta-ligands and receptors, but more abundant for proliferative genes.
Third, TGFBR2 deletion in second heart field derived cells were embryonically lethal, with significant dilatation of the outflow tract in the mice. And finally, second heart field specific deletion of LRP1 led to aortic pathologies in mice, supporting the importance of second heart field derived cells in maintaining ascending aortic wall integrity.
Dr. Carolyn Lam:
Wow. Could you just sum up the clinical implications for us, Greg?
Dr. Greg Hundley:
Well, Carolyn, I knew you were going to ask me that. So, these results indicate that heterogeneity of the embryonic origins of smooth muscle cells and fibroblasts contributes to complex mechanisms of vasculopathy formation, which should be considered when investigating the pathogenesis of thoracic aortopathies.
Dr. Carolyn Lam:
Wow, thanks Greg. Well, my next study is also a translational study, and this one provides a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type one diabetes. So, this is from Dr. Biddinger from Children's Hospital Boston and colleagues. In order to define the mechanisms by which insulin controls plasma cholesterol levels, the authors knocked down the insulin receptor, FOXO1, and the key bioacid synthesis enzyme, CYP8B1, in mice. They measured bioacid composition, cholesterol absorption, and plasma cholesterol. In parallel, they measured markers of cholesterol absorption and synthesis in humans with type one diabetes treated with ezetimibe and statins in a double blind crossover study.
Dr. Greg Hundley:
Oh, wow, Carolyn. So, experiments in both animal models and in human subjects. So, what did they find?
Dr. Carolyn Lam:
Insulin, by inhibiting FOXO1 in the liver, reduces 12 alpha hydroxylated bio acids, reduces cholesterol absorption and reduces plasma cholesterol levels. Thus, type one diabetes leads to a unique set of derangement in cholesterol metabolism with increased absorption rather than increased synthesis. These derangements are reversed by ezetemibe, which is a cholesterol absorption inhibitor, but not simvastatin, which is a cholesterol emphasis inhibitor. So, taken together, these data suggest that a personalized approach to lipid lowering in type one diabetes may be more effective, and highlight the need for further studies specifically in this group of patients.
Dr. Greg Hundley:
Nice, Carolyn. Well, we've got some other really interesting or articles in the issue. And first, from the mail bag, there's a Research Letter from Professor Bers, entitled "Empagliflozin Reverses Late Sodium Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murray Model of Heart Failure with Preserved Ejection Fraction." Carolyn, there's another research letter from Professor Shu entitled, "Activation Of INKY Cells at the Maternal Fetal Interface that Predisposes Offspring to Cardiac Injury." Also, there's a really nice, in depth article entitled, "Takasubo Syndrome Pathophysiology Emerging in Concepts and Clinical Implications." And it's from Dr. Trisha Singh.
Dr. Carolyn Lam:
Nice. We also have an ECG challenge by Dr. Mugnai on “A Tachycardia in Disguise” and a Perspective piece by Dr. Alexander on “Equipoise in Clinical Trials: Enough Uncertainty [but] in Whose Opinion?” Isn't that interesting? Wow, thanks, Greg. Now, though, let's go on to this super exciting feature discussion on screening for atrial fibrillation in older adults' primary care.
Dr. Greg Hundley:
You bet.
Well, listeners, we are here for the feature discussion, now, on this March 29th issue. And we have with us Dr. Steve Lubitz, from Mass General and Boston, and our own associate editor, Dr. Mark Link, from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen.
So, Steve, we're going to start with you. Can you describe for us some of the background information that went into the construct of your study, and then what was the hypothesis that you wanted to address?
Dr. Steven Lubitz:
Sure. Well, thanks for the opportunity to talk with you today about our work. So, as we know, AFib is a common and more bitter arrhythmia. And the first manifestation of AFib can be stroke in a substantial number of individuals. Strokes from atrial fibrillation or debilitating, but they can be prevented using oral anticoagulants if we know who has atrial fibrillation.
But atrial fibrillation can be a symptomatic and it's possible, therefore, that screening pre-AFib could lead to new diagnoses and ultimately improve outcome by enabling stroke prevention. Point of care screening for AFib has been embraced by some guidelines for individuals age 65 or older, such as those in Europe, and mobile technology has now evolved and enables rapid mask screening using handheld ECGs, single lead ECGs, which obviates the need and expense of performing 12-lead ECGs to screen for AFib.
Nevertheless, though, some guidelines have suggested that data are insufficient to recommend screening AFib using ECGs, such as those from the United States Preventative Services Task Force. We tested whether screening individuals age 65 or older at the time of a primary care clinic visit using a single lead ECG would lead to an increased rate of detection of AFib in contemporary United States practices.
Dr. Greg Hundley:
Very nice. And so, maybe describe for us this task force, and also what was your study design and, again, your study population?
Dr. Steven Lubitz:
Sure. So, specifically our study design, we performed a cluster randomized control trial in which primary care practice clinics were randomized to the screening intervention or to usual care, and patients aged 65 or older arriving for a primary care visit with their provider were eligible for participation. Patients were offered screening by practiced medical assistants at the time of their vital sign assessments, and screening was performed, if they consented, within a live core cardio mobile single ECG device, which was affixed to an iPad and stationed in the clinic.
The results of the screening were made available to the providers at the time of the visit, and then the provider was able to make any and all decisions about subsequent management, confirmation or treatment. The primary outcome was a new diagnosis of Afib made in the medical record at one year following the start of the screening intervention, and the outcome was ascertained using the electronic health record and then manually adjudicated. We powered the study to detect a difference of nearly 0.5% in the rate of atrial fibrillation diagnoses at 12 months between the screening and usual care arms.
Dr. Greg Hundley:
And how many patients did you enroll? And then what were your study results?
Dr. Steven Lubitz:
Well, eight practices were randomized to the screening arm and eight practices to the usual care arm. And in total, that equated to about 15000 patients without a history of atrial fibrillation in the screening arm and 15000 patients in the control arm without a history of atrial fibrillation. The mean age was about 74, about 60% were female, 82% were white. And the mean chad-vad score was 3.4.
We observed several main findings. The first is that, of the individuals in the screening arm, 91% were screened at least once. And this is the largest point of care screening study to date. The rate of screening in the intervention arm was substantially greater than any other contemporary trial, point of care, single ECG screening. We think that high rate of compliance with the intervention reflects patient enthusiasm for screening and a widespread feasibility of incorporating single ECGs into the routine vital sign practice workflow.
Secondly, the primary endpoint, however, incidence of new AFib diagnoses at 12 months, was 1.72% in the screening arm, and 1.59% in the usual care arm, which equates to a risk difference of .13%. That was not statistically significant in the overall sample. We observed a substantial difference in new AFib diagnoses among those aged 85 or older in pre-specified subgroup analyses, 5.56% in the screening arm and 3.76% in usual care arm, which corresponds to a risk difference of 1.8%, where a number needed a screen of about 55, raising the possibility that point of care single ECG screening among the oldest and highest risk individuals might be effective. But this finding warrants future study.
Third, we observed a shift in the location of diagnosis. So, they fit with a higher likelihood of diagnosis at a primary care practice encounter in the screening arm, as compared to the usual care arm, which is as expected. And the implications on downstream management pathways, cost of care, other downstream work flows is unknown at the moment.
And lastly, we observed it in anticoagulation use was high, even among those with AFib diagnosed in the screening arm, which is a reassuring finding, suggesting that clinicians recognized that AF detected using this single lead point of care screening is likely to represent high burden, persistent AF that carries a substantial risk of stroke.
Dr. Greg Hundley:
Very nice. Well, Mark, I know you review many papers for us here at Circulation. What attracted you to this particular paper?
Dr. Mark Link:
This issue of point of care screening for AFib is a very hot topic. We all know that clinically diagnosed AFib carries with it a high risk of stroke, but what we don't know is incidentally found Afib, or nonclinically found Afib, what does that mean? This was one of the largest, if not actually the largest, study of point of care screening. And the i-cors are a very accurate device, or reasonably accurate device. So, we thought it's an important contribution to the literature. I think it surprised the authors, as well as us, there wasn't a difference in the diagnosis of AFib between the two arms. I think all of us would've expected to see that. But we're still learning a lot about point of care screening, and we're not to the point where we know what to do yet.
Dr. Greg Hundley:
And Mark, what are some of your thought? Steve raised the point that, in that subgroup, greater than age 85, any additional insights there?
Dr. Mark Link:
Yeah. I think that, if you can enrich your group with people that are more likely to have AFib, and the older you get, the more likely you are to have AFib, you are more likely to find Afib. But then treating people over age 85 also becomes a little bit riskier, with both anticoagulants and antirhythmic drugs and ablation.
Dr. Greg Hundley:
Great points. Well, Steve, coming back to you, what do you see as the next study to be performed, really, in this sphere of research?
Dr. Steven Lubitz:
Thanks. I think I proposed two additional lines of inquiry. At first, I think our hypothesis generating observation to the point of care screening with a single EDCG can lead to higher rates of AFib detection among the oldest individuals, age 85 or older, with a small number needed to screen warrants, replication, and the downstream implications of that on stroke and bleeding merit further evaluation.
I think secondly, given the proliferation of wearable technology, future studies should examine the effectiveness of detecting perccismal atrial fibrillation for preventing downstream adverse events, including stroke. This point of care screening is likely to detect the highest burden persistent forms of atrial fibrillation in contrast to some of the wearable technology, like consumer wearable technology, that might detect paroxysmal atrial fibrillation, more commonly.
Dr. Greg Hundley:
Ah, great point. And Mark, how about you? Anything to add? What future study do you see needs to be performed in this space?
Dr. Mark Link:
It's clear from a number of studies that the longer that you monitor someone, the more likely you are to get a diagnosis of AFib. And that's pretty clear. This was a 30 second monitor. We have a number of studies that have shown two week and ILS monitoring is far more likely to get a diagnosis of AFib. But what we don't know is, if making that diagnosis of AFib makes any difference on ultimate outcomes. That's the studies that we need to see, is does treatment of incidentally found AFib improve clinical care.
Dr. Greg Hundley:
Very good. Well, listeners, we want to thank Dr. Steve Lubitz from Mass General in Boston, and also Dr. Mark Link from UT Southwestern in Dallas, bringing us results from this study indicating that screening for atrial fibrillation using a single lead EKG at a primary care visit did not affect new atrial fibrillation diagnoses among those that were aged 65 years or older. There was, perhaps, a difference in those aged greater than 85 years, but more research is to come in that space. And, of course, looking for peroxisomal AFib with handheld devices is another area you yet to be investigated.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week, On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, join authors Maryjane Farr and Josef Stehlik as they discuss their Perspective article "Heart Xenotransplant: A Door That Is Finally Opening."
Dr. Carolyn Lam:
Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, at VCU Health in Richmond, Virginia.
Dr. Greg Hundley:
Well, Carolyn, this week's feature, very interesting, xenotransplantation, where organs from other species are transplanted into humans. And it's a perspective piece. And so, we're going to get a weighted conversation from two different individuals that have a different perspective on the topic.
Dr. Greg Hundley:
But, before we get to that, how about we grab a cup of coffee, and start with some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
Absolutely, Greg. Although man, that is a big hook you just gave us. Xenotransplantation is seriously, seriously, a hot topic. Can't wait to learn more.
Dr. Carolyn Lam:
But, for this first paper I want to talk about, well, we know that sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing, can identify carriers of pathogenic, or lightly pathogenic, variants. However, to what extent do these variants associate with clinically meaningful phenotypes, and what do we know about variants of uncertain significance?
Dr. Carolyn Lam:
So to answer this question, Dr. Dan Roden, from Vanderbilt University, and his colleagues, looked at 10 arrhythmia susceptibility genes, that were sequenced in more are than 20,000 participants without an indication for arrhythmia genetic testing in the eMERGE III study, which is a multi-center prospective cohort. Variants, previously designated pathogenic, or likely pathogenic, were identified in 120 individuals, or 0.6% population. And electronic health records revealed an over-representation of arrhythmia phenotypes. Some variants of uncertain significance were also found in individuals with arrhythmias and patch clamping, confirmed reclassification, to likely pathogenic.
Dr. Greg Hundley:
Really interesting results from this eMERGE III study, Carolyn. So what's the take home message?
Dr. Carolyn Lam:
As genetic testing becomes more common, the combination of electronic health records and in vitro testing, will help classify variant pathogenicity. Population screening has the potential to identify patients with undiagnosed Mendelian rhythm disorders. However, we need to consider the pros and cons of such an approach. And this is discussed in an accompanying editorial by doctors, Walsh, and Bezzina, and Wilde, from Amsterdam University Medical Center.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my first paper comes to us from Professor Karl Heusler from the University of Wurzburg. Carolyn, this study was a pre-specified analysis of the anticoagulation using the direct factor Xa inhibitor, apixaban, during atrial fibrillation catheter ablation comparison to vitamin K antagonist therapy, or the AXAFA–AFNET 5 trial. And it randomized 674 patients with atrial fibrillation, in a one-to-one fashion, to uninterrupted apixaban, or vitamin K antagonist therapy, prior to first time ablation, with a goal to assess the prevalence of magnetic resonance imaging detected ischemic brain lesions, and their association with cognitive function, three months after first time ablation, using the continuous oral anticoagulation in patients with paroxysmal atrial fibrillation.
Dr. Carolyn Lam:
Huh. Nice. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. They found that brain MRI detected chronic white matter damage, as well as, acute ischemic lesions, were frequently found after first time ablation for paroxysmal atrial fibrillation, using uninterrupted oral anticoagulation. Including, 27.2% of those receiving apixaban, and 24.8% of those receiving the vitamin K antagonists. So Carolyn, no difference there. MRI detected acute ischemic brain lesions were not associated with cognitive function at three months after ablation. And then, Carolyn, the lower Montreal Cognitive Assessment scores, both before and after ablation, were associated with older age only, highlighting the safety of atrial fibrillation ablation on uninterrupted oral anticoagulation.
Dr. Carolyn Lam:
Oh, thank you, Greg. Well, my next paper talks about basilar artery occlusion, which we know is a devastating condition without definitive evidence to guide treatment. Now, while we do know that faster treatment times with endovascular therapy is associated with better outcomes in the anterior circulation of the brain. What about this relationship for basilar artery occlusion? See? So that's the question that this paper sought to answer, and it's led by Dr. Smith from University of Calgary in Alberta, Canada, and colleagues. They used individual level patient data from the Get With The Guidelines-Stroke nationwide US registry, prospectively collected from January 2015 to December 2019, and identified 3015 patients with basilar artery occlusion treated with endovascular therapy.
Dr. Greg Hundley:
Ah, Carolyn. And so what did they find here?
Dr. Carolyn Lam:
So, here are the results. Treatment of basilar artery occlusion with endovascular therapy, within six hours of last known well, is associated with better outcomes, compared to treatment after six hours. Including, lower odds of mortality and higher odds of reperfusion, independence, and discharge home.
Dr. Carolyn Lam:
There was a non-linear association between, faster treatment with endovascular therapy for basilar artery occlusion, and better outcomes, with the greatest per hour improvement in outcomes seen within six hours of the last known well. In summary, results indicate that, faster treatment with endovascular therapy may improve outcomes in basilar artery occlusion. Efforts should therefore be made, to optimize workflow, including pre-hospital, inner-hospital, intra-hospital processes, to achieve rapid treatment with endovascular therapy in acute stroke with basilar artery occlusion.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science. And Carolyn, as we know, pulmonary hypertension can be caused by chronic hypoxia, leading to hyperproliferation of pulmonary arterial smooth muscle cells, and apoptosis-resistant pulmonary microvascular endothelial cells. And then, upon re-exposure to normoxia chronic hypoxia induced pulmonary hypertension in mice, is reversible. So in this study, the authors led by Dr. Christine Veith, from Justus Liebig University in Giessen, aimed to identify novel candidate genes involved in pulmonary vascular remodeling, specifically, in the pulmonary vasculature.
Dr. Carolyn Lam:
Ah, a very interesting and important topic. So what, or how, did they do this, Greg?
Dr. Greg Hundley:
Right, Carolyn. So following a microarray analysis, the investigative team assessed the role of secreted protein, acidic, and rich in cysteine, or SPARC, using lung tissue from idiopathic pulmonary arterial hypertension patients, as well as from chronic hypoxic mice. In this experiment, the mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia, at different time points
Dr. Carolyn Lam:
Okay, so what were the results?
Dr. Greg Hundley:
Okay, Carolyn, the big drum roll. So the microarray analysis of the pulmonary vascular compartment, after laser micro dissection, identified SPARC as one of the genes down-regulated at all reoxygenation time points that were investigated. Intriguingly, SPARC was vice versa, up-regulated in lungs, during development of hypoxia induced pulmonary hypertension in mice, as well as in idiopathic pulmonary hypertension. Although, SPARC plasma levels were not elevated in pulmonary hypertension.
Dr. Greg Hundley:
Transforming growth factor, or TGF-beta 1, or hypoxia induced factor to a signaling pathways, induced SPARC expression in human pulmonary arterial smooth muscle cells. In loss of function studies, SPARC silencing enhanced apoptosis, and reduced proliferation. And so Carolyn, in conclusion, these authors provide evidence for the involvement of SPARC in the pathogenesis of human pulmonary hypertension, and chronic hypoxia induced pulmonary hypertension in mice, most probably, by affecting vascular cell function.
Dr. Carolyn Lam:
Wow. Thanks for that, Greg. Well, let me give a tour of what else there is in today's issue. There's a letter from Dr. Ng on could cardiologists support, improve, the cardiovascular risk of GnRH agonists. There's a Case Series, by Dr. Blumer, on [entitled] Hemophagocytic Lymphohistiocytosis Associated with Endocarditis: A Case Years in the Making.” There's a Perspective piece by Dr. Hillis on [entitled], Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game?”
Dr. Greg Hundley:
And Carolyn, from the mailbag, we have a Research Letter, from Professor McFadyen entitled, Inherited Thrombophilias are Associated with a Higher Risk of COVID-19 Associated Venous Thromboembolism, a Prospective Population Based Cohort Study.
Dr. Greg Hundley:
Well, now onto that perspective and discussion from two viewpoints on xenotransplantation.
Dr. Carolyn Lam:
Xenotransplantation. Cool. Let's go.
Dr. Greg Hundley:
Well welcome everyone, to this feature discussion. And today, we're taking a little bit of a, different tact, and we are going to discuss a perspective piece. As you know, usually we will discuss an original article, but we have a perspective. And we have with us, the two authors that created this perspective. Dr. Jane Farr from UT Southwestern, in Dallas, Texas, and Dr. Josef Stehlik, from University of Utah. Welcome to you both.
Dr. Greg Hundley:
And listeners, our discussion today is on cardiac xenotransplantation, taking a heart from another species and implanting it in a human subject. So Josef, we'll start with you. Could you tell us a little bit about the history of cardiac xenotransplantation, and what are some of the obstacles that have to be overcome, if we're considering performing this procedure in a patient?
Dr. Josef Stehlik:
Greg, thank you for that question. The concept of xenotransplantation has been around for a long time, with the biggest attraction being, a large and ideally safe source of organs for our patients. As far as cardiac xenotransplantation, the first human art xenotransplant was done in 1964, in a man with terminal heart failure, who received a chimpanzee heart at the University of Mississippi.
Dr. Josef Stehlik:
The patient didn't survive the surgery, and the way it was done back then, brought up a number of ethical issues, and other issues as well. And so, the next xenotransplant was not done until 1984, in a neonate with hypoplastic left heart syndrome, at Loma Linda University. You might have heard the term, Baby Fae, before. And this infant survived about 20 days, and so we couldn't consider it, long term success. However, these two first xenotransplant brought up some important issues that would be studied for years to come. And I think, that the biggest lesson was that, the intra-species immune barriers were a formidable obstacle, and that really, new technologies, and then new medications, would probably have to come into the clinical arena, before we could do it again.
Dr. Greg Hundley:
Very nice. Well listeners, now we're going to turn to our second author on this particular paper. And Jane, can you describe some of the circumstances pertaining to this most recent cardiac xenotransplantation? What transpired, and what's been the outcome with that individual?
Dr. Maryjane Farr:
Thanks, Greg. And thanks for having us here on this program today. So the circumstance around this particular groundbreaking transplant was such that, there was a critically ill patient. This man who was in cardiogenic shock. Both sides of his heart were not working. He was on life saving temporary mechanical support with VA ECMO. And he unfortunately, despite his cardiogenic shock, he was not eligible for standard allotransplantation.
Dr. Maryjane Farr:
Part of that story was really about, not meeting standard criteria for organ transplantation, probably just about anywhere, in terms of a long history of, maybe not taking his meds, or taking care of himself. And there's, certain criteria that he didn't fit into. And he actually had been assessed, as I understand it, by a number of programs, before the University of Maryland approached him with this possibility.
Dr. Maryjane Farr:
One other option that could have been taken, was a mechanical circulatory assist device. But as I say, both sides of his heart were not working, and so really, total cardiac replacement was really his only option.
Dr. Greg Hundley:
And so Jane, do we know anything about what happened? How did the surgical procedure go? Do we know anything about the outcomes?
Dr. Maryjane Farr:
This is of course, patient privacy. So what we know is really, what's in the public arena. And it's actually, there's been a lot of transparency, which has been terrific, by the patient, and the family, and the doctors, because this is such groundbreaking information. But this patient was truly critically ill. There was some paperwork done to try to get FDA approval for emergency experimental surgery, with xenotransplantation. And of course, all the research at University of Maryland, and in many other centers, nationally, and internationally, have been done over the years. And so finally, there was an approval to do this, and it was basically a scheduled surgery.
Dr. Maryjane Farr:
And as I understand it, it went just like any other transplant surgery. There was obviously, a procurement team for the genetically modified pig. There was cold storage of the device. Transport, at least as far as to the next operating room, or however it went. And then, standard implantation, and release of cross clamp, and perfusion. And at least by what you can read about, the heart started to work almost immediately. And then of course, I think that's the easy part. It was really all the intense and multi blockade immunosuppressive therapy, which is really, the challenge of this type of therapy.
Dr. Greg Hundley:
Very nice. Well, Josef, Jane's alluded to this a little bit, but who would be a candidate for this therapeutic, this form of therapy?
Dr. Josef Stehlik:
Greg, so that's an excellent question. And I would like to address it. Before I do that, maybe we should also mention, very briefly, a little bit of the science behind the genetically engineered pig, that Jane mentioned.
Dr. Josef Stehlik:
There were three main things that have been done, and what enabled that is gene editing. And here, I would like to actually mention Dr. Mario Capecchi, who received a Nobel Prize in 2007, for his groundbreaking work at the University of Utah, by describing mouse gene knockout. That has been part of what has been used for engineering, of course, in newer approaches, like CRISPR.
Dr. Josef Stehlik:
Some of the things that have been done is that, the highly antigenic carbohydrates that pigs have on their cell surface, have been edited out. There have been genes that have been edited out and in, connected to coagulation and compliment, to prevent clotting and bleeding in the organ and the recipient after transplant.
Dr. Josef Stehlik:
And of course, one thing that it's very relevant also to our COVID pandemic, there has always, with xenotransplantation, been a question. Could there be trans-species infection? And pigs do have endogenous retroviruses that are parts of their genome, and those have been edited out as well. And so in this way, some of the previous obstacles have been removed.
Dr. Josef Stehlik:
So to your question, who might be a candidate? And I absolutely agree with Jane, that in the first step, it should really be patients who are not candidates for other clinically approved approaches, like allotransplantation from human donors, or mechanical assist, that can be durable, and those are the characteristics that the patient met. And I think, the next patients that will come now, hopefully, will probably be in the same category.
Dr. Josef Stehlik:
Now, I believe, and again, this is a little bit of a speculation, that the next step will be patients who are not eligible for transplant, but who may be eligible for durable ventricular assist devices. And our goal will be to show, that survival and quality of life after xenotransplantation can approach survival and quality of life, on LVADs. And of course, LVADs are evolving, as well.
Dr. Josef Stehlik:
And then, to some degree, it might be the choice of the recommendation of the team, of the multidisciplinary team. What is the best match for the patient? And to some degree, I think patient preference, to really share decision making in patient preference.
Dr. Josef Stehlik:
And in the next step, I believe, that's what we are hoping for, that at some point, we will achieve is that, xenotransplant will rival the outcomes of human allotransplantation. And so, that will be probably, the next group of patients. How long this will take is to be seen. But I think, that it addresses your question, who could be the candidates for xenotransplant in the future?
Dr. Greg Hundley:
Very good. And Jane, Josef was touching on a topic here. How do the anti-rejection treatments differ in xenotransplantation, as compared to allograft transplantation?
Dr. Maryjane Farr:
And so, that's been the thing for all these decades. And so, the first thing is, genetically engineered xenotransplant organs, that can mitigate some of the anticipated xenoantigenic responses.
Dr. Maryjane Farr:
So first, these carbohydrates that we do not see, so they are foreign to us, so there can be acute fulminant rejection. So that's, one step, and the gene knockout can take care of that mostly, but not completely. And then there's humeral rejection, and then, cellular rejection.
Dr. Maryjane Farr:
The cocktail that gets put together for a xenotransplant includes, some of the things that we standardly use, like steroids, ATGAM, or antithymocyte globulin, which is a generalized T and B-cell depleting therapy. What's nuanced, and there's also some role for anti-CD20 B-cell therapy, but what it is nuanced in xenotransplant is anti-CD40 monoclonal antibody therapy. And that was specifically developed, and then studied in heterotopics, or non-human primate pig transplant. Because what turns out is that, the robust T-cell responses, by what's called the indirect pathway, really requires significant costimulatory blockade, where anti-CD40 therapy has been critically important, and well studied by these scientists and others at the University of Maryland, and elsewhere.
Dr. Maryjane Farr:
And as I understand it, anti-CD40 was really, is the basis, the backbone, of this therapy. And then there's one last thing. And that is, temsirolimus, which is a pro drug of proliferation signal inhibitor therapy, that we standardly use in transplant. That's utilized to arrest the further growth of the xenotransplant. So that sounds like it's the cocktail, and there's some published reports, on these scientists using just such cocktail in their non-human primate transplant models.
Dr. Greg Hundley:
Well, listeners, we've heard a really interesting story here. But now, let's ask these experts, first, Josef, and then, Jane. Josef, moving forward, what are the concerns that you really see in this aspect of research?
Dr. Josef Stehlik:
Greg, I think, one of the issues that will have to be addressed, are ethical considerations. And we've seen, that after the news of xenotransplant was made public, there has been a lot of discussion among public about ethics of xenotransplant. I think it will be important to really proactively address that.
Dr. Josef Stehlik:
One aspect from the past is, we knew that primate xenotransplant have not been embraced by the public, just because of the closeness of primates to humans. I think, some of that will be mitigated, now that we are using pigs. But of course, there are many who feel strongly about humane treatment of animals. And so I think, regulation will need to be established that will address that, and that will make both the professionals and the wary public, comfortable with this approach.
Dr. Josef Stehlik:
And another thing that will need to be addressed, and Jane talked about it a little bit is, what parts of care for xenotransplant will be different from human allotransplant. Right? So how do the assessment of the biopsies differ? Right? We'll probably have a new grading scheme looking at xenotransplant. Should the antimicrobial prophylaxis be different? So we do prevent the possibility of trans-species infections we haven't seen before, et cetera. So there would be a lot of work for the transplant teams to do, as well.
Dr. Greg Hundley:
And, Jane.
Dr. Maryjane Farr:
Yes. One thing that's hard, this is amazing science, and this is a huge opportunity to transplant more patients, many of whom die on the wait list every year. But what really needs to be understood also, as we move into this area, and this is where us, as clinicians, get involved in some of these conversations in particular, is that this patient actually wasn't eligible for transplant. And these are very, very difficult decisions that centers are tasked to make.
Dr. Maryjane Farr:
It can get really tricky, and there's lots of patients who say, "Okay, I'm not a transplant candidate.", because of this or that, or the other reason. And there's, some reasons that are more important than others. They'll say, "Transplant me anyway. Give me a heart that you might turn down. Just give me a chance." And we don't do that. And insurance companies don't pay for that. And we have to actually find a way to be rational in our approach.
Dr. Maryjane Farr:
But truly, acknowledging that, if we had more resources, we could probably expand transplant even with the organs that we do have, because we turn down about, probably about 40% of organs, and maybe even more, every year, because we want to match the best organs. So it's really important that xenotransplant, in centers that can do this, demonstrate that this therapy works, and it provides a good quality and quantity of life, for at least, to be reasonable. And once you get there, then you can start to talk about, whether you need to think about allocation, and all that. So you can see how the conversation's going to go on for the next 10 years, about how this fits in.
Dr. Greg Hundley:
You both alluded to the fact, we need more research. And so, incrementally, for maybe each of you in 30 seconds. What do you see as the next research study that needs to be performed in this space? First, Josef, and then again, Jane.
Dr. Josef Stehlik:
That's a tough question, but I'll try to address it. I think, it will be a little bit in parallel to the first human allotransplant. Now that we've figured out the procedure and the organ that we can use, I think, it will be research focused on the care of the transplant recipient. And the task, number one, will be to identify immunosuppression that will be safe and effective, to protect this heart from dysfunction for many years after transplant.
Dr. Greg Hundley:
And Jane?
Dr. Maryjane Farr:
Yeah. You need to do a case series. The handful of centers in this country, and maybe the world, but I only know about this country, that have been studying and working towards this day, should take the lead. University of Maryland has taken the lead, and there are other centers who have been thinking hard about this, and preparing for this time for a long time, and they should lead the way, and try to do this with all the expertise that they've already built. And then as time passes, we can see what their outcomes are, and then we can start to think about, should there be a randomized controlled clinical trial? What should we compare it against? Who should be offered the opportunity? But at first, we need to find that there's safety and efficacy in the patients that are selected, and also, they themselves select, to go through this operation and therapy.
Dr. Greg Hundley:
Well listeners, we want to thank Dr. Jane Farr and Dr. Josef Stehlik, for providing their perspective on a recent procedure, involving the xenotransplantation of a genetically engineered porcine heart, into a human subject with advanced biventricular heart failure, that was not well suited for human heart allograft transplantation.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily, those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.
This week, join author Tristram Bahnson and Associate Editor Changsheng Ma as they discuss the article "Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results from the CABANA Trial."
Dr. Carolyn Lam:
Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Guess what, Greg? For today's feature paper, we are going to be looking at a very interesting analysis from the CABANA trial, this time, looking at the association between age and outcomes of catheter ablation versus medical therapy for atrial fibrillation. Cool, huh? Okay, but first, let's go through some other important papers in today's issue. Why don't I let you go first?
Dr. Greg Hundley:
Well, Carolyn, my first paper pertains to the cost effectiveness of coronary artery bypass surgery, and it comes to us from the STICH trial.
Dr. Carolyn Lam:
Ah, very important question, but please remind us what the STICH trial is again.
Dr. Greg Hundley:
Right, Carolyn. So the Surgical Treatment for Ischemic Heart Failure trial, or STICH demonstrated that coronary artery bypass grafting reduced all-cause mortality rates out to 10 years compared with medical therapy alone in patients with ischemic cardiomyopathy and reduced left ventricular function, defined as an ejection fraction of less than or equal to 35%. Now in this study, the authors led by Dr. Derek Chew at University of Calgary examined the economic implications of these results using a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG versus medical therapy alone, using patient-level resource use and clinical data collected from the STICH trial.
Dr. Carolyn Lam:
Again, really important study. And what did they find?
Dr. Greg Hundley:
Right, Carolyn. So first, using their patient-level simulation model incorporating resource use and clinical data collected from the STICH trial, they found that coronary artery bypass grafting was estimated to cost $63,989 per quality-adjusted life year gain compared to medical therapy alone. Second, in STICH eligible patients with left ventricular ejection fraction of less than 35% in coronary artery disease amenable to CABG, routine use of CABG increased the quality-adjusted life expectancy compared to medical therapy alone for an increased cost within current benchmarks for good value in healthcare within the United States. Then finally, Carolyn, together with the improved clinical outcomes seen in the 10 year extended follow-up of STICH, the findings in this study provide additional economic support for the use of coronary artery bypass grafting in patients with ischemic cardiomyopathy eligible for STICH.
Dr. Carolyn Lam:
Wow, thanks Greg. Well, this next study contributes to the understanding of the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease. Interesting? Well, listen up. This is from Dr. deVries from UT Health Science Center at Houston and colleagues who aimed to quantify remaining lifetime risk and years free of coronary heart disease according to polygenic risk and the AHA's Life's Simple 7 guidelines in the population base cohort of ARIC. As a reminder, the Life's Simple 7 by the AHA consists of smoking status, body weight, total cholesterol, blood glucose, blood pressure, physical activity, and diet.
Dr. Greg Hundley:
Ah, Carolyn. So genes versus lifestyle. So what did they find?
Dr. Carolyn Lam:
Participants with high polygenic risk may offset their lifetime risk of coronary heart disease by up to 50% through managing their health according to the Life's Simple 7's recommendations, depending on ancestry. Individuals with high polygenic risk scores and ideal Life's Simple 7 scores had 4.5 to 20 more coronary heart disease free years than individuals with high polygenic risk scores, but low Life's Simple 7 scores and again, depending on ancestry. Appropriate management of lifestyle and clinical risk factors of coronary heart disease play larger roles in the overall lifetime risk of coronary heart disease than presently available genetic information. Thus, communicating the effects of Life's Simple 7 measures and polygenic risk on coronary heart disease in terms of absolute risk may have important implications for education, policy, and environmental changes, which can benefit not only high risk individuals, but the whole population.
Dr. Greg Hundley:
Wow, Carolyn, really informative study and so nicely summarized. So Carolyn, my next paper comes to us from the world of preclinical science and it's from Professor Yan from Shanghai, Ruijin University School of Medicine. So Carolyn, previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure. However, the underlying mechanisms often remain unclear. Now since kinases have been reported to modulate mitochondrial function team investigated the effects of dual specificity tyrosine regulate kinase one B on mitochondrial, bio energetics, cardiac hypertrophy, and heart failure.
Dr. Carolyn Lam:
Wow. Okay. So what did they find Greg?
Dr. Greg Hundley:
Right, Carolyn. So this team found that Dual Specificity Tyrosine-Regulated Kinase 1B, our DYRK1B expression was clearly up regulated in failing human myocardium as well as in hypertrophic mirroring hearts and cardiac specific DYRK1B over expression resulted in cardiac dysfunction, accompanied by a decline in the left ventricular ejection fraction, as well as the fraction shortening. And it increased left ventricular myocardial fibrosis. Carolyn in striking contrast to DYRK1B over expression, the deletion of DYRK1B mitigated tack-induced cardiac hypertrophy and heart failure. In addition, the authors found that DYRK1B was positively associated with impaired mitochondrial bio-energetics by directly binding with stat three to increase its phosphorylation and nuclear accumulation. Thereby ultimately contributing toward the down regulation of PG C one alpha. Now, furthermore, the inhibition of DYRK1B or stat three activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bio-energetics.
Dr. Carolyn Lam:
Cool, Greg. So could you give us a take home?
Dr. Greg Hundley:
Right. So in summary then, Carolyn, taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1 beta in mitochondrial bio-energetics and the progression of cardiac hypertrophy in heart failure.
Dr. Carolyn Lam:
Fantastic. Thanks, Greg. Well, other papers in today's issue include an exchange of letters between Doctors Nie and Wollert on the article myeloid derived growth factor protects against pressure overload induced heart failure by preserving sarcoplasmic reticulum calcium, ATPase expression in cardiomyocytes. There's an AHA update [AHA Advocacy Page] paper by Dr. Churchwell on improving heart health through value-based payment. An ECG Challenge by Dr. Murphy on a “Curious ECG Morphology of a Cardiac Device.” An On My Mind paper by Dr. Figtree on “Sublingual Nitrates for Patients as a Default in the Post ACS Discharge Pack. Is the Time for a Rethink?”
Dr. Greg Hundley:
Right? Carolyn. Boy, this issue is really packed with great articles. There's a Perspective piece from Professor Stewart entitled “Myocardial Edema Provides A Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.” There's a wonderful Frontiers in medicine piece from Professor Kandzari entitled “A Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document from the Hypertension Academic Research Consortium.” And then finally, Carolyn, there's a Research Letter from Professor Wold entitled “E-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice. Well, Carolyn, how about we get onto those results from the CABANA trial?”
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Greg Hundley:
Well, listeners, we are now here for our feature discussion and we have with us today, Dr. Tristram Bahnson from Duke University and one of our own Associate Editors, Dr. Changsheng Ma from Beijing. Welcome gentlemen. Tristram, we will start with you first. Could you describe for us some of the background pertaining to this particular research study and what was the hypothesis that you wanted to address?
Dr. Tristram Bahnson:
Sure. Being an active electrophysiologist, a challenge we've had over the years is to try to figure out for whom catheter ablation would be a preferred therapy. I've had the privilege of being part of the CABANA study team over the last several years. As listeners might recall, the CABANA trial was a very large trial looking specifically at hard endpoints, including mortality, to try to determine whether or not catheter ablation provides significant benefits to patient. Apart from what we already knew over the years, which is the catheter ablation was more effective than drug therapy to reduce AFib recurrences. That study, the CABANA proper study was published in 2019.
Dr. Tristram Bahnson:
In the course of that study, pre-specified subgroup analyses were done initially reporting unadjusted outcomes for important clinically relevant subgroups. We found in that initial study that patients with heart failure, minorities, and patients of young age in particular appeared to do better with catheter ablation than with drug therapy. So with that as background, the CABANA study team embarked to focus on each of those subgroups and the heart failure paper was published in 2021, the minorities paper also in 2021 and the subject of our discussion now, the relationship between age and outcome in the CABANA study cohort is a subject of study today.
Dr. Greg Hundley:
Describe just quickly Tristram the hypothesis you wanted to test here and then in order to test that hypothesis, what was the study population that you included and what was your study design?
Dr. Tristram Bahnson:
So the focus was on the relationship between age and outcome in CABANA, and this was pre-specified substudy of the CABANA population. So it's probably worthwhile going over who got into the CABANA trial and to remind folks the CABANA trial enrolled 2,204 patients across 126 sites at 10 countries and randomized them one to one to a treatment strategy of either catheter ablation or drug therapy for simple traumatic atrial fibrillation that in the judgment of the treating physicians warranted therapy, patients had to have had at least two episodes of PAF or one episode of persistent AFib documented by ECG or ambulatory recordings within the six months prior to enrollment and they hadn't have failed more than one anuric drug. In other words, they would have to have been reasonable candidates for drug therapy, should they be so randomized.
Dr. Tristram Bahnson:
In addition, patients that were less than 65 years of age, had to have some additional factors that would increase the likelihood that outcome events would occur. They had to have a CHADSVASC score greater than one. That was not required of the older subjects follow up was 48 and a half months for the population at large, with the interportal range of follow up between 30 and 62 months. The patients had regular follow up every three months for the first year and then six months thereafter. In addition, 1,240 patients received a recording device that allowed them to provide either prescribed episodic recordings or recordings for when they were symptomatic and they also provided 96 hour holters every six months throughout the duration of the trial.
Dr. Tristram Bahnson:
So that's the population that we were working with. The study design, as I said, focused on trying to tease out the relationship between age and outcomes and the primary outcomes of the CABANA trial included the primary outcome, which was a composite. It included all cause mortality, disabling, stroke, serious bleeding or cardiac arrest, and the key secondary endpoints that were looked at included mortality and cardiovascular hospitalization and AF recurrence.
Dr. Greg Hundley:
Very nice. Describe for us your results.
Dr. Tristram Bahnson:
So we actually took a deeper dive into the subgroup of age, and we did a couple things that we thought would be valuable. One was to consider age as a continuous variable because after all, it's pretty arbitrary to bin people into age groups. I think the initial analysis did so with the CABANA proper publication in 2019 to correspond with the break points that we use for CHADSVASC scoring, but we elected to consider age as a continuous variable and we also elected to do adjusted Cox proportional hazard models to account for the various clinical factors that of course varied with age, such as their CHADSVASC score, the occurrence of structural heart disease, like valvular heart disease or coronary disease, the proportion of women, which typically increases with age and did so in this population. The key endpoints that we examined were the CABANA endpoints, including the primary composite endpoint of total mortality, mortality, or CB hospitalization and AF recurrence.
Dr. Tristram Bahnson:
So at the end of the day, we had 766 patients who were less than 65, 1,130 that were between 65 and 74 and 308 that were greater than 75. Mind you, CABANA admitted patients with any kind of AFib. As a matter of fact, more than half of the study population had persistent or longstanding persistent atrial fibrillation, which is not typical of many studies that have been published, looking at the relative benefits of catheter ablation. We had an unexpected finding that was hinted at, at the initial CABANA study and that was the benefit of catheter ablation was greatest in the younger patients and the benefits of catheter ablation relative to drug therapy seemed to decrease with advancing age at enrollment, which was the age criterion that we based the analysis this on and that this effect was primarily driven by changes in mortality.
Dr. Tristram Bahnson:
For the composite endpoint in CABANA, which was total mortality, serious stroke, serious bleeding and cardiac arrest, we saw that the adjusted hazard ratio increased average of 27% for every decade in advancing age, where the age was defined as that at enrollment, and for the total mortality endpoint, the adjusted hazard ratio increased an average of 46% for every 10 year increment in age at enrollment. For all age groups, catheter ablation was superior to drug therapy, a relative to a reduction in AFib consistent with many other studies. The benefit was a reduction in the adjusted hazard ratio of about 50%. So catheter ablation was agnostic to age in terms of the benefit of reducing AFib, but was not agnostic to age with result to these mortality inclusive endpoints. We did notice that there was a trend towards a relative benefit of drug therapy for the oldest age group, but we interpreted that result with caution for a variety of reasons. The oldest age group was least well represented and comprised less than 10% of the CABANA population and less than half of the next best well represented age group, which was the less than 65's.
Dr. Tristram Bahnson:
In looking carefully at the data, we could find no plausible explanation for why the older age group might do better with drug therapy. Again, it was not significant by an intention to treat analysis, but there was a trend towards drug therapy getting better with the oldest age group. We noticed that there was no excess mortality in the old age group within six months of treatment, so it didn't seem like it was related to some adverse procedural effect. We saw no evidence of more advanced forms of AFib in the oldest age group, because they had as good AFib suppression as others, and had the same distribution of paroxysmal versus persistent forms of AFib as the other age groups. There was no difference in crossover after all, if more patients in the old age group crossed over from drug to ablation therapy, who might expect that to be a confounder.
Dr. Tristram Bahnson:
We did see something that was very unusual and unexpected, which is that the mortality of the oldest age group treated with drugs was actually less than their mortality in catheter ablation, which is the issue at hand, but also less than the other age groups, which was unexpected and even less than all but the youngest age group treated with catheter ablation. So we can't explain this finding. It was not statistically significant. At the end of the day, we don't believe that elderly patients who have drug refractory AFib that is symptomatic should be denied ablation.
Dr. Greg Hundley:
Well, thank you so much, Tristram, for these very intriguing results. Changsheng, you have many papers that come across your desk. What drew you to this particular paper?
Dr. Changsheng Ma:
Yes. Dr. Bunch and colleagues should be commanded for the understand and taking important subgroup analysis of CABANA study. There has also been interest in whether the risk and the benefit of ablation may be modulated by patient age. The current analysis suggests that the related benefit of ablation was characterized for those less than 65 years of age are a tiny bit by the increasing age. It is important to emphasize that the current analysis result should not be interpreted to suggest that the cancer ablation has less value in idly patients. As a casual ablation must treated before recurrence across all age groups.
Dr. Changsheng Ma:
The current analysis is assuming we should know age related increase in safety constant in patients and taking ablation therapy. So we must be cautious not to over incorporate the result of the sub-group analysis, especially in the context of CABANA trial, treating in the permanent effect of ITT analysis. So I think it can be a possible that reach age related gradings in the relatively treatment benefits of the ablation is finding a challenge. Secondly, the CABANA trial was not a oral subgroup analysis. So the variation of treatment effect across the different age group were in the further resource. That's my opinion.
Dr. Greg Hundley:
Thank you very much. Well, gentlemen, what do you see is the next study that needs to be performed in this sphere of research and Tristram, we'll start with you.
Dr. Tristram Bahnson:
Well, clearly the clinical task at hand, for those of us who treat patients is to advise patients about relative benefits of therapy when there are choices at hand. And in the case of atrial fibrillation, the fundamental choice obviously is whether or not to pursue catheter ablation or to pursue medical therapy, either for rhythm or rate control. An important part of that decision making is to understand which patients would derive the most benefit from one versus the other therapy. And that need is perhaps the genesis of why we embarked on these subgroup analysis, which admittedly need to be interpreted with caution are not powered to give definitive results, but can certainly help guide future research. So we have noted in the CABANA trial that heart failure patients might do better and that's consistent with other studies looking specifically at heart failure with reduced ejection fraction. So we're contemplating additional studies to help tease that population out since in CABANA, in particular, our heart failure population was mostly those with a preserved ejection fraction and clinical heart failure.
Dr. Tristram Bahnson:
With regard to age, I think it'll be important to do studies to try to understand what factors resulted in the young patients apparently doing better with ablation. Again, this is hypothesis generating in terms of our result with this paper. So it'd be very interesting to find out whether there are some subsets of patients with younger ages or patients who have the relevant characteristics of the young age patients who would derive particular benefit from catheter ablation. This would obviously require a variety of approaches, including prospective randomized studies and carefully done population studies. So this issue about which patients really derive a significant mortality benefit it from catheter ablation is an important one that has not yet been teased out completely.
Dr. Greg Hundley:
Thank you. And Changsheng, do you have anything to add?
Dr. Changsheng Ma:
Yes. I think two streams say it's a very important topic for, you know, who have more and more, the older patients. So we need to answer the question, how about the real influence of age on the outcomes of the atrial fibrillation patients with ablation. So in future, we should consider randomized trial, but I think it's very difficult. So maybe we have to wait more and more, you know, other study to have a trend, how about the outcome for all the patients. It becomes too difficult for a new randomizedtrial.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Tristram Bahnson from Duke University and Dr. Changsheng Ma from Beijing for bringing us the results from this substudy of the CABANA trial indicating that the mortality related benefits of catheter ablation for atrial fibrillation appeared to decrease for every 10 year increment in age, above the age of 65 years. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for please visit ahajournals.org.
This week, join author Marco Valgimigli and Associate Editor Mark Link as they discuss the original research article "Amulet or Watchman Device for Percutaneous Left Atrial Appendage Closure: Primary Results of the SWISS-APERO Randomized Clinical Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage fast as a journal and editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, Associate Editor, Director of Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I've got a personal interest in this feature paper that's coming up. I've always been very intrigued with the left atrial appendant closure. Well guess what? This is the results of the Swiss-Apero Randomized Clinical Trial, comparing the Amulet with the Watchman device for percutaneous left atrial appendage closure, really interesting stuff coming right up, but let's hold everyone in suspense. As we go through some of the other favorite papers in today's issue. Would you like to go first?
Dr. Greg Hundley:
You bet Carolyn, this first paper really pertains to driving restrictions and earlier arrhythmia is in patients receiving a secondary prevention, implantable cardioverter defibrillator, and it comes to us from Dr. Christian Steinberg. So Carolyn, regulatory authorities of most industrialized countries recommend six months of private driving restriction after implantation of a secondary prevention ICD and these driving restrictions result in significant inconvenience in social implications. And so Carolyn, the purpose of this study was to assess the instance rate of appropriate device therapies in contemporary recipients of a secondary prevention ICD using a retrospective across three Canadian tertiary care centers enrolling 721 consecutive patients with new secondary prevention ICD implants between the years of 2016 and 2020. And they were followed for a median of 760 days.
Dr. Carolyn Lam:
Nice. An important question. So what did they find Greg?
Dr. Greg Hundley:
Right Carolyn. So they found that the cumulative incidents of arrhythmic syncope resulting in sudden cardiac incapacitation was 1.8% within the first 90 days, and subsequently dropped to 0.4% between 91 and 180 days after ICD insertion. So Carolyn the incidence rate of appropriate therapies resulting in sudden cardiac incapacitation in contemporary recipients of a secondary prevention ICD is much lower than previously reported and significantly declines after the first three months, lowering driving restrictions to months after the index cardiac event seems safe and revision of the existing guidelines should be considered in countries still adhering to a six month period.
Dr. Carolyn Lam:
Oh, love it Greg. Elegant study with clinically impactful results as with the next paper, I'm going to talk about a post talk analysis of the Danish trial in which authors led by Dr. Boas from Denmark and Dr. Bower from Austria and their colleagues. And what they did is they tested whether periodic repolarization dynamics or P R D, which is a marker of repolarization instability associated with increased sympathetic activity. Could indeed identify patients with non-ischemic cardiomyopathy that may benefit from prophylactic ICD implantation. So, 748 patients were included in this P R D sub-study. And they were included if they had a 24 hour whole term monitor recording at baseline with technically acceptable ECG signals during the night hours. P R D as a reminder of periodic repolarization dynamics was assessed using wavelet analysis according to previously validated models.
Dr. Greg Hundley:
Very interesting, Carolyn. So what did they find?
Dr. Carolyn Lam:
Periodic repolarization dynamics was independently associated with mortality. More over P R D was significantly associated with mortality in the control group, but not in the ICD group in this Danish trial. There was a significant interaction between P R D and effect of ICD implantation on mortality, such that patients with higher P R D had greater benefit in terms of mortality reduction with the ICD. Based on P R D the investigators could identify a new group of patients where prophylactic ICD implantation was associated with a significant absolute mortality reduction of 17.5% after eight years corresponding to a number needed to treat of only six. So this is the first sub-study of Danish to identify a marker on top of age, that can predict the treatment effect of prophylactic ICD implantation in patients with nonischemic cardiomyopathy.
Dr. Greg Hundley:
Very nice Carolyn. Well, my next paper comes to us from Dr. Kory Levine from the Washington University School of Medicine. And Carolyn recent studies have established that cc chemokine receptor type two are CCR2 marks the pro inflammatory subsets of monocytes, macrophages and dendritic cells that contribute to adverse left ventricular remodeling and heart failure progression. Now elucidation of the effector mechanisms that mediate adverse effects of CCR2 plus monocytes, macrophages and dendritic cells could yield important insights into therapeutic strategies to suppress myocardial inflammation.
Dr. Carolyn Lam:
Hmm, indeed. And so what did these author determine regarding the suppression of myocardial inflammation?
Dr. Greg Hundley:
So Carolyn this team utilized mouse models of re perfused myocardial infarction, and angiotensin two and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate cc chemokine ligand 17. They found that cc chemokine ligand 17 serves as a pro-inflammatory mediator of CCR2 macrophages and dendritic cells, and their results suggest that inhibition of cc chemokine ligand 17 may serve as an effective strategy to promote T-cell regulation recruitment, and thereby suppress myocardial inflammation.
Dr. Carolyn Lam:
Wow, thanks, Greg. That was beautifully summarized great stuff. Well, there are other exciting articles in today's issue. There's an exchange of letters between Doctors Nagareddy and Spear on “Interleukin One Alpha as a Central Regulator of Leukocyte Endothelial Adhesion in Myocardial Infarction and Chronic Kidney Disease. There's an ECG challenge by Dr. Yang entitled, “A Fatal Case of Y QRS tachycardia following Sintilimab treatment for lung cancer. It can happen.” There's an On My Mind paper by Dr. Faed on “CYP2C19 Genotyping in Anticoagulated Patients Post PCI: Should it be Routine?”
Dr. Greg Hundley:
Great, Carolyn and I've got a Research Letter from Professor Poo entitled “Efficient in Vivo Hemology- Directed Repair within Cardiomyocytes.” Well, how about we get onto that feature, discuss and learn more about Watchman devices and left atrial appendage closure.
Dr. Carolyn Lam:
Ooh, let's go.
Dr. Greg Hundley:
Well, listeners. Now we are onto the feature discussion today, and we're so privileged to have with us, Dr. Marco Valgimigli from Bern, Switzerland and our own Associate Editor, Dr. Mark Link from UT Southwestern. Welcome gentlemen. Well, Marco, we will start with you. Can you describe for us a little bit of the background material as to why you wanted to perform this study and what was the hypothesis that you wanted to address?
Dr. Marco Valgimigli:
But thank you so much for having me left atrial appendage closure is a therapeutic option for a patient who have formal indication to oral anti-population because of atrial fibrillation yet have some relative or absolutely contraindication to the treatment because mainly of high bleeding risk features, mainly because of previous bleeding complications. The two most frequently use device to accomplish that procedure are from one side Watchman, which is FDA approved. And on the other hand, the Amulet, which has been historically the device, which has been most frequently used in Europe, these two devices have been formally compared in one head to head study, which is Amulet IDE and also reported in the journal some month ago. However, it was important also to compare the new Watchman iteration, which the Watchman Flex, which was not part of the original Amulet IED, which only compared Amulet with Watchman 2.5.
Dr. Marco Valgimigli:
Before we set up this multicenter study, which recruited patients across eight centers and four European countries, we roughly screened 450 patients. And we ended up randomizing 222 to either of these two device being Amulet or Watchman. We set up this study to answer a superiority hypothesis, actually, of Amulet versus Watchman and we assume that Amulet would be superior compared to Watchman with the respect to the need for crossover to a known randomly allocated device or LA Patency at 45 day SCCTA.
Dr. Greg Hundley:
Very nice Marco. And so now describe for us your study design. And then what was your study population?
Dr. Marco Valgimigli:
That was an investigate initiated and conducted multicenter study, which took place across eight centers in four European countries. We screened roughly 450 patients to be able to randomize. Finally, 222 were evenly allocated to either of these two device. We selected patients with either fibrillation and form lead for oral anti-regulation to with relatively high chat box score on average four and very high has bled at least three or greater. In fact, 95% of our patient had prior bleeding before being considered for the study.
Dr. Greg Hundley:
Very good. And describe for us your results.
Dr. Marco Valgimigli:
So the superiority that we assumed was actually not met. The primary point, which was again, crossover to a known allocated device or patency rate at 45 day SCCTA was pretty much similar with rates being 68% in the Watchman group and 70% in the Amulet group. So basically no real difference. We did see though some interesting differences with respect to some key secondary endpoints.
Dr. Greg Hundley:
And describe those.
Dr. Marco Valgimigli:
So for example, the type of leaks that was recorded was actually different with respect to the two devices with intra device leaks, being much more frequent with Amulet and peri device leak, being much more frequent with Watchman. Also the rate of any or major procedure complications were slightly yet significantly higher in the Amulet group. And interestingly as well, we had some minor differences with respect to the device related thrombosis, which was numerically slightly higher in Watchman as compared to Amulet also, we performed at 45 day TEE, Transesophageal Echo and with that respect, we did see a slightly, yet numerically and significantly higher rate of peri device leak, detected at Transesophageal Echo with Watchman as compared to Amulet, which is in a way reflecting our SCCTA findings.
Dr. Greg Hundley:
Very nice. And so lots of results comparing these two devices for a left atrial appendage closure. So Mark, you see many papers come across your desk. What attracted you to this particular paper?
Dr. Mark Link:
Yeah, this is a very important clinical paper. The left atrial occlusion devices are going to continue to be used and with increasing frequency and there can be very beneficial. The Amulet is not approved in the United States. And so comparison between Watchmen and the Amulet are very important, both for the US and for Europe and the rest of the world. And that's why we were attracted to this paper, it's a nice randomized paper comparing the two most commonly use devices.
Dr. Greg Hundley:
Help us put the results of this study into the context in really how we might manage patients and how we're considering these devices, both from the European perspective and then also here in the US.
Dr. Mark Link:
I think what this study shows is that they're more or less equivalent and there may be theoretical reasons why one may be better than the other, but in this trial it didn't really come out. So I think the Amulet used more in Europe. The Watchman is used exclusively here, but I think this opens a window for the Amulet to come to America also and be approved by the FDA.
Dr. Greg Hundley:
Very good, well, coming back to you, Marco, where do you see is the next study that needs to be performed in this arena of research?
Dr. Marco Valgimigli:
I think now we have relatively effective device in accomplishing what we would like to accomplish. Namely sitting the LAA for preventing subsequent thromboembolic events. However, the procedure despite operators have been growing in terms of interest and experience is still associated with some degree of complications. Some of them are minor, but some of them are not. I think the next future, we should try to minimize those complication to the lowest possible event so that this procedure can potentially be also offered to a broader patient population, perhaps not just as a replacement of oral anticoagulation, but perhaps in association with oral anticoagulation to further minimize the stroke and other thrombotic events.
Dr. Greg Hundley:
And Mark, do you have anything to add here?
Dr. Mark Link:
Yes. I think what we need more information on is two things. One is procedural complications, procedural complications were higher with the Amulet device. And is that because it was a newer device and people are just learning how to use it, or is there something there that's really important? So that's one and then the really important one is long term clinical outcomes. This was a relatively short term trial when you're talking about strokes and anticoagulation. And so what I'd like to see is longer term follow up with both devices in the future.
Dr. Greg Hundley:
Well, thank you Mark. So now Marco, do you have any additional studies that you're performing really on this same dataset?
Dr. Marco Valgimigli:
Well, I actually fully agree with Mark, very long term follow up is absolutely mandatory in this patient population. And I'm very glad to announce that this Swiss Apero study that we have been discussing will actually continue. Continuing patients follow up five years so that we will have much more clinical information, at least comparative effectiveness, clinical information between two devices. And also we'll be performing at 13 months, a second SCCTA to better understand the dynamic nature of these peri device or inter device list, whether they actually do see over time and which of them may or not play a clinical role.
Dr. Greg Hundley:
Very nice well listeners, we want to thank Dr. Marco Valgimigli from Bern, Switzerland and our own associate editor, Dr. Mark Link from UT Southwestern for really bringing us this very important paper that compared the results of the Watchman, which is for primarily used in the US versus the Amulet, primarily used in Europe, a left atrial appendage closure device. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Speaker 5:
This program is copied right of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
This week, join author Makoto Hibino and editorialist Christoph Nienaber as they discuss the article "Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies" and accompanying editorial "Taming Hypertension to Prevent Aortic Dissection: Universal Recognition of a "New Normal" Blood Pressure?"
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week's feature discussion. Oh, very interesting. We are going to delve into results from the Japan specific health checkup study, as well as the UK Bio bank study and also a meta-analysis of several cohorts and investigate the relationship between hypertension and the future risk of aortic dissection. Well, Carolyn, but first, how about we grab a cup of coffee and delve into some of the other articles in this issue, and I'll go first?
Dr. Carolyn Lam:
Please do.
Dr. Greg Hundley:
I'm going to discuss with you the AVATAR trial.
Dr. Carolyn Lam:
Hold on, Greg, remind us, the AVATAR trial?
Dr. Greg Hundley:
Right, Carolyn. So the aortic valve replacement versus conservative treatment in asymptomatic, severe aortic stenosis or the AVATAR trial is an investigator initiated international prospective randomized control trial that evaluated the safety and efficacy of early SAVR or surgical aortic valve replacement in the treatment of asymptomatic patients with severe aortic stenosis, according to common criteria.
Dr. Greg Hundley:
So for example, the valve area is less than one centimeter squared with an aortic jet velocity of greater than four meters per second, or a mean trans aortic gradient of greater than 40 millimeters of mercury. They also, all of the patients had normal LV function and negative exercise testing was mandatory for inclusion.
Dr. Greg Hundley:
And so these authors, led by professor Marco Banovic from the University Clinical Center of Serbia, tested the primary hypothesis that early SAVR would reduce the primary composite endpoint of all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure as compared to a conservative strategy, according to guidelines. And the trial was designed as event driven to reach a minimum of 35 pre-specified events. The study was performed across nine centers in seven European countries.
Dr. Carolyn Lam:
Wow. A big important study. What did they find?
Dr. Greg Hundley:
Right, Carolyn? So they had 157 patients and they age average, 67 years and 57% were men and they were randomly allocated to early surgery, so 78 were in that group, or conservative treatment, and 79 were in that group. The follow-up was completed in May of 2021 and the overall medium follow was 32 months, 28 months in the early surgery group and 35 months in the conservative treatment group.
Dr. Greg Hundley:
There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment arm. So Carolyn, in asymptomatic patients with severe aortic stenosis, early surgery reduced the primary composite all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared to the conservative treatment. And so, Carolyn, this randomized trial provides preliminary support for early SAVR once aortic stenosis becomes severe, regardless of symptoms.
Dr. Carolyn Lam:
Wow. Interesting. Well, this next paper that I'm looking at describes a novel therapeutic target that, listen up, can lower plasma cholesterol and prevent thrombosis simultaneously.
Dr. Greg Hundley:
What? Are you sure about this? All right, Carolyn. All right. Describe this for us.
Dr. Carolyn Lam:
Well, I'll tell you what that target is. It is the coagulation factor prekallikrein, which I'm going to call PK, prekallikrein. Okay. Now, as a reminder, coagulation cascades are activated by tissue factor initiated extrinsic pathway and the contact system initiated intrinsic pathway. Both of which converge into the common pathway. Plasma kallikrein is a serine protease playing a crucial regulatory role in the intrinsic pathway and is generated from the liver expressed prekallikrein, a pro enzyme encoded by the KLKB one gene.
Dr. Carolyn Lam:
Now that was the background. In the current study, Drs. Song and Luo from Wuhan University in China and their colleagues identified that the plasma coagulation factor prekallikrein or PK interacts with the LDL receptor and induces its degradation in the lysosomes. In young Chinese Han adults serum PK concentrations positively correlate with LDL cholesterol levels. In hamsters genetic ablation of the KLKB one decreases plasma lipid levels through up-regulating LDL receptor in a manner additively to the PCSK nine inhibitor cyclocumarol.
Dr. Carolyn Lam:
Injections of the anti PK neutralizing antibody in mice and knock down of the KLKB one gene in rats also increased hepatic LDL receptor levels and reduced plasma cholesterol levels. Furthermore, in mice with ample E deficient background PK absence arrested the progression of atherosclerotic lesions. So in totality, these results suggest that PK, remember that's prekallikrein, regulates both LDL and thrombosis, and that PK inhibition can be an attractive therapeutic strategy to lower plasma cholesterol and prevent thrombosis simultaneously.
Dr. Greg Hundley:
Very nice, Carolyn. Well, before we get to our feature discussion on aortic dissection, I've got a paper that pertains to preclinical science and involves the study of aortic dissection. And it comes to us from Professor Aijun Sun from the Shanghai Institute of Cardiovascular Diseases at the Song Hang Hospital in Futon University, the Institute of Biomedical Science in Futon University.
Dr. Greg Hundley:
So Carolyn, the development of thoracic aortic dissection is closely related to the extracellular matrix degradation and the vascular smooth muscle cell transformation from contractile to synthetic type and legumin degrades the extracellular matrix components directly, or by activating downstream signals. However, the role of legumin in the vascular smooth muscle cell differentiation and the occurrence of thoracic aortic dissection, that remains elusive or unsolved.
Dr. Carolyn Lam:
Oh, so what did this study show?
Dr. Greg Hundley:
Right, Carolyn. So these authors found that the elevation of legumin is observed in thoracic aortic dissection tissues of both human subjects and in mice and deletion or pharmacologic inhibition of legumin rescues BAPN induced thoracic aortic dissection development in mice by alleviating extracellular matrix degradation and the vascular smooth muscle cell transformation. Carolyn, legumin depletion may represent a novel therapeutic strategy for thoracic aortic dissection and further studies are required to explore the diagnostic value of serum legumin as a novel biomarker for thoracic aortic dissection.
Dr. Carolyn Lam:
Wow. That's cool. Thanks, Greg. Well, there are other really cool papers in today's issue. There's a Cardiovascular Case Series by Dr. Bockus on a “Heart of Gold: A Scintillating Leading Pericardial Effusion. And I'll give you a hint, it's a case of cholesterol pericarditis. There are letters by Drs. Lucas and Taegtmeyer regarding the article “One Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage B HFpEF” with a response by Dr. Levine. There are highlights from the Circulation Family of Journals by Sara O'Brien.
Dr. Greg Hundley:
Well, Carolyn, I have some other papers to discuss in this issue as well. First, there's an On My Mind piece from Professor Lawler entitled, “What Are Adaptive Platform Clinical Trials, and What Role May They Have in Cardiovascular Medicine?” Next, there's an In Depth piece from Professor Damman entitled Evidence Based Medical Therapy in Heart Failure Patients With Reduced Dejection Fraction and Chronic Kidney Disease. And then finally, Professor Yoshida has a Research Letter entitled The Efficacy and Safety of Edoxoban 15 Milligrams According to Renal Function in Very Elderly Patients With Atrial Fibrillation, a Sub-Analysis of the Elder Care AF Trial. Wow, Carolyn, how about now we get onto that feature discussion.
Dr. Carolyn Lam:
Oh, let's go Greg.
Dr. Carolyn Lam:
For our feature discussion today, we are talking about aortic dissection and the association with hypertension or elevated blood pressure. Now at first sight, you may think, well, we all know that hypertension and elevated blood pressure is an important risk factor for aortic dissection, but I'd like you to question, do we really know?
Dr. Carolyn Lam:
Surprisingly few prospective studies have been published. We know that aortic dissection is an extremely important and serious complication, but it's low incidence means we need huge numbers to be able to answer questions such as, what blood pressure does the start taking off at? For example, is it systolic or diastolic blood pressure and so on? Well, guess what? We finally, I think, have some of the best evidence on this topic published in today's issue of Circulation.
Dr. Carolyn Lam:
And I'm so proud to have the first and corresponding author with us, Dr. Makoto Hibino from the University of Toronto to discuss his fantastic paper. As well as an editorialist, Dr. Christoph Nienaber from Imperial College, London, who will discuss the significance of this paper. Well, let's start with you, Dr. Habino or Makoto, if you don't mind, could you please tell us what you did and what you found?
Dr. Makoto Hibino:
Thank you, Carolyn. So it's my honor to be here to present my case in this podcast. So first, some of the recent data shows that the number of aortic dissection operation and this increasing trend, depending on countries and given the critical nature of aortic dissection preventive strategy against aortic dissection is expected. On the other hand, hypertension is still global issue and is responsible for constant number of deaths from cardiovascular diseases, including aortic dissection, but due to the relatively rare instance of dissection and acute critical nature of the disease, the available epidemiological evidence has been limited. So this time we wanted to investigate how the relationship of hypertension and blood pressure with the instance of the aortic dissection is, in terms of strengths association and the shape of the association.
Dr. Makoto Hibino:
We also hypothesized that association may not be leading a relationship. And what we did is our study is consist of three parts. The first two parts are original cohort studies using a Japanese specific health checkup study and UK Bio bank study in both of which we prospectively followed about half a million general population and analyzed the hazard risk of other aortic dissection instance for hypertension and systolic and diastolic blood pressure using Cox proportional analysis. And the last part is meta-analysis including eight cohort studies and examine the robustness and shape of the association between hypertension and systolic and diastolic blood pressure and the risk of aortic dissection.
Dr. Carolyn Lam:
Wow. So a huge study across diverse cohorts. What did you find?
Dr. Makoto Hibino:
Yes. So in both of our cohort studies, there was significant risk of aortic dissection for hypertension and systolic and diastolic blood pressure as a continuous variable. Also, there was increasing trend in hazard ratios for categorical systolic and diastolic blood pressure with two to five, for higher risk in the highest systolic blood pressure category and four to 12 for higher risk in the highest diastolic blood pressure category in the meta-analysis. The summary relative risk shows that those with hypertension has threefold risk of aortic dissection and the robustness of the result confirmed with the sensitivity and subgroup analysis. Lastly, in the non-linear dose response, meta-analysis, there was very strong dose response relationship between systolic blood pressure and aortic dissection with evidence of non-linearity. And similar, but still, those response relationship was found between diastolic blood pressure and aortic dissection. This analysis showed that the risk of aortic dissection was significant at systolic blood pressure more than 132 millimeter mercury, and diastolic blood pressure more than 75 millimeter mercury suggesting a risk of aortic dissection, even in non-hypertensive population.
Dr. Carolyn Lam:
Wow. That last part really grabbed me. And I think I should repeat that the risk was significant at the systolic blood pressure of only 132 and a diastolic blood pressure of 75. That's really striking. Chris toff, would you agree with me when I said, I think this is like the best data that we have now, sort of correlating blood pressure and hypertension with aortic dissection. I loved your editorial by the way.
Dr. Christoph Nienaber:
Thank you very much. I'm pleased to have the chance to write this editorial. Because, when I reviewed the article, I was thrilled of the data and the fact that somebody some consortium had managed to pool data from two different, let's say population studies in two different gene pools in Japan and in the UK together. And finding in a very granular way, that even within the normal spectrum of blood pressures, up to let's say 140 systolic, we find an increasing risk of dissection with a high normal blood pressure as compared to a low normal blood pressure. This has been very convincingly shown by Makoto's analysis. The entire group has to be congratulated for that fantastic idea. Collaboration from two different ends of the world, and then coming up with a similar conclusion in both populations, tells us that this is a general principle at work, that works in both gene pools in both Asian, as well as European populations, and tells us how important it is to keep an eye on blood pressure and even manage blood pressure within the normal range to a low normal in the future.
Dr. Carolyn Lam:
And I love the way you articulated that in that beautiful editorial, but could I now ask your thoughts, both of you, what are the clinical implications of this? I love Chris toff, that you discussed in your editorial, well, do we now lower the thresholds for treatment? Because aortic dissection is not the most common of incidences, right? So does lowering the blood pressure even more or targets come at a price? Or what should we be thinking of now, clinically?
Dr. Christoph Nienaber:
We are not treating dissection. We are trying to prevent dissection by gauging or gouging to a low normal blood pressure with various drugs and combinations of drugs in patients that are considered to be at risk with a slightly elevated blood pressure. So in the future, it's not enough to accept 140 systolic or 90 diastolic we should really pay attention to strictly lowering blood pressure in the idea of preventing vascular events.
Dr. Christoph Nienaber:
And that was considered to come at a price, but we have of course, reassuring data from Hope, from Sprint recently published that showed that even the low normal doesn't hurt. I mean, you have a lower risk of cardiovascular events, generally speaking, shown in Sprint with a low normal blood pressure. It comes a little bit at the expense of watching renal function, but that doesn't contribute to kind of prognostic sequelae. You just have to pay attention to it. You would not run any additional risk by lowering the blood pressure to a normal low blood pressure. And that's, I think, the convincing message, and even with a low incidence of the most important vascular accidents, such as dissection, you could prove that, or the group could prove that in almost 3000 patients that suffered from dissection, that whole pool of analyzed data. So again, I have to congratulate to this fantastic and convincing results.
Dr. Carolyn Lam:
Thank you. And Makoto, what do you think are the most important clinical take home messages from your study?
Dr. Makoto Hibino:
Yes. So let me, a little bit, step back to the summary of our findings. So our findings is so that this is a study is a fast summary of the evidence from the prospective stakeholder studies on the association of blood pressure and hypertension with the risk of aortic dissection. And this study improves the evidence base from being based on the case studies or single study to actual estimate of the relative risk. So also, with further study are needed, the current results suggests that the reducing blood pressure either through a healthier lifestyle or medication may reduce the instance of aortic dissection and furthermore the optimal target blood pressure may even lower than the current cut for hypertension. So from my perspective given the little rare instance of aortic dissection, intensive blood pressure management may be more effective or efficient in high risk population, such as those with bicuspid aortic valve or those with very ill medical follow for aortic aneurysm and those with genetic background. So further study in a specific subgroup, is warranted.
Dr. Carolyn Lam:
Thank you. And Chris toff, that's very interesting because I buy your argument too, that on the other hand, going lower, even in non-high risk, doesn't really come at a price as far as we can see. So what do you think Chris toff, what do you think are the further studies that are needed?
Dr. Christoph Nienaber:
Well, I was intrigued to see in their analysis that even the subgroups of patients, including patients with hereditary connective tissue disorders, survivors of previous dissection, patients with other conditions, including diabetes, et cetera, they're all across the board, benefited from low blood pressure adjust or adjustment to a low blood pressure. That gives me confidence to recommend to my colleagues, not only here, but in my further environment to follow those patients that are identified either as risk groups or with a slightly elevated blood pressure to definitely lower the blood pressure to lowest, lower to blood pressure with those side effects.
Dr. Carolyn Lam:
Nice. These are association studies just to take a step back rather than sort of treatment target studies, although we've discussed some of the treatment target studies, but I have to really agree that it's some of the strongest association data that I can frankly think of for blood pressure and aortic dissection. We're just so grateful that it has been published in Circulation. And thank you so much, Chris toff, for your elegant editorial, that really puts things in perspective with a very important final key take home message.
Dr. Carolyn Lam:
And with that, well listeners, you heard it right here on Circulation on the Run from Greg and I thank you for joining us this week. And, don't forget to tune in again next week.
Speaker 5:
This program is copyright of the American heart association in 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more, please visit ahajournals.org.
This week, our very own Carolyn Lam is in the author role along with author Vlado Perkovic, Associate Editor Naveed Sattar, and Guest Editor John McMurray as they discuss the articles "Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial" and "Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: A Pooled Analysis of SUSTAIN 6 and LEADER Trials."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
I have a confession. I am nervous because right after this, Dr. Greg Hundley is going to interview me and, thank goodness, not just me, but really, really interesting other authors and editors with feature papers, all about GLP-1 receptor agonists and the SGLT-2 inhibitors. Very, very, very hot topic. Do listen up! But for now, Greg, you're going to be nice, right? How would you start?
Dr. Greg Hundley:
Well, thank you, Carolyn. I am really looking forward to that. Maybe we'll have a few quiz questions in there. Before we get started, how about we grab a cup of coffee? I am going to bring to our listeners a paper from the world of preclinical science. It's from Professor Vincent Christoffels from Amsterdam. Carolyn, there's a pathogenic variant in the fifth exon of TBX-5 entitled PG125R. It's found in a Dutch atypical Holt-Oram syndrome family with early onset atrial fibrillation. These investigators modeled this in a mouse. Carolyn, this is the first human pathogenic variant based on a patient family in this key cardiac transcription factor that's been explored in an in-vivo animal model.
Dr. Carolyn Lam:
Wow, that's interesting. So, what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. The investigative team identified widespread electrophysiological transcriptional and epigenetic changes including coding and non-coding RNA, chromatin accessibility, and H3K27ac associations in the atria of TBX5-PG125R heterozygous mice distinct from the changes in the atria of TBX5 insufficient animals.
Dr. Carolyn Lam:
Okay. Could you give us the clinical take home message, Greg?
Dr. Greg Hundley:
Right, Carolyn. What these authors really have found is that the characterization of the TBX5-BG125R mouse model... it indicates that a patient-specific pathogenic variant in TBX5 induces changes in regulatory element activity, an altered balance in the regulatory network of atrial cardiomyocytes, and clinically relevant changes in cardiomyocyte function. So therefore, Carolyn, this work may provide insight into the epigenetic changes and transcriptional underpinning of arrhythmias in the general population caused by small increases in TBX5 expression also caused by common variants predisposing ones to atrial fibrillation.
Dr. Carolyn Lam:
Wow. Thanks Greg. Well, guess what? I've got an interesting mouse model to share about as well. This next paper comes from co-corresponding authors, Drs. Chen, Fu, and Wu from UCSD. What they do is provide insights into possible underlying factors in a molecular mechanism responsible for left ventricular noncompaction cardiomyopathy. Now, we know this condition, but... It was discovered half a century ago, yet owing in part to the lack of a suitable mouse model that faithfully mirrors that selective left ventricular vulnerability in patients, the actual mechanisms underlying susceptibility of the left ventricle to dilatation dysfunction in this condition actually remain unknown. Well, until now.
Dr. Greg Hundley:
Wow, Carolyn. So, what actually did this investigative team do, and what did they find?
Dr. Carolyn Lam:
At the basis of their study is a transcription factor. This is PRDM16. This transcription factor has previously been implicated in this condition through characterization of defects associated with the 1P36 syndrome. What the authors did this time, though, is they generated two new conditional knockout mouse models of PRDM16. Their subsequent characterization of the phenotype is a tour de force of gene expression analysis that uses a myriad of functional genomic approaches, including RNA-seq, ChIP-seq, single cell RNA-seq spatial transcriptomics.
What they found is cardiomyocyte specific ablation of PRDM16 in mice indeed caused left ventricle specific dilation and dysfunction, as well as biventricular non-compaction. In other words, fully recapitulating the left ventricular noncompaction syndrome in patients. Mechanistically, PRDM16 functions as a compact myocardium enriched transcription factor which activated compact myocardial genes while repressing trabecular myocardial genes in the left ventricular compact myocardium. Consequently, PRDM16 knockout cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes and/or neurons and chamber specific transcriptional regulation by PRDM16 was in part due to its cooperation with left ventricular and rich transcription factors.
Dr. Greg Hundley:
Carolyn, wow. Mechanistic understanding now for cardiovascular noncompaction. This is really exciting research. Clinically, how can we interpret this work from this animal model?
Dr. Carolyn Lam:
Thought you may ask. This study provides a unique left ventricular noncompaction mouse model for developing therapeutic interventions for any person with a left ventricular dilation and dysfunction, which emerge as the most important disease features in this condition. Improper specification of compact or trabecular cardiomyocytes is likely the common mechanism in the pathogenesis. Spatial single cell gene expression profiles in normal or disease conditions can be shown in this example to facilitate future studies for identifying new targets. This paper is accompanied by an editorial by Drs. Mably, Joe Wu, and Dr. Wang.
Dr. Greg Hundley:
Very nice Carolyn. Well, there are some other articles in this issue, and before we get to that feature forum let's go through those with our listeners. First, Carolyn, I've got a Research Letter from Professor Cornel entitled "Long Term Efficacy of Colchicine In Patients With Chronic Coronary Disease With Insights From LoDoCo2."
Dr. Carolyn Lam:
Wow. There's an exchange of letters between Drs. Wang and Ji regarding the article "Histidine Triad Nucleotide Binding Protein-1 Attenuates Cardiac Hypertrophy Via Suppressing Homeobox A5 Expression," Global Rounds paper by Dr. Indolfi on the universal healthcare system and cardiovascular disease burden in Italy. There's a cardiovascular case series by Dr. Raber on a pacemaker red herring and a hypertrophic cardiomyopathy copycat. Finally, there's a Perspective piece by Dr. Drakos on a mechanical bridge to recovery as bridge to discovery learning from few and applying to many.
Dr. Greg Hundley:
Well, Carolyn, I can't wait to get to this feature forum discussion, and I get a chance to interview you.
Dr. Carolyn Lam:
Ah! All right, let's go.
Dr. Greg Hundley:
Welcome listeners. We have on this February 22nd a forum feature discussion where we have two papers that we are going to present, and oh, what an honor it is. Guess who I get to interview first? Dr. Carolyn Lam from the National Heart Center of Singapore, along with a guest editor, Dr. John McMurray from Glasgow University in Scotland, followed by another paper from Dr. Vlado Perkovic from the Georgia Institute for Global Health in Sydney, Australia. Then lastly, Dr. Naveed Sattar, one of our associate editors who also comes to us from Glasgow, Scotland. Welcome to all of you.
Well, Carolyn, we're going to start with you today. I know you've got a paper combining the use of GLP-1 receptor agonists with SGLT-2 receptor antagonists. Can you tell us, Carolyn, a little bit about the background that went into this study? What was the hypothesis that you wanted to test?
Dr. Carolyn Lam:
Happily, Greg. First of all, what a pleasure to be sitting on the opposite side of the mic, if I might say so, and a real privilege to be speaking on behalf of the AMPLITUDE Executive and Steering Committee about this paper. The whole idea is that we know that SGLT-2 inhibitors and GLP-1 receptor agonists are the rage being recommended for their reduction in cardiovascular events in patients with Type 2 diabetes. However, they appear to do this by complimentary mechanisms. That really raises the tantalizing question of, "Can we combine them?"
Now, What do I mean by that? Well, GLP-1 receptor agonists are known for their reduction in the risk of atherosclerotic ischemic events, particularly like stroke, that benefit being greater, whereas a relatively modest effect on kidney function, perhaps heart failure. Whereas SGLT-2 inhibitors more impressively reduce the risk of heart failure, kidney function decline, kidney outcomes, and so on with a modest effect on myocardial infarction and perhaps no effect on stroke. So, you see, very complimentary. The whole question was, "What would it be like to combine these treatments?" And, in the absence of a trial that actually does a two by two randomization perspective or anything, we decided to look back at the AMPLITUDE-O trial, which was a large multinational trial of patients with Type 2 diabetes randomized to the GLP-1 receptor agonist efpeglenatide versus placebo, but was unique in including the largest proportion thus far of concurrent SGLT-2 inhibitor use in these prospective GLP-1 receptor agonist trials to date.
Dr. Greg Hundley:
Very nice. And so, you've told us a little bit about your study design. How about specifically your study population? And then, Carolyn, what did you find?
Dr. Carolyn Lam:
All right. So, of the 4,076 participants in the AMPLITUDE-O trial, 618 reported SGLT-2 inhibitor use at baseline. They were fairly similar to those not receiving SGLT-2 inhibitors. They had similar age and body mass index, but were less likely to be women, they had a longer duration of diabetes, similar history of cardiovascular disease, but lower prevalence of prior heart failure and lower blood pressure, HB A1C, LDL cholesterol, and albuminuria, but similar GFR.
When we looked at the effect of efpeglenatide in the presence or absence of baseline SGLT-2 inhibitor use, we basically found no difference. The P for interaction for each of these outcomes was basically not significant, whether we were looking at MACE and expanded MACE, which included revascularization and angina on top of standard MACE, whether we were looking at a renal composite or a composite of MACE and death, or whether we were looking at heart failure hospitalization. Which, by the way, all of these were significantly reduced by efpeglenatide, and so, similarly, whether or not there was a baseline SGLT-2 inhibitor. Very importantly, side effects were also similar whether or not patients were on an SGLT-2 inhibitor concurrently. This bodes really well for the combination.
Dr. Greg Hundley:
Very nice Carolyn. Well, John, as a guest editor to Circulation, several papers often come your way each year. What in intrigued you about this particular manuscript?
Dr. John McMurray:
Well, exactly as Carolyn said, Greg, this asks a question and gives some of an answer to a question that all of us are asking which is, "Should we be using these two drugs together? Do they have complimentary additive benefits, or are those benefits independent of each other?" I think, as Carolyn said, her data from the AMPLITUDE-O trial, which was a fantastic trial, go some way towards addressing that.
And, Carolyn, I wondered... Maybe to give some more context to these really interesting data... I think this question was asked the other way around. I think our colleagues in the DECLARE–TIMI 58 trial looked at it in reverse. They were able to look at adding of an SGLT-2 inhibitor to the subset of patients who were in a GLP-1 receptor agonist. What... Can you remind us what they found, because I think that's an interesting alternative approach to this?
Dr. Carolyn Lam:
Excellent point, John, thank you. Because DECLARE was so big a trial that even though the percentage of patients on a concurrent GLP-1 receptor agonist was a bit smaller if you look at percent, it was still a very large subgroup. Thankfully, those results were extremely consistent with what we are seeing, too.
In a trial of an SGLT-2 versus placebo, the SGLT-2 inhibitors benefits were regardless of concurrent GLP-1 receptor agonist, and we showed the mirror image of that. Again, I think with the totality of evidence, it's very reassuring and also very important because to truly answer this, we would need a huge prospective randomized two by two trial, or... Which, I think will not be feasibly accomplished except in a pragmatic trial.
Dr. John McMurray:
Carolyn, maybe one very last point to make again about context, which Greg asked about. Here, we're talking about the primary, secondary prevention of cardiovascular events. You mentioned heart failure, which we're both very interested in. That's intriguing, because it looks to me like the heart failure was largely the prevention... perhaps the incident heart failure. I think there is still a question mark about the role of GLP-1 receptor agonists as a treatment for prevalent heart failure. Do you agree? Do you think that's still an unanswered question? Or, do these results in some way make you more comfortable about using GLP-1 receptor agonists in patients with established heart failure?
Dr. Carolyn Lam:
Wow. Again, an excellent question. These data reassure me that if I had a patient with Type 2 diabetes who developed heart failure and still required glucose control I would be very comfortable continuing a GLP-1 receptor agonist, because many of these patients in this trial who got heart failure obviously didn't drop out of the trial. They continued on the GLP-1 receptor agonist and the safety profile looks okay. However, I do not agree that the GLP-1 receptor agonists have become a treatment for heart failure the same way the SGLT-2 inhibitors have. That would require, in my mind, evidence in a prospectively defined validated population of heart failure, with known ejection fraction or not. And, to be even more provocative, I suppose, even perhaps without diabetes. Now, that would really put the nail in the coffin, if I may. Basically exactly what you did, John, in DAPA HF.
Dr. John McMurray:
All right, to finish on a provocative comment for the audience just before we leave this segment, it may of course depend on the heart failure phenotype type as well. In all of these trials, we're never really sure whether the patients have HFpEF, HFrEF, or a combination. So, lots of questions still.
Dr. Greg Hundley:
Very nice. Well, thank you so much, Carolyn and John.
Listeners, next we want to turn to our second feature article. This one is from Dr. Vlado Perkovic. Vlado, welcome. You have a paper involving GLP-1 receptor agonists and focusing on renal disease. Can you describe for us a little bit about the background pertaining to your paper, and what was the hypothesis that you wanted to address?
Dr. Vlado Perkovic:
Thanks so much, Craig, and thanks for having me here. It's such a joy to be part of this conversation. Our paper was a post hoc analysis of two completed clinical trials, the LEADER and SUSTAIN trials that looked at liraglutide and semaglutide, respectively, compared to placebo in people at high cardiovascular risk. We wanted to ask the question of... in more detail, the effects of these agents collectively and individually on important kidney outcomes to try and understand whether the GLP-1 receptor agonist, which, as Carolyn says, have clearly had significant benefits for MACE in particular, might also have the sorts of benefits that we've seen, for example, with SGLT-2 inhibitors on renal outcomes recognizing the massive burden of ill health, premature mortality, morbidity, economic, and social costs that go along with kidney disease as a complication of diabetes. What we've done here is we've pulled the data from the two trials and looked at them collectively and individually to try and unpack the effects of GLP-1 receptor agonists on a range of kidney outcomes.
We've looked at different thresholds of loss of kidney function. Traditionally we've used doubling of creatine, which equates to a 57% loss of kidney function. More recently, we've moved to a 40% loss of kidney function as being a good outcome in kidney trials. There's been a push for 30 and 50% outcomes to be used. Here we wanted to look really comprehensively at all of those outcomes, as well as the outcomes of change in albuminuria and change in EGFR slope, where we had more power, perhaps, to detect differences between the agents. Our hypothesis was that GLP-1 receptor agonists would have evidence of kidney protection. We thought up front that the likelihood was the kidney protection would be consistent at different levels of kidney function and might be similar between different agents. But, that wasn't what we ended up finding.
Dr. Greg Hundley:
Very nice. So, you mentioned the SUSTAIN and the LEADER trials. Can you describe for us a little bit more, and some of the specifics, perhaps, to your study population? And then, walk us through your study results.
Dr. Vlado Perkovic:
Yeah, so very happy to do that. Thank you. As I say, these trials were primarily cardiovascular outcome trials that were designed to assess the cardiovascular effects of the GLP-1 receptor agonists and therefore the populations reflect that intent with people who had preexisting cardiovascular disease primarily. What we found when we looked at the results was evidence of perhaps modest reduction in some of the renal outcomes based on different thresholds of loss of kidney function of the order of 10 to 20% overall when we looked at the pooled study population. Of course, that compares to a much more significant 30 to 40% reduction in the risk of these same outcomes when we look at drugs like SGLT-2 inhibitors.
Overall, they didn't appear to be quite as effective. But, we were somewhat surprised when we started to dig into the data in more detail in that we found that people who had reduced kidney function based on a lower EGFR, particularly an EGFR below 60, or those who had either micro or macro albuminuria, the benefits of treatment appeared to be greater in absolute and proportional terms. It also was much clearer, such that in people who had both had reduced EGFR and an increased level of albuminuria, there were reductions in the risk of the constant renal outcomes of approximately 40%, suggesting that these drugs may be particularly effective in people with established kidney disease, which... there's a novel finding today.
We were able to dig into that in more detail, looking at albuminuria and EGFR slope and effectively found consistent results for those outcomes as well, giving us some confidence that the findings perhaps were more likely to be real. We, in addition, looked at the different drugs and found some evidence that high dose semaglutide... in particular, one milligram weekly dose, and appeared to be more effective than the lower dose of semaglutide or liraglutide for some of those intermediate markers, if you like.
Dr. Greg Hundley:
Very nice. Naveed, now, as the associate editor, what intrigued you about this particular study? What drew your attention to it and caused you to bring it through that review process to our readers?
Dr. Naveed Sattar:
Yeah. Thanks Greg, and thanks Vlado. Now, I think this is a lovely study. I think we've been familiar with the effect of GLP-1 and albuminuria for a long time. I think that's fine, but not... that doesn't really float everyone's button. You know, albuminuria is not necessarily a hard endpoint. But, EGFR and EGFR slopes are becoming something that people are starting to become interested in as a marker of future diabetic kidney disease in end stage kidney disease. Vlad could probably comment on that. I think there was a suggestion if you meta-analyze all the GLP-1 trials, which we did recently on the back of efpeglenatide, both Carolyn and John were co-authors.... that there's a suggestion that GLP-1 may actually improve hard kidney outcomes. This paper, on the back of that, with a detailed look at EGFR slopes and different thresholds, does further support the fact that liraglutide and semaglutide do slow kidney outcome progression, particularly in those who've already got a degree of kidney damage.
Now, the context of that is actually really important in the sense that Vlado and colleagues and nephrologists around the world are very excited about the SGLT-2 inhibitors. But, also having another drug on top of that would might further slow kidney damage is excellent, particularly in a population which also has more atherosclerotic cardiovascular disease. These drugs could therefore have a double benefit, not only slowing kidney damage, but also preventing atherosclerotic cardiovascular disease and the population at high risk of both conditions. Of course, the future then also, as John mentioned, will be, "what about the benefit on top, and going forward in heart failure as well?" I think this study looks... well, adds to the support that GLP-1 receptor agonists actually improve hard kidney outcomes. I think that's the realization. But, going back to Vlado, I'd be interested to get his comment of, "Well, does this study and associated evidence now lead you to think when should we be using these drugs in our patients with chronic kidney disease?" That probably is the question, Vlado.
Dr. Vlado Perkovic:
Yeah. That's an important question. I think, Naveed, for us as a community. I think one of the nice things is that we can use these drugs in people with kidney disease already. They're approved, and we don't have the same sort of EGFR restrictions as we've had with SGLT-2 inhibitors. But, what we really want to know is, "What are the benefits that we're offering to our patients, and at what price might that come? Is there an increased risk of adverse events in this very sensitive population?"
Of course, the only way to answer those questions is to test it prospectively, which we're now doing in the FLOW trial, where we're randomized three and a half thousand people on semaglutide and placebo. So, over the next couple of years we will answer that question more definitively I hope. We're particularly focused on people with kidney disease in that trial. But of course it also... These data, if they're confirmed in that trial, raise important questions, I think, about the mechanism of the renal effect that needs teasing out. If they're truly more effective in relative terms, as well as absolute terms, in people who've got established kidney disease what does that tell us about the way that they might be providing that renal benefit? And its relative interaction, not only with SGLT-2 inhibitors, but also with mineralocorticoid receptor antagonists, which have recently additionally been shown to be beneficial on the kidney in the FIDELITY and the FIGARO trials.
Dr. Greg Hundley:
Very nice. Well, Naveed, you have led us and Vlado into our next very quick rapid fire question for our listeners, in working through each of you, both as authors and editors, what do you see is the next study to be performed in this sphere of research? Carolyn, we'll start with you, then John, then Vlado, and then Naveed.
Dr. Carolyn Lam:
Well, I think I alluded to it a little bit earlier that what we'd, of course, really love is a prospective randomized trial looking at the combination of the treatments versus placebo and versus one of each only. That sounds like pie in the sky, though. Maybe a pragmatic trial. Maybe an... Oh, John, shut your ears, but maybe looking back at real world data to look at this a little bit better. We're going to need a little bit more, at least I think, also to reassure ourselves that the combination is really safe in these patients.
Dr. Greg Hundley:
John?
Dr. John McMurray:
I think we need to know about GLP-1 receptor agonists in patients who don't have Type 2 diabetes because I think it's going to be critically important going forward to know whether this is just about dysglycemia and glucose lowering, which it seems probably isn't. Because my interest is in heart failure, of course, I would like to see these drugs tested in patients with symptomatic heart failure and both the major heart failure phenotypes with and without Type 2 diabetes.
Dr. Greg Hundley:
Vlado?
Dr. Vlado Perkovic:
Yeah, I'd support what John says and add people with and without diabetes in kidney disease as well to that group, as we've seen with DAPA-CKD study. I think the other really big opportunity for us here that's been highlighted by work done by John and others is the possibility that we might dramatically reduce the prevalence of these terrible complications of diabetes by using combination therapy and multi-drug combination therapy. Potentially, we've got not just the GLP-1 receptor agonist and the SGLT-2 inhibitors, but we've got MRAs and other drugs, depending on which outcome we're talking about. If these drugs are truly independent, as Carolyn's important work suggests, we could have a major impact at a population level on the prevalence of these terrible disorders in our patients.
Dr. Greg Hundley:
And finally, Naveed.
Dr. Naveed Sattar:
Yeah, thanks. I'm glad I'm not the only one who upsets John McMurray now and again, but it's probably good for him. What I would say is I agree with all the comments thus far. I would love the fact that with the newer stronger GLP-1s giving us additional weight loss, and, perhaps, with the combined GLP-1 GIP drugs, I would love if we could test them early in diabetes, actually, to actually reverse diabetes, as it were. And, can we delay these complications for 5-10 years, and perhaps with combination SGLT-2? Of course, we can't really do that now because of the costs, but going forward... And, John and I have had lots of conversations about multi-morbidity and obesity is being a big driver to all of that. Now we've got class of drugs coming that actually could cause significant weight loss and improve multiple outcomes that we've discussed: kidney, heart failure, atherosclerotic cardiovascular disease, and also possibly improve patients quality of life, particularly if the weight loss is quite substantial. I would love if we target that, but I think that's partly linked to some of the answers that've already been heard.
Dr. Greg Hundley:
Well, listeners, we want to thank our investigators, Dr. Carolyn Lam and Dr. Vlado Perkovic, and also our editors, Dr. John McMurray and Dr. Naveed Sattar for bringing us these two papers. The first highlighting that the efficacy and safety of GLP-1 agonists appear independent of concurrent SGLT-2 inhibitor use. And the second paper, emphasizing that GLP-1 receptor agonists offer renal protection, particularly in those with advanced renal disease.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.
Speaker 7:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.
This week's episode is special: Circulation is proud to present the 6th annual Go Red for Women issue podcast. Please join Sana Al-Khatib and James de Lemos as they welcome authors Michelle Albert and Sadiya Khan as they discuss their articles "Shining a Light on the Superwoman Schema and Maternal Health" and "Geographic Differences in Prepregnancy Cardiometabolic Health in the United States, 2016 Through 2019." Then Sana presents an overview of the other exciting articles in this important issue.
Dr. Sana Al-Khatib:
Hello, and welcome to this special Circulation on the Run podcast, focused on the sixth Go Red For Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I have the pleasure of co-leading the sixth Go Red for Women issue with, my friend and colleague Dr. Biykem Bozkurt. Very excited to introduce Dr. James de Lemos, the executive editor for Circulation, who will co-host this part of the podcast with me. Welcome, James.
Dr. James de Lemos:
Well, Thanks. I'm delighted to be here.
Dr. Sana Al-Khatib:
The theme of our podcast today is social determinants of health. We will discuss a perspective article in the issue, titled The Interplay of Sex with Social Determinants of Health in Cardiovascular Diseases, led by Dr. Michelle Albert, who is a cardiologist at the University of California in San Francisco. We will also discuss a research letter on geographic disparities in pre-pregnancy cardiometabolic health in the United States from 2016 to 2019, led by Dr. Sadiya Khan, a cardiologist at Northwestern Medicine in Chicago. Welcome, Doctors Albert and Khan.
Dr. Michelle Albert:
So pleased to be here. An honor to be part of the Go Red issue.
Dr. Sadiya Khan:
Thank you for having us.
Dr. Sana Al-Khatib:
Wonderful. So we'll start with the discussion and turn it over to you, Dr. de Lemos, to ask the first question.
Dr. James de Lemos:
Well, thanks, Sana. Michelle, let's start with you. I love the title of your essay. I'd like you to sort of orient our listeners as to why this title, why the topic and what you write about in your piece.
Dr. Michelle Albert:
Thank you, James. The title of the essay or Perspective is “Shining a Light on the Superwoman Schema and Maternal Health.” We felt, along my coauthors, Dr. Rachel Bond and Dr. Annette Ansong--Dr. Ansong is a pediatrician, actually. Dr. Bond is also a cardiologist. We felt that it was really important to put forward the psychological parts of the maternal health crisis as a major social determinant of health. Most often, the focus is only on the other risk factors that we know of, like hypertension, diabetes and obesity. And while those are also extremely important, it is actually the interplay between those risk factors and social factors, including racism, including access to care, that actually drive the maternal health crisis for women of color. Particularly for black women, who have about three to four times the mortality and pregnancy complications, compared to white women.
Dr. James de Lemos:
Michelle, one thing that you've really defined your career by is moving to the biology of adversity. I thought the figure in your paper was striking. Can you expand a little bit on what you mean by this, and how these social determinants and the pernicious effects of things like racism and psychological stress, translate into the biology that I think Sadiya will tell us about, even in her research letter?
Dr. Michelle Albert:
Yes, James. As you know, I've had a longstanding research history and portfolio, looking at the interplay between biology and social factors, coined the biology of adversity. The adversity part of this is something, we often think about the ACEs, adverse childhood experiences, and think about how those relate to health outcomes, including cardiometabolic and cardiovascular health outcomes. But as we think about adults, actually, it's the adult environment that actually defines adversity for children. Certainly, as it pertains to black women and other women of color, there are certain special circumstances that get embedded into the whole framework of the biology of adversity, that lead to poor overall cardiovascular outcomes, but also maternal and non-maternal health outcomes. So conceptually speaking, the framework of the biology of adversity is the incorporation of stressors into the brain. That then results in a hyper inflammatory milieu, combined with dysregulation of the hypothalamic pituitary access, as well as the flight or fright hormones or the up-regulation of the sympathetic nervous system. And actually importantly, the down-regulation of the parasympathetic nervous system, which is an area that is actively under research currently, that then results in the downstream cascade of health effects. For black women, this is characterized by, in part, the Superwoman Schema, which includes several major themes. The first major theme is the history of oppression and racism and sexism. Also, a history of disappointment, the influences of spiritual values and form other influences, interplayed. These are stressors that incorporate with other stressors. And then there's an interplay with subscales, that focus on the ability to succeed, despite limited resources. Putting others ahead of yourself. So less self-care for yourself, but putting self-care of others ahead of your self-care, the lack of showing vulnerability, as well as suppressing one's emotions. So, all of these things interact with behavior and genetics, as well as epigenetics, to flow into that cascade of the biology of adversity. For me, I gave this presentation four years ago now, at American Heart Association, where I sort of reformatted this whole biology of adversity to incorporate the Superwoman Schema, which was first defined or characterized by Cheryl Woods-Giscombé, who is a PhD scientist in the United States.
Dr. Sana Al-Khatib:
Now, that was very helpful and insightful, Michelle. Could you tell us about, what are the main next steps that need to be done in this area, that you think are going to be important to move this line of research forward, so that we can actually change this situation and really improve healthcare for these women?
Dr. Michelle Albert:
Well, I like to think of the answers to that question on several levels. So, I think one of the first levels is ensuring that women, especially women of color and specifically black women, are aware of the fact that hypertension, preeclampsia and eclampsia are risk factors, not only for their pregnancy, but also for cardiovascular disease later on, and for their children developing hypertension and cardiovascular disease later on. So, I think education is really important, on one level. On the next level is, actually having a continuum of care, where women are asked to get early prenatal care, even when they're contemplating pregnancy. So that they can be screened for hypertension, diabetes and their stressors, assessed and put in contact with resources. Having doulas, midwives involved in this process, as well as cardiologists who are involved in the pregnancy setting, as well as post-pregnancy for these women. Then, there's an advocacy initiative that has to take place, that focuses on getting aid. Kamala Harris has put forward a bill to actually do just that for maternal health, focusing on racism and bias in healthcare, because black women across the spectrum of socioeconomic status, experience poor maternal health outcomes. So, this is not only an access to care issue. It's not only a socioeconomic status issue. It is an issue that pertains to the women not being listened to, with racism and other stressors. I can't stress those first two things more, the whole discrimination part of it, and dumbing down the concerns of black women. Then, I think on a research perspective, certainly the American Heart Association has got now this HERN Network, which is a network that's going to focus on research around maternal health. So in that context, figuring out the best care models for women. Understanding the biology and how it interplays with poor outcomes later on, is also very important. One point around the biology that I want to point out for, let's say, African American women and actually Asian women as well, is that there's a higher prevalence of fibroids. There's very little research focusing on fibroids and its importance on maternal health outcomes and even the care for those women. Frankly, in my mind, a lot of that has to do with bias and how we value the healthcare of certain groups of women over other groups of women. So, those are some of the things, in terms of the solutions.
Dr. Sana Al-Khatib:
Absolutely. Before we move on to the presentation by Dr. Khan, are there any final words Michelle, that you'd like to share with the group, in terms of any final wisdom, so to speak, that you want to leave the listeners with?
Dr. Michelle Albert:
Yeah. I would just say that the maternal health crisis is preventable and it is tied into... Much of our audience are going to be healthcare providers. To the healthcare providers, I'm going to say, you really, really need to listen to these women when they tell you that they're experiencing certain symptoms. You also need to dig deeper to find out about their concerns, especially their stressors, in addition to making sure their blood pressure is controlled and that their weight is managed.
Dr. James de Lemos:
Well, thank you, Michelle. We'll turn to Sadiya now, and her team's research letter on geographic differences in pre-pregnancy cardiometabolic health in the US. For our listeners, I think what you'll see, if you read this paper, is how remarkable the research letter format is, and how much information Dr. Kahn and her team have conveyed in this really, really powerful letter, that I think has major public health implications. Sadiya, do you mind orienting our listeners to what you studied and how you did it?
Dr. Sadiya Khan:
Thanks, James. And again, thank you for the opportunity to join you guys in this podcast. I think Michelle very eloquently set up the preface for this research letter, which was understanding that health in pregnancy begins before conception. That was really the reason we wanted to focus on health factors, particularly cardiometabolic health factors, like body mass index, diabetes status and hypertension status in the pregnant individual, prior to pregnancy. The second piece of this that we were really interested in, is that we had observed that there are significant differences across the United States, in maternal morbidity and mortality outcomes. There are much higher rates of pregnancy-related deaths occurring in the South and Midwest, compared with other states in the US. That led us to ask this question, if we're able to better describe or define health prior to pregnancy, will we see similar patterns? We used the Centers for Disease Control Natality database, which includes all live births in the United States. So, the strength of this dataset, is that this is a surveillance system employed by the CDC, to monitor and record health outcomes of the pregnant individual and the newborn in the United States. Using this dataset, we were able to display maps for pre-pregnancy cardiometabolic health and look at changes from 2016 to 2019. Unfortunately, there's not much positive news, in that we've seen continued declines in favorable or optimal pre-pregnancy cardiometabolic health, which we defined as having a normal BMI and the absence of diabetes or hypertension. In addition, we saw that the levels of favorable pre-pregnancy cardiometabolic health were lower in the South and Midwest. It starts to set up some questions about upstream social determinants of health, that may be playing an important role as we start to address this problem at the individual level, but also at the societal and population level.
Dr. Sana Al-Khatib:
Very interesting and important findings there, Sadiya. Are you planning to work on additional research, to build on the research that you were publishing in this issue?
Dr. Sadiya Khan:
One of the most important questions that came from this are, what are the potential ways to start to address and support care for pregnant individuals, or as I think is Michelle really nicely put it, is for preconception care. So, thinking more about the reproductive life course before pregnancy, as well as during and after pregnancy. For that, one of the things that seems to be potentially really important, could be how Medicaid expansion has helped in states that have expanded, and differences between states that have or have not expanded Medicaid. Knowing that, that probably isn't sufficient, but it has that been helpful.
Dr. James de Lemos:
Yeah. I was struck, Sadiya. I mean, Michelle's essay and your research project really shine a bright and distressing light on maternal health in the US, I think and the crisis that we're under, that many of us don't even maybe recognize is happening. The time trends you showed were, to me, striking, giving over such a short period of time, how much maternal cardiovascular health has declined. It seems, indirectly at least maybe, that declining at a higher rate than overall cardiovascular health. I first applaud you for writing on this topic because I think it brings this issue to light, in terms of a public health crisis, frankly. But I wonder if you have any thoughts on why specifically, things are declining at such a higher rate for pregnant women or pre-pregnant women, maybe relative to national trends? Maybe they're not. Maybe this is what's happening across all age and gender demographics.
Dr. Sadiya Khan:
It's a really important observation. I agree with you. It seems like it's much more striking in this concentrated and focused group of individuals, that are pregnant and giving birth. It's possible because of the age range that we focus on, the 20 to 44 year old age range, that there are potentially more significant declines happening during this time period. We know cardiovascular health in general, appears to have some age-dependent dips, generally around adolescence. That early adulthood, college age period seems to be where a lot of cardiovascular health decline happens. So, I think that's what we're observing, as we're seeing these more striking trends in this age group. But it would be interesting to know, compared to non-pregnant individuals and across the life course, if that is in fact, the case.
Dr. Sana Al-Khatib:
Then I'll ask you what I asked Michelle, Sadiya. Any final words of wisdom that you'd like to share with our listeners?
Dr. Sadiya Khan:
I don't know if I'll be able to speak as eloquently as Michelle did. I think her responses really capture both of these papers and thinking about ways forward, about how we can dress the maternal health crisis. But I think that the word that she used, that really sticks with me and is one of the reasons that I'm so passionate about this work, is that this is preventable. That there are so many different things that could be in place, whether it's at the individual clinician and patient level, at the individual health system level, at the state level, as we looked at here, but really at the national level as well. I think we have a lot of work to do, but there's a lot of things that we know can help.
Dr. Sana Al-Khatib:
Great. Wonderful. James, any final words from you before we wrap up this part of the podcast?
Dr. James de Lemos:
First, Sana and the rest of the Circulation team, I congratulate you on another spectacular Go Red issue, that really is such an important endeavor. You and Biykem have done an incredible job leading this. I thank Michelle and Sadiya for coming on today, but also for their work. I think raises the stakes here, that we've got a public health crisis affecting women, and disproportionately affecting black women in the United States. It's underappreciated. I think you both point out that it's preventable. So, I think it's a call to action. It's a really well stated and an important topic.
Dr. Sana Al-Khatib:
Wonderful. Well, thank you so much, James and Sadiya and Michelle. Thank you so much for submitting your excellent work to us. Thank you for being with us today. This concludes this part of the podcast. Thank you. Next, I'm excited to provide you with a brief overview of the issue. We have two original articles. One is on genes that escape X-chromosome inactivation, modulate sex differences in valve myofibroblasts. This one was submitted to us by Dr. Kristi Anseth and her team. The study elucidated sex dependencies in myofibroblasts activation pathways and transcriptome analyses and small molecule interventions, implicating genes that escape X-chromosome inactivation, in regulating sex differences in the progression of aortic valve stenosis. The authors highlight the importance of considering sex as a biological variable, to understand molecular mechanisms underlying aortic valve stenosis and help guide sex-based precision therapies. The second original article is by Dr. Elena Aikawa and her team. It is on Prothymosin Alpha, a novel contributor to estradiol receptor alpha-mediated CD8+ T-cell activation and recognition of collagen cross-reactive epitopes in rheumatic heart valve disease. This paper provides novel findings that will likely have clinical impact down the road. As the authors pointed out, understanding the Prothymosin Alpha and estrogen sensitivity mechanisms to control the CD8 T-cell function may indeed provide insights into treatment for rheumatic heart valve disease. In this issue, we have three research letters. One letter was on the geographic disparities in pre-pregnancy cardiometabolic health in the US. You just heard about this paper in the first part of the podcast. Another letter, by Dr. Pradeep Natarajan and his team, offers information on the microvascular outcomes in women with a history of hypertension in pregnancy. It highlights that hypertensive disorders of pregnancy, especially preeclampsia, are independently associated with reduced microvascular indices. The investigators called for further research, to translate these findings into cardiovascular risk reduction strategies for women with these conditions. The third research letter, by Dr. Androulakis and his team, provides insights from cardiac magnetic resonance and angiography screening on spontaneous coronary artery dissection, also known SCAD. Theirs was the largest cohort of SCAD patients screened for peripheral vascular pathology by magnetic resonance and geography, to date and one of the largest to assess the SCAD-related impact size and relevant associations. They concluded that cardiac magnetic resonance has valuable contribution to the investigation of SCAD patients. In this issue, we have six perspective papers. In addition to the Perspective paper that you heard about from Dr. Michelle Albert, there are five perspective articles that span topics of great clinical and research relevance and importance. One perspective article, led by Dr. Carolyn Lam, tackles incorporating sex and gender into the design of cardiovascular clinical trials, a very important topic. Dr. Lam highlights the importance of sex and gender to the optimal interpretation, validation and generalizability of cardiovascular clinical trial results. Another perspective by Dr. Kathryn Lindley presents a call for action to address increasing maternal cardiovascular mortality in the US. This actually ties in with the initial part of the podcast. Dr. Lindley offers insightful suggestions, regarding strategies that could improve maternal cardiovascular care. Another perspective by Dr. Anne Curtis, addresses sex differences in response to rhythm management devices. Dr. Curtis reminds us that the conclusion that should be drawn from the many studies that have been conducted on cardiac rhythm management devices, is that these devices are indeed effective in both men and women, but they're still significantly underutilized in women eligible for those therapies. Dr. Curtis calls on us to be ever vigilant, to provide sex-neutral medical care to all patients, when clinical trials don't provide a strong rationale to do otherwise. I'm quoting her here. Another perspective paper by Doctors Mauricio and Khera, addresses statin use in pregnancy. They raise the of whether it is indeed time for a paradigm shift. This article was prompted by the FDA's request to remove the pregnancy Category X label for statins that was issued in July of 2021. The authors encouraged clinicians to use shared decision making. They add that those with atherosclerotic cardiovascular disease events, especially recent ones, should be encouraged to continue statins during pregnancy or resume them as soon as possible, if they're withheld. For those with heterozygous familial hypercholesterolemia, previously reasonable LDL control and no manifest vascular disease, there may be more tolerance for statin deferral during pregnancy, but they definitely highlight the need for dedicated research in this area. The last perspective, led by Doctors Okwuosa and Zaha tells clinicians what they should know about sex differences in cardio-oncology. They highlight sex differences in cancer and cancer treatment, cardiovascular diseases and the intersection of these conditions, that are likely to be quite helpful for clinicians taking care of such patients. Don't forget to check out the Pathways to Discovery section, where you will find a very interesting and motivating dialogue between Dr. Maryjane Farr and Dr. Biykem Bozkurt in which Dr. Bozkurt describes her career journey. I personally enjoyed reading that interview and found it quite inspiring. In closing, I want to express my deepest gratitude to my co-editor Dr. Bozkurt, the Editor-in-Chief for Circulation, Dr. Joseph Hill, the Executive Editor for Circulation, who was with us at the beginning of the podcast, Dr. James de Lemos and all the authors who submitted the research for this issue. I also want wholeheartedly thank and acknowledge the Circulation Associate Editors and Staff, who work tirelessly to enable us to produce an excellent Go Red for Women issue. I am very excited about this issue and hope that you will like it as much as I do. This concludes our Go Red for Women issue, Circulation on the Run podcast. Thank you for listening.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join author David Webb and Editorialist Steven Smith as they discuss the original research article “Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?"
Dr. Carolyn Lam:
Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries.
Dr. Carolyn Lam:
The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death.
Dr. Carolyn Lam:
The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment.
Dr. Carolyn Lam:
The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada.
Dr. Carolyn Lam:
The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction.
Dr. Carolyn Lam:
So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] “Why Are We Still Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion.
Dr. Carolyn Lam:
For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that.
Dr. David Webb:
So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure.
Dr. Carolyn Lam:
Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found?
Dr. David Webb:
So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer.
Dr. Carolyn Lam:
And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension?
Dr. David Webb:
Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated.
Dr. Carolyn Lam:
So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be?
Dr. Steven Smith:
Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results.
Dr. Steven Smith:
As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen
Dr. Carolyn Lam:
Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David?
Dr. David Webb:
Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures.
Dr. David Webb:
And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects.
Dr. Carolyn Lam:
And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most important unanswered questions?
Dr. Steven Smith:
Yeah, it's a great question. If I could piggyback on David's answer, I think one of the really interesting findings from this study is that we see these blood pressure changes even after only two weeks of therapy, so this is not something that requires some chronic, very high dose of acetaminophen to start experiencing these blood pressure changes. Obviously a lot of people are on acetaminophen, as David mentioned all over the world. Many of those patients, of course, are on it for chronic therapy, for example, for osteoarthritis, but a lot take it much more sporadically or for short term use. And I think it's telling that we see these blood pressure changes pretty rapidly after starting therapy.
Dr. Steven Smith:
As far as unanswered questions go, I think Dr. Webb summarized some of those already, but I guess what I would add is we still lack some clarity on what the ultimate outcomes of these blood pressure changes are. Obviously we know that blood pressure is highly correlated with adverse cardiovascular outcomes, as well as other outcomes, but the data showing an increased cardiovascular risk with acetaminophen is a little bit more murky. And so I do think there's still some question as to how this translates to increased cardiovascular risk, and I totally agree with David that the evidence supporting efficacy of acetaminophen is so weak at this point for most things, it may be a moot point. We may want to just move on from acetaminophen to the extent that we can, because it seems to have some risks, or at least some concern for risks, without a lot of evidence.
Dr. Carolyn Lam:
Wow. Thank you so much, gentlemen, for this. It's just amazing discussion, but even more so for publishing such an important study and such an elegant editorial in our journal. I think this is one that not only may change practice, but changes my personal perception and things that I'm going to do immediately.
Dr. Carolyn Lam:
Thank you very much audience. I'm sure you agree. This was incredible. Do tune in again next week for another episode of Circulation On The Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join senior author Louise Olde Nordkamp, Editorialist Sana Al-Khatib, and Associate Editor Mark Link as they discuss the original research article Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in "Transvenous and Subcutaneous Implantable Defibrillators: An Analysis of All Appropriate Therapy in the PRAETORIAN trial" and the editorial "Just When We Thought the Debate About the Value of Anti-Tachycardia Pacing Was Over Perplexing Results from the PRAETORIAN Trial Emerged."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, your host and Associate Editor from the National Heart Center and Duke National University of Singapore. And as you can tell, I am sorely missing my co-host, Dr. Greg Hundley, who cannot make it today, but yet I am so excited to tell you about the wonderful papers in today's issue. Now, right after these summaries, we will be discussing appropriate shocks and anti-tachycardia pacing in transvenous and subcutaneous implantable defibrillators. A really interesting analysis from the PRAETORIAN trials. The results may surprise you as they did for me. I really highly recommend you listen to the discussion, important clinical take home messages there. Now, though, let me tell you about some original papers in today's issue. We know that symptomatic children with catecholaminergic polymorphic ventricular tachycardia and that's a mouthful.
Dr. Carolyn Lam:
So, I'll abbreviate it as CPVT. They are at risk for recurrent arrhythmic events, beta blockers decreases risk, but are some types of beta blockers better than others in this regard? That's what coauthors and corresponding authors, Dr. Peltonberg and van de Werf from University Medical Center, Amsterdam and colleagues looked at. Studying 329 patients with RYR2 variant carrying symptomatic children from two international registries of patients with CPVT, these authors found that beta-1 selective beta blockers were associated with a higher risk for arrhythmic events, defined as syncope, appropriate ICD shock, sudden cardiac arrest, or sudden cardiac death. And this was compared with non-selective beta blockers. The difference in non-selective versus beta-1 selective beta blockers was driven by a significantly lower risk for arrhythmic events in patients treated with nadolol compared with metoprolol, bisoprolol, and atenolol. So, what are the clinical implications? Well, symptomatic children with catecholaminergic polymorphic ventricular tachycardia should preferably be treated with nadolol or another non-selective beta blocker such as propranolol should nadolol be unavailable.
Dr. Carolyn Lam:
The next paper deals with the super hot topic of myocarditis-related COVID-19 vaccination in adolescents and young adults. Now, suspected myocarditis temporarily related to COVID-19 vaccination has been reported in adolescents above 12 years old and young adults since the emergency use authorization of the Pfizer COVID-19 vaccine. And this is particularly in male adolescents and young adults. Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccine, of course, has important public health implications in the decision to vaccinate youth. So, these authors led by corresponding author, Dr. Truong from University of Utah and Primary Children's Hospital from Salt Lake City in Utah, retrospectively collected data on patients younger than 21 years old presenting before July 2021 with suspected myocarditis within 30 days of COVID-19 vaccination. And they found that in 139 adolescents and young adults with 140 episodes of suspected myocarditis, 49 of which were confirmed and 91 were probable.
Dr. Carolyn Lam:
And these were at 26 centers. Most patients were male and white with a median age of 15.8 years. Suspected myocarditis occurred in 98% following mRNA vaccine with 94% following the Pfizer vaccine, 91% occurring after the second dose. Symptoms started a median of two days after vaccination. The most common symptom was chest pain. 26 patients or 19% were in the ICU. Two were treated with inotropic vasoactive support and none required ECMO or died. The median hospital stay was two days. So, while the majority of patients with suspected vaccine associate myocarditis had normal ventricular systolic function on echocardiogram, many had abnormal findings suggestive of myocarditis on cardiac MRI in the setting of elevated troponin and electrocardiographic changes. The take home message is that despite lab and cardiac MRI evidence of cardiac injury, the majority of adolescents and young adults with suspected myocarditis following COVID-19 vaccination have rapid recovery of symptoms and a mild clinical course. Further studies are needed to better understand the timing of resolution of myocardial injury, mechanisms of myocardial injury, and the long term outcomes.
Dr. Carolyn Lam:
The next paper is the first study to look at examining the genetic architecture of the plasma protein using whole-genome sequencing in persons of African ancestry and really provides a chance to look at rare ancestry specific variation. Authors led by corresponding author, Dr. Gerszten from Beth Israel Deaconess Medical Center in Boston, Massachusetts performed proteomic profiling of 1,301 proteins in 1,852 black adults from the Jackson Heart Study using aptamer-based proteomics or the SOMAscan. Whole-genome sequencing association analysis was ascertained for all variants with minor allele count of five or greater. Results were validated using an alternative antibody-based proteomic platform, the Olink platform as well as replicated in the multiethnic study of atherosclerosis or MESA, and the HERITAGE family study. A huge amount of work. So, this large study added 114 novel genomic [inaudible 00:07:00] associated with protein levels and an additional 217 novel sentinel variant protein relationships. Novel cardiovascular findings included genetic variant associated with amyloidosis in persons with African ancestry shown to be associated with retinol binding protein four levels, even in those without cardiomyopathy implicating it as a potential biomarker.
Dr. Carolyn Lam:
Taken together, these results provide evidence of the functional importance of variants in non-European populations and suggest new biological mechanisms for ancestry specific determinants of lipids, coagulation, and myocardial function. And this is discussed in an excellent editorial by Professor Dr. Schunkert from German Heart Center, Munich. And the final original paper deals with high-salt intake, which we know to be the leading dietary risk factor for cardiovascular disease. We also know that clinical evidence suggests that high-salt intake is associated with non-alcoholic fatty liver disease. Now, could the two be linked, in other words, could hepatic steatosis induced by high-salt diet mediate cardiovascular damage and how? This is exactly what these authors did. Corresponding author, Dr. Zhu from Army Medical University in Chongqing, Institute of Hypertension in China and their colleagues in an elegant series of mouse experiments demonstrated that reduced SERT three expression in the liver is an important mediator of salt-induced hepatic inflammation and steatosis.
Dr. Carolyn Lam:
High-salt diet inhibits the transcription of SERT three through epigenetic modification mechanisms resulting in the persistence of hepatic inflammation in the liver. Notably, the over expression of SERT three in the liver using an adeno-associated virus eight vector or activation of SERT three by metformin effectively relieved the progression of persistent hepatic damage in mice and thus counteracted salt-induced cardiovascular damage. Taken together, these findings suggest that the MK SERT three pathway may be a promising interventional target for treatment of persistent cardiovascular damage in populations exposed to high-salt diet, and finally rounding up the other papers in today's issue, there's an AHA Update by Dr. Lloyd-Jones on the power of patient stories to inspire us to prevent cardiovascular disease and death, personal reflections on AHAs scientific sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30 years of no-touch saphenous vein harvesting, a timely jubilee gift.
Dr. Carolyn Lam:
There's a Frontiers paper by Dr. Rivard on a tremendous contribution on atrial fibrillation and dementia, a report from the AF Screen Interventional Collaboration. And finally a research letter from Dr. Joe on genetic proliferation tracing revealing a rapid cell cycle withdrawal in pre-adolescents cardiomyocytes. Well, that wraps it up for the summaries. Now, let's go on to our feature discussion.
Dr. Greg Hundley:
Welcome listeners to our feature discussion today on this February one. And we're very excited because we have three individuals that will be discussing this paper, Dr. Louise Olde Nordkamp from Amsterdam, Netherlands, the primary author. Dr. Sana Al-Khatib, who is our editorialist for this paper. And finally, Dr. Mark Link, who is our associate editor. Welcome to you all. Louise, we're going to start with you. Can you describe for us some of the background pertaining to why you formulated this study and then what was the hypothesis that you wanted to address?
Dr. Louise Olde Nordkamp:
Yes. Thank you very much for joining this podcast on our study. Our study was designed because in ICD therapy, antitachycardia pacing, ATP has been developed as a painless method to terminate ventricular arrhythmias, and it might decrease the number of appropriate shocks. But on the other hand, ATP might also be given unnecessarily for VTs that would've been ended spontaneously and might even accelerate VTs. The reported efficacy ranges from 52 to 81%, and some studies have observed even higher mortality in patients treated with ATP. The subcutaneous ICD has been developed 10 years ago approximately, and it's completely extra thoracic. And due to this extra thoracic design, it is incapable of providing pacing therapy including ATP. And this was a pre-specified analysis from the PRAETORIAN trial, which was a randomized trial comparing the transvenous and the subcutaneous ICD. And in this pre-specified secondary analysis, we're aimed to determine the efficacy of ATP, the safety of ATP and shocks by comparing appropriate therapies in both arms. So, both the SICD and transvenous ICD, and specifically, we investigated whether ATP reduced the number of appropriate ICD shocks.
Dr. Greg Hundley:
Very nice. And so describe for us a little bit more the study population and the design particularly of the PRAETORIAN trial.
Dr. Louise Olde Nordkamp:
Yeah. So, we published at PRAETORIAN trial in August 2020, in The New England Journal of Medicine and it was the first randomized trial to compare the subcutaneous ICD with the transvenous ICD in patients with a regular ICD indication, but without a pacing requirement. And in 39 census throughout Europe and US of 849 patients were randomized to either the subcutaneous and transvenous ICD in a one-to-one ratio. And during a median follow up of 49 months, the rate of the primary endpoint composite of device related complications and inappropriate shocks were similar between the subcutaneous ICD and the transvenous ICD arm. But here we looked at the appropriate therapy in the study. So, it was defined as both ATP or shock therapy and appropriate therapy was also defined as therapy for ventricular arrhythmias. The PRAETORIAN trial population in overall was, as I said before, regular ICD population with a median age of 63 years, 20% were female. Two-third of patients had an ischemic cardiomyopathy and 20% of patients had a secondary prevention indication.
Dr. Greg Hundley:
Very nice. And so tell us your study results.
Dr. Louise Olde Nordkamp:
Our findings were that in this trial, there was no significant difference in number of patients with appropriate therapy, so shocks and ATP. There were 86 patients in the SICD group and 78 patients in the transvenous ICD group. But patients in the subcutaneous ICD group were one and a half times more likely to be treated with at least one shock. So, if we look at shocks only, and that has a hazard ratio of 1.52 and that was statistically different of significance between the groups. The first shock efficacy was similar in the SICD and in the transvenous ICD. And the first ATP attempt successfully terminated 46% of all monomorphic VTs, but it accelerated through arrhythmia in 9.4%. And although, ATP successfully terminated 46% of all monomorphic VTs, the total of number of shocks, as I said before, was not statistically different between the two groups.
Dr. Louise Olde Nordkamp:
So, we looked at discrete episodes where ATP does reduce the number of appropriate shocks. But when we looked at storm episodes, which was defined as more than three shocks within 24 hours, we saw that there was a higher number of shocks in the transvenous ICD arm, despite a randomized design of the trial and the distribution of shocks between the discrete and the storm episode was there for opposites in the SICD, in the transvenous ICD. So, there was a high number of shocks in storm episodes in the transvenous ICD group, which can partly explain by the number of patients and electrical storms in this group, because there was 10 patients with an SICD who had an electrical storm and there were 18 patients with a transvenous ICD who had an electrical storm. So, patients with appropriate therapy had therefore almost twofold increased risk of an electrical storm in the transvenous ICD arm.
Dr. Greg Hundley:
Very nice. Listeners, next, we're going to turn to the associate editor for this paper, Dr. Mark Link, and Mark, you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Mark Link:
Thanks, Greg. And thanks, Louise for contributing this papers. We were really very happy to have it. And the reason that we were happy to have it is that this is a very important question in our clinical practice. That is, should we give a patient a subcu ICD or a transvenous ICD? Then, there are risk and benefits of both. It's a discussion that I have multiple times a week with patients. And so getting data on the efficacy of shocks and the efficacy of ATP is very, very important for us as we will discuss this with our patients. So that's why we really like this paper, because we thought it was very clinically relevant to our readership and to the practicing EP community.
Dr. Greg Hundley:
Very nice. Next listeners, we're going to turn to our editorialist, Dr. Sana Al-Khatib from Duke University and Sana, help us put the results of this study in perspective with other research in the field of both subcutaneous and transvenous pacing.
Dr. Sana Al-Khatib:
Yeah, no, absolutely. I'd like to start by congratulating the authors on this paper, I really enjoyed reading it and thank you for sending it to circulation. I also enjoyed writing the editorial. So, certainly this paper provided results that have challenged some of the findings of prior studies, in the sense that several prior studies had shown that antitachycardia pacing reduces the risk of shocks, improves patients outcomes. And that's not at the expense of them having syncope or having adverse events. And this was the case in those trials even for faster ventricular tachycardia. So in this particular study, they excluded patients with slower ventricular tachycardia, but I would also say that several of the prior studies had looked at antitachycardia pacing for faster VT and showed better outcomes.
Dr. Sana Al-Khatib:
And so, this study certainly makes us question some of those findings, but really I feel like it will be a great impetus for different researchers to look at this question in relation to the newer generation of transvenous ICDs as well as even potentially looking at the combination of the subcutaneous ICD with perhaps leadless pacemakers that could deliver antitachycardia pacing, which is an area of research that we're going to hear more about.
Dr. Greg Hundley:
Very nice. And Sana, that really leads us into our next round of questions with our panelists. We'll start with you first, Louise, what do you see is the next focus of research that'll be performed in this space?
Dr. Louise Olde Nordkamp:
So, I think the efficacy and also the potential harm of ATP should be studied more thoroughly. So, I think a randomized trial with ATP as a main focus, because this was a secondary analysis, is the first step to do. And moreover as Dr. Al-Khatib already mentioned is that new innovations are ongoing with a leadless pacemaker in addition to a subcutaneous ICD and these clinical results will be gathered in the coming months and years. And that is really interesting to look at as well.
Dr. Greg Hundley:
And Mark, can you share your thoughts?
Dr. Mark Link:
Yeah. This study brings up many questions, tying in the leadless pacemaker with the subcu ICD is certainly one that's being explored by a number of manufacturers right now, ways to make shocks less painful also would be very critical. I mean, I think that the storms often are because of the catecholamine surges that occur with shocks, if you could make shocks less painful, that would be very keen. And that's been a focus of some researchers for quite some time without good results at the time. And then, increasing the efficacy of ATP because there was a signal here that ATP could, what did generate faster VPs and VFs. And so, the prevention of that I think is very crucial.
Dr. Greg Hundley:
Very nice. And Sana, do you have anything to add?
Dr. Sana Al-Khatib:
Yeah, no, absolutely. I completely agree with what was said. I truly feel that this is an area where we're going to see a lot of research being done. We have new algorithms of antitachycardia pacing, Greg, that are being developed and incorporated into devices that use machine learning, which is really exciting. So, trying to look at hard outcomes related to those and comparing them with, as I mentioned, the subcu ICD combination with a leadless pacemaker would be really interesting. And then, this whole question about the electrical storm, I commend the authors for looking at that, but as they pointed out this was a secondary analysis and the numbers that they had were pretty small. So, trying to look at those findings in a larger population of patients really designed to look at that question would be important.
Dr. Greg Hundley:
Very nice. Listeners, we want to thank our electrophysiology panelists today, Dr. Louise Olde Nordkamp, Dr. Sana Al-Khatib, and Dr. Mark Link for bringing us the results from this trial indicating that really there was no difference in observed shock efficacy of the subcutaneous compared with the transvenous ICDs. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2022. The opinion expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join authors Christopher Granger and Anthony Carnicelli, as well as Associate Editor & Editorialist Shinya Goto as they discuss the article "Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex" and accompanying Editorial "Patient Level Meta-Analysis: End of the Era for DOAC Developmental Trial in AF Patients?"
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I'm so excited about our feature discussion today. It is about DOACs versus warfarin in patients with atrial fibrillation, a really important patient-level network meta-analysis of randomized control trials with interaction testing by agent six. So you can already tell something very, very clinically relevant and important discussed by not only the authors, but our dear associate editor and editorialist.
Dr. Carolyn Lam:
Okay. You just got to tune in, but first I'm going to start us off with some coffee, as well as a description of this first paper in today's issue. The 2018 AHA ACC multi-society cholesterol guidelines states that statin therapy may be withheld or delayed among intermediate risk individuals in the absence of coronary artery calcium.
Dr. Carolyn Lam:
However, two traditional cardiovascular risk factors associate with incident atherosclerotic cardiovascular disease events among individuals with zero coronary artery calcium over the long term? Well, this is the question that investigators decided to answer in today's paper and they're led by Dr. Virani from Baylor College of Medicine in Houston, Texas.
Dr. Carolyn Lam:
They studied 3,416 individuals with coronary artery calcium score of zero at baseline from the MESA study, which is a prospective cohort study of individuals free of clinical atherosclerotic cardiovascular disease at baseline. Among these individuals with zero coronary artery calcium, cigarette smoking, diabetes and hypertension were found to be independently associated with incident atherosclerotic cardiovascular disease events over long-term follow up.
Dr. Greg Hundley:
Ah, very interesting. Another piece of information relating to how we might use coronary artery calcium scores in, it sounds like, a high-risk patient population. So, Carolyn, what's the take-home message here?
Dr. Carolyn Lam:
Well, even if individuals have a coronary artery calcium of zero, if they are current smokers, if they have diabetes melitis or hypertension, initiation and long-term use of statin therapy, along with a heart healthy lifestyle and risk factor modification may still be warranted as part of the patient/clinician risk discussion.
Dr. Greg Hundley:
Very interesting Carolyn. Well, I've got a clinical study to tell you about. And, Carolyn, as you know, obesity and diabetes are associated with a higher risk of heart failure and the inner relationships between different measures of adiposity, including overall obesity, central obesity, fat mass, and diabetes status for heart failure risk, are not well established.
Dr. Greg Hundley:
And so this investigative group, led by Dr. Ambarish Pandey, from UT Southwestern Medical Center, looked at the ARIC, the visit five in ARIC and CHS, the visit one, and cohorts together, and they were obtained from the NHLBI BioLINCC. They were harmonized and pooled for the present analysis, excluding individuals with prevalent heart failure.
Dr. Greg Hundley:
So using multi-variable adjusted fine-grade model models were created to evaluate the associations of body mass index, waist circumference, and fat mass with risk of heart failure in the overall cohort, as well as among those with, versus without, diabetes at baseline.
Dr. Greg Hundley:
And the population attributable risk of overall obesity with BMI greater than 30 kilograms per meter squared, abdominal obesity with waist circumference greater than 88 and 102 centimeters in women and men, respectively, and high fat mass above the sex-specific median for incident heart failure, was evaluated among participants with and without diabetes.
Dr. Carolyn Lam:
Ooh, I'm so in interested in this topic. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So a large study, it included 10,387 participants, about 53% from ARIC, 25% had diabetes, and the median age was 74 years. And higher levels of each adiposity measure were significantly associated with higher heart failure risk. The population-attributable risk percentage of overall obesity, abdominal obesity, and high fat mass for incident heart failure was higher among participants with diabetes versus those without diabetes.
Dr. Greg Hundley:
And so, Carolyn, we can conclude from this research that higher BMI, higher waist circumference and higher fat mass, are strongly associated with greater risk of heart failure among older adults, particularly among those with prevalent diabetes.
Dr. Carolyn Lam:
So, so nicely done. Thank you, Greg. Well, the next paper talks about common ancestry-specific ion channel variants and how they predispose to drug-induced arrhythmias. Now, we know that multiple reports associate the cardiac sodium channel gene Scn5a variants, and these are the specific variants, S1103Y and R1193Q, with Type 3 congenital long QT syndrome and drug-induced long QT syndrome.
Dr. Carolyn Lam:
These variants are, however, two common in ancestral populations to be highly arrhythmogenic at baseline. The S1103Y allele frequency, for example, is 8.1% in Africans and the R1193Q is 6.1% prevalent in East Asians. So the investigators, led by Dr. Roden from Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues, determined the effect of the S1103Y variant on QT intervals among 1,479 Africans from a large electronic health record with no confounding medications or diagnosis of heart disease.
Dr. Carolyn Lam:
Now, while both the specific variants generated increased late sodium current, baseline action potential durations in cardiomyocytes from induced pluripotent stem cells carrying these variants were unexpectedly normal. The re-polarizing potassium current, IKR, was markedly increased in these induced pluripotent stem cells with the variants, accounting for normal baseline action potential duration but, with exposure to an IKR blocker, they displayed exaggerated action potential duration prolongation and after depolarizations.
Dr. Greg Hundley:
Wow, Carolyn, interesting. So tell us, what are the clinical implications of this really exciting research?
Dr. Carolyn Lam:
Yeah. So here's the take-home message. These common ancestry-specific variants do not affect baseline re-polarization, despite generating an increased late sodium current. So the authors propose that increased re-polarizing potassium current, IKR, serves to maintain normal re-polarization, but increases the risk of manifest QT prolongation with IKR blocking in these variant carriers. So we need to be aware of that and, further, these findings highlight the need to include ancestral diversity in genomic and pharmacogenomic studies.
Dr. Greg Hundley:
Oh, wow. Beautifully described, Carolyn. I really appreciate that. Just excellent discussion. Well, Carolyn, my next paper comes to us in an investigation regarding doxorubicin or anthracycline-associated induced cardiotoxicity. So, Carolyn, multiple pharmacogenetic studies have identified the synonymous genomic variant rs7853758 and the intronic variant rs885004 and SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity.
Dr. Greg Hundley:
However, the true causal variant, or variance, of this cardioprotective mechanism at this locus, the role of SLC28A3 and other solute carrier transporters in anthracycline-induced cardiotoxicity and the suitability of solute carrier transporters as targets for cardioprotective drugs has not been investigated.
Dr. Carolyn Lam:
Wow. Got it. So what did these investigators do and find, Greg?
Dr. Greg Hundley:
Right. So Paul Burridge and his colleagues at Northwestern University found that the patient-specific cardiomyocytes recapitulate the cardioprotective effect of the cGAS-identified SLC28A3 locus, and the authors functionally confirmed for the first time, the role of SLC28A3 in doxorubicin-induced cardiotoxicity.
Dr. Greg Hundley:
And a novel genetic variant, the rs11140490, is the potential causal variant in the SLC28A3 cardioprotective locus. And finally, Carolyn, the solute carrier transporter inhibitor desipramine protects against doxorubicin-induced cardio toxicity through decreasing the intracellular uptake of doxorubicin into the heart.
Dr. Carolyn Lam:
Wow. That is a lot of data. Could you summarize it for us, Greg?
Dr. Greg Hundley:
Right, Carolyn. So these investigators provide two potential therapeutic options to attenuate doxorubicin-induced cardiomyopathy, either repurposing FDA-approved desipramine, or therapy with long non-coding RNA SLC28A3-AS1. Also, Carolyn, they propose that a simple clinical test to detect the presence of rs11140490 can be used to predict that a patient will be less likely to experience doxorubicin-induced cardiomyopathy, and that, perhaps with future clinical trials, it may be possible for these patients to be treated with a longer duration, that is a higher accumulative dose of doxorubicin, to enhance the efficacy of their chemotherapy.
Dr. Carolyn Lam:
I love the way you took that home for us. Thank you, Greg. Well, also in today's issue is a Research Letter by Dr. Chen on multifaceted spacial and functional zonation of cardiac cells in an adult human heart.
Dr. Greg Hundley:
Right, Carolyn. And Professor Constantine has a Letter to the Editor entitled Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia. Well, Carolyn, how about we get onto that feature article and learn about DOACs versus warfarin in this very large network meta-analysis?
Dr. Carolyn Lam:
Yes, yes, yes. Let's go, Greg. Thanks.
Dr. Greg Hundley:
Welcome, listeners, to our feature discussion today. And we're very fortunate. We're going to review the utility of DOACs in patients with atrial fibrillation. And we have with us two of the authors of this original research, Dr. Anthony Carnicelli from Duke University, and Dr. Chris Granger from Duke University.
Dr. Greg Hundley:
Additionally, we have with us our associate editor, Dr. Shinya Goto, from Japan. Welcome, gentlemen. Anthony, we'll start with you. Describe for us a little of the background information pertaining to your study and what was the hypothesis that you wanted to address?
Dr. Anthony Carnicelli:
Yeah, thanks so much, Greg, for having us here to discuss this. I started working in the DOAC space when I was a resident at Brigham and Women's Hospital with mentorship from Dr. Bob Guigliano there, and was really fortunate to connect with Dr. Granger when I came to Duke for a fellowship, and we had this unique opportunity to take data out of the four largest trials of anticoagulants in the atrial fibrillation, and take individual patient data from these international centers and combine them to form the combined AF database from which we did this analysis.
Dr. Anthony Carnicelli:
So a very unique opportunity here to have individual patient-level data from over 70,000 patients, and perform this analysis. And, really, what we aimed to do was to do the kind of highest quality meta-analysis using network meta-analysis methods to investigate the relative safety and efficacy of DOACs versus warfarin and a broad and diverse, but randomized, population of patients with atrial fibrillation.
Dr. Greg Hundley:
Very good. So you started to describe for us your study population and your study aligns. So tell us a little bit more, who were these patients, and then maybe specifically give us a little bit of the outline of your meta-analysis.
Dr. Anthony Carnicelli:
Yeah, so these were, again, a very broad patient group, but from kind of 10,000 feet, this was a population of patients with atrial fibrillation who were at risk of stroke, from CHADS score perspective. So there are some nuances from each of the included studies, of course, regarding the individual risk of stroke from one study to the next. But largely, as I mentioned, in patients with non-valvular atrial fibrillation randomized to either DOAC or warfarin.
Dr. Anthony Carnicelli:
And, from a method standpoint, we are fortunate at Duke and at DCRI, to have an expert in the network, meta-analysis methodology, whom we've worked with, Dr. Bonnie Huang, who helped to put together the analysis here and to proceed with this kind of network methodology.
Dr. Anthony Carnicelli:
And so, again, our goal was to evaluate the overall safety and efficacy of DOACs versus warfarin, but then also to dive into some specific subgroups, both from a categorical covariant perspective, and then also to evaluate some continuous covariants, specifically age, and to assess gender across the entire spectrum of continuous age in our population, which, of course is a unique opportunity in the individual patient-level data.
Dr. Greg Hundley:
And, Anthony, you had, gosh, it looks like over 70,000 patients in this particular analysis. Tell us a little bit about the results.
Dr. Anthony Carnicelli:
Yeah, so interesting, actually, and I agree that the biggest strength of our meta-analysis is the individual patient-level data and also the profound number of randomized patients included. So I think, from a high level, the most important results to highlight are the fact that there is a 19% relative risk reduction in stroke or systemic embolism among patients who are randomized to DOACs compared to warfarin, with an 8% reduction in all-cause death and a 55% reduction in intracranial hemorrhage.
Dr. Anthony Carnicelli:
So a massive reduction in the most feared complications of both atrial fibrillation and then also those associated with systemic oral anticoagulation. We also found a trend towards less bleeding in patients randomized to the standard-dose DOAC group, as well.
Dr. Greg Hundley:
Very good. Well, Chris, we're going to turn to you. What an exciting discovery here, and beautiful methodology. I wonder, in addition to what Anthony has shared with us, were there particular outcomes that were pertinent to men versus women or perhaps related to age?
Dr. Christopher Granger:
Yeah, Greg. So, again, we're proud of this as being really the state-of-the-art ability to evaluate safety and efficacy in this incredibly important population of patients with Afib and at risk for stroke, and to be able to dive into the subgroups and to the individual outcomes, even the less common outcomes. And one of the most striking things, and this really reinforces prior data, but with the greatest confidence of any study ever done, there was this 55% at reduction in intracranial hemorrhage and 19% reduction in total stroke and systemic embolism, really highlighting that these drugs are clearly better than warfarin, from reinforcing the guidelines.
Dr. Christopher Granger:
And the message with the subgroups is there was really a remarkable amount of consistency. And specifically in the older population where people are really concerned about anticoagulation, there was a clear and consistent major advantage of DOACs over warfarin. Men versus women, clear, clear, compelling benefit of DOACs over warfarin across each of these outcomes, including mortality, by the way, 8%. But highly statistically significant reduction in total mortality.
Dr. Christopher Granger:
A couple of the interesting ones, there was some effect modification. In other words, some evidence of an even greater benefit in patients who were not previously on a vitamin K antagonist or who had lower creatinine clearance, really important group, right? The renal impairment group.
Dr. Christopher Granger:
And then there was a greater benefit of lower risk of bleeding for patients with low body weight. And, in fact, the younger population, if anything, had a greater benefit with respect to less bleeding. And the bleeding is so important, Greg and Shinya, right? Because that's the major reason that people are not using anticoagulation, warfarin or DOACs, for this large population of patients who are untreated. And I hope this meta-analysis will be viewed as evidence that have really safe and effective treatments that are underused for this population that we're concerned about bleeding.
Dr. Greg Hundley:
Excellent. Thanks so much, Chris. Well, Shinya, you see a lot of papers come across your desk. What attracted you to this particular paper? And then can you help us put these results in the context with others that have evaluated the utility of DOACs in patients with atrial fibrillation?
Dr. Shinya Goto:
Thank you, Greg. Let me congratulate for Anthony and Chris and also group for conducting this great work. I mean, combine AF with amazing success for sharing the clinical trial database. So that all the four with a DOAC available is approved by each country based upon individual trial. Individual trial itself, large enough, right? Include more than 10,000 patient, but this time the [OSA 00:19:49] accumulated all four DOAC trial database together so that it is easy to say clinical trial data sharing provided robust evidence.
Dr. Shinya Goto:
But it is difficult, actually, to conduct it. I really commended OSA to conduct this success. So the data is predicted, I would say. Individual clinical trial itself shows lower risk of bleeding in DOAC as compared to warfarin. But this paper really provides the first time standard dose of DOAC reduce the risk of stroke and systemic embolism and death as compared to warfarin.
Dr. Shinya Goto:
So I really commented OSA. So this paper have a strong impact on the medical care. DOAC rapidly change the standard of care already. But superior efficacy was shown only in a few dose of DOAC, like 150 milligram BID of dabigatran, 60 milligram QD edoxaban, and five milligram apixaban. But this combined AF provides a stronger and a trustable robust evidence DOAC is better than warfarin.
Dr. Greg Hundley:
Very nice. Well, gentlemen, I want to turn back to you. I'll start with Anthony and then Chris, and then Shinya. Anthony, what do you think is the next study to be performed, really, in this space?
Dr. Anthony Carnicelli:
Well, it may be a bit of a pitch, but I mean, we have many opportunities in the combined AF data set to perform additional analyses, but I think that one of the most important next steps in this space that I'm most excited about is with respect to the newer oral anticoagulants that are coming down the pike.
Dr. Anthony Carnicelli:
For example, the Factor 11 inhibitor space. I mean, I think that there is another opportunity in the near future to potentially revolutionize the systemic anticoagulation space. And I think that data from combined AF could potentially be used to help continue moving the ball forward, again in the development of newer agents. So I think that's probably the thing that I'm most excited about in this space.
Dr. Greg Hundley:
Very good. And, Chris?
Dr. Christopher Granger:
Greg, I think there's so many unanswered questions and I think, as Tony points out, this highlights the fact that we know a lot, but there's a lot of unanswered questions. And those, some of the ones that I'm most interested in are low burden AFib, this AFib that we're detecting now with smart watches and devices, and what we do with that. And patients with renal impairment, including all the way down to renal failure, where those are relatively underrepresented, including in the combined AF data set.
Dr. Greg Hundley:
Very good. And, Shinya?
Dr. Shinya Goto:
Yeah. Yeah, Anthony and Chris talked about a little bit the plans to space, but I insist there is a lot of space that also could do with the combined AF database. We can expect a lot of sub-analysis, like you conducted as a continuous variable in this paper, but you can do that with eGFR as continuous variable, PMI as continuous variable. So we can expect a lot of sub-analysis. Probably, this is the end of publication from the individual DOAC development trial. You change the game with the combined AF data set.
Dr. Greg Hundley:
Very good. Well, listeners, we want to thank Dr. Anthony Carnicelli, Dr. Christopher Granger and our own associate editor, Dr. Shinya Goto, for bringing us this very interesting result from the meta-analysis that, compared to warfarin, DOACs have a more favorable efficacy and safety profile among patients with atrial fibrillation. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join author Mohamed Abdel-Wahab and Associate Editor Stefan James as they discuss the article "Comparison of a Pure Plug-Based Versus a Primary Suture-Based Vascular Closure Device Strategy for Transfemoral Transcatheter Aortic Valve Replacement: The CHOICE-CLOSURE Randomized Clinical Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, a very interesting topic, looking at closure devices at the sites of access for patients that are undergoing TAVR procedures. But before we get to that, how about if we grab a cup of coffee and start with some of the other articles in the issue. Would you like to go first?
Dr. Carolyn Lam:
I would love to and I would like to describe not just one, but two articles from recent SGLT2 inhibitor trials. So, the first paper is an analysis of the DAPA-HF trial. Now we know that circulating high sensitivity, cardiac troponin T predominantly reflects myocardial injury. And higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction or HFrEF. But what about the prognostic significance of changes in high sensitivity troponin T over time and the effects of Dapagliflozin and on clinical outcomes in relation to baseline levels, as well as the effect of dapagliflozin on the high sensitivity troponin T levels? Well, this is what this study answers. It's a biomarker substudy of the DAPA-HF trial from Dr. Berg of the TIMI study group at Brigham women's hospital and colleagues.
Dr. Greg Hundley:
Wow. Carolyn, very interesting. So remind us about the DAPA heart failure trial. What was it about?
Dr. Carolyn Lam:
Ah, well, DAPA-HF was a randomized double blind placebo control trial of dapagliflozin in patients with symptomatic HFrEF defined by injection fraction 40% or less wherein dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure events. And in today's biomarker substudy increases in high sensitivity, cardiac troponin T over a one year interval of time were highly predictive of subsequent risk of worsening heart failure and cardiovascular death. The effect of dapagliflozin on the primary endpoint was consistent irrespective of baseline troponin T concentration with no evidence of attenuated treatment benefit in those with very high troponin T concentrations.
Dr. Greg Hundley:
Very interesting Carolyn. Now you've got another study. Is this one on EMPA?
Dr. Carolyn Lam:
You are right. Thank you. The next paper is and analysis of the Emperor-Preserved trial. As a reminder, Emperor-preserved study the SGLT2 inhibitor empagliflozin in patients with HFpEF this time, which is a left ventricular ejection fraction above 40, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. The current paper evaluated the efficacy of empagliflozin on health related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varied according to baseline health status.
Dr. Greg Hundley:
Very nice, super review Carolyn. So what were the results of this study?
Dr. Carolyn Lam:
In Emperor-Preserved, baseline health status and quality of life did not influence the magnitude of effect of empagliflozin on the risk of cardiovascular death or hospitalization for heart failure. Empagliflozin improved health status and quality of life as assessed by the Kansas city cardiomyopathy questionnaire across all domains and at all measured time points. Thus an effect that appeared early and was sustained for at least one year.
Dr. Greg Hundley:
Very nice. So two really informative papers on SGLT2 inhibitors. Well Carolyn, I'm going to turn the conversation to the world of preclinical science and talk about Titin. So Carolyn, titin truncation variants are the most common inheritable risk factor for dilated cardiomyopathy and their pathogenicity has been associated with structural localization. The A-band variants with overlapping myosin heavy chain binding domains appear more pathogenic than the I-band variants and the mechanisms for this are not well understood. So these investigators led by Dr. Hinson at the Jackson Laboratory for genomic medicine, performed a study demonstrating why A-Band variants are highly pathogenic for dilated cardiomyopathy and how they could reveal new insights into dilated cardiomyopathy pathogenesis. Titin functions and therapeutic targets were assessed.
Dr. Carolyn Lam:
Wow, interesting. So what did they enroll in? How did they do this? what did they find?
Dr. Greg Hundley:
Great Carolyn, so human Cardiomyocytes and cardiac micro tissue functional assays revealed that highly pathogenic A-Band Titin truncation mutations generate four shortened titin poisoned peptides and diminish full length, titin protein levels. While less pathogenic I-band titin mutations only diminish titin protein levels. And so Carolyn, the authors developed a one and done, genome editing therapeutic approach using CRISPR technology to repair the reading frame of Titin truncation mutations in cardiomyocytes. And therefore these genome editing therapeutics could correct the underlying genetic lesion responsible for dilated cardiomyopathy due to these Titin mutations.
Dr. Carolyn Lam:
Wow. Interesting. One and done genome editing. You learn something new every day with circulation. You've got another paper?
Dr. Greg Hundley:
Yes, Carolyn. Thank you. And so this paper comes to us from Dr. Beiyan Zhou From the Yukon health, school of medicine and again, from the world of preclinical science. So Carolyn, while several interventions can effectively lower lipid levels and people at risk for atherosclerotic cardiovascular disease, cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to this cardiovascular event risk. Now monocytes and macrophages play central roles in atherosclerosis, but previous work has yet to provide a detailed view of macrophage populations involved in increased atherosclerotic cardiovascular disease risk.
Dr. Carolyn Lam:
Huh? Okay. Well, I'm super excited to hear what these investigators did Greg.
Dr. Greg Hundley:
Right, Carolyn. Well these authors developed a novel computational program. They call AtheroSpectrum, which identified a specific gene expression profile associated with inflammatory macrophage foam cells. And additionally, a subset of 30 genes expressed in circulating monocytes jointly contributed to the prediction of symptomatic atherosclerotic vascular disease. So therefore Carolyn, in the future, perhaps incorporating this new pathogenic foaming gene set with known risk factors may significantly strengthen the power to predict atherosclerotic cardiovascular disease risk.
Dr. Carolyn Lam:
Wow. Super interesting and well summarized. Thank you, Greg. Well also in today's issue, there's a Perspective by Dr. Kirtane on “The Long-Awaited Revascularization Guidelines are Out. What's In Them?” A Research Letter by Dr. Laffin on rise in blood pressure observed among us adults during the COVID 19 pandemic.
Dr. Greg Hundley:
Very Nice Carolyn. Well in our Cardiovascular News Segment, there's a piece on metabolic risk factors and how they drive the burden of Ischemic heart disease. Well, what a great issue here and now, how about we get onto that feature discussion?
Dr. Carolyn Lam:
Very Cool. Closure devices after TAVR. Here we go.
Dr. Greg Hundley:
Well, listeners welcome today to our feature discussion and we have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we are going to discuss some issues pertaining to transcatheter aortic valve replacement, in terms of access to the arteries in the lower extremity. Welcome Mohamed. And can you start with, what was some of the background that led you to perform your study and what was the hypothesis that you wanted to address?
Dr. Mohamed Abdel-Wahab:
Thank you, Greg. And thank you for having me here. So as you mentioned, there are several cardiovascular procedures that currently require large-bore arterial access. The most common of these procedures is transcatheter aortic valve replacement. But there are other procedures as well, like endovascular aortic repair, mechanical circulatory devices. All of these require large-bore arterial access and of course, closure afterwards. And what we were interested in looking at was whether different types of vascular access site closure devices or strategies behave differently in the setting. Particularly in the setting of transcatheter aortic valve replacement. The reason behind this is that for many years, we only had one technique, to percutaneously close arterial access sites after these procedures. And these were mainly based on suture based devices or suture based techniques. Very recently, alternative techniques based on collagen plugs have been introduced.
Dr. Mohamed Abdel-Wahab:
And we know these types of devices or closure techniques from usual coronary intervention procedures for smaller access sites or for smaller sheath size. But they have been developed a step further for these large-bore procedures. These newer devices, particularly what we call the MANTA device, which is based on the collagen plug has been shown in initial visibility studies and also in registry based analysis to be very safe and effective. It leads to a very rapid hemostasis. And data from observational studies have suggested that it may be even superior to the suture based techniques, largely based on what we call the ProGlide device or the [inaudible 00:10:56]. And this is actually what we were aiming to look at. To compare these two different strategies based on two different devices. The suture based, the classical suture based technique using two ProGlides compared to the newer plug based technique using the MANTA in a population treated with TAVR.
Dr. Greg Hundley:
Very nice. And describe for us, your study design. And then also maybe explain a little bit more about the study population. Who did you include in this study?
Dr. Mohamed Abdel-Wahab:
So the design was more or less, very inclusive. So we designed the trial to more or less represent real word population. More or less [inaudible 00:11:40] population receiving transcatheter aortic valve replacement. So we included patients, of course where the procedure is being thought to be indicated and feasible by a multidisciplinary heart team. And also where the heart team thought that the transfemoral access route, which is the main route for the majority of patients, is obtainable and use of a percutaneous closure device is also possible.
Dr. Mohamed Abdel-Wahab:
Of course we had some exclusions. For example, patients where the use of a surgical access technique was necessary. They couldn't be naturally included in the trial. Patient that already had complications related, for example, to previous coronary angiogram PCI at the access site, they couldn't be included. But we were more or less, very inclusive in this trial. The trial population reflects the patients that are currently being treated with TAVR, so more or less an elderly population. More or less equally split-by males and females, which is very particular, again to the TAVR population. So this is a little bit different than the population that receives PCI, where we usually have a predominantly male population. This is not the case here. So these are the broad lines. Also reflecting current practice, the population that has been included in the trial is more or less overall, an intermediate risk population, when you look at the surgical scores.
Dr. Greg Hundley:
Very nice. So this was multicenter and then also patients were randomized to each of the two therapies, I believe. And was that a one to one randomization?
Dr. Mohamed Abdel-Wahab:
Exactly. So it was a multicenter trial. Patients were randomized between these two techniques. We mentioned the ProGlide based and the MANTA based in 1:1 fashion. And steering committee of course was more or less dominated by interventional cardiologists. Of course, in the context of this particular trial setting, the trial was only performed in Germany and it was an investigative initiated trial, not sponsored by the industry.
Dr. Greg Hundley:
Very nice. And can you describe for us, Mohamed, your results?
Dr. Mohamed Abdel-Wahab:
Yes. We actually hypothesized based on the observational data we have, that we will have less vascular complications with the MANTA based technique or the collagen based technique. At the end of the day, what we observed is completely the opposite. So the primary endpoint of the trial, which was what we call major and minor vascular complications defined according to the standardized criteria provided by the valve academic research consortium. These events occurred significantly more common in patients that were randomized to the MANTA based technique, as opposed to the ProGlide based technique, which was statistically significant.
Dr. Greg Hundley:
And did you observe those results across both the men and the women? And also, were there any differences in the results related to participants' age?
Dr. Mohamed Abdel-Wahab:
Yeah. So there were no interactions with various subgroups, both the predefined ones, including age and sex, as you mentioned. But also we looked at some post hoc subgroups, including for example, whether this is being affected by the size of the access vessels or by the presence and location of calcification, for example. But there were no interactions in all subgroups we looked at, with one exception which was chronic renal insufficiency. But all other subgroups showed actually no significant interaction, favoring the suture based, ProGlide based technique in all subgroups.
Dr. Greg Hundley:
Very good. And so can you describe in terms of, for individuals performing TAVR procedures and obtaining access, how do we use the results of your study to inform how we might move forward with closure of the artery in the future?
Dr. Mohamed Abdel-Wahab:
I mean, the first thing I would like to stress is the importance of doing randomized trials in general. Because I think this is not the first time we see opposite results when we are comparing randomized evidence with the evidence from observation studies, with the known limitations of observational comparative analysis. The second thing I think is really reassuring that the suture based technique that we know and that we have been using for many years now is safe and appears to be even more effective than the newly developed plug based technique. So this is one important information I think from this trial. The third piece of information is that the recently developed plug based technique, although being inferior in the study, it still may have some advantages in selected patients. And this is what we probably need to look at in a little bit more details in the future.
Dr. Mohamed Abdel-Wahab:
For example, what we realized from the study is that it could be a good option as a bailout device. So in some cases where the suture based technique has failed in the study, the crossover to the MANTA device was successful in the majority of cases. And may lead or help avoid complex endovascular interventions and implanting for example, stents or covered stents or even doing surgery. So this is something that is a nice observation from the dataset we have, but of course needs validation in larger studies.
Dr. Greg Hundley:
Very nice. And so really you've answered, kind of one of our key questions is, your thoughts on the next study that you see needs to be performed really in this area of research?
Dr. Mohamed Abdel-Wahab:
Yeah, so I think there are several things. One thing is, again, to look at potential patient subgroups that may benefit from the plug based device from the beginning. So probably it's not something that we should be using as a default strategy based on the results of this trial. But there could be certain subgroups we need maybe to dig a little bit more into the details or subgroups, if you wish to say so. Look a little bit more granularly at some patient groups that could benefit. But as mentioned, I think that the bailout indication is a very interesting one and needs to be looked at.
Dr. Mohamed Abdel-Wahab:
Not only in the TAVR setting, but also in the setting of other procedures. Such as for example, the use of mechanical circulatory assist device or ECMOs, where it may be difficult to apply these sutures post hoc. So the sutures that we apply during a TAVR procedure and what we use in this trial, this is the so-called preclosure technique. So you apply the sutures after gaining access. Then you insert your large-bore sheaths through the procedure. And then the sutures are already there and you can close the access site, usually without problems. Which is difficult, if you obtain access, for example, with an ECMO or an Impella. And then after a couple of days, you need to close it. So the sutures are not yet in place. In this particular scenario, it may be beneficial to use a plug afterwards. Or as a bailout device as previously Mentioned.
Dr. Greg Hundley:
Very nice well listeners. We want to thank Dr. Mohamed Abdel Wahab from Leipzig Germany for bringing us this study indicating that among patients treated with transfemoral TAVR, this pure plug based vascular closure technique using the MANTA VCD was associated with a higher rate of access site or access related vascular complications. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more, please visit AHA journals dot org.
This week's Feature is a Panel Discussion. Circulation invited the Young Investigator Finalists who had a Simultaneous Publication for AHA's 2021 Sessions. Please join authors Amgad Mentias, Matthew Burrage, Shaan Khurshid, Sevedeh Maram Zekavat, and Neel Butala as they discuss their articles.
Dr. Greg Hundley:
Welcome listeners to this very special January 11th issue of Circulation on the Run. And I'm going to tell you why it's special. I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia and also associate editor at Circulation. Why is this issue special? Because we have the opportunity to speak with finalists for several of the awards that were presented or that these investigators presented for at the American Heart Association sessions. And so we have with us today, five early stage investigators and we are going to hear about each of their research projects and the manuscripts that are coming out and are published in this issue. Want to welcome all five of you and we'll introduce one at a time as we work through their research projects. And the first is Dr. Amgad Mentias from Cleveland Clinic and he was in the session competing for the Elizabeth Barrett-Connor Research Award for early career investigators in training. Welcome Amgad. And we'll start with you. Can you tell us a little bit about the background for your study and what was the hypothesis that you wanted to address?
Dr. Amgad Mentias:
Hi, Dr. Hundley. How are you? Thank you so much for inviting me today. A little background, we know that community economic distress affects outcomes in patients with heart failure. It actually affects both short term and long-term outcomes. What was not studied on a nation level before is how is that impact different or if it's actually different between different races. In White patients and Black patients and Hispanic patients, what would be the differentiated effect of community economic distress on their short and long-term outcomes with heart failure after a heart failure admission?
Dr. Greg Hundley:
Absolutely. And so that hypothesis that you were going to address, what were you hypothesizing here?
Dr. Amgad Mentias:
We were hypothesizing that each race has probably some shared risk factors but also some specific risk factors. We were hypothesizing that the community level economic distress effect on heart failure outcomes is not homogeneous or not exactly the same between all races.
Dr. Greg Hundley:
Very nice. And so what was your study design? And describe a little bit for us the study population.
Dr. Amgad Mentias:
We included the Medicare population. We included patients who were admitted with a primary diagnosis of heart failure from the years 2014 till 2019. We included patients from Black and White and Hispanic races or ethnicities. And we only included the first admission for a patient if the patient was admitted more than once during these years. That was the study population. And we had about 1.6 million White patients and about 205,000 Black patients and around 89,000 Hispanic patients.
Dr. Greg Hundley:
Great. And so was this a cohort design?
Dr. Amgad Mentias:
Yes, it was a cohort design. The study start date was when they were admitted to the hospital for our mortality outcome and when they were discharged from the hospital for readmission outcomes. And then we followed them in time up to one year.
Dr. Greg Hundley:
Very nice. And so tell us, what did you find?
Dr. Amgad Mentias:
Our primary exposure of interest, like we said, was economic distress and race and our primary outcome was three things, mortality, the second thing is readmission burden, which is number of admissions over time the patient is alive and third thing is home time how many days the patient spends at home, out of the hospital and out of skilled nursing facilities and LTACs. And we looked at these outcomes at three different points, at 30 days, at six months and at one year follow up. Initially we did an interaction and that is to see whether our hypothesis, that the effect is different or not between a race and term and the economic distress term. And the interaction was significant, in all three outcomes. Then we went deeper and we started to study each race separately and see how economic distress affects their outcomes. We defined economic distress by distress score called the distressed community index, which is a composite measure of seven things, including education of the people in the zip code, unemployment, poverty rate and income in the zip code compared to the state level and that stuff.
Dr. Amgad Mentias:
We actually found that in White patients, economic distress was actually associated with adverse outcomes in the short and long term. In Black patients, it was affecting the outcomes more robust and more evident in the long term, not in the short term. We also found the geographic location and their approximate location, whether it's urban or rural, residential zip code also affected outcomes. We found that in all races being in a rural distressed community had the highest posterity and the highest admission burden and the worst home time compared to other communities. In fact, people in distressed urban communities had comparable outcomes. People in rural, non-distressed communities had comparable outcomes to urban distressed. We found that the rural location and approximate location near resources affected outcomes in all races but specifically also in Black patients.
Dr. Greg Hundley:
Very nice. And how do you put your results in context with others that are doing research in this area?
Dr. Amgad Mentias:
We show that the interplay between economic distress and societal factors and different things for heart failure is very complex and there is a complex interplay between different factors. I think it's very important for health policies that targeting improvements in community with economic distress and access to care, they are key to improving outcomes and reducing racial disparities among patients with heart failure.
Dr. Greg Hundley:
Beautiful. Well, Amgad, we want to congratulate you on this just excellent work in identifying associations between community level economic distress and risk of adverse outcomes across different race ethnic groups. Congratulations to you.
Dr. Greg Hundley:
Well listeners, next we're going to turn to Matthew Burrage from University of Oxford. And Matt was a finalist for the Melvin Judkins Early Career Clinical Investigator Award. Matt, just like with Amgad, could you tell us a little bit about the background that went into your research project? And what was the hypothesis that you wanted to address?
Dr. Matthew Burrage:
Yeah, certainly. And thank you very much for the invitation to take part in this discussion. Really it's a pleasure to be here. The inspiration for this study was really driven by the difficulties that we've been having in trying phenotype heart failure with preserved ejection fraction or HFpEF, given that until very recently, there were really no therapeutic agents that have significantly improved outcomes for this population. This is despite the fact that around half of all heart failure is classified as HFpEF. And so the thought is that this is a very heterogeneous population but when you dig down into the physiology, there seems to be a central mechanism which involves impairment of myocardial relaxation and in a subsequent rise in intracardiac filling pressures. And this is something that's often unasked by exercise and typically this then results in pulmonary congestion and symptoms of breathlessness. And so some recent translational studies suggests that abnormal cardiac mitochondrial function and energetics may be a unifying feature in the pathogenesis of HFpEF.
Dr. Matthew Burrage:
And given that we know myocardial contraction is dependent on cardiac energy metabolism and that diastolic relaxation is even more energy dependent, we hypothesized that impairment of myocardial energetics may underpin a lot of the physiological changes in the heart that occur during exercise and thus could potentially present a metabolic basis that underlies symptoms in patients with HFpEF, with the hope that this could then lead to new translational drug targets for HFpEF in the future. But then alongside this as well, there's been some really pivotal work on pulmonary congestion during exercise in HFpEF that's been led by Barry Borlaug's group at the Mayo Clinic as the main determinant of patients' symptoms. This has been very well validated against invasive hemodynamics. The second component of our study was to see if we could noninvasively assess pulmonary congestion during exercise and HFpEF. And so to do this, we developed and implemented a new MRI sequence that could quantitatively assess changes in lung water.
Dr Greg Hundley:
Very nice. How did you address the hypothesis in terms of your study design and your methodology?
Dr. Matthew Burrage:
This was a prospective study that followed essentially a basket trial design, where we recruited four distinct groups of participants that were felt to really encompass the spectrum of worsening diastolic dysfunction in HFpEF, which was based on clinical scoring systems, blood biomarkers and echocardiography. We recruited 43 participants split across this group and so we had a cohort of age matched, healthy controls. We had patients with cardiometabolic risk factors for HFpEF like diabetes and obesity who were included essentially if you think of it like a pre-HFpEF group, patients with carefully clinically phenotyped HFpEF and then a cohort of patients with cardiac amyloidosis. And the amyloid group was recruited really as a positive control, that the proof of principle lung imaging sequences, as the presence of restrictive physiology in those patients meant they would be the group that would be far most likely to develop pulmonary congestion during exercise.
Dr. Matthew Burrage:
And so each participant underwent blood sampling, a targeted echocardiogram, they had magnetic resonance spectroscopy to assess myocardial energetics and cardiac metabolism. We do this by measuring the phosphocreatine to ATP ratio and also a cardiopulmonary exercise MRI. The exercise protocol for the study was a fixed low intensity workload of 20 Watts for six minutes with the patient supine within the MRI scanner using an ergometer. And then during exercise, we did whole heart free breathing cine stacks to assess cardiac volumes at rest and exercise, as well as performing our custom proton density weighted lung imaging sequence to look at changes in pulmonary congestion. And if you're interested, the whole rest and stress protocol together can be done within about 15 minutes.
Dr. Greg Hundley:
Wow. Boy, very exciting. Exercise during an MRI scan. Matt, we're very anxious to hear, what did you find?
Dr. Matthew Burrage:
The key findings from this study is that there really is a clear gradient myocardial energetic impairment that exists across the spectrum of diastolic dysfunction and HFpEF phenotypes of increasing clinical severity and worsening diastolic function. And this gradient of impaired myocardial energetics was associated with progressively abnormal exercise responses compared to normal physiology in the age matched controls. And so a greater degree of energetic deficit was linked to impaired left ventricular systolic and diastolic functional reserve. It was also linked to altered right ventricular reserve and abnormal RV-PA coupling and also to exercise induced pulmonary congestion.
Dr. Matthew Burrage:
And we also showed that the pulmonary congestion or changes in lung water could be quantitatively assessed using our new proton density lung imaging sequence and that there is a subgroup of patients with HFpEF who do demonstrate transient pulmonary congestion during exercise that we can assess noninvasively. Overall, the findings suggest a pathway where impaired energetics are linked to patient symptoms and they do this by limiting cardiac reserve during exercise and promoting pulmonary congestion. There seems to be a really important role of resting cardiac energetics in signaling the abnormal ability of the heart to perform high energy consuming processes like active diastolic relaxation and augmentation of contractility and then this leads of course to the downstream effects that we see.
Dr. Greg Hundley:
Very nice. And you were able to even also observe the lung water. It sounds like, help us put this in context for our listeners of how do your results really advance some of the understanding of the pathophysiology of heart failure with preserved ejection fraction?
Dr. Matthew Burrage:
I think one of the key impacts of this study is the fact that the heterogeneity of clinical HFpEF syndromes has been such a major challenge to efforts to develop new therapies to improve symptoms and prognosis in these patients. Pathophysiological phenotyping may represent an important step towards targeting the right therapies to the right patients and specifically targeting myocardial energy metabolism may be a promising therapeutic strategy to improve cardiac reserve and potentially reduce pulmonary congestion in patients with HFpEF. And this really builds on all the translational studies that exist today and have gone before it.
Dr. Matthew Burrage:
Hopefully the mechanistic insights that we get from this could lead to some new translational drug targets, which can be tested against myocardial energetics in patients to see if this metabolic substrate is modifiable. And if this then leads to improvements in symptoms and outcomes. The second aspect very quickly, relates to the evaluation of patients with breathlessness, particularly because invasive hemodynamic assessments may not be possible in all patients who have breathlessness on exertion. The lung water imaging represents a potentially new diagnostic tool that can help to differentiate HFpEF from other causes of dyspnea and I think this is some something that may have a lot of direct clinical applications for patient diagnostics for a wide range of conditions in future.
Dr. Greg Hundley:
Very nice. Well, thanks so much for what outstanding work, identifying this myocardial energetic deficit and then linking that to both cardiac performance, as well as the development of pulmonary congestion.
Dr. Greg Hundley:
Well listeners, we are going to switch to our third author today, Dr. Shaan Khurshid from Mass General and Shaan was a finalist for the Samuel A. Levine Early Career Investigator Award. And so, Shaan, can you give us a little bit of the background information pertaining to your study? And what was the hypothesis that you wanted to address?
Dr. Shaan Khurshid:
Thanks for having me, it's a pleasure to be here. A little bit of background that predicting the risk of atrial fibrillation or AF, may increase the efficiency of AF screening and effectively prioritize individuals for preventive interventions that are designed to reduce the risk of incident AF in the first place. And to that end, risk of AF can be estimated with reasonable accuracy using clinical factors. We already know that. And for example, the CHARGE-AF score is a well validated score that been used in multiple settings. More recently, work suggests that artificial intelligence or AI enabled analysis of the 12 lead electrocardiogram can extract latent information that may be relevant for predicting AF risk. Past models however, have had some limitations. They've utilized very short time intervals. They have not incorporated survival time and censoring with is important for prognostic models. They are kind of a black box and therefore difficult to interpret and they haven't undergone a broad external validation.
Dr. Shaan Khurshid:
Therefore, in this current study, we sought to develop a deep learning model, utilizing the 12-lead ECG to predict risk of incident AF at five years. We call this model ECG-AI quote unquote and compared the performance of ECG-AI directly to the CHARGE-AF clinical risk score that I was mentioning. We also sought to assess a model that combines both ECG-AI and CHARGE-AF to each score alone. We hypothesized that the ECG-AI model utilizing 12-lead ECG could improve the ability to predict five year AF risk as compared to clinical risk factors alone. And we felt that such a model may have practical applications, particularly since wearable devices like smart watches are increasingly able to provide single lead ECGs.
Dr. Greg Hundley:
Really nice. Sounds like a very interesting application of artificial intelligence with electrocardiograms in assessing patients with atrial fibrillation. Can you describe for us your study population and your study design?
Dr. Shaan Khurshid:
Of course. We trained our models utilizing a retrospective cohort. The training population was 45,000 individuals receiving regular primary care at Massachusetts General Hospital or MGH. We then validated our models in three completely independent samples, an MGH internal test set, so individuals from MGH but were not included in training, a separate set of primary care patients at Brigham and Women's Hospital and the UK Biobank Prospective Cohort Study in the UK. The total population in which the models were validated was over 83,000. ECG-AI itself was trained as a convolutional neural network, which was inputted with 10 seconds of the 12-lead ECG and utilized a specialized loss in encoding function that incorporated survival time and censoring in order to produce a five year risk estimate for each individual. We trained models utilizing all ECGs available for each person but evaluated the models utilizing a single ECG alone. We compared each model, ie. ECG-AI, CH-AI and CHARGE-AF by incorporating risk estimates into analogous Cox proportional hazards model so we could compare them apples to apples and calculated traditional epidemiologic metrics of prognostic model performance, including discrimination, calibration and reclassification.
Dr. Greg Hundley:
Very nice. And so what did you find, John?
Dr. Shaan Khurshid:
From our study, we had two major findings. First, the ECG-AI model consistently discriminated five year AF risk comparably to the CHARGE-AF 11 component clinical risk score with C statistics ranging from 0.7 to 0.8. Second, the CH-AI model, which was the combination of ECG-AI and CHARGE-AF, consistently offered greater discrimination than either model alone. Both AI models were very well calibrated across the three test sets with calibration error consistently less than 1%. The ECG-AI and CHARGE-AF scores were moderately correlated, suggesting that the AI model is able to leverage clinical risk factor information extracted from the ECG, yet also adds something further.
Dr. Shaan Khurshid:
Saliency analyses, which are a method of determining which areas of the ECG are most relevant for the model's prediction, highlighted the P-wave and surrounding regions, which provides important evidence of biologic plausibility in our models. Importantly, in sub-analyses assessing the AI models, including only one lead of the 12-lead ECG, we found that model performance was similar, suggesting that AI models utilizing only single lead ECGs may also be effective. We also found that the models performed reasonably well in individuals with prevalent heart failure and stroke, which are populations in whom AF risk destination is particularly relevant.
Dr. Greg Hundley:
Very nice. And so clinically, moving forward, how do we put your results in the context of really where you see this field moving and how we might use it to identify patients at risk of atrial fibrillation?
Dr. Shaan Khurshid:
We're excited. Our work we think provides an important demonstration that ECG-AI based models can utilize a 12-lead ECG to estimate future risk of AF up to five years. And importantly, the AI models were generalizable, providing good discrimination across three large and independent datasets spanning two continents. We're most excited about this finding that models perform well when utilizing single lead ECG data alone, which has important ramifications for wearable devices. In particular, one could imagine a future application of AI in which a wearable device is able to not only be used to screen for atrial fibrillation or AF, but also stratify an individual's risk for AF utilizing ECG based analysis and therefore potentially prioritizing that individual for preventive interventions and also potentially determining how intensely to screen that individual all in a single closed group.
Dr. Greg Hundley:
Excellent. Wow, Shaan, just beautiful presentation, listeners. Really discussing how the artificial intelligence assessment of these EKGs may enable efficient quantification of the future risk of developing atrial fibrillation.
Dr. Greg Hundley:
Well listeners, we're going to turn now to our fourth presenter, Maryam Zekavat from the Bird Institute, Yale University. And Maryam was a finalist for the Genomic and Precision Medicine Council's Early Career Investigator Award. Welcome Maryam. And can you describe for us some of the background pertaining to your study? And what was the hypothesis you wanted to address?
Dr. (Sevedeh)Maryam Zekavat:
Absolutely. And thank you for the invite to be part of this podcast. The title of the work that we presented and that was published in Circulation is Deep Learning of the Retina Enables Phenome and Genome-wide Analyses of the Microvasculature. And so as a little bit of a background, we know that the microvasculature has key roles in maintenance of organ health and that microvascular disease is implicated in conditions across all organ systems. Here, to study the human microvasculature noninvasively, we used data across about a 100,000 retinal fundus photographs. And the purpose of our work was really to address two main things.
Dr. (Sevedeh)Maryam Zekavat:
First, an unbiased assessment of the phenotypes associated with the retinal microvasculature had yet to be performed and that motivated us to ask our first question, namely, what information can the retinal vasculature provide on future ocular and systemic disease risk? And then secondly, therapies such as anti-VEGF, which pharmacologically influence vascular density, are the mainstay of treatment for multiple ocular conditions, including wet AMD, proliferative diabetic retinopathy, as well as many cancers. However, an unbiased screen of genetic targets for other treatments that may influence the microvascular has yet to be performed. And so that motivated us to ask for our second question, namely, what genes influence the retinal vasculature? And so from there, I'll go to our hypothesis, which was that analyses of retinal fundus photos may enable an understanding of the connection between microvascular geometric indices, diseases and genetics.
Dr. Greg Hundley:
Very nice. And so boy, I heard you had almost a 100,000 participants involved in this study. Tell us a little bit about your study design and clarify for us, where did you get all these patients from? What was your study population?
Dr. (Sevedeh)Maryam Zekavat:
Yeah, of course. The study list we utilized the UK Biobank, which is a cohort of half a million individuals, including over a 100,000 fundus photographs from about 50,000 individuals. We first implemented deep learning to remove poor quality images and then to segment out the vasculature fundus photos. And then from there, we went on to quantify two vascular features, branching complexity as measured using fractal dimension and also vascular density. And lastly, we performed phenome and genome-wide association studies to understand how these vascular geometric indices influenced disease risk and what genetic factors influence the vasculature.
Dr. Greg Hundley:
Excellent. And tell us, what did you find?
Dr. (Sevedeh)Maryam Zekavat:
Yeah. First using deep learning, we were able to successfully perform image quality control and vessel segmentation to extract two geometric features of the retinal vasculature. Next through phenome-wide analyses, we identified that lower retinal vascular fractal dimension and density were significantly associated with higher risk for incident mortality, as well as cardiometabolic conditions, including hypertension and type 2 diabetes, heart failure and renal failure among others. And also multiple incident ocular conditions, including future risk of retinal detachment. Thirdly, genome-wide association of these two geometric indices identified seven and 13 novel loci associated with vascular fractal dimension and vascular density respectively. And these were enriched in pathways linked to angiogenesis, such as VEGF, angiopoietin and WNT signaling pathways, as well as inflammation via interleukin and cytokine signaling. And then fourth, through Mendelian randomization for genetic causal inference analysis, we identified that a genetic risk for hypertension and type 2 diabetes is associated with lower microvascular density and that a genetic risk for lower microvascular density is associated with increased risk of retinal detachment.
Dr. Greg Hundley:
Wow. Really interesting. The intersection of this beautiful phenotype characterization of the retina with this genetic information. Where do you see this research moving forward in the future?
Dr. (Sevedeh)Maryam Zekavat:
Yeah, so clinically these findings may support the use of retinal microvascular indices for risk prediction and disease monitoring of systemic and ocular conditions. And of course, further assessment of the identified biological pathways influencing the microvasculature can potentially lead to therapies for not only retinopathies but also other conditions linked to microvascular disease, including oncologic, renal and cardiovascular conditions. And more broadly, our results illustrate the potential for using deep learning on retinal imaging to understand the microvasculature with wide applications across diseases. And of course, more research is needed to evaluate the added benefit, in addition to existing clinical predictors and the feasibility for incorporation into clinical workflows.
Dr. Greg Hundley:
Just beautiful. And thank you so much Maryam and for highlighting for us, the results of your study, indicating that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights on genes and biological pathways that influence microvascular indices.
Dr. Greg Hundley:
Well listeners, now we are going to turn to our last speaker today and it's Dr. Neel Butala from Mass General, Beth Israel. And he also was a finalist for the Samuel A. Levine Early Career Investigator Award. Welcome, Neel. And could you describe for us the background pertaining to your study and what hypothesis did you want to address?
Dr. Neel Butala:
I appreciate the opportunity to be here and chat with you. And so there's conflicting evidence on the optimal duration of dual anti-platelet therapy, which is DAPT, after drug eluting stent implantation. Older studies, such as the DAPT study show fewer ischemic events with more bleeding, with longer DAPT duration and our site and the guidelines for DAPT duration after PCI but newer studies show similar ischemic events and actually less bleeding with shorter DAPT, even among those with high ischemic risk at baseline. We wondered whether the DAPT study, which is the only study powered to detect ischemic endpoints and still influences a major cardiovascular guidelines still applies to contemporary practice.
Dr. Neel Butala:
And so we asked two key questions. Now, number one is a US contemporary real world population of patients receiving PCI, different from the DAPT trial population. And again, the DAPT trial enrolled between 2009 and 2011. And here we hypothesized that the populations are probably a little different. And number two, we asked how would trial treatment effects change if a real world population had been enrolled instead? And here we hypothesized that perhaps the ischemic benefit of longer DAPT would actually go away, would be similar to the newer trials that have been done.
Dr. Greg Hundley:
Very nice. And describe for us your study design and your study population.
Dr. Neel Butala:
Yeah. We compared characteristics between DAPT study patients, with those of a more contemporary real world cohort of NCDR cath PCI registry patients. And to do this, we used novel transportability methods to really create a propensity score model to predict an individual's likelihood of trial participation based on patient characteristics. And this type of propensity score model actually gives us inverse probability weights, which we used to reweight the DAPT study patients based on the distribution of characteristics in the real world patients. The intuition here is really to up weight the trial patients with characteristics more common in the real world and down weight trial patients with characteristics less common in the real world. We then compared treatment effects in the DAPT study patients with those of the reweighted DAPT study patients to understand whether DAPT study results would change if a real world population had been enrolled instead.
Dr. Greg Hundley:
Very nice. And what were the results associated with these comparisons?
Dr. Neel Butala:
First, we found that trial and real world populations were different. We found that the contemporary real world population was older, less likely to be White, more likely to have comorbidities and then more likely to present with ACS. Additionally, nearly a 100% of real world patients received a second generation drug eluting stent versus only 58% of trial patients. And then these differences led to differences in the estimated average treatment effects of DAPT, to the results of the DAPT study. And the real world treatment effect in reducing ischemic endpoints is actually no longer present but the increase in bleeding persisted. And so we found that the average top line treatment effect in the DAPT study may not be applicable to contemporary practice. We did find however, the DAPT score in the subgroup did still identify subsets of patients who may benefit from prolonged DAPT beyond one year after PCI in the contemporary population.
Dr. Greg Hundley:
Very nice. And so clinically as we're managing patients, how would we interpret your results and help us with clinical management today?
Dr. Neel Butala:
Yeah, great question. These results really harmonize the DAPT trial with results of newer clinical trials of DAPT duration, which all demonstrate the safety of shorter duration DAPT to reduce bleeding risk and these results more broadly illustrate the importance, the nuance interpretation of clinical trials to guide clinical decision making and really highlight the risk of simply applying the top line trial results to all patients in contemporary practice, even beyond the study. These results emphasize the importance of accounting for patient specific factors and leveraging risk scores when available in deciding how clinical trials results actually apply to a particular patient. And finally, the results actually illustrate the importance of continually evaluating the generalizability of cardiovascular trials to ensure that the guidelines reflect treatment effects in contemporary clinical practice. And the methods that we use in the study can actually be used to do this in RCTs more broadly.
Dr. Greg Hundley:
Very nice, Neel. And thank you for really bringing us this study highlighting the differences between patients and devices used in contemporary clinical practice compared with those in the DAPT study. And how they were associated with attenuation of benefits and greater harms attributable to prolonged DAPT duration.
Dr. Greg Hundley:
Well listeners, what an exciting day. Getting to see these papers in print and also have these early stage investigators from the 2021 sessions that were finalists in many of these competitions, we're so grateful to Amgad Mentias, Matt Burrage, Shaan Khurshid, Maryam Zekavat and Neel Butala for their time today.
Dr. Greg Hundley:
On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
Please join author George Dangas and Associate Editor Brendan Everett as they discuss the article “Colchicine in Cardiovascular Disease.”
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley: Welcome, everyone, to 2022. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Carolyn, oh, we're starting off the year with a twist on the feature article. It's a review article on colchicine and cardiovascular disease.
But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue?
Dr. Carolyn Lam: Absolutely. The new year is starting off with a bonanza issue. This first topic is so important. We know that various non-invasive, intermittent rhythm monitoring strategies have been used to assess arrhythmia recurrences in atrial fibrillation ablation trials. But the question is, what is the frequency and duration of non-invasive rhythm monitoring that accurately detects arrhythmia recurrences and approximates the atrial fibrillation burden derived from continuous monitoring using the gold standard, implantable cardiac monitor?
Now to answer this question, investigators Jason Andrade and colleagues from the Montreal Heart Institute, who looked at the rhythm history in 346 patients enrolled in the CIRCA-DOSE trial. They reconstructed the rhythm history using computer simulations and evaluated event-free survivals, sensitivity, negative predictive value, and AF burden in a range of non-invasive monitoring strategies including those used in contemporary AF ablation trials.
Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they find?
Dr. Carolyn Lam: Detection of arrhythmia recurrence following ablation was highly sensitive to the monitoring strategy employed between trial discrepancies and outcomes, in fact, may reflect these different monitoring protocols. Binary efficacy outcomes, such as time to AF recurrence, appeared to underestimate the true impact of catheter ablation on the burden of atrial arrhythmia.
The most commonly performed intermittent rhythm monitoring techniques, like short duration 24- or 48-hour ambulatory Holter, they do miss a substantial proportion of arrhythmia recurrences and significantly overestimate the true AF burden in patients with recurrences. So based on measures of agreement, serial long-term, that is four seven-day or two 14-day intermittent monitors accumulating at least 28 days of annual monitoring provide estimates of AF burden that are comparable with the implantable cardiac monitor.
However, implantable cardiac monitors outperform intermittent monitoring for arrhythmias and should be considered the gold standard for clinical trials.
Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of clarification on monitoring of AF burden. Well, my first paper comes to us from Dr. Prabhakara Nagareddy from The Ohio State University, The Wexner Medical Center.
Carolyn, acute myocardial infarction results in an overzealous production and infiltration of neutrophils in the ischemic heart, and this is mediated in part by granulopoiesis induced by the S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed neutrophils.
In this study, Carolyn, the investigators evaluated a hypothesis as to whether IL-1 beta is released locally within the bone marrow by inflammasome prime and reverse migrating neutrophils.
Dr. Carolyn Lam: Ah, okay. So what did they find, Greg?
Dr. Greg Hundley: Okay, Carolyn. In response to myocardial infarction, the NLRP3 inflammasome prime neutrophils upregulated CXCR4 and reverse migrated to the bone marrow, where they adhered to adhesion molecules like P-selectin on the bone marrow endothelial cells.
Second, Carolyn, in the bone marrow, the inflammasome prime neutrophils released IL-1 beta through gasdermin-dependent conduit pores without undergoing the mandatory pyroptosis.
Third, genetic and/or pharmacological strategies aimed at limiting reverse migration of inflammasome prime neutrophils to the bone marrow or release of IL-1 beta, both suppressed granulopoiesis and improved cardiac function in mouse models of myocardial infarction.
So Carolyn, therefore, strategies aimed at targeting specific signaling pathways within the neutrophils or reducing retention of the inflammasome prime neutrophils in the bone marrow may provide novel avenues to regulate inflammation and improve cardiac outcomes.
Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so nicely. Well, the next paper deals with my favorite topic, heart failure with preserved ejection fraction of HFpEF, and this time looks at mechanisms of sinoatrial node dysfunction.
The investigators, led by Dr. Cingolani from Smidt Heart Institute at Cedars-Sinai Medical Center, sought to investigate the role of the intrinsic pacemaker on chronotropic incompetence in HFpEF. They performed extensive sinoatrial node phenotyping, both at baseline and after stress in the well-characterized Dahl salt-sensitive rat model of HFpEF.
These rats exhibited limited chronotropic response associated with intrinsic sinoatrial node dysfunction, including impaired beta-adrenergic responsiveness and an alternating leading pacemaker within the sinoatrial node. Prolonged sinoatrial node recovery time and reduced sinoatrial node sensitivity to isoproterenol were confirmed in the two hit mouse model. Adenosine challenge unmasked conduction blocks within the sinoatrial node, which were associated with structural remodeling.
Finally, single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the membrane clock or iron channels and the calcium clock of the spontaneous calcium release events.
Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data here. So what were the clinical implications?
Dr. Carolyn Lam: Yeah, it's a really great study. Two models of HFpEF-consistent result in an important topic. Basically, here at the take-home messages. Provocative testing can be valuable to elicit functional abnormalities to facilitate HFpEF diagnosis and considering the exceptionally high clinical and epidemiologic convergence between AFib and HFpEF, sinoatrial node dysfunction may underlie the development of abnormal atrial rhythms in HFpEF.
Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF, again, one of your favorite subjects. Next, we're going to turn to a paper from Dr. Jian Li from the Peking Union Medical College Hospital. Carolyn, doxycycline has previously been demonstrated in a retrospective study to be associated with greater survival in patients with light chain AL amyloidosis.
Therefore, Carolyn, this group prospectively compared the efficacy of bortezomib, cyclophosphamide, dexamethasone, or cyclophosphamide B or D, and cyclophosphamide B or D combined with doxycycline for cardiac amyloidosis.
Dr. Carolyn Lam: Cool. So what did they find, Greg?
Dr. Greg Hundley: Carolyn, this was a multi-center, open-label, randomized controlled trial, and 140 patients underwent randomization. The primary outcome was two-year progression-free survival. Progression-free survival was defined as the time from randomization to death, hematologic progression or organ progression, and that's the heart, the kidney, or the liver.
And so Carolyn, these investigators in this trial demonstrated that doxycycline combined with cyclophosphamide B or D failed to prolong progression-free survival or cardiac progression-free survival compared with cyclophosphamide B or D alone in patients with cardiac AL amyloidosis.
So Carolyn, a negative study that's quite informative and a very nice editorial that accompanies this article pertaining to future directions for management of AL cardiac amyloid.
Dr. Carolyn Lam: Indeed important. Thank you. And there are other important papers in today's issue. There's a Research Letter by Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial.
Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got a big list today. First, Dr. Churchwell has an AHA update on the need for policy change to improve maternal cardiovascular health. Next, Dr. Piazza has a Perspective piece on expanding the role of coronary CT angiography in interventional cardiology. There's an ECG challenge from Dr. Yarmohammadi entitled “Dancing Bundles with Stable Sinus Rhythm.” And next, we have our own Darren McGuire who, in this issue for all of 2021, is really recognizing our outstanding reviewers.
And we want to thank all the listeners and everyone that reviews for us in this journal. Such an important feature and aspect to the publication of the wonderful articles that we receive. And then finally, there are some highlights from the circulation family of journals. Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and its use in cardiovascular disease.
Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone.
Dr. Greg Hundley: Welcome listeners to this January 4th feature discussion. This week, we're deviating a little bit because we are going to have an author discuss one of our in-depth reviews. As you know, we select those occasionally where they're is a topic that's very relevant in cardiovascular medicine and an investigator or team of investigators or authors will put together a very nice review of a topic.
This week, we're going to talk about colchicine, and we have with us Dr. George Dangas from the Icahn School of Medicine at Mount Sinai and our associate editor, Dr. Brendan Everett, who manages this paper and he is from Brigham and Women's Hospital. Welcome, gentlemen. George, we'll start with you. George, why colchicine? Can you tell us a little bit about mechanism of action? Tolerability? Why would we want to use this particular agent in patients with cardiovascular disease?
Dr. George Dangas: Thank you very much for the opportunity to join this interesting podcast. Colchicine is indeed an interesting drug. It's been around for centuries, in all honesty. In general, I would say it's a mild anti-inflammatory and in general, it's rather well tolerated. We'll go into those perhaps a little bit later.
The precise mechanism is actually interestingly not quite defined. It may have a few ways to act by blocking perhaps the chemotaxis of the leukocytes or the adhesion of the leukocytes or the ability to release their granules, et cetera, but there isn't a specific major one that is targeting. Perhaps, it's targeting more than one mechanism in a mild way, and I think that goes into each utility, as well as the absence of the major side effect that might limit it.
Dr. Greg Hundley: Very nice. So you started to mention the word utility, so maybe let's go through some clinical indications, or clinical uses perhaps rather than indications, can you tell us a little bit about its use in individuals with pericarditis?
Dr. George Dangas: I think this is where it started to enter the cardiovascular field because we all recognize that pericarditis is an inflammatory disease and inflammation of the pericardium of different reasons perhaps. And anti-inflammatory drug is rather fitted to treat an inflammatory disease and besides, it's not like we had any other drug, in all honesty. Clearly, recurrent pericarditis might be treated with steroids for example, but steroids is not something any cardiologist would jump as a first line and give high doses and all that.
Colchicine made its way to pericarditis like acute or recurrent pericarditis, post-cardiac cardiology syndrome, restless syndrome or the specific post-cardiac surgery, major inflammation. And indeed has a daily dosage perhaps with some loading dose or double the daily dosage or something initially and then we give it for a prolonged period of time in order to suppress.
I would say this is a reasonable choice rather than jumping to the steroid. And of course, you reserve the steroid for the, I would say, more severe or more recurrent cases. I think everybody understands this type of activity. There've been quite a few clinical studies in this aspect. Again, in the absence of a competitor, I think it's a winner in this area.
Dr. Greg Hundley: Very nice. And then, how about atrial fibrillation? Are there uses of this colchicine in patients with atrial fibrillation?
Dr. George Dangas: Well, again, it's very interesting that a lot of atrial fibrillation, it may be in some ways inflammatory in origin. And quite frankly, we had an interesting [inaudible 00:14:50] clinical trial in American Heart Association in 2021. I'd like to point out here, the study that postoperative atrial fibrillation was mitigated when, during cardiac surgery, there was a slicing of the posterior pericardial. This allowing the inflammation in some ways that's related there.
To me, that was a very interesting observation, though I related to colchicine because it validates the fact that there is something inflammatory in pericardial that related with the postoperative atrial fibrillation. So along these lines, let's go back to colchicine, Afib, and postop Afib, and post-ablation I would say patients. Again, there are risks of some inflammation and that's where the theory of a mild, rather well-tolerated, anti-inflammatory might come in. And there's been few studies, not a large definitive study, but several studies that are the, I would say, component with interesting results with colchicine in these patients.
Dr. Greg Hundley: Very good. Another area of cardiovascular disease that's emerging literally with some demonstrable results using colchicine is the realm of ischemic heart disease. Can you walk us through some of the utility myocardial infarction or maybe even post-percutaneous coronary artery intervention?
Dr. George Dangas: Again, the hallmark in this type of diseases, cardiovascular disease or coronary heart disease, is the hallmark of role of inflammation in this disease. And we know very well from the studies of the C-reactive protein, importance is a marker of inflammation. Very, very important in the CAD as well as in even the treatment with the antibody canakinumab a little bit earlier in the CANTOS trial a few years earlier at the very high level inhibited inflammation had a benefit and colchicine comes in maybe a milder anti-inflammatory about this agent, but at the same time with significantly less cause and significantly better recognition among the clinicians and a lot less, I would say, tolerability problems or issues are less unknowns. And I think that's where it comes in.
The difficulty has been that whenever you go to cardiovascular, the cardiovascular, I would say coronary artery disease specifically, ACS and all that, the level evidence required for the doctors to believe in a therapy is very different than the areas we discussed before where there's little bit of a pericardial disease, for example, not that many drugs, all of a sudden, coronary artery disease, the bar is so high, and that's where the difficulty has been.
There've been several studies. They've been interesting results with some benefits, particularly due to the decrease in inflammation and the secondary prevention, one can say. That is really the hallmark of where it aims to benefit in the secondary prevention, but there hasn't been one massive study with clearly superb results. I would say adequately powered single study that is missing in some ways.
But several studies have been, again, very, very encouraging, but we learned that there's no much point if loading a lot of doses of high doses of colchicine, and it's a little bit better, again, when you aim with a daily dose towards reduced recurrences, particularly if you started early after an acute event.
Dr. Greg Hundley: Very nice. Well, listeners, we're going to now turn to our associate editor, Dr. Brendan Everett, from Brigham and Women's Hospital. Brendan, you have a lot of papers come across your desk. First and foremost, what attracted you to this particular article?
Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and his team for putting together a really nice paper. It's great to have this kind of paper come into my inbox. That's specifically because colchicine, I think, has exploded as a really important novel therapy even though the therapy itself is perhaps hundreds of years old, as you heard George say a moment ago, but its role in treating cardiovascular diseases has really begun to emerge rapidly.
I think there's a tremendous amount of enthusiasm for other ways to treat our patients who have really a recalcitrant cardiovascular disease, whether that's pericarditis, atrial fibrillation or I think, importantly, ischemic heart disease, because that's such a common disease and something where we're always looking for new ways to help patients live longer with fewer recurrent events. And so this paper I thought did a really good job of capturing the existing evidence for these conditions and some others and giving us a sense of where the strengths of that evidence lay and where the weaknesses were.
I thought particular strength was in the tables where the authors laid out each of the trials and the results of the trial, their endpoints, where the benefit was potentially. And also importantly, where risks were seen because I think that's one of the really important questions that remains open with respect to colchicine therapy when we begin to talk about using it in a vast population of people with stable ischemic heart disease or post-myocardial infarction ischemic heart disease.
Dr. Greg Hundley: Brendan, tell us a little bit about those risks.
Dr. Brendan Everett: I'd be happy to do that. I want to emphasize before I dive in that I think the benefits that George has laid out are important, and I don't want to overshadow what the major trials have seen. But I think the thing that it is at least a little bit of the fly in the ointment, if you will, for colchicine in ischemic heart disease is that a couple of the large trials have shown an increased risk of non cardiovascular mortality or bad non-cardiovascular outcomes.
And that's of concern, I think, as we saw in the CANTOS trial, which was the monoclonal antibody trial for canakinumab that George mentioned earlier, there was an increase in infection-related mortality. And so whenever you use an anti-inflammatory drug, you're worried about whether or not you're blunting other compensatory mechanisms that the body has to protect against infection and other diseases.
I think it's likely that these findings are the play of chance, but we don't know for sure. For example, in the COLCOT trial, which I think is probably the largest and most interesting trial, which was designed and run in Canada, there was a slightly higher level of pneumonia in patients who got active therapy as compared to placebo.
And then, two of the trials that were published more recently including LoDoCo2, which was a trial of about 5,000 patients run in the Netherlands and Australia. There was actually a marginally increased risk of non-cardiovascular mortality. That didn't reach statistical significance, but it was awfully close, and I think it gave people some concern.
And then, there was also the COPS trial. Again, all these are really outlined in wonderful detail in the manuscript where there was a slight increase of total death and non-cardiovascular death. These events are few, but they're in a direction in two trials, and so they make people a little bit worried. I think the other thing that I noticed was the high prevalence of myalgia as a side effect.
I think, Greg, you're always interested in the clinical implications and yesterday I was in clinic and saw a young patient who had had pericarditis. He had been prescribed colchicine by his primary care physician, and he literally couldn't stand and walk up straight because of the amount of abdominal pain he had, which was unusual. To be honest, I've given colchicine to a hundred patients at least, and none of them have had that profound of a side effect, but it's at least worth considering that some patients will not tolerate the therapy because of adverse effects.
Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for each of you, first George and then Brendan. George, balancing some of the efficacy and then some of the concerns, what do you see is the next studies to be performed really in this sphere of research?
Dr. George Dangas: This is a great question. And indeed, the concerns one can say or the issues, I would say, regarding this drug, are indeed real because any drug that suppresses inflammation has this risk. There are two ways one can address those. One is with term administration. You don't prescribe it as an annuity forever, but you prescribe it in a three- to six-month or one-month or try to control the time. I think this is done in clinical practice, in all honesty.
I don't think that people are prescribing colchicine for life. Same way when we prescribe statins, for example. On the other hand or from investigational point of view, I think the two sets of information we need and, in all honesty, when you investigate issues regarding mortality or these are rare events, there's only one. You need a very large trial or a very large register. A very large trial preferably and colchicine being an often genetic drug, funding sources are rather limited, but we have NIH chipping in with some funding periodically and that might really be needed.
So I want to outline that in the last table of our very large, I would say large table of our manuscript but were very happily outlined many ongoing trials. There are, in atrial fibrillation, three coronary artery disease. One in PCI and two in stroke. Something we didn't touch up again. But again, there's the question of inflammation in stroke. I think there's a lot of work ongoing. Perhaps you can see some meta-analysis, again, in order to get a handle of those risks, but at a rather low rate. It's just a difficult thing to come around.
Dr. Greg Hundley: Very good. Brendan, anything to add?
Dr. Brendan Everett: I would just add I agree a hundred percent with George just said. I think the only missing piece there is heart failure, which I think is and many have shown that there's an inflammatory component to heart failure, whether it's heart failure with reduced ejection fraction or preserved ejection fraction.
And the timing of when that intervention might be, whether it might be before the development of symptoms or because there's a lot of trials out there that have struggled with this question and have unfortunately failed to show any benefit, I would just encourage the listeners of the podcast to look at this paper because it's a really marvelous compilation of the evidence for what is a really hot topic in cardiovascular medicine, a really important topic for a lot of the reasons that George mentioned. It's just very well done and comprehensive.
Again, kudos to the authors for making such a great effort at putting something together that has a lot of clinical relevance, I think, and also points the way forward for research as you ask, Greg.
Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. George Dangas from Icahn School of Medicine in Mount Sinai and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital for bringing us this data pertaining to colchicine benefits, as we know in acute and recurrent pericarditis, but also emerging indications related to post-procedural atrial fibrillation or coronary artery disease. And really, colchicine's targeting of cardiovascular inflammation is being helpful in those alleviating those processes.
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.
Dr. Greg Hundley: This program, this copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
In this week’s edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation.
Dr. Amit Khera:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do.
Dr. Amit Khera:
And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself.
Dr. Vanessa Blumer:
Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US.
Dr. Vanessa Blumer:
I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure.
Dr. Amit Khera:
Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself.
Dr. Pishoy Gouda:
Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training.
Dr. Pishoy Gouda:
Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome.
Dr. Amit Khera:
Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome.
Dr. Xiaoming (Ming) Jia:
Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology.
Dr. Amit Khera:
Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome.
Dr. Peder Langeland Myhre:
Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago.
Dr. Amit Khera:
Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please.
Dr. Sonia Shah:
Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now.
Dr. Amit Khera:
Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works.
Dr. Amit Khera:
And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing?
Dr. Vanessa Blumer:
Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media.
Dr. Vanessa Blumer:
So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way.
Dr. Amit Khera:
Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research.
Dr. Xiaoming (Ming) Jia:
Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts.
Dr. Amit Khera:
Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art.
Dr. Amit Khera:
And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet?
Dr. Pishoy Gouda:
Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content.
Dr. Pishoy Gouda:
So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future.
Dr. Amit Khera:
Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both.
Dr. Amit Khera:
And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians.
Dr. Peder Langeland Myhre:
Yes. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most.
Dr. Amit Khera:
Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all.
Dr. Amit Khera:
Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space?
Dr. Sonia Shah:
Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals.
Dr. Amit Khera:
Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months?
Dr. Xiaoming (Ming) Jia:
I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well.
Dr. Amit Khera:
We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes.
Dr. Amit Khera:
Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it.
Dr. Peder Langeland Myhre:
Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing.
Dr. Peder Langeland Myhre:
So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family.
Dr. Amit Khera:
Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media?
Dr. Pishoy Gouda:
Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me.
Dr. Amit Khera:
Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore.
Dr. Amit Khera:
So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit.
Dr. Vanessa Blumer:
Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out.
Dr. Vanessa Blumer:
I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it.
Dr. Amit Khera:
Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so.
Dr. Sonia Shah:
Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved.
Dr. Amit Khera:
Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal.
Dr. Amit Khera:
Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.
Please join Guest Host and Associate Editor Mercedes Carnethon and author Christine Albert as they discuss the article "Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, today's feature paper is such an important question clinically. It's something I've asked myself and so I cannot wait to discuss it in greater detail. It refers to the effect of long-term marine omega-3 fatty acid supplementation, and the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. So it talks about a systematic review and meta-analysis published in this week's issue.
Dr. Carolyn Lam:
All right. Okay. You got to wait in suspense, as do I, and let's discuss other papers, very important papers in today's issue too. I'd like to start with a bit of a quiz. So Greg, for converting atrial fibrillation, is the anterior-lateral or anterior posterior electrode position better? What's your guess?
Dr. Greg Hundley:
Oh, wow, Carolyn. That's interesting. We put these pads on and we kind of just follow the directions on whatever the particular device says. Interesting question. It's a guess, Carolyn, it's a guess. Antro-lateral?
Dr. Carolyn Lam:
Smarty pants. Well, let's see. Frankly I didn't know the answer. It's just such an elegant question, isn't it? To answer in a study. And this is exactly what Professor Løfgren from Randers University Hospital and Denmark and colleagues did. They performed a multi-center investigator initiated open label trial, where they randomly assigned 468 patients with atrial fibrillation scheduled for elective cardioversion to anterior-lateral versus anterior-posterior electrode position.
Dr. Carolyn Lam:
The primary outcome was the proportion of patients in sinus rhythm after the first shock. And so drum roll. The primary outcome occurred in 54% assigned to an anterior-lateral electrode position. And in 33% assigned to an anterior-posterior electrode position, a significant risk difference of 22% in favor of the anterior-lateral electrode position.
Dr. Carolyn Lam:
Cheers, Greg. There were no significant differences between groups in any safety outcomes and the superiority of the anterior-lateral electrode position was statistically significant both after the initial low energy shock and after a final high energy shock. So this study really suggests a practice change in the standard approach to electrode positioning for cardioversion in favor of anterior-lateral electrode position.
Dr. Greg Hundley:
Very nice, Carolyn. Very nice. Well, I'm going to come at you using your heart failure expertise and ask you a quiz here in just a second. But first I want to introduce this paper from Dr. Javier Barallobre-Barreiro from King's College London. Okay, Carolyn, here's your quiz. Do you think that the extracellular matrix fibrosis contributes to LV dysfunction in heart failure patients?
Dr. Carolyn Lam:
Absolutely.
Dr. Greg Hundley:
Very nice. I think, of course, you are correct. So Carolyn, remodeling of the extracellular matrix is a hallmark of heart failure and this team's previous analysis of the secretome of mirroring cardiac fibroblast returned ADAMTS5, a disintegrin and metalloproteinase with thrombospondin motifs 5 as one of the most abundant proteases. So ADAMTS5 cleaves chondroitin sulfate proteoglycans such as Versican. The contribution of ADAMTS5 and its substrate Versican to heart failure is unknown.
Dr. Carolyn Lam:
Ah, so what did the authors find, Greg?
Dr. Greg Hundley:
Well, first Carolyn, there was a methodologic advance here. Left ventricular tissues from 86 heart failure patients and non-failing controls were analyzed by quantitative mass spectrometry, constituting the largest proteomics analysis on human heart failure today. And so what did they find? Accumulation of proteoglycan Versican was regulated by ADAMTS5, that disintegrin and metalloproteinase with thrombospondin motifs 5, and was associated with the reduction in proteins involved in intercellular communication. And Carolyn, interestingly, proteoglycan accumulation in ischemic heart failure was attenuated by beta blocker administration.
Dr. Carolyn Lam:
Oh, that's very interesting. Could you put that all together for us? What's the clinical implications, Greg?
Dr. Greg Hundley:
You bet, Carolyn. So proteoglycan secretion by cardiac fibroblast constitutes an important component of cardiac fibrosis after ischemic heart failure, just like you stated at the beginning with your quiz answer. This contributes to impaired cardiac function and besides their negative chronotropic and inotropic effects, beta blockers may modulate extracellular matrix remodeling.
Dr. Carolyn Lam:
Wow, nice, Greg, thank you for that. I've got another original paper and it deals with the very important topic of endothelial to mesenchymal transition. Now it has been reported that cardiac endothelial cells contribute to a substantial proportion of myofibroblast through this process called endothelial to mesenchymal transition. Lineage tracing studies have demonstrated that myofibroblasts are derived from expansion of resident fibroblasts rather than from transdifferentiation from endothelial cells.
Dr. Carolyn Lam:
However, it remains unknown whether endothelial cells can transdifferentiate into myofibroblast reversibly or would these endothelial to mesenchymal transition genes just transiently activated in endothelial cells during cardiac fibrosis? So these authors, corresponding authors, Dr. Sun from Shanghai Jiao Tong University School of Medicine, Dr. Lui from Price of Wales Hospital and Chinese University of Hong Kong, as well as Dr. Zhou from the University of Chinese Academy of Sciences in Shanghai and their colleagues.
Dr. Carolyn Lam:
What they did is they used the dual recombination technology to generate a genetic lineage tracing system for tracking endothelial to mesenchymal transition in cardiac endothelial cells and their genetic fate mapping results basically showed that although mesenchymal gene expression was activated in cardiac endothelial cells throughout the endothelial to mesenchymal transition in the developing heart, the endothelial cells do not transdifferentiate into myofibroblasts, nor do they transiently express some known mesenchymal genes during homeostasis or fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblast by activating mesenchymal gene expressions are in fact the major contributors to cardiac fibrosis.
Dr. Greg Hundley:
Ah, Carolyn, very interesting. So can you put this together? What are the clinical implications?
Dr. Carolyn Lam:
So what it really says is that it's the resident fibroblasts that are converted to myofibroblast by activating mesenchymal genes. These are the ones that represent a major therapeutic target and really unraveling these mechanisms, driving endothelial to mesenchymal transition in such a detailed way, provided new insights into therapeutic development to target cardiac fibrosis.
Dr. Greg Hundley:
Wow, Carolyn. You know, two really good preclinical science articles speaking to us about myocardial fibrosis.
Dr. Carolyn Lam:
Well, there are other papers in today's issue too. There's a Perspective piece by Dr. Christopher Lamb on “Liver Cirrhosis and Hepatocellular Carcinoma After the Fontan Operation: Reaching Clarity in the Face of Uncertainty. And this is paired with a Research Letter by Dr. Toshio Nakanishi on incidents and expected probability of liver cirrhosis and hepatocellular carcinoma after the Fontan operation.
Dr. Greg Hundley:
Very nice, Carolyn, and I've got an “In the News” piece from Bridget Kuehn entitled “Centering Equity in Cardiovascular Care as Michelle Albert Lays Out a Roadmap for our Profession.” Well, Carolyn, how about we learn a little more about those long term marine omega-3 fatty acid supplementations and the risk of atrial fibrillation?
Dr. Christine Albert:
Oh, I can't wait. Let's go, Greg.
Dr. Mercedes Carnethon:
Thank you so much for joining us for today's episode of Circulation on the Run. My Lame is Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and Associate Editor at Circulation. And I have the great pleasure today of having a conversation with a long time friend, Dr. Christine Albert from the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles.
Dr. Mercedes Carnethon:
And today I've got the great pleasure of hearing directly from Christine about a wonderful original research piece that is being featured in Circulation about the effect of long term marine omega-3 fatty acid supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. And the exciting innovation of this piece that we'll dig into is what we're learning from the systematic review and meta-analysis that Dr. Albert and her team carried out. So, thank you so much for joining us today, Christine.
Dr. Christine Albert:
Well, thank you, Mercedes. It's really great to be here.
Dr. Mercedes Carnethon:
Great. Well, I'd just like to launch with you telling us a little bit about the study, what you found, why you decided to conduct this meta-analysis and review.
Dr. Christine Albert:
Yeah. Great. So my first author, Dr. Baris Gencer and I decided to do this because we actually had participated in a randomized trial called the Vital Rhythm Trial, where we actually randomized people to omega-3 fatty acids and atrial fibrillation, and found a slightly elevated risk, but it wasn't significant. And at that time, a number of other articles came out saying that there really was an increased risk of atrial fibrillation.
Dr. Christine Albert:
So we wanted to put together the data to see what the combined data, our data, that's been published before, on this sort of long term treatment with omega-3 fatty acids and atrial fibrillation. As you may know, there have been studies that have looked at short term treatment, and specifically for atrial fibrillation, and did not find benefit. So this is why we went ahead and did this study. And what we did is we were able to find seven randomized trials that collected data on atrial fibrillation that had randomized people to omega-3 fatty acids over an average of about five years of follow up between all the different trials. And we found that when you combine all these trials together, you actually see that there is a slightly elevated risk of atrial fibrillation in the participants that were randomized to the omega-3 fatty acids.
Dr. Mercedes Carnethon:
Thank you so much for that summary, Christine. I think the findings themselves surprised me. This is not my primary area of work, but we hear so much about supplements and their benefits that I thought it was really telling to actually have these data coming from a large number of studies, and particularly large studies that suggest that there is a risk to benefit ratio that we need to consider. How would you recommend that clinicians weigh this evidence that you've generated today?
Dr. Christine Albert:
So I think that it's got to be individualized. There are benefit, as you said, of these omega-3 fatty acids. And I think it's just awareness, awareness that this potentially is a risk. If you have a patient on omega-3 fatty acids and they start to have atrial fibrillation, there could be a link. Also when you talk about it with patients, I think it's reasonable, especially with the higher doses, we can just discuss that this is a potential side effect. Does it prevent you from using it? I don't think so. I think you have to look at what is, again, as you said, the risk benefit ratio for the individual patient. And as I alluded to, we did do a dose analysis and we found that the risk was primarily seen, and it was higher, in those that were given more than a gram of omega-3 fatty acid a day.
Dr. Christine Albert:
However, I will say that the trials are very different when you take a meta-analysis, it's really hard to say, "What is the cause of the differences between trials?" You know, these trials that had the higher dose, the reduce it trial that used just a purified EPA was very different than the dose of the medication that was used in vital, different than the type of medication that was used in strength. And as you know, there's the whole debate about the placebo and reduce it versus strength. And so there are other differences, but one thing that is pretty consistent is that most of the point estimates are on the side of harm. So there is the thought that I think this is potentially very real and we should be considering it when we use these supplements.
Dr. Mercedes Carnethon:
You know, that's a really nice summary which really launches me into two subsequent questions. The first would give you the opportunity to speculate beyond the findings in your particular study, and this is one of the benefits to me of this Circ on the Run podcast, because you, of course, produced excellent science and weighed all of your findings based on what you found. But can you tell me, based on your experience, could you speculate about what you think the mechanism of elevated risk of atrial fibrillation is, particularly with those higher doses?
Dr. Christine Albert:
Yeah, no, it's interesting. You know, if you look at the epidemiology for this, Mercedes, it was totally inconsistent. When I postulated doing the vital rhythm trial, I actually have to be honest with you, I thought that there might be an increased risk, because when you look at some of the data of what these omega-3 fatty acids do, they increase vegal tone, they lower heart rate. They can actually slow conduction. So potentially those electrophysiologic actions might, might allow atrial fibrillation to emerge in people who are susceptible.
Dr. Christine Albert:
On the flip side, all of those things might be good for ventricular arrhythmias. So you see, if you look at the literature, there's benefits for…sudden death and epidemiologic studies and in some of the randomized trials, but then when you look at atrial fibrillation, at least the short terms, really didn't show a benefit. And again, that point estimate was more towards harm.
Dr. Christine Albert:
And then when you look at epidemiologic studies, looking at fish consumption, there's actually a lot of studies that suggest that people who eat more fish get more AFib. So it is really paradoxical. And we know as electrophysiologist that atrial arrhythmias and ventricular arrhythmias are not the same, we give drugs to prevent atrial arrhythmias that then cause ventricular arrhythmias. So it is interesting. And I think it's something that hopefully some of our translational scientists will help us to figure out.
Dr. Mercedes Carnethon:
All those contradictions are so challenging, but you were certainly speaking my language in describing the hypothesized mechanisms. It calls to mind, back in the day, in your early research on sudden cardiac death that I was citing as part of my dissertation work in epidemiology. So thank you for that.
Dr. Christine Albert:
Yeah.
Dr. Mercedes Carnethon:
You know, the second question that builds off of that is I thought that the figure where you display the heterogeneity by the dosage of omega-3's really underscores the argument that you were just presenting. What I was wondering is, did you happen to study heterogeneity by any other characteristics, particularly sex or age?
Dr. Christine Albert:
That would be fantastic to be able to do, unfortunately, because it's a summary level meta-analysis, we really can't do that. And that's one of the things that we'd love to do in collaboration with some of these authors if they would like to do that, is to really get that sort of paid participant level data, so we could do those kinds of analysis.
Dr. Christine Albert:
But what we did do is sort of separate out studies that had like confirmed AF, studies that had incident AF versus recurrent AF, so things where the studies were completely different, we were able to look for heterogeneity and we didn't find anything that suggested that there was heterogeneity on that basis. But there's a number of things that I would love to look at and age is definitely one of them, and also sex. And actually looking at, which would be really interesting, is to look at the omega-3 or EPA and DHA levels in these individuals. And again, I think each study has sort of tried to do it on their own and you can't because there's just not enough data. So putting all this data together would be great to have a better understanding of what's going on.
Dr. Mercedes Carnethon:
Oh, it sounds speaks to a number really thoughtful future directions for this work. One of the benefits of me being able to speak with you today in my role as a guest podcast host, but I was also the Associate Editor for the piece and was really excited when it came in. The discussions that we had amongst the editors about this were really very stimulating and raised a number of questions that led to you responding and making some modifications and explaining certain things. Could you tell our audience, why did you select trials over a certain size? You know, quite often we do meta-analyses in order to pull together smaller studies, but why did you choose larger studies?
Dr. Christine Albert:
I think it was so that, there were two criterias, one was larger and one was long term, because we felt that the smaller studies had been merged together previously and we wanted to have at least some data on atrial fibrillation. One of the problems I think that I think I want to emphasize a little bit here about research in general in cardiovascular disease is that until now, most studies hadn't really measured atrial fibrillation, and I think it's really important. And I think you can see, you can find off target effects of some of the agents that we use for cardiovascular disease on atrial fibrillation. So for instance, the Statin Trials, everybody said, "Oh, well statins might lower atrial fibrillation," but then nobody measured atrial fibrillation, so we never knew. And then people went back and tried to measure it as a side effect or something that has all kinds of biases to it.
Dr. Christine Albert:
So I think that what is exciting about this work is that both reduce it and strength and vital, pre-specified that they were going to look at atrial fibrillation. And so if we do that, we may actually find other agents that are beneficial, not just harm, but beneficial, like the SGLT2 inhibitors, there's lots of hypotheses. So the reason that we did pick the bigger trials was that we wanted to find trials that really kind of looked at atrial fibrillation, had enough power to look at atrial fibrillation and then over a long term, a follow up to gather enough events.
Dr. Mercedes Carnethon:
Again, it has been such a pleasure to hear directly from you. I really hope that our listeners today and our readers of The Journal will dig into this in the same way that we have as editors and really appreciate the thoughtfulness with which you've presented this outstanding work. So I want to thank you so much, Dr. Albert for joining us today.
Dr. Christine Albert:
Thank you for having me.
Dr. Mercedes Carnethon:
I guess I will sign off now. This is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine and Associate Editor for Circulation.
Disclaimer:
This program is copyright of the American Heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart Association. For more, visit ahajournals.org.
Please join Guest Host Mercedes Carnethon, author Jason Roberts, and Associate Editor Vlad Zaha as they discuss the article "Epigenetic Age and the Risk of Incident Atrial Fibrillation."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature we're going to learn more about the risk of incident atrial fibrillation, but as that pertains to epigenetics. But before we get to that feature, how about we grab a cup of coffee and get started on some of the other articles in the issue. Would you like to go first?
Dr. Carolyn Lam:
I would love to. And the first paper I want to highlight asks the question, are social economic variables associated with 30 day survival after out of hospital cardiac arrest. And this comes from Dr. Jonsson from Karolinska Institute in Stockholm, Sweden, and colleagues. They linked data from the Swedish Registry of Cardiopulmonary Resuscitation with individual level data on social economic factors. In other words, educational level and disposable income, all from statistics, Sweden. And what they found was that both higher disposable income and higher educational level independently associated with better 30 day survival following out of hospital cardiac arrest. The relationship between disposable income and 30 day survival was more robust for mediating factors compared to educational level.
Dr. Greg Hundley:
Oh, wow Carolyn. Really interesting in a very, what I would call hot topic these days. So what are the clinical implications of this particular study?
Dr. Carolyn Lam:
Well, the results really highlight the importance of preventive efforts aimed at patients with lower social economic status. And these preventive actions could include both early recognition and warning signs and for example, CPR and AED training. So very lovely paper there.
Dr. Greg Hundley:
Absolutely. Very nice Carolyn. Well, my first paper comes to us from Dr. Nan Wang from Columbia University Medical Center. And Carolyn this paper focuses on a common genetic variant called link RS 3184504, and it is associated with increased platelet and neutrophil counts, coronary artery disease, thrombotic stroke, and autoimmune diseases. And so this research group previously has shown that hematopoietic link deficiency synergizes with hyperlipidemia to promote platelet production and activation, neutrophilia, platelet neutrophil aggregates, atherosclerosis and arterial thrombosis, all of those things. So platelet activation and platelet neutrophil interactions have been shown to promote neutrophil extracellular traps or net formations. So nets are formed when neutrophils release their contents leading to the formation web-like structures made of DNA, myeloperoxidase, citrullinated histone and proteases that entrap and kill bacteria. Now, while nets may help to suppress infection, the formation of nets called NETosis in blood vessels can promote atherosclerosis and thrombosis. And so this study was undertaken to investigate the hypothesis that linked deficiency might promote NETosis leading to formation of unstable atherosclerotic plaques, and arterial thrombosis.
Dr. Carolyn Lam:
Wow. What a really neat hypothesis and NETosis. I learn new things all the time. So what do they find?
Dr. Greg Hundley:
Right Carolyn. First of all, hypercholesterolemic mice with hematopoietic link deficiency displayed accelerated arterial thrombosis with nets in thrombi and these changes were reversed by PAD4 deficiency or OxPL antibodies. Second, linked deficient platelet from hyperlipidemic mice expose and release increased OxPL when activated promoting NETosis, when incubated with link deficient neutrophils. Third, an AntiOxPL antibody reduced OxPL levels, NETosis and arterial thrombosis specifically in link deficient mice, and finally Carolyn targeting atherothrombotic risk using OxPL antibodies might be particularly effective in genetically defined populations with reduced link function or increased JAK-STAT signaling.
Dr. Carolyn Lam:
Wow. Okay. So they proved their hypothesis. Could you sum it up for us, Greg?
Dr. Greg Hundley:
You bet Carolyn. So this foundational work suggests that perhaps future studies targeting NETosis and OxPL in patients carrying the common link loss of function variant, could reduce atherothrombotic risk.
Dr. Carolyn Lam:
Wow. Thanks, Greg. My next paper is super interesting in its approach. Listen up. Now the assessment of the relationship between myocardial ATP production and cardiac workload. We know is important for better understand disease development and choice of nutritional or pharmacological treatment strategies. So what Dr. Berndt from Charity University and colleagues did, was they developed a comprehensive physiology based mathematical model of cardiac energy metabolism. And this model is called cardiokine one. And what it does is it recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. The model encompassed all pathways along, which the possible energy delivering substrates like glucose, long chain fatty acids, keto bodies, acetate, branch chain, amino acids are utilized.
Dr. Carolyn Lam:
They use the proteomic space, the abundance of metabolic enzymes and cardiac tissue to generate individualized metabolic models of cardiac energy metabolism. And so to prove their case, they further applied this approach to the left ventricles of controls in patients with mitral insufficiency and aortic stenosis, and showed that despite overall preserved systolic function, the ATP producing capacity of these left ventricles of patients with valvular dysfunction was generally diminished and correlated positively with mechanical energy demand and cardiac output.
Dr. Greg Hundley:
So Carolyn really interesting findings. Sort of linking metabolism them with ventricular dysfunction in those with valvular heart disease. So what were the clinical implications here? What's the take home?
Dr. Carolyn Lam:
Well, this methodology is just awesome, but what they also found I think is a very important physiological principle. And that is, while metabolic capacity have a significant correlation with biomechanical properties like myocardial power and cardiac output, they can also vary considerably between individual patients and therefore help us to understand in future perhaps why some patients develop heart failure over time while others with similar hemodynamic conditions do not. So just interesting. I think it just opens the space to a lot more.
Dr. Greg Hundley:
Absolutely beautiful summary there Carolyn. Well, in the rest of the mailbag for this issue, we have an exchange of letters between Professors Hu and Trifon on the previously published paper, entitled “Short Term Treatment with Aspirin plus Clopidogrel Compared to Monotherapy of Aspirin May Not Significantly Decrease the Risk of Stroke Recurrence.” Also, there's a Research Letter from Professor Catalucci entitled, “Nano miR-133A Replacement Therapy, Blunts Pressure Overloaded Induced Heart Failure.” And then finally Carolyn, there's an In-Depth article from Professor Aengevaeren entitled, “Exercise-Induced Cardiac Troponin Elevations From Underlying Mechanisms to Clinical Science.” Well Carolyn, how about we get onto that feature discussion and learn more about incident atrial fibrillation and the age of epigenetics.
Dr. Carolyn Lam:
Let's go.
Dr. Mercedes Carnethon:
Welcome to this episode of Circulation on the Run, where we're going to have a very exciting discussion about a paper on epigenetic age and the risk of incident atrial fibrillation. We're extremely excited to have the lead author here with us, Dr. Jason Roberts from the Population Health Research Institute, McMaster University and Hamilton Health Sciences in Ontario Canada. And I am really excited to host this episode alongside the handling editor. My name is Mercedes Carnethon and I'm the professor and vice chair of Preventive Medicine at the Northwestern University School of Medicine. And I'm pleased to be hosting this with Dr. Vlad Zaha from UT Southwestern Medical School, who was the associate editor who handled the piece. So I'm really excited to jump right into this because I think there's a lot that we can all learn from this. So welcome Jason, and thank you so much, Vlad.
Dr. Jason Roberts:
Thank you so much for having me, it's a delight to be here.
Dr. Mercedes Carnethon:
So Jason, tell us a little bit about the rationale for this study, what you found and what it means.
Dr. Jason Roberts:
Absolutely. So as a cardiac arrhythmia specialist, I see a lot of patients with atrial fibrillation. And in 2021, our understanding of its underlying pathophysiology still remains modest. Our treatment strategies for the condition are also somewhat modest, although catheter ablation and antiarrhythmic drugs can potentially be very effective. In the context of these limitations, they're also exacerbated to some extent by the prevalence of atrial fibrillation, increasing dramatically in developed countries. Part of this is related to the obesity epidemic. Things like hypertension increasing becoming more common, but because atrial fibrillation is age dependent and because of our aging populations in developed countries, this is felt to have a major contribution to the growing prevalence of atrial fibrillation. Unlike obesity and hypertension and other risk factors, which are potentially modifiable, chronological aging is viewed as non-modifiable. It's not something that we can tackle. That said, we know within the population and just from personal experience that people age at different rates. There are some people that are 65 who behave more like they're 50, other people that are 50 who behave more like they're 65.
Dr. Jason Roberts:
And in that context, biological aging, we wondered whether or not, does biological aging independent of chronological aging potentially impacts the risk of atrial fibrillation. If that was the case, because there are gradually accumulating to suggest that biological aging is potentially modifiable, that could potentially open up the possibility of tackling aging as a respective for atrial fibrillation. So that drove us to ask this question. In terms of what we found in the approach that we used. So we used our biological marker of aging, was something called an epigenetic clock. So it's been found that modifications to DNA, specifically methylation at CpG at dinucleotides, they correlate with aging. This has been appreciated for a few decades. It was initially felt that with aging, methylation levels gradually reduced over time. But with more careful interrogation, it's shown that there's patterns. Some methylation areas increase, other methylation areas there's decreases.
Dr. Jason Roberts:
And Steve Horvath, who is a scientist at UCLA has found that using mathematical algorithms, you're able to very accurately ascertain chronological age based on the patterns of DNA methylation, he's called these things epigenetic o'clock. That said, even though they very accurately ascertain chronological age, they aren't perfect in each individual in terms of matching up to their chronological age, but that's actually turned out to be a good thing. So when people, their epigenetic age is older than their chronological age, they're said to have positive epigenetic age acceleration. They may be biologically older than their actual chronological age. And then the reverse also holds. So using this concept of epigenetic age acceleration, we ask whether or not do people that are older biologically on the basis of their epigenetic age, do they have an increased risk of atrial fibrillation? And then we tackle that using a few different core works that I'm certainly happy to elaborate on in terms of what we found.
Dr. Jason Roberts:
So we used three population based cohorts from the United States, the well known Framingham Heart Study, the Cardiovascular Health Study and Eric as well. There were approximately just under 6,000 people from those studies that had undergone genome wide methylation analysis that in the enabled us to calculate their epigenetic ages. The follow period for these people was just under 13 years. And then we look to see whether or not these epigenetic clocks associated with instant atrial fibrillation. In these cohorts, we look at five different clocks. So there's the Horvath Clock and the Hannum clock that were designed to predict chronological aging. The more recent clocks, things like DNAm PhenoAge and DNAm GrimAge are more designed to predict aspects of clinical phenotype and also mortality. We found that in unadjusted analyses, all of these clocks were associated with atrial fibrillation. When we then adjusted for multiple different clinical variables, we found that the DNAm PhenoAge clock and the DNAm GrimAge clock continued to exhibit statistically significant associations with atrial fibrillation.
Dr. Jason Roberts:
Interestingly, the multi-variable adjustment, one concern is, do these clinical factors, are they confounders where we should be adjusting, or are they potentially mediators. If we adjust for mediators that potentially masks the effect of the clock. But regardless of how we treat them both DNAm PhenoAge and DNAm GrimAge, we're associated with increased risks of incident atrial fibrillation. Alluding to the possibility that biological aging independent of chronological aging is important in terms of determining risk for atrial fibrillation. And it may be that if we're able to modify biological aging, we could potentially reduce the risk of atrial fibrillation. So that's the study in a nutshell.
Dr. Mercedes Carnethon:
No, that is really exciting. You said something early on about chronological age being immutable. And I would have to say, both Vlad and I are not aging. And in fact, we are going in the opposite direction. If only this were not just an audio podcast, you would see that I steadily gotten younger and younger and I'm suddenly about 25 now. But no, these are really important findings. I really like the innovation of using multiple different strategies to characterize epigenetic age and genetic aging. So tell me Vlad, I want to turn to you. When this came across your desk, what excited you about this particular piece and why did you think that it would be of great interest to our readership?
Dr. Vlad Zaha:
Good morning Merci and Jason. This is a great question. And as in associate editor at Circulation for the bridging discipline section, it was fascinating to see this topic coming on my desk, thinking about all the genome wide association studies in nature of fibrillation and predisposition to atrial fibrillation, that in that case would not be changed by interventions because of different loci that would be determined. This was coming as a completely new perspective that was opening some new potentials. And it was very interesting to see some of the findings.
Dr. Mercedes Carnethon:
Certainly. So Jason, I have a question. So what surprised you about the findings of this particular study?
Jason Roberts:
Yeah, that's a great question. So we had hoped that biological aging would be associated with atrial fibrillation. I think the concept of being able to tackle biological aging is exciting. In terms of what surprised us, I guess we were hoping for these results, I guess.
Dr. Mercedes Carnethon:
Yeah.
Dr. Jason Roberts:
But we were…Yeah. So I guess we were pleasantly surprised that our hypothesis was born out. It's important to note that the epigenetic clocks don't tell the full story with chronological aging. So after we insert the clock into the model, chronological age continues to remain associated with instant atrial fibrillation. So this measure biological aging is just part of the story. So I think that's very important. I had wondered whether or not inserting the epigenetic clocks would that potentially eliminate the subsequent association of chronological aging. So that finding suggests it's part of the story.
Dr. Jason Roberts:
I think that in terms of the overall concept, the idea of this being reversible really excites me. In terms of the approach of how to reverse biological aging. Right now healthy lifestyle seems to be very important. I think it provides more evidence to suggest to patients with atrial fibrillation, living healthy from a diet perspective, from exercise, keeping your weight under control, all of these things that seem to impact epigenetic aging and biological aging can be helpful for preventing atrial fibrillation. So I think that can help reinforce this message to our patients.
Dr. Jason Roberts:
I think ultimately in terms of where we'll be at in 15 to 20 years, it's possible that new therapies in the future are developed that are able to more powerfully address biological aging. As you alluded to, will it be possible to reverse biological aging as you and Vlad are experiencing that?
Dr. Mercedes Carnethon:
Most definitely. Yes.
Dr. Jason Roberts:
I think it may be possible. This is an intense area of investigation that's being pursued and it's still in its relative infancy. But I think that could it be small molecules? Could it be potentially gene editing that can help adjust biological aging and not only increase lifespan, but also health span? I think those concepts are really exciting.
Dr. Mercedes Carnethon:
I completely agree. There's a lot of richness in this paper and I think our readership is going to really enjoy digging in. Part of the richness is the use of three different cohorts and the use of multiple measures of epigenetic age. And I think you provided a really nice description of the unique information that each of these markers of epigenetic age provide. One thing I note are differences in the strength of association across the different measures of epigenetic age, which I think makes sense, because you said they characterize different aspects of the phenomenon, but I also see what looks like some variability across the cohorts with Framingham in particular seeming to stand out. And that being the only cohort that is 100% one race. It's white. Versus both the cardiovascular health study and the Eric study, which have more diverse study populations. I'm wondering what your hypothesis is about the differential strength of association that it seems Framingham is demonstrating and what you think is possibly the source of those differences.
Dr. Jason Roberts:
Yeah. I think those are great questions for all of genetics. The question is, does it apply to all races? For example, polygenic risk scores. It seems like when a polygenic risk scores develop for one race, it may not perfectly translate over to other races. So how relevant is that for epigenetic age acceleration. In this study, I think it's difficult to make definitive conclusions about it. We needed the three cohorts to have adequate statistical power in terms of being able to determine a differential effect of race. I think it would really be primarily hypothesis generating. We weren't really powered to look at the different races. So it's difficult for me to comment.
Dr. Jason Roberts:
I think ultimately and I want to believe anyways, that epigenetic age acceleration is relevant to all races, but in terms of, was it race that drove the differential impacts that we saw to some extent in terms of the magnitude of the hazard ratios, it's difficult to know in terms of tests for interaction and were these actually truly statistically different. We weren't adequately powered to address that hypothesis. So it's difficult for me to comment in a definitive matter I'd say. And sorry to cop out on…
Dr. Mercedes Carnethon:
No, not at all. I mean, I think there are a lot of things where there is no firm answer and that was just one of my hypotheses when I saw what was going on differently across the cohorts. I think that's a perfectly reasonable answer that sets us on a course for thinking about how we set up future studies. So I wanted to turn to you Vlad for the closing frame around this. As the editor, how do you hope that our readership will use these findings?
Dr. Vlad Zaha:
That is an excellent question. I was going to follow on this excellent unpacking of the core messages of the manuscript by Jason here to get his perspective as an electrophysiologist into what these type of work may represent for the everyday life of an electrophysiologist in the connecting with the patients and how would this type of approach influence, and maybe now, maybe later when our treatment for atrial fibrillation.
Dr. Jason Roberts:
Yeah. So that's a great question. I think, as I alluded to some extent before, as far as reinforcing healthy lifestyle, I think this provides more evidence in that respect. So we know that things like excessive alcohol consumption, being excessively obese, poor diets, not engaging in enough exercise, all of those things seem to accelerate your epigenetic age. And those are all things that we think or feel that are important with atrial fibrillation in terms of driving the path of physiology and people progressing. So I think this gives more data to us to reinforce the patients that in addition to the treatments that we're offering in terms of catheter ablation and antiarrhythmic drugs, the concern is that the substrate can continue you to progress. And that's likely driven by to some extent these modifiable risk factors. So keeping all of these under best control as possible, and hence trying to slow your biological aging as much as possible.
Dr. Jason Roberts:
I think that this will provide us more motivation to push these messages to our patients. A lot of patients can sometimes be like, "Let's just get on with a catheter ablation and I want to get on with my life…" but it really I think, provides more data to suggest that modifying these very important risk factors that can lead to accelerated biological agents, is very important. And in terms of the future as mentioned, so chronological aging, as people get older, people view it as, "Well, there's nothing I can do, and I'm just going to get gradually more and more unhealthy." I think, and this is somewhat futuristic, but to what extent can we slow biological aging? Can we potentially reverse it in the future? There's certainly lots of very compelling and interesting animal work and people are starting to delve into this in a big way.
Dr. Jason Roberts:
And not only to increase lifespan, will we some day live until we're 200. Who knows? But the concept of prolonging your health span as well. So the number of healthy years that you have before your body starts to gradually give way, I guess to some extent. Hopefully in the future will have therapies that will help keep us healthy. And if we do that increased health span, I think this data suggests that atrial fibrillation will be one thing that benefits from this. So hopefully in the future, maybe in terms of curbing the AFib pandemic, being able to address biological aging will help push things in the right direction.
Dr. Mercedes Carnethon:
Well, thank you so much Jason. And thank you so much Vlad for your thoughtful questions. I really like that the final bottom line leans towards my area as an epidemiologist, which is maintaining and promoting healthy lifestyles as a way to hopefully help prevent some of the difficulties of atrial fibrillation and its long-term outcomes. Really pleased to have you on this episode of Circulation on the Run, Jason, and thank you again Vlad, and I hope everyone enjoys this episode of the journal and has an opportunity to really dig into this piece. This is Mercedes Carnethon from Northwestern University Feinberg School of Medicine, saying thanks for listening today.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association for more visit ahajournals.org.
Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start?
Dr. Greg Hundley:
Very good.
Dr. Carolyn Lam:
Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG.
Dr. Greg Hundley:
Ah, Carolyn. So what did they find in this subgroup of patients?
Dr. Carolyn Lam:
So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery.
Dr. Greg Hundley:
Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go.
Dr. Greg Hundley:
All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery.
Dr. Greg Hundley:
So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection.
Dr. Carolyn Lam:
Wow, fascinating. So what did today's paper find?
Dr. Greg Hundley:
Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper?
Dr. Carolyn Lam:
Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right?
Dr. Greg Hundley:
Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn.
Dr. Carolyn Lam:
Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs.
Dr. Carolyn Lam:
The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation.
Dr. Carolyn Lam:
But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit.
Dr. Greg Hundley:
Okay. Carolyn, what a beautiful summary here. So what's the take home message here?
Dr. Carolyn Lam:
So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases.
Dr. Carolyn Lam:
Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention.
Dr. Greg Hundley:
Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study?
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Mercedes Carnethon:
Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization.
Dr. Mercedes Carnethon:
And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you.
Professor Gregory Lip:
Hello there.
Dr. Connie Hess:
Thank you for having me.
Dr. Mercedes Carnethon:
Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study?
Dr. Connie Hess:
Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about.
Dr. Connie Hess:
And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI.
Dr. Connie Hess:
And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death.
Dr. Connie Hess:
And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out.
Dr. Connie Hess:
And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction.
Dr. Connie Hess:
Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication.
Dr. Mercedes Carnethon:
All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind?
Professor Gregory Lip:
Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes.
Professor Gregory Lip:
So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding.
Professor Gregory Lip:
We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well.
Dr. Mercedes Carnethon:
Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study?
Dr. Connie Hess:
Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt.
Dr. Connie Hess:
I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic.
Dr. Connie Hess:
A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it.
Dr. Connie Hess:
I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy.
Dr. Mercedes Carnethon:
I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal.
Dr. Mercedes Carnethon:
This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Please join first author Cecilia Bahit and Associate Editor Graeme Hankey as they discuss the article "Predictors of Development of Atrial Fibrillation in Patients With Embolic Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke; National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to analyze the RE-SPECT ESUS trial. What does that pertain to? Well, you're going to have to wait and find out, but it relates to atrial fibrillation and embolic stroke. But before we get to that, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I sure would. Greg, we know that Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease or diabetes. The question is: What are the effects of Icosapent Ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes from the REDUCE-IT trial?
Dr. Greg Hundley:
Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What did it encompass there?
Dr. Carolyn Lam:
The REDUCE-IT trial was a multicenter double-blind, placebo-controlled trial that randomized statin treated patients with elevated triglycerides, who had cardiovascular disease or diabetes, and one additional risk factor, two treatment with icosapent ethyl at 4g daily versus placebo. After a median follow up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina.
Dr. Greg Hundley:
Ah, great summary of the original paper, but now this is sort of a follow-up paper. What did this paper research?
Dr. Carolyn Lam:
Well first, remember they focused on renal function and the median baseline GFR was 75 ml/min with a range of 17 to 123 mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent reduction in both primary and secondary composite endpoints across the baseline GFR categories. Patients with the GFR >60 treated with Icosapent Ethyl had the largest absolute, but similar relative risk reduction for the primary composite endpoint. And while patients with GFR >60 treated with Icosapent Ethyl had the highest numerical rates of atrial fibrillation of flutter and serious bleeding. The hazard ratios for atrial fibrillation flutter and serious bleeding were similar across GFR categories. In summary Icosapent Ethyl reduced cardiovascular events among patients with elevated triglycerides in a well-controlled LDL on statin therapy across a wide range of baseline renal function.
Dr. Greg Hundley:
Oh, Carolyn. Beautiful presentation. That presentation was so good that I know you are ready for a quiz. We haven't had Carolyn's quiz in a week, so we've got to get right back to that.
Dr. Carolyn Lam:
No, we don't (laughs).
Dr. Greg Hundley:
Can you describe the primary sequelae of Hutchinson-Gilford progeria syndrome?
Dr. Carolyn Lam:
Oh wow. Okay. So this is the syndrome where there's premature aging, there's a lot of vascular stiffening, calcification. I'm going to guess some sort of atherosclerotic consequence (laughs).
Dr. Greg Hundley:
Very nicely done Carolyn. Oh my goodness. I need to get you to take my ABIM recertification-
Dr. Carolyn Lam:
(laughing)
Dr. Greg Hundley:
Beautifully done. So Carolyn, this paper comes to us from Dr. Vicente Andrés from Centro Nacional De Investigaciones Cardiovasculares Carlos III, and Hutchinson-Gilford progeria syndrome is a rare disorder characterized, just like you said, Carolyn by premature aging and death, mainly due to myocardial infarction, stroke or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Carolyn, these patients look healthy at birth and symptoms typically emerge in the first or second year of life. In assessing the reversibility of progerin induced damage, and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies.
Dr. Carolyn Lam:
Wow, you've really, really piqued my interest. So what did these investigators do and what did they find?
Dr. Greg Hundley:
Oh Carolyn, very clever design. So the authors use CRISPR-Cas9 technology to generate mice engineers to ubiquitously express progerin while lacking lain A and allowing progestin suppression in lain A restoration in a time and cell type specific manner upon CRE recombinase activation. They characterize the phenotype of these engineered mice and cross them with CRE transgenic lines to assess the effects of suppressing progestin and restoring lain A ubiquitously at different disease stages, as well as specifically in vascular smooth muscle cells and cardiomyocytes. So Carolyn, what did they find? Well, number one, like Hutchinson-Milford progenia syndrome patients, their engineered mice appeared healthy at birth, and progressively developed Hutchinson-Milford progenia syndrome symptoms, including failure to thrive, Lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electric cardiographic anomalies and early death. Their median lifespan was 15 months versus 26 months in the wild types.
Dr. Greg Hundley:
Second, ubiquitous progestin suppression in lain A restoration significantly extended lifespan, when induced in six month old, mildly symptomatic mice, and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon the early intervention. And then finally, Carolyn remarkably major vascular alterations were prevented and lifespan normalized in engineered Hutchinson-Milford progenia syndrome mice when progestin suppression and lain A restoration were restricted to: just Vascular smooth muscle cells and Cardiomyocytes.
Dr. Carolyn Lam:
Wow, just fascinating, but, okay. What is the clinical take home message?
Dr. Greg Hundley:
Right, Carolyn. So these authors findings suggest that it is never too late to treat Hutchinson-Milford progenia syndrome, although the benefit is much more pronounced when progestin is targeted early in mice with mild symptoms. Also, restricting its suppression to Vascular smooth muscle cells in Cardiomyocytes is sufficient to prevent Vascular disease and normalize lifespan in mice, and therefore these data suggest that strategies to treat Hutchinson-Milford progenia syndrome through gene therapy or RNA therapy should consider targeting Vascular smooth muscle cells and Cardiomyocytes.
Dr. Carolyn Lam:
Oh wow. Very, very cool. Well, my next paper is a basic science paper that's significant for both its methods and its results.
Dr. Greg Hundley:
Oh wow, Carolyn, I can't wait. So tell us about this novel methodology.
Dr. Carolyn Lam:
Well, this paper is from Dr. Chang from Westlake University in Hangzhou, China, and colleagues who use a gene editing approach to efficiently institute Exon Skipping without introducing DNA double-strand breaks. So harnessing a fusion of a nuclease defective Case protein, and a cytidine deaminase, which is, we're going to abbreviate it as Targeted AID-induced mutagenesis (TAM) or base editor three (BE3), their approach precisely edited conserved guanines at splice sites, thus abrogating Exon recognition resulting in a programmable skipping of the targeted Exons. Isn't that neat?
Dr. Greg Hundley:
Yeah, it really is sophisticated Carolyn, wow. So what did they do using these methods?
Dr. Carolyn Lam:
A novel mirroring model of Duchenne muscular dystrophy was generated, which recapitulated many cardiac defects observed in the human form of the disease, including dilated cardiomyopathy, reduced left ventricular function and extensive cardiac fibrosis. Using this model, they examined the feasibility of using a cytidine base editor to install Exon Skipping and rescue the dystrophic cardiomyopathy in vivo. A single dose administration of an Adenovirus 9EtAm, instituted over 50% targeted Exon Skipping in the Chengdu muscular dystrophy transcripts and restored up to 90% dystrophin in the heart. And as a result, early ventricular remodeling was prevented and cardiac and skeletal muscle function were improved, leading to an increased lifespan of the mice. Despite gradual decline of the Adenovirus vector and base editor expression, the dystrophin restoration and pathophysiological rescue of muscular dystrophy lasted for at least a year. And so this technique really has the potential to be applied to monogenic human diseases, to modulate Exon Skipping or inclusion. Isn't that cool?
Dr. Greg Hundley:
Absolutely, Carolyn. Beautifully explained.
Dr. Carolyn Lam:
Well, let me end by sharing what else is in today's issue. There's a Perspective piece by Dr. Alexander on “Chest Pain Redux: Updated and Patient Centered.” There is an In Depth paper by Dr. Kroemer on NAD plus metabolism in cardiac health, aging and disease. And there's a Research Letter by Dr. Shepherd on sudden death in female athletes, with insights from a large regional registry in the United Kingdom.
Dr. Greg Hundley:
Very good, Carolyn. What a great issue. Now, how about we get to that feature discussion?
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Greg Hundley:
Welcome listeners to our feature discussion today on this November 30th. And we have with us Dr. Cecilia Bahit from Rosario, Argentina and our own associate editor, Dr. Graeme Hankey from Perth, Australia to talk to us about a paper pertaining to Atrial Fibrillation. Welcome to you both, and Cecilia, we'll start with you. Could you describe for us a little bit of the background information that went into formulating your study, and then what hypothesis did you want to address?
Dr. Cecilia Bahit:
Thank you for the invitation. So we all know that embolic stroke of undetermined source, which is called ESUS isn't just a subset of cryptogenic stroke, and is associated with stroke recurrence about 3-6% per year. And on the other hand, we know that continuous cardiac monitoring in this patient population shows that atrial fibrillation can be detected between 10% at six months or 30% at three years. So the underlying atrial fibrillation may be a mechanism for the recurrent thromboembolic stroke in this patient population. So we know that prior studies have identified some predictors of atrial fibrillation in these patients. And if we are able to identify which patients could benefit from cardiac monitoring and have a higher yield to detect atrial fibrillation, we could do a better job at treating them. So, that was our idea behind the paper. So using the RE-SPECT ESUS trial, which was a trial that included patient with ESUS stroke and were randomized to the bigger trend versus Aspirin, we look at predictors of atrial fibrillation unassociated regarding stroke.
Dr. Greg Hundley:
Very nice. And so, now was this a sub-study here and maybe define for us a little bit, your study design and specific study population.
Dr. Cecilia Bahit:
So this was a secondary analysis of a randomized clinical trial that as mentioned it was not a sub-study, it was a secondary analysis. We thought all along to do it because of the interest of the clinical question. We look at the total patient population was 5,390 patients. And we looked at those patients who developed atrial fibrillation during the 19 months of follow-up. And it was 7.5%, 403 patients developed atrial fibrillation.
Dr. Greg Hundley:
Very good. And what were your results?
Dr. Cecilia Bahit:
So, as I mentioned, we saw that 7.5% of our patient population developed atrial fibrillation during the follow-up. And we know those patients were older, were like, have higher morbidities, and we assessed, we did an one variable analysis and then a multi-variable analysis, trying to identify predictors for atrial fibrillation. And for our model, we identified different predictors, older age, hypertension, lack of diabetes, and higher body mass index, were independent predictors of atrial fibrillation. So the patients who have atrial fibrillation have a higher recurrence of stroke, it was 7.2 versus four, compared to those that did not have atrial fibrillation.
Dr. Cecilia Bahit:
So I think there's an important part, that 20% of the patient population of the overall trial, this is a little more than a thousand patients, had NT-prob measure at baseline. And when we included this biomarker into the model, only older age and NT-prob were independent predictors of atrial fibrillation. In addition, even though this was not the objective of this analysis, we look at the treatment effect of the bigger trend. And even though we saw that there was a statistical benefit of the bigger trend versus Aspirin in the higher group of these in our score, the overall treatment effect was not there. So we couldn't assess the fact that the bigger trend was better compared to Aspirin in patient with atrial fibrillation, but of course the numbers were very small.
Dr. Greg Hundley:
Very good. Thank you so much for that wonderful description. And Graeae, now we'll turn to you as associate editor for us at Circulation, and also the editorialist on this particular paper. What caught your attention about this particular study and the results from the many papers that really come across your desk.
Dr. Graeme Hankey:
Thank you, Greg. And congratulations to Cecilia and her RE-SPECT ESUS colleagues. I mean, this is a landmark study, the RE-SPECT ESUS study, and just to go back, embolic stroke of undetermined source is really common. About one in four ischemic strokes, we don't know the cause of, and it's one of the major subtypes of cryptogenic stroke is an embolic ischemic stroke in which the source could have come from the heart or the aortic arch or the carotids. And we're not really sure. And we think that some of these patients have occult atrial fibrillation, but we can't pick it up at the time. So one way is to try and monitor them with prolonged ECG monitoring. And another way is to actually treat them with anticoagulation because we know that, that's more effective in people with cardio embolic stroke. And so RE-SPECT ESUS and NAVIGATE ESUS used the latter strategy and said, let's see if treating people with ESUS with anticoagulation is more effective than antiplatelet therapy.
Dr. Graeme Hankey:
And both studies were not significant in terms of showing that Dabigatran or Parovarian for NAVIGATE ESUS was more effective than antiplatelet therapy. So we're left now with this default that all patients with ESUS just get Aspirin, but we have a hunch that some of them actually have cardiogenic embolism and are being undertreated with Aspirin and need anticoagulation. So it's a heterogeneous entity, but we're treating it homogeneously with a sort of weak antiplatelet. So we want to try and find out who's going to get AF or who's already got it that is occult. And this study is a really great and prospective study with 5,000 patients as Cecilia said, who of whom 7% did develop AF just through annual ECG reporting and just with symptom reporting. And that's probably an under report. You know, if they'd had monitoring, they probably would've found about 20 or 30% would've developed AF during that time of 19 months follow up.
Dr. Graeme Hankey:
And it's the first study to really then show that not just the AF people had a higher stroke rate, but in that group who they predicted to be at high risk of AF with older age and the NT-prob, that the high risk group had a significant reduction with Dabigatran versus Aspirin in that high risk group. It's just, when you look for hetero homogeneity or heterogeneity across the risk groups, it wasn't quite significant. And that might be because it's not significant or it might be that study was underpowered to look at those three, across those three risk subgroups. And also it might be a bit confounded because of it, the patients weren't randomized according to their risk status for AF, they were just randomized, whether they had ESUS, so it's further excited us that there might be a subgroup who needs anticoagulation. And that's why the ARCADIA trial is ongoing now, looking at where the people with ESUS who have high risk of AF benefit from a apixaban versus aspirin.
Dr. Greg Hundley:
Very nice. And so, with these results that we have here, maybe come back to Cecilia, what do you think would be the next series of studies that needs to be performed in this area of research?
Dr. Cecilia Bahit:
Well, there's one side that's ongoing as Dr. Hankie mentioned, but I think we should be able to identify which patients have a higher risk of atrial fibrillation and those patients who use cardiac monitoring for long term to identify atrial fibrillation and to treat properly. So I think that would be key in this area.
Dr. Greg Hundley:
Very nice. And Graeae, what are your thoughts?
Dr. Graeme Hankey:
Yes. Well, one way is to have our ESUS patients have prolonged ECG monitoring by implantable loop recorders, for example, and then those who develop AF randomizing them to anticoagulation versus antiplatelet therapy. Although if they declare themselves with AF they're usually just go straight onto anticoagulation therapy. So the burning question is, in these people with ESUS who haven't declared themselves as AF, but have predictors of AF like those shown in RESPECT ESUS, like older age, high blood pressure, high BMI ,prob, and perhaps echo features, like left atrial size or ECG features like lots of premature atrial contractions or P wave of abnormalities.
Dr. Graeme Hankey:
Are these, the subgroups or even LV dysfunction, are these subgroups who need to be more specifically targeted in a randomized trial rather than the whole group of ESUS. And also with longer follow up. NAVIGATE ESUS stopped after 11 months. The bigger RESPECT ESUS stopped after a median follow up of 16 months and the curves were diverging. Maybe with five years follow up, a lot of these people would've developed AF and would've benefited from longer term anticoagulation, but the trials were stopped early, because there wasn't a signal of benefit and there was an early risk of bleeding with anticoagulation.
Dr. Greg Hundley:
Very good. Well listeners, this has been a really interesting study and we want to thank Cecilia and Graeme for sharing results of the RESPECT ESUS study, highlighting that, in patients with embolic stroke of undetermined source, atrial fibrillation occurs and is a possible source of this stroke, and then also older age, and elevation of NT-prob can be associated with development of atrial fibrillation, subsequent to that stroke event.
Dr. Greg Hundley:
Well listeners, we want to wish you a great week. And on behalf of Carolyn and myself, look forward to catching you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.
Please join first author Yuan Lu and Guest Editor Jan Staessen as they discuss the article "National Trends and Disparities in Hospitalization for Acute Hypertension Among Medicare Beneficiaries (1999-2019)."
Dr. Carolyn Lam:
Welcome to Circulation on the Run: your weekly podcast, summary and backstage pass to the journal and it's editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, and director of Pauley Heart Center at VCU health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, today's feature discussion is about the national trends and disparities and hospitalizations for hypertensive emergencies among Medicare beneficiaries. Isn't that interesting? We're going to just dig deep into this issue, but not before we discuss the other papers in today's issue. I'm going to let you go first today while I get a coffee and listen.
Dr. Greg Hundley:
Oh, thanks so much, Carolyn. My first paper comes to us from the world of preclinical science and it's from professor Christoff Maack from University Clinic Wursburg. Carolyn, I don't have a quiz for you, so I'm going to give a little break this week, but this particular paper is about Barth syndrome. Barth syndrome is caused by mutations of the gene encoding taffazin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Now beyond the first months of life, Barth syndrome cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, one of your favorites, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced Barth syndrome cardiomyopathy to mitochondrial formation of reactive oxygen species. Since mitochondrial function and reactive oxygen species formation are regulated by excitation contraction coupling, these authors wanted to use integrated analysis of mechano-energetic coupling to delineate the pathomechanisms of Barth syndrome cardiomyopathy.
Dr. Carolyn Lam:
Oh, I love the way you explained that so clearly, Greg. Thanks. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. Well, first defective mitochondrial calcium uptake prevented Krebs cycle activation during beta adrenergic stimulation, abolishing NADH regeneration for ATP production and lowering antioxidative NADPH. Second, Carolyn, mitochondrial calcium deficiency provided the substrate for ventricular arrhythmias and contributed to blunted inotropic reserve during beta adrenergic stimulation. And finally, these changes occurred without any increase of reactive oxygen species formation in or omission from mitochondria. So Carolyn what's the take home here? Well, first beyond the first months of life, when systolic dysfunction dominates, Barth syndrome cardiomyopathy is reminiscent of heart failure with preserved rather than reduced ejection fraction presenting with progressive diastolic and moderate systolic dysfunction without relevant left ventricular dilation. Next, defective mitochondrial calcium uptake contributes to inability of Barth syndrome patients to increase stroke volume during exertion and their vulnerability to ventricular arrhythmias. Lastly, treatment with cardiac glycosides, which could favor mechano-energetic uncoupling should be discouraged in patients with Barth syndrome and left ventricular ejection fractions greater than 40%.
Dr. Carolyn Lam:
Oh, how interesting. I need to chew over that one a bit more. Wow, thanks. But you know, I've got a paper too. It's also talking about energetic basis in the presence of heart failure with preserved ejection fraction, but this time looking at transient pulmonary congestion during exercise, which is recognized as an emerging and important determinant of reduced exercise capacity in HFpEF. These authors, led by Dr. Lewis from University of Oxford center for clinical magnetic resonance research sought to determine if an abnormal cardiac energetic state underpins this process of transient problem congestion in HFpEF.
Dr. Carolyn Lam:
To investigate this, they designed and conducted a basket trial covering the physiological spectrum of HFpEF severity. They non-invasively assess cardiac energetics in this cohort using phosphorous magnetic resonance spectroscopy and combined real time free breathing volumetric assessment of whole heart mechanics, as well as a novel pulmonary proton density, magnetic resonance imaging sequence to detect lung congestion, both at rest and during submaximal exercise. Now, Greg, I know you had a look at this paper and magnetic resonance imaging, and spectroscopy is your expertise. So no quiz here, but could you maybe just share a little bit about how novel this approach is that they took?
Dr. Greg Hundley:
You bet. Carolyn, thanks so much for the intro on that and so beautifully described. What's novel here is they were able to combine imaging in real time, so the heart contracting and relaxing, and then simultaneously obtain the metabolic information by bringing in the spectroscopy component. So really just splashing, as they might say in Oxford, just wonderful presentation, and I cannot wait to hear what they found.
Dr. Carolyn Lam:
Well, they recruited patients across the spectrum of diastolic dysfunction and HFpEF, meaning they had controls. They had nine patients with type two diabetes, 14 patients with HFpEF and nine patients with severe diastolic dysfunction due to cardiac amyloidosis. What they found was that a gradient of myocardial energetic deficit existed across the spectrum of HFpEF. Even at low workload, the energetic deficit was related to a markedly abnormal exercise response in all four cardiac chambers, which was associated with detectable pulmonary congestion. The findings really support an energetic basis for transient pulmonary congestion in HFpEF with the implication that manipulating myocardial energy metabolism may be a promising strategy to improve cardiac function and reduce pulmonary congestion in HFpEF. This is discussed in a beautiful editorial by Drs. Jennifer Hole, Christopher Nguyen and Greg Lewis.
Dr. Greg Hundley:
Great presentation, Carolyn, and obviously love that MRI/MRS combo. Carolyn, these investigators in this next paper led by Dr. Sara Ranjbarvaziri from Stanford University School of Medicine performed a comprehensive multi-omics profile of the molecular. So transcripts metabolites, complex lipids and ultra structural and functional components of hypertrophic cardiomyopathy energetics using myocardial samples from 27 hypertrophic cardiomyopathy patients and 13 controls really is the donor heart.
Dr. Carolyn Lam:
Wow, it's really all about energetics today, isn't it? So what did they see, Greg?
Dr. Greg Hundley:
Right, Carolyn. So hypertrophic cardiomyopathy hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic arrangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced crystal density coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, the hypertrophic cardiomyopathy hearts failed to up-regulate mitophagic clearance.
Dr. Greg Hundley:
So Carolyn, in summary, the findings of this study suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with hypertrophic cardiomyopathy, and these results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing myocardial injury.
Dr. Carolyn Lam:
Wow, what an interesting issue of our journal. There's even more. There's an exchange of letters between Drs. Naeije and Claessen about determinants of exercise capacity in chronic thromboembolic pulmonary hypertension. There's a "Pathways to Discovery" paper: a beautiful interview with Dr. Heinrich Taegtmeyer entitled,"A foot soldier in cardiac metabolism."
Dr. Greg Hundley:
Right, Carolyn, and I've got a research letter from Professor Marston entitled "The cardiovascular benefit of lowering LDL cholesterol to below 40 milligrams per deciliter." Well, what a great issue, very metabolic, and how about we get onto that feature discussion?
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Greg Hundley:
Welcome listeners to our feature discussion today. We have a paper that is going to address some issues pertaining to high blood pressure, or hypertension. With us, we have Dr. Yuan Lu from Yale University in New Haven, Connecticut. We also have a guest editor to help us review this paper, Dr. Jan Staessen from University Louvain in Belgium. Welcome to you both and Yuan, will start with you. Could you describe for us some of the background that went into formulating your hypothesis and then state for us the hypothesis that you wanted to address with this research?
Dr. Yuan Lu:
Sure. Thank you, Greg. We conducted this study because we see that recent data show hypertension control in the US population has not improved in the last decades, and there are widening disparities. Also last year, the surgeon general issued a call to action to make hypertension control a national priority. So, we wanted to better understand whether the country has made any progress in preventing hospitalization for acute hypertension. That is including hypertension emergency, hypertension urgency, and hypertension crisis, which also refers to acute blood pressure elevation that is often associated with target organ damage and requires urgent intervention. We have the data from the Center for Medicare/Medicaid, which allow us to look at the trends of hospitalization for acute hypertension over the last 20 years and we hypothesize we may also see some reverse progress in hospitalization rate for acute hypertension, and there may differences by population subgroups like age, sex, race, and dual eligible status.
Dr. Greg Hundley:
Very nice. So you've described for us a little bit about perhaps the study population, but maybe clarify a little further: What was the study population and then what was your study design?
Dr. Yuan Lu:
Yeah, sure. The study population includes all Medicare fee-for-service beneficiaries 65 years and older enrolled in the fee-for-service plan for at least one month from January 1999 to December 2019 using the Medicare denominator files. We also study population subgroups by age, sex, race and ethnicity and dual eligible status. Specifically the racial and ethnic subgroups include Asian, blacks, Hispanics, North American native, white, and others. Dual eligible refers to beneficiary eligible for both Medicare and Medicaid. This study design is a serial cross sectional analysis of these Medicare beneficiaries between 1999 and 2019 over the last 20 years.
Dr. Greg Hundley:
Excellent. Yuan, what did you find?
Dr. Yuan Lu:
We actually have three major findings. First, we found that in Medicare beneficiaries 65 years and older, hospitalization rate for acute hypertension increased more than double in the last 20 years. Second, we found that there are widening disparities. When we look at all the population subgroups, we found black adults having the highest hospitalization rate in 2019 across age, sex, race, and dual eligible subgroup. And finally, when we look at the outcome among people hospitalized, we found that during the same period, the rate of 30 day and 90 day mortality and readmission among hospitalized beneficiaries improved and decreased significantly. So this is the main findings, and we can also talk about implications of that later.
Dr. Greg Hundley:
Very nice. And did you find any differences between men and women?
Dr. Yuan Lu:
Yes. We also looked at the difference between men and women, and we found that actually the hospitalization rate is higher among females compared to men. So more hospitalizations for acute hypertension among women than men.
Dr. Greg Hundley:
Given this relatively large Medicare/Medicaid database and cross-sectional design, were you able to investigate any relationships between these hospitalizations and perhaps social determinants of health?
Dr. Yuan Lu:
For this one, we haven't looked into that detail. This is just showing the overall picture, like how the hospitalization rate changed over time in the overall population and by different population subgroups. What you mentioned is an important issue and should definitely be a future study to look at whether social determine have moderated the relationship between the hospitalization.
Speaker 3:
Excellent. Well, listeners, now we're going to turn to our guest editor and you'll hear us talk a little bit sometimes about associate editors. We have a team that will review many papers, but when we receive a paper that might contain an associate editor or an associate editors institution, we actually at Circulation turn to someone completely outside of the realm of the associate editors and the editor in chief. These are called guest editors. With us today, we have Dr. Jan Staessen from Belgium who served as the guest editor. He's been working in this task for several years. Jan, often you are referred papers from the American Heart Association. What attracted you to this particular paper and how do you put Yuan's results in the context with other studies that have focused on high blood pressure research?
Dr. Jan Staessen:
Well, I've almost 40 years of research in clinical medicine and in population science, and some of my work has been done in Sub-Saharan Africa. So when I read the summary of the paper, I was immediately struck by the bad results, so to speak, for black people. This triggered my attention and I really thought this message must be made public on a much larger scale because there is a lot of possibility for prevention. Hypertension is a chronic disease, and if you wait until you have an emergency or until you have target organ damage, you have gone in too late. So really this paper cries for better prevention in the US. And I was really also amazed when I compared this US data with what happens in our country. We don't see any, almost no hospitalizations for acute hypertension or for hypertensive emergencies. So there is quite a difference.
Dr. Jan Staessen:
Going further on that, I was wondering whether there should not be more research on access to primary care in the US because people go to the emergency room, but that's not a place where you treat or manage hypertension. It should be managed in primary care with making people aware of the problem. It's still the silent killer, the main cause of cardiovascular disease, 8 million deaths each year. So this really triggered my attention and I really wanted this paper to be published.
Dr. Greg Hundley:
Very nice. Jan, I heard you mention the word awareness. How have you observed perhaps differences in healthcare delivery in Belgium that might heighten awareness? You mentioned primary care, but are there any other mechanisms in place that heighten awareness or the importance?
Dr. Jan Staessen:
I think people in Belgium, the general public, knows that hypertension is a dangerous condition. That it should be well treated. We have a very well built primary care network, so every person can go to a primary care physician. Part of the normal examination in the office of a primary care physician is a blood pressure measurement. That's almost routine in Belgium. And then of course not all patients are treated to go. Certainly keeping in mind the new US guidelines that aim for lower targets, now recently confirmed in the Chinese study, you have to sprint three cells. And then the recent Chinese study that have been published to the New England. So these are issues to be considered. I also have colleagues working in Texas close to the Mexican border at the university place there, and she's telling me how primary care is default in that area.
Dr. Jan Staessen:
I think this is perhaps part of the social divide in the US. This might have to be addressed. It's not only a problem in the US, it's also a problem in other countries. There is always a social divide and those who have less money, less income. These are the people who fell out in the beginning and then they don't see primary care physicians.
Dr. Jan Staessen:
Belgium, for instance, all medicines are almost free. Because hypertension is a chronic condition prevention should not only start at age 65. Hypertension prevention should really start at a young age, middle age, whenever this diagnosis of high blood pressure diagnosis is confirmed. Use blood pressure monitoring, which is not so popular in the US, but you can also use home blood pressure monitoring. Then you have to start first telling your patients how to improve their lifestyle. When that is not sufficient, you have to start anti hypertensive drug treatment. We have a wide array of anti hypertensive drugs that can be easily combined. If you find the right combination, then you go to combination tablets because fewer tablets means better patient adherence.
Dr. Greg Hundley:
Yuan we will turn back to you. In the last minutes here, could you describe some of your thoughts regarding what you think is the next research study that needs to be performed in this sphere of hypertension investigation?
Dr. Yuan Lu:
Sure. Greg, in order to answer your question, let me step back a little bit, just to talk about the implication of the main message from this paper, and then we can tie it to the next following study. We found that the marked increase in hospitalization rate for acute hypertension actually represented many more people suffering a potential catastrophic event that should be preventable. I truly agree with what Dr. Staessen said, hypertension should be mostly treated in outpatient setting rather than in the hospital. We also find the lack of progress in reducing racial disparity in hospitalization. These findings highlight needs for new approaches to address both the medical and non-medical factors, including the social determinants in health, system racism that can contribute to this disparity. When we look at the outcome, we found the outcome for mortality and remission improved over time.
Dr. Yuan Lu:
This means progress has been made in improving outcomes once people are hospitalized for an acute illness. The issue is more about prevention of hospitalization. Based on this implication, I think in a future study we need better evidence to understand how we can do a better job in the prevention of acute hypertension admissions. For example, we need the study to understand who is at risk for acute hypertensive admissions, and how can this event be preempted. If we could better understand who these people are, phenotype this patient better and predict their risk of hospitalization for acute hypertension, we may do a better job in preventing this event from happening.
Dr. Greg Hundley:
Very nice. And Jan, do you have anything to add?
Dr. Jan Staessen:
Yes. I think every effort should go to prevention in most countries. I looked at the statistics, and more than 90% of the healthcare budget is spent in treating established disease, often irreversible disease like MI or chronic kidney dysfunction. I think then you come in too late. So of the healthcare budget in my mind, much more should go to the preventive issues and probably rolling out an effective primary care because that's the place where hypertension has to be diagnosed and hypertension treatment has to be started.
Dr. Greg Hundley:
Excellent. Well, listeners, we've heard a wonderful discussion today regarding some of the issues pertaining to hypertension and abrupt admission to emergency rooms for conditions pertaining to hypertension, really getting almost out of control. We want to thank Dr. Yuan Lu from Yale New Haven and also our guest editor, Dr. Jan Staessen from Louvain in Belgium. On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions express by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit aha journals.org.
Please join authors Babken Asatryan and Anwar Chahal, and Associate Editor Ntobeko Ntusi as they discuss the Primer article "Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health at Richmond, Virginia. Well, Carolyn this week, our feature discussion, we're not going to go with one of our original articles, but we are going to feature a primer and a primer is a state of the art review article. The topic is going to be on arrhythmogenic cardiomyopathy and we'll be looking at the role of inflammation and the immune response in arrhythmogenic cardiomyopathy. But before we get to that feature, how about we grab a cup of coffee and talk about some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I would, because guess what? I'm going to be talking about prescription opioids. We know these are a major contributor to the ongoing epidemic of persistent opioid use. What do you think is the incidence after cardiac implantable electronic device procedures? Greg, let's start with a Greg Hundley quiz. I'll give you multiple choice, how about that? Do you think it is 1%, 10%, 25%. 50%?
Dr. Greg Hundley:
All right, Carolyn, I'm going to guess here. I'm going to go 10%.
Dr. Carolyn Lam:
Smart. Well, guess what? Today's paper actually gives us insight into that question, it's from Dr. Frankel from the hospital of the university of Pennsylvania and his colleagues, and these authors performed a retrospective cohort study using data from a national Administrative Claims Database from 2004 to 2018 of patients undergoing cardiac implantable electronic device procedures. Adult patients were included if they were opioid naive during the 180 day period before the procedure and did not undergo another procedure with anesthesia in the following 180 days.
Dr. Carolyn Lam:
Persistent opioid use, which is what we're interested in, was defined by filling an additional opioid prescription more than 30 days following the procedure. So, here's your answer. Of the more than 143,000 patients meeting these inclusion criteria, 11%, so you were right Greg, 11% filled an opioid prescription within 14 days of surgery. Among these patients, persistent opioid use occurred in 12.4% of patients, 30 to 180 days after surgery. The likelihood for developing persistent opioid use was increased for patients who had a history of drug abuse, pre-operative muscle relaxant or benzodiazepine use or opioid use in the prior five years. Also, patients who have prescribed more than 135 milligrams of oral morphine equivalence had a significantly increased risk of persistent opioid use.
Dr. Carolyn Lam:
Now, this is important because all physicians who perform cardiac implantable electronic device procedures and care for these patients should be aware of the risk of persistent opioid use. This is discussing in editorial by Dr. Kandil from UT Southwestern.
Dr. Greg Hundley:
Very interesting Carolyn, so connecting sometimes the prescription use of opioids after cardiac implantable electronic devices. Great presentation. Well, my first paper comes to us from the world of preclinical science and it's from our prior editor in chief Dr. Joseph Loscalzo from Brigham and Women's Hospital and the Harvard Medical School. So Carolyn, interferon gamma, producing CD4 positive and CD8 positive T-lymphocytes, have been identified as the predominant pathological cell subsets in human atherosclerotic plaques.
Dr. Greg Hundley:
While the immunological consequences of these cells have been extensively evaluated, their interferon gamma mediated metabolic effects on endothelial cells remains unknown. So Carolyn, the purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine interferon gamma on human coronary artery endothelial cells.
Dr. Carolyn Lam:
Interesting. So what did Dr. Loscalzo and colleagues find?
Dr. Greg Hundley:
Right, Carolyn. So, the authors found that interferon gamma impairs endothelial glucose metabolism via altered tryptophan metabolism while depleting NAD plus, which results in a metabolic shift toward increased fatty acid oxidation, and therefore, Carolyn, this work suggests a novel mechanistic basis for pathologic T-lymphocyte endothelial interactions in atherosclerosis, mediated by interferon gamma, linking endothelial glucose, tryptophan, and fatty acid metabolism with NADH and ATP generation and their adverse endothelial functional consequences.
Dr. Carolyn Lam:
Oh, very nice, Greg. Thank you. The next paper describes a comprehensive characterization of cardiomyopathy caused by filament C truncating variance.
Dr. Greg Hundley:
Whoa. Okay, Carolyn. Now what is filamin-C?
Dr. Carolyn Lam:
I thought you may ask and I wasn't going to quiz you, see Greg? The filamin-C gene can cause a striated muscle protein that crosslinks actin and anchors cell membrane proteins to the cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the co-corresponding authors of today's paper Drs. Mestroni and Taylor from University of Colorado, Denver Anschutz Medical Campus, analyzed longitudinal clinical data from an international multicenter cohort of 85 carriers of this filamin-C truncating variants. And this is what they found.
Dr. Carolyn Lam:
First, the cardiomyopathy associated with filimin-C truncating variants appeared to be a disease with heterogeneous phenotypic presentation, ranging from typical dilated cardiomyopathy to arrhythmogenic, right ventricular cardiomyopathy, and with frequently overlapping forms.
Dr. Carolyn Lam:
Number two, left ventricular ejection fraction was associated with the risk of death, either all cause or non-arrhythmic, heart transplantation, or LVAD, but not with the risk of sudden cardiac death or major ventricular arrhythmias, highlighting the need for alternative strategies of stratification of the arrhythmic risk in these patients with the filimin-C truncating variant cardiomyopathy.
Dr. Carolyn Lam:
And number three, this cardiomyopathy was associated with a high risk of ventricular arrhythmias with frequencies of life-threatening ventricular arrhythmias, not significantly different from things like Lamin and desmoplakin cardiomyopathy.
Dr. Greg Hundley:
Well, Carolyn, just fantastic. My next paper comes to us from Professor Lena Claesson-Welsh from Uppsala University and Carolyn, palmdelphin belongs to the family of paralemmin proteins implicated in cytoskeletal regulation and single nuclide polymorphisms in the palmdelphin locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis, and predict the severity of the disease.
Dr. Carolyn Lam:
Wow, interesting. Palmdelphin, great. So tell us, what did they find and what are the clinical implications please?
Dr. Greg Hundley:
Right, Carolyn, great question. So first, calcific aortic valves stenosis patients with the single nucleotide polymorphism RS754 3130 express reduce palmdelphin levels in valve endothelial cells, which shows hallmarks of palmdelphin deficiency, such as loss of cytoplasmic RanGAP1, altered nuclear morphology and nuclear rest of P53 of P21. Carolyn, second, gene-regulatory changes affecting actin reorganization, are detected in seemingly healthy regions of calcifying bowels, in agreement with disturbed actin-dependent processes, being an early event, instigating the calcific process. And so Carolyn, the take home message is that palmdelphin is prominently expressed in endothelial cells and the presence of the palmdelphin single nucleotide polymorphism correlated both with a Barrett endothelium and calcific aortic valve stenosis suggesting that endothelial cell dysfunction is essential in development of calcific aortic valve disease.
Dr. Carolyn Lam:
Oh, wow, wow. Thank you for translating that into the clinical implication. Thanks Greg. Let's maybe discuss what else is in today's issue. There's a prospective piece by Dr. Kirchof entitled “In Patients With Recently Diagnosed Atrial Fibrillation, Think Anticoagulation And Rhythm Control.” There's an exchange of letters between Drs. Liao and Hakala regarding the article Cardiovascular Risk Factor Trajectory Since Childhood And Cognitive Performance In Midlife, The Cardiovascular Risk In Young Finns, study.
Dr. Greg Hundley:
And Carolyn, I've got a research letter from Professor Ramin entitled “Association Between Sarcomeric Variants In Hypertrophic Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel Oxygen-Sensitive CMR Approach.” Well, how about now we get onto that primer feature discussion relating to arrhythmogenic cardiomyopathy?
Dr. Carolyn Lam:
Yay. All right, let's go, Greg.
Dr. Greg Hundley:
Well, listeners, we are now onto our feature discussion and this week we've got a different aspect to the feature discussions. We're going to work through a review article and what we call as a primer. It's one of our state-of-the-art family of publications, where we take a topic and perform a review on a new evolutionary concept that might be occurring in a particular field. This week, we are going to discuss arrhythmogenic cardiomyopathy and we have with us two of the authors of this primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr. Anwar Chahal from Lancaster, Pennsylvania. And of course, as always, we invite one of our associate editors and we have with us this week Ntobeko Ntusi from South Africa. Welcome gentlemen and Babken, let's start with you. Can you give us just a little bit of review regarding arrhythmogenic cardiomyopathy? We hear that term as opposed to arrhythmogenic right ventricular cardiomyopathy, and then maybe also, what are the underlying fundamental histopathologic and pathophysiologic findings associated with this disease?
Dr. Babken Asatryan:
Thank you, Greg. It's really an absolute pressure being here and thank you for your invitation again. So arrhythmogenic cardiomyopathic is genetically-determined heart disease and the common cause of sudden cardiac death in individuals younger than 40 years of age, it's characterized pathologically by fibrosis and/or fibro fatty infiltration of the myocardium. This infiltration provides a substrate for electrical and stability and leads to ventricular arrhythmias ranging from isolated premature ventricular contractions to sustain ventricular tachycardia and ventricular fibrillation. Live ventricular arrhythmias are cardio manifestations of the orthogenic cardiomyopathy, and they typically occur at early stages of the disease, preceding pathological and functional abnormalities. We call that a concealed stage of the disease.
Dr. Babken Asatryan:
The typical form for arrhythmogenic cardiomyopathy, which has been previously termed as arrhythmogenic right ventricular cardiomyopathy, primarily affects the right ventricle and has been recognized for decades. Following implementation of postmortem autopsy, increased use of contrast, enhanced cardiac MRI, and improved understanding of the genotype phenotype correlations, more recently cases with more pronounced left ventricular involvement have been discovered as well as cases with biventricular involvement of the disease.
Dr. Babken Asatryan:
Nowadays, we believe that around 60% of cases have also left ventricular involvement, even if they're diagnosed based on the 2010 task force criteria for arrhythmogenic cardiomyopathy. Causative variants in desmosomal genes are identified in about 60% of patients with typical arrhythmogenic right ventricular cardiomyopathy.
Dr. Babken Asatryan:
Recently, there have been studies reporting non-desmosomal gene variants in patients with arrhythmogenic right ventricular cardiomyopathy, as well as in those left ventricular and biventricular forms of the disease. But the left ventricular form is quite new to us, so we are learning a lot every day about this disease.
Dr. Babken Asatryan:
The pathogenesis of this condition appears to be quite complex. We know that these pathogenic variant in desmosomal genes can initiate several pathways and these could be gene dependent. What we do know, that these eventually lead to fibrosis and fibro fatty infiltration of the myocardium, which is the hallmark feature of arrhythmogenic cardiomyopathy.
Dr. Greg Hundley:
And patients present generally when, in terms of lifespan?
Dr. Babken Asatryan:
So, patients present in between 30 to 40 years of age, there's a typical presentation for arrhythmogenic cardiomyopathies but young presentations are also common nowadays, particularly. So, programs in families, they usually present 30 to 40 years of age. But in families, we do discover patients who have typical arrhythmogenic right ventricular cardiomyopathy or left and right ventricular involvement were younger at age, but they still need the criteria.
Dr. Greg Hundley:
And then when we diagnose this condition, do we also need to think about, at least clinically, looking for other affected individuals within a family?
Dr. Babken Asatryan:
Absolutely. So most of the arrhythmogenic biventricular cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy cases are autosomal dominant diseases. So, this means if an individual carries a pathogenic variant in one of the genes responsible for the condition, the likelihood that the first degree family members will carry the same variant is about 50%. The disease however, presents with reduced penetrance and variable expressivity. Some of the family members may have just arrhythmias and others may develop arrhythmias and structural heart disease. And some of the individuals who carry pathogen occurrence in desmosomal are the genes responsible for the condition may not show phenotype at all. So, that makes the decision-making in families quite challenging.
Dr. Greg Hundley:
Very nice. Well, thank you so much Babken and now, we're going to turn to one of your co-authors, Anwar and Anwar, in this primer, you start to present a new sort of theme, that inflammation actually may play a role in this disease, at least in terms of adverse events. Can you describe a little bit what your team was thinking here and what took you in this direction and what are some of the research that you've revered here that supports this new line of thinking?
Dr. Anwar Chahal:
Thanks, Greg and Ntobeko, for first, the kind invitation to come on this podcast. I must add that I normally listen to the podcast and very much enjoy it, so it's a great honor and privilege for us.
Dr. Anwar Chahal:
Let me contextualize it, I think it's important to think about what are problems are when we evaluate cases, whether that's the program or the family members, and try to determine what's actually going on. There's been a number of changes over the last 15 years that really evolve around a better understanding and the availability of multimodality imaging, which has altered the way we evaluate these cases. If you look at the 2010 taskforce criteria, for example, they talk about volumetric changes and injection fractions by echo or MRI, and even ventriculogram synapse on fluoroscopy, which I don't think many people do anymore, but they don't mention gadolinium enhancement, and there is an updated version that will come out and talk about that, and the advantages of MRI and even contrast-enhanced CT, and now 18F-FDG, CT PET imaging.
Dr. Anwar Chahal:
So, the patient journey and the problem that we face is that actually some people present with very unusual features, chest pain, troponin rise, undergo coronary angiography, normal coronary arteries, or unobstructed coronary arteries. We put them through MRI scanners and we see a little bit of gadolinium enhancement. We follow them over the next five years or so, and it develops into taskforce criteria, positive ARVC. So, that's the sort of clinical angle where we've started to see this.
Dr. Anwar Chahal:
As we put people through scanners, we see the hearts lights up on PET scanners, pretty reproducibly and reliably, that tells us that there's some inflammation there. We look back into the literature and actually very, very early work that was done, autopsy-based, some of it endomyocardial biopsy-based describing lymphocytic infiltrates. Usually that's dry, as you say, or sterile, but there have been reports of even viral pathogens.
Dr. Anwar Chahal:
That's where it stirred this debate up for us about whether there's this signal that we're seeing there, what is it? What's actually going on? It raises a question, we recognize the other mechanisms, the fiber fatty replacement, the apoptotic pathways, that contribute to that. But there's such variable expressivity with this disease. It's a difficult disease to pin down and it raises a question. What are these other effect modifiers? Is there something else that we do not recognize? And that's really what's driven this.
Dr. Anwar Chahal:
Our group of co-authors are leaders in the field. Some of them are colleagues in veterinary medicine, Dr. Anna Geltser, and we work together on boxer dog patients. So, she is a practicing vet and a scientist, and has lots of boxer dogs with arrhythmogenic cardiomyopathy. We've been looking at how we could utilize that as a model to test some of the findings that we have in humans and pioneering work really by Bob Hamilton in Toronto, in this paper where they described anti-DSG2 antibodies, which were found not only in humans, whatever the underlying genotype, but also in boxer dogs with arrhythmogenic cardiomyopathy. And that's been followed up with work from Europe, describing anti-heart antibodies, anti-intercalated disk antibodies.
Dr. Anwar Chahal:
It doesn't really matter what the genotype is, but we're seeing these antibodies there and we're seeing these positive scans indicating inflammation. So the big question is, is this inflammation of primary insult or is it secondary? Is it that the heart in somebody with a genetic cardiomyopathy is predisposed, maybe the remodeling is affected. Bob Hamilton thinks this is probably the best explanation to explain why, whatever the genotype, that these antibodies were positive, that actually that myocardium becomes exposed. The epitope of DSG is now exposed to the immune system, which mounts an antibody response, and hence you see the rise in these antibodies, but it's possible it could it be primary as well. With COVID, and this is a bit of a stretch, so just bear with me there, with COVID we've been recognizing that there's myocardial injury.
Dr. Anwar Chahal:
There's not as much myocarditis as we expected, but there's been, with virus SARS-CoV-2, we know regular human coronavirus is a recognized cause of viral myocarditis. So, the question really arose are we going to see a lot more of this myocarditis? In our lab discussion, it was, "Well, do you think we're going to see something similar in that we've seen with arrhythmogenic cardiomyopathy, these genetically predisposed individuals are more likely to get invaded? Now, we haven't really seen that with COVID and I won't delve too much into it, but going back to the classical viral infections that we see with myocarditis, here's a really, really interesting biological link. Most of them invade through the desmosome, so with SARS-CoV-2, we see the ACE2 receptors as the way the virus really invades. But with these regular coxsackie virus, for example, parvovirus, a lot of them invade through the desmosome, and that's where we thought, here's a link.
Dr. Greg Hundley:
Very nice. Ntobeko, you see a lot of papers come across your desk. What attracted you to this group of investigators and this particular review article?
Dr. Ntobeko Ntusi:
Thank you very much, Greg. I want to start by congratulating Babken, and Anwar for a really fantastic submission, which as an associate editor, was an absolute pleasure to handle. There really are six things that stood out for me about this article. The first one really relates to the question that you ask Babken, which relates to the nomenclature and people have traditionally thought of this is a disease of the right ventricle. I think it's now timely to consider a clear change in nomenclature, that recognizes not only right ventricular involvement, but also left ventricular involvement. And the common finding of biventricular disease in patients with ACM.
Dr. Ntobeko Ntusi:
The second really important contribution for me from this primer was that we've always thought of arrhythmogenic cardiomyopathies as a genetic disorder with abnormalities in the genes, encoding components of the desmosome. Many groups recently, including our own group that described novel mutations for arrhythmogenic cardiomyopathy in adhering to poultry and other genes outside of the desmosome are showing that the genetic underpinnings are much wider. But the key contribution here is really the consideration of the centrality of inflammation to the pathogenesis of this disease. Anwar has spoken to some length about that, so I won't rehash those comments, but for me, what is key for future work in this area is really to clarify whether the inflammation, as in with many other forms of cardiovascular disease, is merely an epiphenomenon, or whether it plays a critical role in the causal pathway for the phenotypes that we see.
Dr. Ntobeko Ntusi:
The next important feature for me was the review of the literature and evidence in the association with myocarditis. So, we've seen lots of case reports and small case series showing young people presenting with myocarditis and meeting either the Dallas criteria histologically, or the Lake Louise criteria on imaging, and then subsequent genetic testing confirming the diagnosis of an arrhythmogenic cardiomyopathy. I thought for the first time with quite a compelling review of the link between these two.
Dr. Ntobeko Ntusi:
The fourth important contribution relates really to the contribution of imaging modalities, both in diagnostics, but critically in risk stratification for this clinical entity. And for me, the importance of cardiovascular magnetic resonance, either with planimetric mapping or late gadolinium enhancement to really add to our ability to predict future events.
Dr. Ntobeko Ntusi:
Then there's been quite a number of publications in the last five years that have clarified our understanding of the at risk patient with arrhythmogenic cardiomyopathy who's likely to suffer a sudden cardiac death event. This tends to be somebody who was young, who was male, who has a history of documented non-sustained ventricular tachycardia or a history of syncope and on ECG, quite extensive T wave inversion. So again, this is nicely reviewed, and we think about those as candidates who'll benefit from implantation of an ICD.
Dr. Ntobeko Ntusi:
Then I thought for me, the last really nice contribution from this piece was the review of advancing our understanding of the hot phase. So in all forms of heart muscle disease, we speak of the presentation of patients with the chest pain syndrome, with a troponin leak, but unobstructed coronaries. On further investigation, we don't really find any other evidence of an inflammatory event. We call this a hot phase. And in some case reports in small case series, endomyocardial biopsy has revealed the association of these, whether in TCM, HCM, or arrhythmogenic cardiomyopathy with lymphocytic infiltration. I thought this was all very nicely reviewed.
Dr. Ntobeko Ntusi:
So, the question that really left me with having read this review, was whether in the future, we may actually need to consider targeting inflammatory pathways as a therapeutic target in this heart muscle disorder. Thanks Greg.
Dr. Greg Hundley:
Yes. Thanks so much in Ntobeko. You've really led us to the next question that I'm going to ask both Babken and Anwar, you've discussed where do you feel this field is moving and what is the next study or series of studies we need to perform. Babken, first you, and then Anwar. Babken, what do you think is the next study to be performed in this space?
Dr. Babken Asatryan:
I so much agree with Ntobeko, that perhaps understanding better what can be targeted in these patients, in order to prevent development of phenotype or least to prevent cardiac events, is perhaps the most important next step. In our first figure, we have summarized this potential mechanisms, involving inflammation leading to with arrhythmogenic cardiomyopathy in these patients. We have also highlighted the potential mechanisms that perhaps in the future can be targeted. This could include both targeting the inflammatory cytokines, as well as the primary agents that cause the myocardial inflammation in patients, depending on the results that we will receive over the next years and perhaps animal models should be the next step to better understand how similar arrhythmogenic cardiomyopathy phenotype, where inflammatory contributors to the phenotype are important. And then we can understand whether this can be the same in humans as well.
Dr. Greg Hundley:
Very nice. And Anwar, do you have anything to add?
Dr. Anwar Chahal:
Yes. So, agree with that. I guess I would add what are we doing to try to help decipher this? So some of the work that we're doing, I mentioned earlier with the boxer dog patients, who have arrhythmogenic cardiomyopathy. So some of the aspects that we're actually looking at is taking swab cells to see if we can phenotype as a alternative tender myocardial biopsy. And one of the co-authors, Angeliki Asimaki, really pioneered that as a alternative tool because the desmosis are ubiquitous and this may help us phenotype patients better. But also, we want to look at using that as a tool in the pheno copies of arrhythmogenic cardiomyopathy. So we would advocate, re-phenotyping people as well as possible and trying to use some of these techniques.
Dr. Anwar Chahal:
The next thing we're really looking at is antibody based tools, either working with collaborators, who've already described these antibodies such as anti-DSG2, anti-heart antibody, and anti-skeletal disc to see if we can develop those and perhaps identify others in both human and ox models. And that will then hopefully open the way for us to develop therapeutics that may be able to target those and address that, and maybe use these antibodies as markers to see disease progression, or halting of disease.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Babken Asatran from Bern, Switzerland, Anwar Chalal from Lancaster, Pennsylvania, and our own associate editor, Ntobeko Ntusi from South Africa, really helping us see this new scientific consideration regarding the potential role of inflammation in causal pathways of adverse manifestations of arrhythmogenic cardiomyopathy. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.
Please join author Maria Nunes and Associate Editor Ntobeko Ntusi as they discuss the article “Incidence and Predictors of Progression to Chaga Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.”
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this feature this week, we're going to talk about Chagas disease and we have some really important long-term, really for the first time, observational data and a cohort that's been followed in Brazil. And it's just a wonderful discussion from a team that's been working very hard in this area over an extended period of time. But before we get to that, how about we grab a cup of coffee and get started on some of the other articles in this issue? Would you like to go first?
Dr. Carolyn Lam:
I would. And with your coffee, I would like to tell you about non-combustible nicotine or tobacco products. Fancy a smoke with your coffee? Well, you know that those are novel forms of nicotine consumption composed of things like nicotine vaping products that vaporize the nicotine-containing fluids and heated tobacco products that really heat the tobacco products without combustion. Now, these have recently gained popularity because they're portrayed as being safer modes of smoking compared with the traditional combustible cigarettes. However, their associations with subsequent cardiovascular disease risks are still unclear. So Greg, here's today's quiz. Gosh, I miss our quizzes. What do you think? Are they safer or are they not?
Dr. Greg Hundley:
Oh, Carolyn, you're catching me on this and I never know which way to go, but I'm going to guess not. How about you tell us?
Dr. Carolyn Lam:
Well, the paper will tell us, and this is from co-corresponding authors Dr. Lee from Seoul National University Bundang Hospital and Dr. Park from Seoul National University College of Medicine and their colleagues. And they basically studied more than 5,000,000 adult men who underwent health screening examinations during both a first and second phase of health screening periods from the Korean National Health Insurance Service Database spanning 2014 to 2018. Initial combustible cigarette smokers who subsequently quit that cigarette smoking and converted to a non-combustible nicotine or tobacco product use was associated with a lower incident cardiovascular disease risk compared to those who continue the combustible cigarette use. However, compared with combustible cigarette quitting without using these non-combustible substitutes, those who ceased smoking but continued with the non-combustible products was associated with a higher cardiovascular disease risk. So the take home message is although the non-combustible nicotine or tobacco products may be associated with a lower cardiovascular disease risk compared with continued combustible cigarette smoking, those who quit without using these substitutes may benefit the most in reducing the risk of developing future cardiovascular disease events. And this is discussed in a wonderful editorial by Dr. Auer, Diethelm and Berthet.
Dr. Greg Hundley:
Very nice, Carolyn. Great presentation and really new information in this space. Well, my paper comes from the world of preclinical science and it involves long noncoding RNAs. And Carolyn, they are important regulators of biological processes involved in vascular tissue homeostasis and cardiovascular disease development. And so, the current study, led by Professor Lars Maegdefessel from Karolinska Institute, assessed the functional contribution of the long noncoding RNAs myocardial infarction associated transcripts and their relationship to atherosclerosis and carotid artery disease.
Dr. Carolyn Lam:
Hmm, interesting. They are the rage, these lncRNAs. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So long noncoding RNAs possess key regulatory functions directly interacting and mediating expression and functionality of proteins, other RNAs, as well as DNA. Next, the long noncoding RNA myocardial infarction associated transcript plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high risk patients with vulnerable plaques. And so, Carolyn, the take home therapeutic targeting of the long noncoding RNA myocardial infarction associated transcript, using antisense oligonucleotides, well that offers novel treatment options for patients with advanced atherosclerosis in the carotid arteries that are at risk of stroke.
Dr. Carolyn Lam:
Oh, very interesting. So from the preclinical world back to the clinical world with an important clinical trial. Now, we know that percutaneous closure of the left atrial appendage is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amplatzer Amulet Left Atrial Appendage Occluder IDE trial, called the Amulet IDE trial, was designed to evaluate the safety and effectiveness of the dual seal mechanism of the Amulet left atrial appendage occluder compared with the WATCHMAN device. And here, 1,878 patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned to undergo percutaneous implantation of a left atrial appendage occluder with the Amulet occluder or a WATCHMAN device. And the primary end points included safety, which was a composite of procedure-related complications all cause death or major bleeding at 12 months, and effectiveness, which was a composite of ischemic stroke or systemic embolism at 18 months. They also looked at the rate of left atrial appendage occlusion at 45 days. And this paper is from Dr. Lakkireddy and colleagues from Kansas City Heart Rhythm Institute.
Dr. Greg Hundley:
Well Carolyn, these devices, they are really being heavily tested in patients with atrial fibrillation. So what did they find?
Dr. Carolyn Lam:
The Amulet occluder was non-inferior with respect to safety and effectiveness compared to the WATCHMAN device, and superior with respect to left atrial appendage occlusion; however, procedure-related complications were higher with the Amulet occluder, largely related, perhaps, to more frequent pericardial effusion and device embolization. And the authors noted that the procedure-related complications decreased with operator experience; however, I think all of this still needs to be further investigated. Well, those were really nice original papers, but let's also discuss what else there is in today's issue. There is an exchange of letters between Drs. Mueller and Allen regarding the article “Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite U.S. Cohort.” There's a perspective piece by Dr. Olson, “Toward CRISPR Therapies for Cardiomyopathies.”
Dr. Greg Hundley:
And Carolyn, I've got a research letter from Professor Layland entitled “Colchicine in Patients with Acute Coronary Syndromes: Two Year Follow Up of the Australian COPS Randomized Clinical Trial.” Well, what a great set of papers that we've discussed. Now, let's get on to that feature discussion and learn a little bit more about the longitudinal history and progression of cardiovascular disease and patients with Chagas disease.
Dr. Carolyn Lam:
Yay. Let's go, Greg.
Dr. Greg Hundley:
Well, listeners, we are here for our feature discussion today and a very exciting one we have, pertaining to Chagas disease. And we have with us today Dr. Maria Nunes from Belo Horizonte, Brazil, and also one of our Associate Editors, Dr. Ntobeko Ntusi from Cape Town, South Africa. Welcome to you both. And Maria, we'll start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address?
Dr. Maria Nunes:
Yes, thank you for these opportunities. My main hypothesis is that Chagas disease is the major cause of dilated cardiomyopathy in endemic areas. So we selected patients without cardiomyopathy at baseline to see if the Trypanosoma cruzi seropositivity is a predictor of further developing of cardiomyopathy.
Dr. Greg Hundley:
Very nice. And so tell us, how did you construct this study? What was your design? And then also, maybe describe for us how you selected the participants for this study.
Dr. Maria Nunes:
We selected the participants from two blood donor centers. One in Sao Paulo and one in Montes Claros, which is north of Minas Gerais State. We select blood donors because it's the way that we have Chagas disease’s screening tests. And in asymptomatic patients, usually at the hospital, patients comes to us with heart failure or a kind of symptoms related to Chagas disease. Our main goals in this study is to select healthy participants based on the screen test of Trypanosoma cruzi. So the population was blood donors selected from two centers.
Dr. Greg Hundley:
Very good. And then again, your study design. So did you follow these two groups of individuals longitudinally over time, and for how long?
Dr. Maria Nunes:
Yes, we have different visits of this study with the patients initially was selected at first in 1996 and 2002. At this time, they don't have cardiovascular exams. And our study actually is starting 2008 to 2010, and we select all these patients with all comprehensive cardiovascular evaluation with the clinical examination, echocardiogram and electrocardiogram, and then just the baseline for our patient population. And we follow them 10 years on average until 2018, 2019.
Dr. Greg Hundley:
Very nice. So it sounded like from individuals in two regions of Brazil, identified those through screening of the blood, and I guess these were blood donors, and then performed a series of cardiovascular exams 2008 to 2010 and followed them for the next 10 years. And you're going to tell us about the results that occurred 2018 to 2019. And so what were those results?
Dr. Maria Nunes:
We found that Trypanosoma cruzi seropositive is a risk factor for developing cardiomyopathy. Nowadays, this is still a risk factor, seropositive without cardiomyopathy at baseline has two times higher risk of developing cardiomyopathy compared to the seronegative controls. And we have also detected that the parasite load or the level of parasite in the blood expressed by antibodies against Trypanosoma cruzi is an important risk factor for disease progression. That means some patients have Chagas disease, but the level of antibodies is not too high. These patients go well. And other hand, the patients with high level antibodies means the parasite load may be higher too. This is the high risk of disease progression to cardiomyopathy or of dying too.
Dr. Greg Hundley:
Very nice. And were there any subgroups of patients where you found these relationships to be particularly more striking? So for example, the elderly, or was there a discrepancy based on sex, men versus women?
Dr. Maria Nunes:
Yes, other studies has already shown that the male gender is a risk factors in Chagas disease. Usually they progress more, they have more severe clinical presentation, usually die at the age between 30 and 50 years old, the most productive years of the life. That's why Chagas is so important here in Brazil and Argentina, in Latin America countries because people die at early ages.
Dr. Greg Hundley:
And your results confirmed what was previously known in that regard.
Dr. Maria Nunez:
Yes, patients with developing cardiomyopathy with heart failure has a high mortality rate. And then even patients with cardiomyopathy detected by exams like based on ECG or echo, they asymptomatic, but they progress more for dying or to develop cardiomyopathy compared to seronegative with similar risk effects for cardiovascular disease, such as hypertension, diabetes, smoking.
Dr. Greg Hundley:
Very good. Well Ntobeko, you see many papers come across your desk as an Associate Editor for Circulation, and what attracted you to this paper and the results that Maria has described?
Dr. Ntobeko Ntusi:
Thank you, Greg. I was attracted to this paper because it's an important natural history study of Chagas disease. But secondly, it's also one of the largest contemporaneous cohorts of Chagas disease which provides important insights and advances in our knowledge with regard to this clinical entity. And for me, there were three things that stood out. The first one was an important description of the outcomes of Chagas cardiomyopathy. The second was the contemporaneous description of the epidemiology in a well-characterized cohort. And the third and novel contribution was the description of the determinants of disease progression. So I thought overall, the really important contribution to the field.
Dr. Greg Hundley:
Very good. And for those that might not live in the endemic area, but might occasionally encounter someone with Chagas disease, what results from this paper can we use to help manage patients in this situation?
Dr. Ntobeko Ntusi:
Thanks, Greg. So this was a study which had a number of really positives. Firstly, it's a large study, it was non acute [inaudible 00:16:42] design and it used PCR for diagnosis. And unlike many other studies, also ascertained antibody levels and had very good clinical characterization, which included electrocardiographic, echocardiographic assessment, including serum assessment of proBNP and CK-MB. And all really important take home messages are for me. The first one is understanding that the relationship of your antibody levels and baseline LV function to mortality. In other words, are finding that in those with existing LV structural abnormalities, or higher levels of antibody titers, mortality was higher. The second important contribution is a description of the incidence of Trypanosoma cruzi, and this was highest as one would expect in the seropositive donors and much lower in seronegative donors. The third important contribution relates to our improved understanding of the determinants of disease progression, which were related to the Trypanosoma cruzi antibody levels.
In other words, the higher your antibody titers, the quicker you progressed to manifest the cardiomyopathic phenotype. And then lastly, the predictors of mortality, which were related to your PCR being positive, as well as your antibody titers. Important is this contribution is there are a number of important caveats. The first is that the study is limited by the huge amount of loss to follow up, which as you can imagine, adds a number of biases to our conclusions. The second is that the observations may of course be confounded by comorbidity in particular because these patients are older and had higher comorbidity. The third is that we assume that the PCR positivity and antibody titers actually correlate with parasite pattern, but in fact, we know that is not always the case. And then lastly, for people who read this paper from non-endemic parts of the world, the result may not be clearly generalizable to those parts of the world.
Dr. Greg Hundley:
Very nice. Well, we've had a great discussion, listeners. From Maria and Ntobeko sort of presenting the paper and then what are some of the take home messages. So now I'd like to go back to both of them and Maria, first you and then Ntobeko. Maria, what do you think is the next study to really be performed in this sphere of research?
Dr. Maria Nunes:
We may should stratify patients with Chagas disease. Those who have high antibodies titers should refer to a kind of treatment or benznidazole treatment. We should intervene in this subgroup.
Dr. Greg Hundley:
Very good. And Ntobeko, anything to add?
Dr. Ntobeko Ntusi:
Yes, Greg, I think that there are two important next steps. The first one is that I think we need other large designed prospective studies that will validate the observations by Dr. Nunes and colleagues. And then the second key step for me would be the design of randomized controlled trials to test therapeutic agents with antitrypanosomal activity to demonstrate their ability to retard or completely block disease progression, which would be a nice way to complete the story.
Dr. Greg Hundley:
Very nice. Well listeners, we've had a great discussion today and we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from South Africa for bringing these really informative results pertaining to Chagas disease, and highlighting the natural history and showing an association between these high titer values and poor cardiovascular outcomes.
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Please join author Ole Fröbert and Associate Editor Dharam Kumbhani as they discuss the article "Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU health in Richmond, Virginia. Well, listeners, this week we've got a really hot feature topic pertaining to flu vaccines, which are coming in the US, North America, South America, coming up soon, and their relationship to myocardial infarction. But before we get to that feature discussion, let's grab a cup of coffee and jump in to some of the other articles in this issue. Oh, wait a minute. Our first article, we've got a co-author here. Carolyn, something about the VICTORIA trial, which you were a part of. Can you tell us a little bit about this?
Dr. Carolyn Lam:
I would love to, and first of all, I'm doing this on behalf of a big team, and I want to really, really call up first Dr. Paul Armstrong who's the senior author from University of Alberta. But let me tell you first about the VICTORIA study. VICTORIA evaluated vericiguat, a soluble guanylate cyclase stimulator, compared to placebo, in patients with heart failure with reduced ejection fraction with a recent worsening heart failure event and the primary result was actually a significant reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization with vericiguat compared to placebo.
Dr. Carolyn Lam:
Now, interestingly though, in VICTORIA, we found that anemia occurred more often in patients treated with vericiguat at a rate of about 7.6% compared to placebo, which was 5.7%. Now, although earlier studies of another soluble guanylate cyclase stimulator like riociguat was found to be associated with anemia. The etiology really remains unknown. In the current paper, we explored the relationship between markers of anemia and vericiguat versus placebo in VICTORIA. We further explored the changes in hemoglobin and hematocrit over the course of the trial and their relationships with the primary composite outcome.
Dr. Greg Hundley:
Carolyn, this is such an important new study heart failure therapy for those with reduced ejection fraction, and again, an important topic related to anemia. What did they find?
Dr. Carolyn Lam:
Thanks, Greg. First, approximately a third of patients in VICTORIA had anemia at randomization, and this is using the standard sex-based definitions. With a lower hemoglobin indeed predicting a higher risk for cardiovascular death, heart failure hospitalization, all-cause mortality. As I had already mentioned, we found more anemia with vericiguat than with placebo. The interesting thing though is after 16 weeks, no further decline in hemoglobin occurred over the remaining and over 96 weeks of follow up, and the ratio of hemoglobin to hematocrit remained constant. Now, overall, the adverse event of anemia occurred in 7.1% of the patients.
Dr. Carolyn Lam:
Importantly, the lower hemoglobin was not related to the beneficial effect of vericiguat over placebo on the primary outcome. Now, I know all of that may be more descriptive and reassuring than really understanding the mechanism by which it occurred. Further mechanistic studies are certainly warranted to better understand the basis of the anemia development, and it's of principle importance because as you said, vericiguat I think it's going to be an important new medication that we can consider in high-risk patients with recent worsening heart failure with reduced ejection fraction.
Dr. Greg Hundley:
Thanks so much, Carolyn, especially the perspective of being an author on this particular study. Well, Carolyn, my next study is going to come to us from Dr. Zhao Wang from University of Texas Southwestern Medical Center, and it's really about the integrated stress response, and that's an evolutionary conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery perfusion is the most effective means to mitigate cardiac damage resulting from myocardial infarction. However, that can cause, as we know, additional reperfusion injury. This study aim to investigate the role of the integrated stress response in myocardial ischemia reperfusion injury.
Dr. Carolyn Lam:
Oh, very interesting. What were the results?
Dr. Greg Hundley:
Right, Carolyn. The authors found that the integrated stress response is activated by ischemia reperfusion injury in the heart, and the perk branch of the integrated stress response protects the heart from ischemia reperfusion injury through inhibition of protein synthesis. Also, Carolyn, mitochondrial complex proteins are selectively suppressed and oxidative stress is reduced by the integrated stress response. Carolyn, the takeaway is that this integrated stress response is cardioprotective against cardiac ischemia reperfusion injury. Perhaps pharmacological stimulation of the integrated stress response at reperfusion, well, that may reduce heart damage and improve cardiac outcomes after ischemia reperfusion injury.
Dr. Carolyn Lam:
Cool. Thanks, Greg. Well, I've got one more paper, and this deals with coronary microcircuitry dysfunction and acute rejection after heart transplantation. Co-corresponding authors, Doctors Lee and Choi from Heart Vascular Stroke Institute in Samsung Medical Center sought to evaluate the prognostic implications of coronary microcircuitry dysfunction assessed by the index of microcircuitry resistance or IMR for the risk of acute cellular rejection after heart transplantation. They did this by prospectively enrolling 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment one month after transplantation.
Dr. Greg Hundley:
Very interesting, Carolyn. What did they find here?
Dr. Carolyn Lam:
IMR measured early after heart transplantation was significantly associated with the risk of acute cellular rejection, and an IMR above or at 15 was highly predictive for the recurrence of acute cellular rejection during two years of follow up following heart transplantation. Adding IMR to the prediction model with clinical variables significantly increase discriminant and reclassification ability for the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, the implications are that early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation, and this is discussed in an editorial by Doctors Fearon and Valentine from Stanford University.
Dr. Greg Hundley:
Very nice, Carolyn.
Dr. Carolyn Lam:
Great. Greg, before we go to the exciting feature discussion, let's round it up by just a quick tour of what else there is in today's issue. There is an exchange of letters between Doctors Pappone Leor on atrial fibrillation as a cardiomyopathy, global rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr. Tsai on grouped beating following acute inferior myocardial infarction, and a research letter by Dr. Salem on electrocardiographic manifestations of immune checkpoint inhibitor myocarditis.
Dr. Greg Hundley:
Great, Carolyn. Well, I can't wait to get to this next feature discussion and learn a little bit more about the relationship between flu vaccines and future myocardial infarction.
Dr. Carolyn Lam:
Today's feature discussion was a really hot topic at the ESC 2021, and in fact, a simultaneous publication. It is about influenza vaccination after myocardial infarction, a very important topic and a very novel paper. We are so pleased to have the first and corresponding author, Dr. Ole Fröbert from Orebro University in Sweden to discuss this paper, as well as our associate editor, Dr. Dharam Kumbhani, from UT Southwestern. Welcome, gentlemen. Only if I could start with asking you to describe the rationale for why you did this study, and then perhaps quickly summarize the results.
Dr. Ole Fröbert:
Yeah, thank you so much, Carolyn. The background of the study was that during influenza epidemics, more people die from cardiovascular causes, and out in the literature, there are numerous observational studies suggesting a protective effect from influenza vaccination on cardiovascular events. There are also three smaller single-center randomized trials supporting these registered findings. Currently influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention guidelines, but uptake is low and vaccination timing is unclarified. Our aim was to determine whether influenza vaccination improves clinical outcomes in patients with a recent myocardial infarction or with high risk corona artery disease.
Dr. Ole Fröbert:
The study was international, multi-centers investigator initiated, double-blind randomized control trial, and we enrolled patients at 30 centers across eight countries in both the Northern and the Southern Hemisphere, Sweden, Denmark, Norway, Latvia, Scotland, Czech Republic, Bangladesh and Australia. We enrolled patients between October 2016 and March 2020. We had quite broad inclusion criteria. We included hospitalized patients with STEMI or non-STEMI, or high-risk stable patients over 75 years of age undergoing an angio or PCI. We excluded patients already vaccinated or intending to be vaccinated during the current season. We also included, of course, patients if they had allergy to X or influenza vaccine, if they had infection or if they were immunosuppressed or previously randomized in the trial.
Dr. Ole Fröbert:
Over these four years of inclusion, we enrolled a total of 2,571 participants. The primary outcome was a composite of all-cause death, MI and stent thrombosis. This outcome occurred in 67 participants assigned influenza vaccine and 91 assigned placebo corresponding to a reduction of the primary endpoint of 28% with a P value of 0.04. Also, rates of all-cause death and of cardiovascular death were reduced and both with a hazard ratio of 0.59 corresponding to a reduction of 41% in all-cause death and cardiovascular death. Based on these results, we think that this trial and what we know from previous smaller trials should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment after an MI.
Dr. Carolyn Lam:
Heartfelt congratulations, Ole. What an elegant intervention in a very frankly challenging situation that the trial obviously carried on through COVID as well, multinational. May I just double check? Was it investigator-led? Because-
Dr. Ole Fröbert:
Yes, this was-
Dr. Carolyn Lam:
That's amazing.
Dr. Ole Fröbert:
... an idea that just popped up, and then yeah, we did it, but it was seven years of work.
Dr. Carolyn Lam:
Wow. Hard work as I can just imagine. First, heartfelt congratulations. Very impactful results. Dharam, could I invite you to put those results in context and why we single this out?
Dr. Dharam Kumbhani:
Yeah. No, thank you, Carolyn. Ole, I want to amplify or recapitulate the amazement and wonder that Carolyn just articulated. I think this is a huge endeavor. It's a very important topic. It's "a fairly simple intervention." It's vaccination, and you've just really shown that even in the acute setting, that A, this is as feasible, B, it is safe, and three, it is effective. I think it's potentially ... Given the magnitude of influenza in the world, I think this has tremendous public health ramifications. I really want to congratulate you and your investigators for pursuing this important question and then just executing this, I'm sure despite multiple challenges over a long period of time.
Dr. Ole Fröbert:
Thank you very much.
Dr. Dharam Kumbhani:
Yeah, no. I guess you already alluded to the fact that this may influence guidelines. As you mentioned, it's a 1B. Maybe get your thoughts, I suppose this may move the needle towards becoming perhaps a little stronger on the recommendation front, both in the US and the European guidelines?
Dr. Ole Fröbert:
Yeah. I think what has been the challenge until now is that many places, of course, you commend patients to take a flu jab when treatment is over in the hospital. But then the responsibility is diffused. Who should take care of that? Is that up to the patient or the primary care physician? Who is in charge? One important finding of this study is, as you said, it's safe. There were no differences, adverse events between the two groups. It's safe and it could be given early. I think a take-home factor from the study is that it should be given at the hospital and it's a responsibility of the cardiologist.
Dr. Dharam Kumbhani:
Yeah, I really like that. Actually, I'm sure this would resonate across the board in the cardiology community. We've taken ownership for starting from statin and now SGLT-2 inhibitors, which kind of ... All of these medications have come from non-cardiology realms, so to say. But now we prescribe those medications. We know they have clear cardiovascular benefits. I suppose you could make a case to say we, the cardiology community, has to adopt this. The implementation gap that exists for a lot of these therapies, that also comes to us and for us to move that forward. It's thought provoking. I certainly felt very strongly after your study. I don't know how you feel about that. We should really be the ones driving this and help with more widespread immunization in these patients.
Dr. Ole Fröbert:
I think because not just this study, but also the previous studies and what we know from observational findings is that this is safe and it works. What we also saw in our study, and it has been indicated in previous meta analysis, is that the maximum effect is seen in the acute setting. It's the acute coronary syndrome patients, the patients we had in our study, that benefit the most. That's also a case for actually doing this in the hospital and not postponing it.
Dr. Carolyn Lam:
Wow. That's amazing. Ole, I do have one question. Just for clarification. You were careful to say that you did this during influenza seasons, right? Coming from my part of the world in Singapore where we don't really have influenza seasons, don't have any seasons, frankly, what would you think? What would you advise?
Dr. Ole Fröbert:
There is influenza seasons in all parts of the world, I'm sorry.
Dr. Carolyn Lam:
True.
Dr. Ole Fröbert:
For example, we had Bangladesh on board in our study. It's in the Northern Hemisphere, but influenza-wise, it's in the Southern, and their season is between May and September. But it's not as clearly defined as the Northern Hemisphere season. It's almost always in two waves during that season. One practical challenge with influenza vaccine is that it's produced for the seasons. It's difficult to say, "Yeah, we can just do it all year round," and also we didn't test that. I, of course, feel we should give it all year round, but it's not available, the vaccine. Perhaps it should be tested, but it is probably difficult to find funding for such a study.
Dr. Carolyn Lam:
Very fair, and thanks for the correction. It's true though. Singapore's on the Equator, so we don't have maybe weather seasons. But yeah, we do get vaccinated for both North and South. It's quite fascinating. But nonetheless, could I now switch topics a little bit and just over the next couple of minutes just ask you, could you please perhaps share with the audience what it was like to work with Circulation, to do this simultaneous publication? You see, our associate editor, Dharam Kumbhani, really leads this effort to get simultaneous a fast-track publication from major conferences, and it means a lot to us that investigators like you chose us. Could you share a bit?
Dr. Ole Fröbert:
Yeah, thank you very much. Overall, it was a pleasure. Of course, we were ... With every study of this size, you are under stress, you get the results late, and there's a conference coming up, and you would like your paper to come out at the same time across to maximize impact and attention. What I really like with working with Circulation was turnaround time was ultra fast, really extremely fast. Of course, we had a lot of questions to our study, but these were ... Some of them of course were quite difficult, but they were fair. In a way, they were also helpful in a way that made it easier to address the questions in a more, you could say, collaborative way. It was very smooth. No hiccups.
Dr. Carolyn Lam:
Thank you. Dharam, any final responses to that?
Dr. Dharam Kumbhani:
No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure to work with you on this. I think we all recognize that this was an important study and wanted to make sure that we were able to accomplish the goal of simultaneous publication. Thank you for working with us on that. I just want to put a pitch in, I think this, for Joe, Dr. Hill and the rest of the editorial team, having a robust simultaneous publication program has been very, very important. We are very committed to working with investigators and authors on this. We are really blessed with our team on the backside that works seamlessly with us nights, weekends, just to get these things done. I just want to end with that to say this is very important for us, and we look forward to the opportunity to work with Ole and others on future papers as well.
Dr. Carolyn Lam:
I love that. Thank you both for being on this podcast today. Today I want to especially call out David Rivera, a wonderful managing editor who really, really is part of leading this entire group that supports us, but also even this very podcast. You've been listening to Circulation on the Run. Thank you, from both Greg and I, for joining us today, and don't forget to tune in again next week. Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Please join author Jonathan Newman and Associate Editor Sandeep Das as they discuss the article "Outcomes of Participants With Diabetes in the ISCHEMIA Trials."
Dr. Carolyn Lam:
Welcome to circulation on the run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts; I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, this week's feature, a couple of weeks ago, we had that feature forum on the ischemia trial. Now we're going to explore some of the outcomes in patients with diabetes, from the ischemia trial in the feature discussion today. But, before we get to that, let's grab a cup of coffee and start in on some of the other articles in this issue. So, how about if I go first, this time? This particular paper, Carolyn, we're going to start on one of your topics. I know you're a fan of diet related interventions. So high intake of added sugar is linked to weight gain and cardio-metabolic risk. And in 2018, the U S National Salt and Sugar Reduction Initiative proposed government supported voluntary national sugar reduction targets.
Dr. Greg Hundley:
This intervention's potential health and equity impacts and cost effectiveness are unclear. And so Carolyn, these authors, led by Dr. Renata Micha from Tufts University, incorporated a validated micro-simulation model - CVD Predict coded in C++, and used it to estimate incremental changes in type two diabetes, cardiovascular disease, quality adjusted life years, cost and cost effectiveness of this national policy. The model was run at the individual level and the model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across three cycles spanning from 2011 to 2016, added sugar related diseases from meta-analysis and policy costs and health-related costs from established sources and a simulated nationally representative us population was created and followed until age 100 years or death with 2019 as the year of intervention start and findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives.
Dr. Carolyn Lam:
Ooooh, You so got my attention, Greg, a very important topic and so, what did they find?
Dr. Greg Hundley:
Right, Carolyn. So achieving the NSRI sugar reduction targets could prevent 2.48 million cardiovascular death related events, 0.5 million cardiovascular disease deaths, and three quarters of a million diabetes cases, gain 6.7 million quality adjusted life years, and save $160.8 billion in net cost from a societal perspective over a lifetime. The policy became cost-effective, defined as less than $150,000 for quality adjusted life years at six years and highly cost-effective at seven years with a cost savings noted at nine years. And therefore, Carolyn, implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains, and cost savings.
Dr. Carolyn Lam:
Wow, thanks Greg. So, moving from a very publicly health focused paper to this paper that really focuses on hypoplastic left heart syndrome with very, very scientifically significant findings. Now, first, we know hypoplastic left heart syndrome is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis is unknown, but hemodynamic disturbances are assumed to play a prominent role. Authors led by Doctors Moretti and Laugwitz from Technical University of Munich in Germany, as well as Dr. Gruber from Yale University School of Medicine, and their colleagues combined whole exome sequencing of parent offspring, trios, transcriptome profiling of cardiomyocytes from ventricular biopsies and immuno-pluripotent stem cell derived cardiac progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as well as single cell gene expression analysis to decode the cellular and molecular principles of hypoplastic left heart syndrome phenotypes.
Dr. Greg Hundley:
Wow, Carolyn, there is a lot of data, very complex preclinical science here. So what did they find?
Dr. Carolyn Lam:
Indeed, Greg. As I said, scientifically incredible and rigorous, and they found that initial aberrations in the cell cycle unfolded protein response, autophagy hub led to disrupted cardiac progenator lineage commitment, consequently, impaired maturation of ventricular cardiomyocytes limited their ability to respond to growth cues. Resulting in premature cell cycle exit and increase apoptosis under biomechanical stress in 3D heart structures. Together, these studies provide evidence that the hypoplastic left heart syndrome pathogenesis is not exclusively of hemodynamic origin, and they revealed novel potential nodes for rational design of therapeutic intervention.
Dr. Greg Hundley:
Wow, Carolyn, we really need research in this topic and this is great preclinical science that we're getting here in our journal. Congratulations to the authors and what a great presentation of that by you. Well, Carolyn and my next paper there remain major uncertainties regarding disease activity within the Retain Native Aortic Valve, as well as bioprosthetic valve durability, following transcatheter aortic valve implantation. And these authors led by Doctor Jacek Kwiecinski, from the Institute of Cardiology, aimed in a multi-center cross-sectional observational cohort study to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement or SAVR.
Dr. Carolyn Lam:
Oh, very interesting. And what were the results?
Dr. Greg Hundley:
An interesting comparison, Carolyn. So in patients with TAVI, native aortic valves demonstrated 18 F sodium fluoride uptake around the outside of the bioprosthesis that showed a modest correlation with the time from TAVI. Next, 18 sodium fluoride uptake in the bias prosthetic leaflets was comparable between SAVR and TAVI groups. Next, the frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echo cardiography 6 and 8% respectively, CT, 15 and 14% respectively, and with PET scanning. Next, baseline 18 F sodium fluoride uptake was associated with subsequent change in peak aortic velocity for both TAVI and SAVR. And on multi-variable analysis, the 18 F sodium fluoride uptake was the only predictor of peak velocity progression. And so Carolyn, therefore, in patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease and across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable midterm durability.
Dr. Carolyn Lam:
Very nice, important stuff.
Dr. Carolyn Lam:
Well, thanks, Greg. Let's tell everyone about the other papers in today's issue. There's an exchange of letters between Doctors Baillon and Blaha regarding the article very high coronary artery, calcium and association with cardiovascular disease events, non-cardiovascular outcomes and mortality from MESA. There's an ECG challenge from Dr. Bell Belhassen on a left bundle branch block, tachycardia following transcatheter aortic valve replacement. And On My Mind paper by Dr. Neeland on cardiovascular outcomes trials for weight loss interventions, another tool for cardiovascular prevention, another Research Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono therapy in heart failure, patients with atrial fibrillation and stable coronary artery disease. So insights from the AFIRE trial, and finally, a Research Letter from Dr. Kumoro three-dimensional visualization of hypoxia induced, pulmonary vascular remodeling in mice.
Dr. Greg Hundley:
Great, Carolyn, and I've got an in-depth piece from Professor Jia Sani entitled breadth of life, heart disease, linked to developmental hypoxia.
Dr. Greg Hundley:
Well, Carolyn, how about we get onto that feature discussion and learn more about results from the ischemia trial?
Dr. Carolyn Lam:
Let's go Greg.
Dr. Carolyn Lam:
Well, we all know how important diabetes is as a risk factor for atherosclerotic coronary disease. And we know it's a very common comorbidity among patients with chronic coronary disease, but the question is do patients with diabetes and chronic coronary disease on top of guideline directed medical therapy and lifestyle interventions, of course, do they derive incremental benefit from an invasive management strategy of their coronary disease? Well, we are going to try to answer that question today in our feature discussion. Thank you so much for joining us today. The first author and corresponding author of today's feature paper, which tells us about results from the ischemia trials. And that's Dr. Jonathan Newman from New York university Grossman School of Medicine. We also have associate editor Sandeep Das from UT Southwestern. So welcome both of you. And if I could please start with Jonathan reminding us, perhaps, what were the ischemia trials and then what you tried to answer and do in today's paper,
Dr. Jonathan Newman:
Of course, Carolyn, and thank you so much for having me and for the discussion with Sandeep. It's a pleasure to be here. So sure has a little bit of background, as you indicated, the ischemia trials basically enrolled and for the purposes of this discussion and this analysis, I'm referring to both the main ischemia trial and the ischemia chronic kidney disease trials. So ischemia CKD under the umbrella of the ischemia trials. Ischemia stands for the international study of comparative health effectiveness with medical and invasive approaches. And the purpose of the trial was to test to see whether a routine invasive approach on a background of intensive guideline directed medical therapy for high risk patients with chronic coronary disease and at least moderate ischemia and obstructive coronary disease documented on a blinded CCTA or computed coronary tomography angiography prior to randomization was associated with benefits for a cardiovascular composite. And we looked in this analysis at whether or not there was appreciable heterogeneity of treatment effect or a difference in treatment effect for patients compared without diabetes in the ischemia trials, in ischemia and ischemia CKD.
Dr. Carolyn Lam:
Great, thanks for lining that up so nicely. So what,
Dr. Jonathan Newman:
So the results of our analysis really highlighted a couple of things that I think you touched upon initially, the first thing that I would highlight is that diabetes was very common in this high risk cohort with chronic coronary disease, over 40% of participants in the ischemia trials, 43% with obstructive coronary disease and moderate to severe, you may have had diabetes. Perhaps not surprisingly patients with diabetes had higher rates of death or MI than those without diabetes. And the rates were highest among those patients that required insulin, had insulin treated diabetes, but using really robust methods to assess for heterogeneity using a Bassen assessment of heterogeneity of treatment effect accounting for violation of proportional hazards. The fact that there was an upfront hazard and a late benefit, we really saw no difference in death or MI, between the invasive or conservative strategies for patients with, or without diabetes over about three years of follow-up.
Dr. Jonathan Newman:
And the results importantly were consistent for ischemia and ischemia CKD and provided the rationale for us when we started by looking to see if the distribution of risk and characteristics allowed the trials to be combined. The study really confirms this higher risk of death or a MI for chronic coronary disease patients who have diabetes extends these findings for those patients with moderate or severe ischemia. And I think really notably also adds information about chronic coronary disease patients with diabetes and CKD. That's sort of the overall findings. And I'm happy to talk in more detail about that.
Dr. Carolyn Lam:
I love the way you explain that Jonathan and especially, going into detail on what was so different about the paper and the really important statistical methods that made these findings robust, very important and impactful findings. If I could ask Sandeep to share your thoughts.
Dr. Sandeep Das:
Thanks, Carolyn. You know, I am just a big fan of everything that's come out of the ischemia group. One of the things that I really most enjoy as a consumer of the literature is when well done studies give me results that are unexpected. And I know it's become fashionable now to say that everybody knew that all along that this is what going to be the result. But honestly, I think we all sort of are many of us thought that there's going to be a subgroup somewhere that's really going to benefit from an invasive approach in terms of preventing heart outcomes. I think the key here that really jumped out at me was that this is identifying what we typically think of is a very high risk subgroup. You know, patients with diabetes patients with multi-vessel coronary disease patients with insulin dependent diabetes.
Dr. Sandeep Das:
And we did see the association with mortality across the increased disease severity and the increased severity of diabetes as expected. But really we didn't see a signal that revascularization, routinely revascularizing patients, even the higher risk patients led to clinically relevant heart outcome benefits. So I thought that that was a really interesting top line finding and really that's kind of. I mean, it would have been interesting if it was the other way too, but it was, it really was kind of the hook that got me into the paper.
Dr. Sandeep Das:
I actually have a question for Jonathan, one of the things that I think we spend a lot of time as an editorial group thinking about and talking about, and we bounce back and forth with the authors a few times was the idea that relatively few of these patients with multi-vessel CAD ended up having CABG. So, you would typically think of diabetes multi-vessel CAD as being a pretty strong signal for patients that may benefit in terms of mortality from having bypass surgery. And here it was a relatively small group about a third, or maybe even less than a third. And I realized up front, they excluded the left main and the patients that had angina had a CTA, et cetera. But what I'd be curious as to your thoughts about, the benefits of bypass surgery and diabetes, which have been established in other trials.
Dr. Jonathan Newman:
It's a great question. And I think we really appreciated the questions from you and from the editors to try and get at some of the nuance with this issue. As you indicated in the ischemia and ischemia CKD trials overall, and the patients in the invasive treatment arm, it was about 25% or so 26% and 15% were revascularized with CABG. Part of the issue here is that it gets a little tricky with the use of CCTA of pre randomization CTA to define coronary artery severity, which was not required in the CKD population due to impaired renal function. But what we can say is among the patients with diabetes and multi-vessel coronary disease, 29% were revascularized surgically in their combined analysis, which is comparable to the 30% in Bery 2d that were revascularized via bypass surgery, as we've discussed. And as you know, the decision for surgical versus percutaneous revascularization in ischemia, as in Barry 2d was non-randomized though we might want to, we really tried to be very, very cautious in terms of comparing revascularization strategies on outcomes for patients with diabetes and multi-vessel CAD, which has you suggested.
Dr. Jonathan Newman:
And as we pointed out, the proportion with multi-vessel CAD was more common amongst in patients with diabetes compared with those patients without diabetes. The other thing I would sort of say in the framework of, the revascularization and strategies for revascularization, comparing, let's say ischemia to Barry 2d or to freedom. Basically we have very little data about revascularization approaches for those patients with creatinine with impaired renal function and, patients with the crediting greater than two were excluded from Barry 2d. So while we had about 15% or so that had severe CKD. So in the GFR, less than 30 are on dialysis. And we know that's an extremely high risk group of patients with diabetes and chronic coronary disease. And we don't have great evidence on which strategy for revascularization if at all provides additional benefit. So I think it's a really a tough question to answer, and we tried to be as judicious as possible in our comments about revascularization approaches, given the nature of the trial design.
Dr. Carolyn Lam:
Gee, thanks so much, Jonathan, for explaining that. So, well, I actually have a related question now, referring to the medical therapy. Can I, sort of ask you about the fact that, these days that the rage is all about GLP one receptor agonist, for example, that are known to reduce the risk of atherosclerotic cardiovascular disease and diabetes. So these ischemic trials, I assume, did not have a high usage of these medications. And what do you think would be the impact, if anything, I suppose even more for guideline directed medical therapy. Huh?
Dr. Jonathan Newman:
Yeah. So it's a great question, Carolyn. As you know, in strategy trials and clinical trials in general, that take a while it's always a real challenge to keep the trial contemporary with current clinical practice, whether it's revascularization strategies or changes in medical therapy. And as you indicated, the real revolution and glucose lowering therapies with profound cardiovascular benefit for patients with diabetes, we worked hard to try and stay up to date and encourage sites around the world with the use of best SGLT2 inhibitors and GLP ones. The rates were very, very low and we don't actually given the fact that the ischemia trials were conducted a real multinational and is really an international trial is over 330 sites worldwide. So we really had to balance the data that we could get from sites with the reality of collecting and running this trial across the whole world.
Dr. Jonathan Newman:
So we don't actually know. We know insulin use or non-use or oral medication use or non-use or no medication use or non-use, but not much more than that. From what, as, you know, unfortunately, even after now, six going on seven years of impressive data for the benefit of these agents, uptake remains low for patients with diabetes, whether it's with coronary disease or heart failure. And there was certainly the case with the trial, which started back in 2015, or sorry, before 2015, even before the results of EMPA-REG. So the rates of those agents were low. I would expect as you indicated that if we did have greater use of these beneficial therapies. Medical therapy may have performed even better and potentially given an added boost potentially for our high risk, even higher risk subgroups that we'd looked at that were available in these trials.
Dr. Carolyn Lam:
Oh, thanks again. I wish we could go on forever, but we've got just a little bit of time left. So I'd like to ask you both for your quick take home messages for the audience. Could I start with Sandeep and then Jonathan?
Dr. Sandeep Das:
Yeah. You know, I think a key take home from this is that, although it may be naively intuitive that a very aggressive invasive strategy would be superior, especially in high risk patients. You know, the data are very, very convincing that it's not. And so therefore I think in an absolute minimum, you have plenty of time and ability to think about these patients carefully, to select who, if anybody would be a great candidate for revascularization, more aggressive therapy and more invasive therapy, but the most patients will do well with conservative management.
Dr. Sandeep Das:
And I think that that's the, that's a real key take home here. And I think that the points that Jonathan raised about, you know, poor uptake of GLP one RAs and SGLT 2 inhibitors in the community as they're so far are key, right? So we have great medicines that we just under used, and that to me is the other sort of clarion call here is that if in the context of a nice trial, that you can see similar result for invasive conservative approaches, then lets, let's get our medical therapy where it needs to be to provide our patients the best outcomes we can
Speaker 3:
Love it, Jonathan.
Dr. Jonathan Newman:
Yeah. So I'm really glad that Sandeep brought up the issue of medical therapy in the trial. And maybe I can take a minute to sort of frame what San kind of build off of what Sandeep just said, you know, we, in the context of this clinical trial, you know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the co-chair and I, we worked very hard with optimizing medical therapy across the trials, for all participants. So really getting patients on the maximum tolerated doses of high-intensity statins, lowering patient's LDL as aggressively as possible evolving our systolic blood pressure targets. And it was extremely challenging. And at the end of the day, we see that patients with diabetes were more likely than those without to get to our LDL goal. We used a threshold problematic concept that that still may be to some extent, but they were less likely to achieve their systolic blood pressure goals.
Dr. Jonathan Newman:
And I think Sandeep was exactly right. We have a way to go with implementing existing therapies, existing medical therapy. There may be a benefit for as demonstrated in Dr. S. for patients that remain highly symptomatic to derive symptom benefit with revascularization. The other context I would sort of add with the medical therapy issue is that despite really aggressive medical therapy, and we really did as much as we could, patients with diabetes still had, a 40, 50% greater risk of death or MI than those without diabetes. So there's still this idea of kind of residual risk. And these were patients with diabetes that were very well managed from a medical and glycemic control perspective. So we still have a lot of work to do. And I think understanding ways we can benefit our patients is really that challenge.
Speaker 3:
Thanks so much, Jonathan, and thank you Sandeep for joining us today.
Speaker 3:
And thank you audience for listening from Greg and I. This has been "Circulation On The Run", please tune in again. Next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit AHJjournals.org.
Please join author Khurram Nasir and Associate Editor Sandeep Das as they discuss the article "Social Vulnerability and Premature Cardiovascular Mortality Among US Counties, 2014-2018."
Dr. Carolyn Lam:
Welcome to Circulation on the Run your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke-National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I'm really excited about today's feature discussion. It's really meaningful on so many levels. It discusses social vulnerability. In other words, social determinants of health and its association with premature cardiovascular mortality among US counties. Now, even as an ex-US person I learned a lot, so everyone is going to want to listen in. But now let's start with going through some exciting papers in today's issue, shall we?
Dr. Greg Hundley:
You bet Carolyn. So, I'm going to grab a cup of coffee and we'll get started with the first article. And really gets into the world of cardiovascular risk and prostate cancer management.
Dr. Greg Hundley:
So, Carolyn in the light of improved prostate cancer survivorship, and the competing risk of cardiovascular disease, there's an ongoing need for rigorous cardio oncology clinical trials. As you probably know, androgen deprivation therapy is a cornerstone of prostate cancer therapy. Through different pituitary gonadotropin releasing hormone receptor mediated mechanisms both GnRH agonists, as well as antagonists, either indirectly or directly inhibit luteinizing hormone secretion, consequently inhibiting testosterone production. These GnRH agonists are the most commonly prescribed form of androgen deprivation therapy with only 3 to 4% of patients receiving a GnRH antagonist.
Dr. Greg Hundley:
So, Carolyn the relative cardiovascular safety of gonadotropin releasing hormone antagonists compared with gonadotropin releasing hormone agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains somewhat controversial. And therefore these authors led by Dr. Renato Lopes from both Brazil, as well as the Duke University Medical Center in Durham, conducted an international multicenter, prospective randomized open label trial, and men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomized one to receive gonadotropin releasing hormone, antagonist degarelix or the gonadotropin releasing hormone, agonist leuprolide for 12 months and the primary outcome was time to first educate major adverse cardiovascular event that combined the endpoints of composite death MI and stroke over these 12 months.
Dr. Carolyn Lam:
Nice Greg, and what did they find?
Dr. Greg Hundley:
Right Carolyn, due to slower than projected enrollment and fewer than projected primary outcome events enrollment was stopped before the 900 plan participants were accrued from May 3rd, 2016 to April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were really balanced between the two study groups. Now Mace occurred in 5.5% of the patients assigned to degarelix and 4.1% assigned to leuprolide and so in summary, Carolyn, this pronounced study is the first international randomized clinical trial to prospectively compare the cardiovascular safety of a gonadotropin releasing hormone antagonist as well as agonist in patients with prostate cancer. And the study was terminated prematurely due to smaller than planned number of participants and events. And so no difference in mace at one year was noted between the two groups and this pronounced study really provides a model for interdisciplinary collaboration between urologists, oncologists and cardiologist with a sheer goal of evaluating the impact of cancer therapies on cardiovascular outcomes.
Dr. Carolyn Lam:
That's so cool, Greg. I heard the presentation of these results at the ESC by Dr. Renato Lopes and it's a really cool and important study, but a paper I want to present is an analysis from Emperor preserved on inpatient and outpatient heart failure events.
Dr. Greg Hundley:
Great. Carolyn, so remind us, what did the Emperor preserved trial show?
Dr. Carolyn Lam:
Emperor preserved showed that in patients with heart failure and preserved ejection fraction empagliflozin reduce the primary endpoint of cardiovascular death or hospitalization for heart failure, primarily related to a lower risk of hospitalizations for heart failure. Greg you're smiling, because you can see me beaming because we finally have a robustly positive outcomes trial in have pep in this trial. Nonetheless in the current analysis, Dr. Milton Packer from Baylor Heart and Vascular Institute and others used prospectively collected information on inpatient and outpatient events, reflecting worsening heart failure, and pre specified their analysis in individual and composite end points.
Dr. Greg Hundley:
I've been in suspense here. What did they find?
Dr. Carolyn Lam:
Empagliflozin reduced the risk of severe hospitalizations as reflected by admissions requiring the use of ionotropic or vasopressor drugs and the need for intensive care. Empagliflozin also reduce the risk of outpatient worsening heart failure events, including the need for urgent care visits, diuretic, intensification, and unfavorable changes in functional class. So, basically benefit across the spectrum. Furthermore, because there's controversy about the effect across the spectrum of ejection fraction. The benefit on total heart failure hospitalizations was found to be similar in patients with an ejection fraction of above 40, but less than 50% and between 50 to 60%, although it was attenuated at the higher ejection fractions and we'll hear a lot of discussions about this.
Dr. Greg Hundley:
Wow, Carolyn. Just more information that keeps coming out about SGLT-2 inhibition. My next paper comes from the world of preclinical science and angiogenesis is a dynamic process, involves expansion of a preexisting vascular network that can incur in a number of physiologic and pathologic settings. But despite its importance, the origin of the new angiogenesis vasculature is really poorly defined in particular, the primary subtype of endothelial cells, whether they be capillary, Venus or arterial that might be driving, this process really remains undefined. These authors led by Dr. Michael Simmons at Yale University school of medicine, fate mapped endothelial cells using genetic markers specific to arterial, Venus and capillary cells.
Dr. Carolyn Lam:
What did they find Greg?
Dr. Greg Hundley:
This team study results found that Venus endothelial cells were the primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterial, venous malformation, and pathologic angiogenesis. And these observations highlight the central role of the Venus endothelium in normal development and disease pathogenesis.
Dr. Carolyn Lam:
Wow. That's really interesting. I don't think I've ever really paid attention to that bit. Venus endothelium. Thank you for that. Now what else is in today's issue? Well, there's an exchange of letters between Doctors Zhang and Liao regarding the article anti hypertrophic memory after regression of exercise induced physiologic, myocardial hypertrophy is mediated by the long noncoding RNA M heart 779, then ECG Challenge by Dr. Ahmed on challenges of interpreting smart watch and implantable loop recorder, tracings. There's cardiology news by Tracy Hampton and Highlights from the Circulation Family of journals by Sara O'Brien. These regular articles are just really worth a read. You learn so much from just these short lovely summaries. There's On My Mind paper by Dr. Meyer on a targeted treatment opportunity for taking advantage of diastolic tone. And there's also a Research Letter by Dr. Brozovich on a rat model of heart failure with preserved ejection fraction changes in contractile proteins, regulating calcium cycling and vascular reactivity.
Dr. Greg Hundley:
These journal issues, there's so much information. I'm in a close out with an in depth piece from professor entitled antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. I really look forward to your feature discussion on the social vulnerability and premature cardiovascular mortality in US countries.
Dr. Carolyn Lam:
Thanks Greg. It's good.
Dr. Carolyn Lam:
Today's feature discussion focuses on an extremely important topic of social vulnerability and premature cardiovascular mortality. So pleased to have the corresponding author of the feature paper, Dr. Khurram Nasir from Houston Methodist and Dr. Alana Morris, who is the editorialist for this paper. And she's joining us from Emory University in Atlanta, Georgia. So thank you both of you for joining and Alana if you don't mind, I'm going to borrow some of the words from your really-excellent editorial to bring us into the discussion. You very nicely brought up that early race and ethnic disparities and a death toll from COVID 19 really, laid the foundation for us having Frank conversations about vulnerable populations and has really brought to light social determinant of health and social economic inequality as risk factors. Now that's, COVID 19. And frankly, if we put everything in a global view of what kills most of us, it's still cardiovascular disease, which is why this paper is just so important, but current recognizing I'm not from the US, lots of our audience are not from the US. Could you please walk us through what your paper looked at and what it means?
Dr. Khurram Nasir:
Sure. Klan, thank you so much for having us today and what a wonderful editorial by Dr. Morris on this. As you pointed out about the COVID challenges, we were all touched by the significant disparities, really in a one of the lifetime crisis, such as COVID. But the reality is that even in times of calm the benefits, for example, cardiovascular disease prevention access have not been shared equally among vulnerable groups. So I'm a preventive cardiologist, and it gives me immense pride that despite being the number one cause of morbidity mortality for so long as a cardiology community, we have made significant strides over the last three decades, cutting into our losses. And if you look at the trends it's appeared and I'm very hopeful that we'll soon be losing the number one killer tag in US. At the same time we are seeing that those cuts are being lost, especially in the young individuals.
Dr. Khurram Nasir:
And at one point while we celebrate these decline. But the thing that bothers many of us that unfortunately these gains have not been equal, especially for our more vulnerable patients. And apart from the well documented, I think racial disparities that we all know and are becoming more aware. I think health disparities also form across various fourth lines and I believe the deepest and more persistent divides is around income. And you can even go a step further in US, unfortunately for our international group is unfortunate fact that in US, your zip code may hold more sway than your genetic code. And an example was made famous in St. Louis, Missouri Del marble award, which is known as the Delmer divide, a title that was made famous by a four minute BBC documentary that showed, that a sharp dividing line between the poor predominantly African American neighborhoods in the north and more affluent, largely white neighborhood in the south with health falling across this divide.
Dr. Khurram Nasir:
And in our practice, we see this phenomenon clearly in our own backyard. So, inspired by this sterling. We wanted to determine that a mirror geographical measure, where we can get insights of conditions where people live, learn, work, play, grow, and age, and commonly now known as the social determinants of health. Can that explain some of these rising risks, especially in the premature cardiovascular disease. So to design this study, we reached out to the CDC social vulnerable, the index that has been created that ranks communities and zip codes based on 15 factors across food domains, socioeconomic status, household composition of disability, that in includes single parents, elderly or children, minority status and language and housing type and transportation, all of them are put together and for each census. And then eventually at the county level, you can classify what their social vulnerability is. And as you know, this was really developed in to identify places where in times of disaster and emergencies, you can focus a little bit more, but we thought about how do we connect this to, for example, our data on mortality from CDC wonder.
Dr. Khurram Nasir:
And once we did that, we found very interesting patterns that across the scale social vulnerability, there is a risk dose dependent fashion and the age adjusted mortality rates for premature cardiovascular disease, which we define as less than 65, went from the least vulnerable and became the worst across the most vulnerable. At the same time, we also found this double jeopardy issues where this association was varied by race, gender, and ruler. And what we found that specifically Non-Hispanic lack individuals were more likely for certain types of cardiovascular, premature, such as stroke and heart failure, mortality, as compared to the rest, even if you were from the least vulnerable to the most women also unfortunately had a twofold higher risk of CBD mortality. And what is becoming clearly this whole ruler urban that a two to five fold risk of CBD mortality was seen among the least vulnerable. So this is in just the motive of our study, what we did and what we found.
Dr. Carolyn Lam:
That is so wonderful. Thank you for setting the context and then just to reiterate, so this was all within the US. Alana, could you maybe help frame how important these findings are for us?
Dr. Alana Morris:
Yes. I think that this analysis is so important, particularly within the context of some of the things that we see happening politically in our country and our landscape right now. And I think we tried to touch on some of those issues in the editorial. Again, I think that the COVID 19 pandemic, if you want to put that against this landscape has really brought into the forefront of our minds, this issue of disparities. Of course, there are many of us who have been thinking about researching and writing about disparities for a long time, but the issue of disparities really, came into the public mindset with the COVID 19 pandemic. The question now is how do we address these as we go forward? And what we're seeing politically is this question of how do we address inequalities that have been present for really since the beginning of time and maybe are widening and perhaps threaten many of the advances that we've made in terms of cardiovascular disease, morbidity, and mortality.
Dr. Alana Morris:
I think we have to think about in the US, universal healthcare coverage, because we have to be able to prevent disease and treat disease. And as current addressed, there are neighborhood zip codes where people not only don't have access to healthcare, but they don't even have access to the ability to promote health. They don't have access to things like parks, where they can exercise. They don't have access to healthy foods or grocery stores and in a country like the United States where there's so much wealth, you need to think about the fact that certain individuals, don't have the ability to access a grocery store, to access healthy food. It's just really striking and mind boggling that we have this, the difference in rural versus urban locations where some of our US residents, unfortunately don't have access to primary care clinicians, certainly not specialty clinicians is really very mind boggling. And we've seen this play out with the pandemic, but hopefully once we get past the COVID 19 pandemic, we still have to come back to a place where again, we're taking care of not only preventives or services to prevent the onset of cardiovascular disease, but certainly once people are diagnosed with cardiovascular disease, we want to get them access to specialty care. So we have to think as a community, how do we prevent disease, but also treat disease once disease is diagnosed within our country.
Dr. Carolyn Lam:
What you just said about the zip code being more powerful about, than the genetic code, that's like a quotable code. It's incredible. And for those of us coming outside of the US, we don't even realize how much that plays a role, even just within the US. But now let's get to exact point that Alana pointed out, which is what are the next steps. And could you maybe suggest Khurram, and Alana maybe come first, but what's the one thing you want to get out or the one next thing that should happen after this
Dr. Alanna Morris:
We put a figure in to the editorial that I think really gets to the heart of the matter, I think that those of us who are in healthcare or those of us who think about public health really would ask the question of, why in a country that has as much wealth as the United States, do we not have universal healthcare, most countries across the world that are in an economic position similar to the United States do have universal healthcare coverage for their residents. And you see much better statistics in terms of longevity for their residents as compared to what we have in the United States. And what you see when you look at the United States is that where there is the most vulnerable residents as per analysis identifies those states are the ones that actually don't have, Medicaid expansion.
Dr. Alanna Morris:
They don't have a safety net for their residents. And so there's really contrast and this disparity that just does not make sense. It does not make sense where there are residents in the United States, which need the most help and they just don't have it. They just are not able to get access to preventive services as well as diagnostic services. And it really just doesn't make sense what we're doing in the United States, in my humble opinion. And I think in the humble opinion of many of us who want to take care of patients, but just cannot, Kern and I both practice in states where this is an issue. And I think that's one big driver. But again, I think when we also think about the built environment in the US and how we think about promoting health and how we talk to patients, when we talk about individuals in the US, we try to give them advice about therapeutic lifestyle changes, how to exercise, how to eat healthy, to prevent disease. That's easier for certain individuals as compared to others, depending upon where you live, depending upon those five digits that make up your zip code. So if we really want our residents to be healthy, we have to create an environment that enables them to do that.
Dr. Carolyn Lam:
Wow, thank you very much. And as I let Khurram have the final words even about where you think mixed research should be. I just want to highlight that incredible figure from your editorial Alana. I mean, it is really started, there are three panels to it, everyone. The first one chose the social vulnerability index, the second, the premature cardiovascular disease mortality, and then the third, the status of Medicaid expansion. And you can see the colors are just vivid in, how it all makes sense and goes together. So pick up our journal and have a look, but then finally Khurram?
Dr. Khurram Nasir:
So, Alana, your figure was fantastic and so much add perspective to our findings. As you were saying, it took me back to 35 years back when, where we are before Medicare disparities, even in access to hospitals were dramatic. So where we practice in the south one third of the hospitals would not admit African Americans even for emergency. Now, this is where the policy comes in and suddenly in 1965 using the carrot of Medicare dollars, the federal government virtually ended the practice of racially segregating patients, doctors, and medical staffs, blood supplies so that is the direction that we need to go from the policy perspective and trying to affect the upstream determinants. Now moving forward, as I think more, and especially as a physician, I think while the census level measures are extremely useful to help refine these policy and focus programs in vulnerable areas.
Dr. Khurram Nasir:
I also think that there is a parallel need to start focusing on similar efforts at the individual level. The first thing is how do we even identify social determinants at this patient level? Are there three main categories, income, education, possibly healthcare, but I think that we need to broaden this. And in the past we have been challenged because we didn't have a set of consensus of the defined SDUH framework. But thankfully now in 2021, we have the healthy people, 2020. Actually for international community, the WHO there is a WHO framework of identifying SDOH at an individual level and in US a more comprehensive Kaiser family foundation. And not only that, we looked at superficially broadly, but we have to go deeper beyond these components of economic instability, education, housing, social context on healthcare beyond insurance, and even food.
Dr. Khurram Nasir:
For example, income and employment are predominant pillars of income stability, but it may not capture the full picture. For example, difficulty paying bills out of pocket cost and death related to medical care, same in education, where we captured the highest degree, but issues around health and digital literacy and language proficiency may be even more important. So not only we have to broaden the scope, but we have to go in depth. And thirdly, what I've realized from these kind of studies that we have to go a step further, that social disparities don't occur in silos. And we have to look at the aggregated information. And maybe it's time to potentially learn from advances in genetics, in what we have learned that manifestation of disease, especially cardio metabolic rather than being influenced by few major genes is manifested secondary to multiple interacting genes. So can we create similar to a poly genetic risk score, which is an aggregation of genetic smaller risk to a relevant something similar called poly social risk score.
Dr. Khurram Nasir:
Now, this is an area that our group has been extensively working. And over the last 12 months, we have tried to construct a comprehensive poly social risk score at an individual level based on almost about 50 sub components of the social determinants. And we have suddenly finding very interesting associations with premature CAD stroke. Almost one in two young individuals with stroke, have the worst poly social risk code at the individual level. I think so the next steps will be definitely validation of this tool, incorporation in practice, whether it's adoption and effective interventions can be tied. But the final thing, what I truly want to say is that I'm hopeful that these efforts, the census level at an individual level, at a societal level and the health system are waking up to the importance of social determinants that we can think outside the box and have strong community partnerships. Multi Pro strategies driven largely by social economic environmental factors. So we can all make a lead towards the mission of achieving social justice and equity that eventually cascades through the health system and beyond. So we had enough time to illuminate the issues and challenges. Now it's the time to act.
Dr. Carolyn Lam:
Thank you so much Kern for a beautiful paper. We are so proud to be publishing it in circulation. And thank you, Alana lovely, editor that we've said so many times. Thank you audience for joining us today. You've been listening to Circulation on the Run from Greg and I please tune in again. Next week,
Dr. Greg Hundley:
This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American heart association for more visit ahajournals.org.
Please join author Milton Packer and Associate Editor Justin Ezekowitz as they discuss the Perspective "Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, it really is so great to be back with you chatting about the papers here in the Journal. Thank you for going solo and for just being the greatest partner on earth. Thank you for that. For everyone listening in, we are back with some gusto and especially with this feature discussion today. You are not going to want to miss it. We are talking to Dr. Milton Packer as well as Dr. Justin Ezekowitz. We are going to compare PARAGON and EMPEROR-Preserved trials in heart failure with preserved ejection fraction. A really interesting discussion you're not going to want to miss, but now let's start with some papers in today's issue. I'd like to start, please.
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
Greg, you know the optimal duration of antiplatelet therapy in patients with high bleeding risk with or without oral anticoagulation after coronary stenting? Well, that still remains a question. Today's paper is a pre-specified subgroup analysis of the MASTER DAPT trial and reports on the outcomes of patients with or without an oral anticoagulation indication in this study.
Dr. Greg Hundley:
Right, Carolyn. Remind us. What was the MASTER DAPT trial? What did it test?
Dr. Carolyn Lam:
Ah. MASTER DAPT investigated an abbreviated or one-month versus a non-abbreviated or three to 12-month dual antiplatelet therapy and a stopping of antiplatelet therapy at six months strategy after coronary stenting in an all-comer population at high bleeding risk.
Dr. Greg Hundley:
Carolyn, what did this subgroup analysis of outcomes in patients with and without oral anticoagulation show?
Dr. Carolyn Lam:
At 12 months of follow-up, ischemic and net risk did not differ with abbreviated versus non-abbreviated anti-platelet regimens in both subgroups, although significantly fewer clinically relevant bleeding events occurred in the group without an oral anticoagulation indication. Whereas only numerically fewer bleeding events occurred in the group with an oral anticoagulation indication that did not reach statistical significance. This subgroup analysis from the MASTER DAPT trial really adds additional evidence that dual antiplatelet therapy beyond one month in patients with or without an indication for oral anticoagulation really has no benefit and only increases bleeding risk.
Dr. Greg Hundley:
Oh, very important finding, Carolyn. Great research. Well, Carolyn, how the extracellular matrix microenvironment modulates the contractile phenotype of vascular smooth muscle cells and confers vascular homeostasis really remains elusive. Thus, these investigators led by Professor Wei Kong at Peking University applied protein-protein interaction network analysis to explore novel extracellular matrix proteins associated with the vascular smooth muscle cell phenotype.
Dr. Carolyn Lam:
Huh. Interesting. What did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. By combining an in-vitro and an in-vivo genetic mice vascular injury model, they identified nidogen-2, a basement membrane glycoprotein, as a key extracellular matrix protein for maintenance of vascular smooth muscle cell identity. Nidogen-2 exerted its protective function via direct interaction and modulation of Jagged1-Notch3 signaling.
Dr. Carolyn Lam:
Wow! Nidogen-2 and Jagged1-Notch3. I always learn so much. What are the clinical implications, Greg?
Dr. Greg Hundley:
Right, Carolyn. Perhaps targeting nidogen-2 to precisely modulate Jagged1-Notch3 signaling, well, that may provide novel therapeutic strategy for atherosclerosis and post-injury restenosis.
Dr. Carolyn Lam:
Very nice. Well, in the next paper, we discuss inflammation in heart failure. We know that inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Interesting, huh? Well, these authors, Dr. Wollert and colleagues from Hannover Medical School in Germany, identified an adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against persistent afterload stress-induced heart failure in mice. Monocytes and macrophages produced myeloid-derived growth factor in the pressure overloaded myocardium to augment SERCA2a expression in cardiomyocyte's calcium cycling and contractility. Myeloid-derived growth factor plasma concentrations were also found to be elevated in patients with aortic stenosis and to decline after aortic valve implantation indicating that pressure overload also triggers myeloid-derived growth factor release in humans.
Dr. Greg Hundley:
Carolyn, really informative preclinical science, but what are the clinical implications?
Dr. Carolyn Lam:
Ah. These observations molecularly defined a feature of the inflammatory response to hemodynamic overload that protects against heart failure development. Inflammation's beneficial trade therefore need to be considered when developing inflammation as a therapeutic target in heart failure. All of this is really discussed in a lovely editorial entitled Inflammation and Heart Failure: Friend or Foe? That's by Drs. Hajjar and Leopold.
Dr. Greg Hundley:
Great job, Carolyn. Well, my next paper focuses on resistant hypertension. Carolyn, although lifestyle modifications generally are effective in lowering blood pressure among patients with unmedicated hypertension or those treated with one to two antihypertensive agents, the value of exercise and diet for lowering blood pressure in patients with resistant hypertension is unknown. To address this, Professor James Blumenthal and co-authors at Duke University Medical Center enrolled 140 patients with resistant hypertension with an average age of 63 years, 48% women, 59% black, 31% diabetes, and 21% with chronic kidney disease and randomly assigned them to A, a four-month cardiac rehab center-based program of lifestyle modification. We're going to call that C-LIFE, consisting of dietary counseling, behavior and weight management, and exercise. Or number 2 or the B, a single counseling session providing standardized education and physician advice. We'll call that SEPA.
Dr. Greg Hundley:
The primary endpoint was clinic measured systolic blood pressure. Secondary endpoints included 24-hour ambulatory blood pressure and selective cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of baroreflex on heart rate; high-frequency heart rate variability to assess vagally-mediated modulation of heart rate; flow-mediated dilation to evaluate endothelial function; and pulse wave velocity to assess arterial stiffness; and then finally left ventricular mass to characterize left ventricular structure and remodeling.
Dr. Carolyn Lam:
Wow! That is a very, first of all, important clinical question. Then also, just very intricate methodology in assessing this. What did they find?
Dr. Greg Hundley:
Right, Carolyn. Between-group comparisons revealed that the reduction in clinic systolic blood pressure was greater in C-LIFE compared with SEPA. Next, 24-hour ambulatory systolic blood pressure also was reduced in C-LIFE with no change in SEPA. Then next, compared with SEPA, C-LIFE resulted in greater improvements in baroreflex sensitivity, high-frequency heart rate variability, and flow-mediated dilation. There was no between-group differences in pulse wave velocity or LV mass.
Dr. Greg Hundley:
Carolyn, diet and exercise can lower blood pressure in patients with resistant hypertension. When delivered in a cardiac rehabilitation setting, a four-month program of diet and exercise as adjunctive therapy, results in a significant reduction in clinic and ambulatory blood pressure, and improvement in selected cardiovascular disease biomarkers.
Dr. Carolyn Lam:
Wow! Really nice, Greg. Okay. Well, looks like we're all going to round up already with what else there is in today's issue. Let me start. There's an exchange of letters between Drs. Fang and Vinceti regarding the article Blood Pressure Effects on Sodium Reduction: Dose-Response Meta-analysis of Experimental Studies.
Dr. Greg Hundley:
Right, Carolyn. I've got a few things in the mail bag. First, Professor Anker has a Research Letter regarding the Kidney Function After Initiation and Discontinuation of Empagliflozin in Heart Failure Patients With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Dr. Gerstenfeld has an ECG challenge entitled Atrioventricular Block with Narrow and Wide QRS: The Pause That Refreshes. Then lastly, Dr. Donald Lloyd-Jones has an AHA update regarding the American Heart Association's focus on primordial prevention. Well, Carolyn, I can't wait to hear this fantastic feature discussion with you and Dr. Packer. How about we jump to that?
Dr. Carolyn Lam:
Great. Let's go, Greg.
Dr. Carolyn Lam:
Because side-by-side exam of PARAGON and EMPEROR is like side-by-side of...
Dr. Justin Ezekowitz:
You can compare our new and our old prime minister much like your paper did.
Dr. Milton Packer:
Yeah, yeah.
Dr. Justin Ezekowitz:
There are [crosstalk] and it could be viewed until they perform in the broader world how it goes. You don't quite know.
Dr. Milton Packer:
The only problem is you can't do a head-to-head comparison of the old prime minister and the new prime minister.
Dr. Justin Ezekowitz:
That is true except that the head-to-head comparison includes excellent care by both the new and the old. I think that comparison's going to be pretty equal. I think we can case-control that one.
Dr. Carolyn Lam:
I really liked that that was politically correct because we are recording. Everybody, welcome to the feature discussion. I am here with Dr. Milton Packer from Baylor and he really needs no introduction. We're discussing heart failure with preserved ejection fraction. As well as our associate editor, Dr. Justin Ezekowitz from University of Alberta. Hence, in case anybody's wondering, we were talking about the Canadian elections. Let's just launch straight into it, a side-by-side comparison of PARAGON and EMPEROR-Preserved. Dr. Packer... Milton, if I may, what in the world drove you to do this?
Dr. Milton Packer:
My God. Oh, my God. Yes.
Dr. Carolyn Lam:
Tell us about what drove you to do this and please, if you could just summarize the results.
Dr. Milton Packer:
Well, let me just say from the outset that this was a commentary, not an original research article.
Dr. Carolyn Lam:
Yes.
Dr. Milton Packer:
The commentary was motivated by two very straightforward observations. We had two large scale outcome trials of two different drugs in heart failure with a preserved ejection fraction. I was privileged to serve as you were, Carolyn, on the leadership committees of both trials. It's not as if we have involvement in only one trial. We have involvement in both trials and we are very proud of that involvement.
Dr. Milton Packer:
One trial came in with a effect size of about 13% on its primary endpoint with a borderline P-value. A second trial, EMPEROR-Preserved, came in with a 21% reduction and its primary endpoint with a really small and persuasive P-value. The two patient populations in the two trials were really amazingly similar. We wanted to understand why it was 21% in one trial and persuasively so and why it appeared to be smaller in the PARAGON trial with sacubitril/valsartan. We thought, well, maybe that difference was related to how endpoints were defined or maybe that difference was related to the influence of ejection fraction. The reason we got excited about that was that as almost everyone knows, PARAGON found an influence of ejection fraction on the effect of sacubitril/valsartan in patients with HFpEF. We found an influence of ejection fraction on the effect of empagliflozin in HFpEF in EMPEROR-Preserved. We wanted to understand whether that influence was similar in the two trials.
Dr. Milton Packer:
Just to make life simple, PARAGON had created certain cut points for ejection fraction. They had presented and previously published in Circulation endpoints based on those cut points of ejection fraction. All we did was we used their endpoints and their cut points, and we put the two trials side by side. We did not do a statistical comparison of the effect size. There're actually no P-values in the whole commentary. But what we wanted to see was: Was the shape of the ejection fraction influence relationship similar or different in the two trials? Well, very simple. In PARAGON, as has been reported, there was a linear relationship: as ejection fraction increased, the effect of sacubitril/valsartan got smaller. In EMPEROR-Preserved, there was also an attenuation at a highest ejection fraction, but the relationship wasn't linear. It was like a hockey stick. It was flat and then went up at an ejection fraction over 62.5, which was the cut point that PARAGON used.
Dr. Milton Packer:
When we compared patients between the low 40s and the low 60s, the effect size in empagliflozin appeared to be larger than the effect size of sacubitril/valsartan in that ejection fraction group using the same endpoints. In fact, for hospitalizations for heart failure, which is really what SGLT2 inhibitors do, it was twice as great with empagliflozin in EMPEROR-Preserved than with sacubitril/valsartan in PARAGON-HF. We thought this was really interesting. We put the pictures up side by side. We wrote a commentary and Circulation was so kind to accept it.
Dr. Carolyn Lam:
Oh, but Milton, you were very, honestly as always, very clever to have done this analysis. But if I could reiterate a few things for the audience, which is very important. First of all, as you rightly first pointed out, it's a perspective piece. It is not a head-on comparison with P-values. It could not be. Let's just also give the audience a bit of background in that PARAGON included patients with an ejection fraction of 45% and above. EMPEROR-Preserved was above 40. PARAGON looked at total heart failure hospitalizations and cardiovascular death as a primary outcome. EMPEROR looked at first cardiovascular death or heart failure hospitalization.
Dr. Carolyn Lam:
Let's just remember the designs were different. Of course in the comparison, PARAGON compared sacubitril/valsartan versus valsartan. I like the way you very carefully wrote in your study that it was more a study of neprilysin inhibition since it's sacubitril/valsartan against valsartan and it was empagliflozin versus placebo. We know that it's important to state that as a basis. Then really important to say to everybody out there, pick up our journal. You must look at this bigger. I myself have already cited it at least twice already, Milton, because people will just naturally ask that. "Are the results different because of ejection fraction or different endpoints?" What you did there in that beautiful figure is that you tried as best as you can to match it up in terms of ejection fraction bins and match it up in terms of hospitalizations. There. I just wanted to state those few things, but I'm really-
Dr. Milton Packer:
Oh, no. No. Carolyn, you're 100% right. That's why there are couple of things. I just want to underscore what you said because I think your points were spot on. First of all, we really lined up the endpoints and the ejection fraction. We tried our best to compare apples and apples. It would not have been a useful exercise for us to compare different endpoints and different ejection fraction subgroups. But I just want to make sure that everyone understands: I'm a big fan of sacubitril/valsartan and I'm a big fan of neprilysin inhibition. As you know, both PARADIGM-HF and PARAGON-HF weren't really tests of sacubitril/valsartan; they were tests of neprilysin inhibition. They were great tests at that. PARAGON in particular was a great test of that. We're comparing neprilysin inhibition and SGLT2 inhibition.
Dr. Milton Packer:
But here's my most important point: we do not want people to choose one over the other. That was not the intent. We think that there are data in patients with certain ejection fractions, let's say between 40 and 60, I'm just creating a range, where both interventions are appropriate. Now I understand there are cost considerations and I don't want to minimize that, but we are not suggesting that anyone prefer one drug over the other. All we wanted to do was we wanted to ask the question: Since the effect size in one trial seemed to be different than the effect size in the other trial, what were the ejection fraction subgroups that represented that difference? We found that the patients with ejection fractions greater than 60, 65% did not contribute to that difference. It was the patients with lower ejection fractions that contributed to the difference. I hope that's helpful.
Dr. Carolyn Lam:
Ah. That's wonderful. Justin, have you recovered from the talk about the Canadian elections?
Dr. Justin Ezekowitz:
Oh. I have indeed.
Dr. Carolyn Lam:
I'm on swinging.
Dr. Justin Ezekowitz:
I have indeed. Thanks for recognizing that Canada just had a major election we carried out in six weeks. But, Milton, I really enjoyed reading this. Maybe I can just ask you about two elements within this perspective piece, which is number 1, what's incredibly concordant is a lack of difference across cardiovascular death for both agents in both trials regardless of the trial differences and the potential differences in patient populations recruited; that's number 1. It's incredibly flat for cardiovascular death.
Dr. Justin Ezekowitz:
But number 2 is there is a danger in comparing trials even non-statistically. That's often a pitfall we get into, but we have to put some frame of reference on that. What is the one or two key things you think differ between PARAGON and EMPEROR-Preserved that you say, "You really need to look at these trials differently"? Those two questions came to mind when looking at this great figure that you produced.
Dr. Milton Packer:
Okay. The first question is so much easier and that is that these drugs don't reduce cardiovascular deaths. Full stop. It's really interesting because sacubitril/valsartan reduces cardiovascular death in people with ejection fractions of 40% or less, but not in patients with ejection fraction greater than that. The primary effect is heart failure hospitalizations. Empagliflozin didn't reduce cardiovascular death even in patients with the ejection fraction less than 40% or greater than 40%. What we're really, really talking about two drugs where the major effect is a reduction in heart failure hospitalizations. That comes out whether you do the analysis as time-to-first-event or total heart failure hospitalizations.
Dr. Milton Packer:
Of course, we're looking forward to the DELIVER trial with dapagliflozin. My own personal expectation is they're going to come out with a very striking effect on heart failure hospitalizations and not on cardiovascular deaths. Cardiovascular deaths in patients with HFpEF is really... It's a hard goal because only half of the deaths are cardiovascular. These patients have so many comorbidities that influence prognosis. The other thing, which is really important, is that heart failure hospitalizations only represented 18% of all hospitalizations in these patients; it's really small. I think of empagliflozin as being a treatment of the heart failure of HFpEF, not a treatment for HFpEF. I hope that makes sense. Justin, what was your second question?
Dr. Justin Ezekowitz:
Absolutely.
Dr. Milton Packer:
Oh, the differences between-
Dr. Justin Ezekowitz:
Yeah. Thank you, Milton.
Dr. Milton Packer:
Okay. There's always differences between two trials. As I said before, Carol and I were involved in both trials. They were done slightly at different times. They didn't overlap. Remember that the cut points in the two trials, one was 40%, one was 45%, really didn't matter to our analysis because we corrected for that in our ejection fraction subgroups. I was actually really much more impressed by the similarities than by the differences, but here's the catch. HFpEF is an incredibly heterogeneous disease. When we look at baseline characteristics, we're looking at means, medians, percentages. We're not picking up on any heterogeneity and there's a lot of heterogeneity. I actually think that HFrEF is a reasonably homogeneous disease. I think HFpEF is an incredibly diverse disease with a whole host of different disorders. What I'm amazed by is that we actually got an effect size that was greater than 20% in an all-comers HFpEF analysis.
Dr. Milton Packer:
But in all honesty, Justin, it wasn't really all-comers. We excluded people with BMIs over 45. There are a lot of patients who are obese and had BMIs greater than 45 who have HFpEF. By the way, especially in Texas. I didn't say that. We didn't enroll those patients. In all honesty, if I had to do it all over again, I would have. By the way, PARAGON didn't enroll them either.
Dr. Carolyn Lam:
Well, this is an incredible conversation. I know that we could just do a whole hour of chatting about what this implies for the higher ejection fraction, what this implies for how we should be treating heart failure. I don't even dare to ask for some last words maybe from both Justin and Milton, but recognizing that the time is short, anything else to add?
Dr. Milton Packer:
I think Justin should do last words.
Dr. Justin Ezekowitz:
Well, let me summarize by saying there is a hockey stick. We love hockey sticks in Canada. A simple and an excellent comparison. I think people should really look at that figure to understand it, but do not undertreat your patients with HFpEF and look at these with a grain of salt. Thanks for joining us, Milton. Thanks, Carolyn.
Dr. Milton Packer:
Thank you so much.
Dr. Carolyn Lam:
On behalf of Greg and I, you've been listening to Circulation on the Run. Thank you so much for joining us today and don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features highlights from Circulation's 2021 Cardiovascular Surgery Themed Issue. Join Executive Editor James de Lemos along with Associate Editors Marc Ruel and Michael Fischbein as they discuss all of the articles found in this special issue.
Dr. James de Lemos:
Hi, my name is James de Lemos. I'm a cardiologist at University of Texas Southwestern Medical Center in Dallas, and the executive editor for Circulation. And I'm standing in for Carolyn and Greg today to host our annual cardiovascular surgery-themed issue podcast. And I'm delighted to be joined by Marc Ruel, professor and chairman of the Division of Cardiothoracic Surgery at the Ottawa Heart Institute, and the director of cardiac surgery content for Circulation, as well as Michael Fischbein, associate professor of cardiothoracic surgery at Stanford and the director of the thoracic and aortic programs there. Marc, thanks for all that you do for Circulation with cardiovascular surgery content and let me turn it over to you to introduce the issue.
Dr. Marc Ruel:
Well, James, thank you very much. We're very delighted to introduce this 2021 cardiovascular surgery-themed issue. We already feel that this is going to put together some of the very best science at the interface between cardiac surgery or cardiovascular surgery, I should say, because there's some peripheral vascular topics as well, cardiology, and as well, mechanistic research. I think you're going to find that this is really a very jam-packed issue that has a lot of important messaging that will change the field going forward.
Dr. Marc Ruel:
Also, this year, I want to highlight a couple of changes in the preparation of the issue. I want to first thank the tremendous contributions over the years to Circulation and to the entire field of cardiac surgery of Tim Gardner. Really, Tim, is an absolute giant. I think he's the only person known to me who was both president of the American Heart Association and of the ATS in the field of cardiac surgery.
Dr. Marc Ruel:
Tim has really paved the way for us to develop and enhance this issue over the years, and I think 2021 is a testament to his legacy, because I would argue it's our strongest issue ever. And I also want to introduce Mike Fischbein, James and everybody, who's associate professor at Stanford. Mike is a thoracic-aortic surgery expert, also runs a translational lab, so has a very dedicated, basic science and translational surgical science expertise. So we're very, very happy to welcome Mike to the themed issue of Circulation.
Dr. James de Lemos:
Well, thanks Marc. We'll do is follow the order of the issue so that our readers and listeners can really get a sense of the content and its various types that we're publishing this year. And the issue starts with a provocative frame of reference piece from Verma and colleagues discussing the surgical left atrial appendage occlusion. Marc, what were your thoughts on that piece?
Dr. Marc Ruel:
It's obviously a game changer in cardiac surgery. I was privileged to serve as a part of the BSMB for this trial, and we can now say we toyed with the decision as to stop the trial at the appropriate time. And that's always a very difficult BSMB decision, which, frankly, you want to get it right, and you don't want to err on either side. Anyways, LAAOS III was recently published and we have a fantastic editorial in Circulation from Subodh Verma, Deepak Bhatt, and Elaine Tseng saying, which essentially highlights the importance of the trial for practice of cardiac surgery.
Dr. Marc Ruel:
It probably is that no patient who comes to cardiac surgery with a history of atrial fibrillation should, based on those findings, not have their atrial appendage ablated. There's already very little caveat, the trial has not shown what was feared prior with regards to an increased incidence of heart failure or symptoms. And really, the surgery has been effective. The ablation of the left atrial appendage is very effective in diminishing the primary outcome or of stroke, ischemic stroke or cerebral hemorrhage.
Dr. Marc Ruel:
And essentially, this was, in most cases, a surgical ablation, so cut and sew. So we don't have all the information about either endovascular devices or even ablative devices at the time of surgery. But it was a very large trial, it was a publicly funded trial. It is really the authoritative information in the field that's available so far.
Dr. Marc Ruel:
Mike, what are your thoughts around this? Do you now come to any one of your patients needing a cardiac surgical cooperation with a history of atrial fibrillation and thinking that I now need to address the left atrial appendage? Is that what you get out of this paper as well?
Dr. Michael Fischbein:
Yeah. Thanks, Marc. I think that's an excellent question. Yeah, now, every patient after this trial, I talk to them ahead of time and offer them to have their appendage ligated in this setting if they have a history of atrial fibrillation. I don't think this adds much to our operation, it doesn't increase much the clamp time. And especially, although the trial was more surgically excising with some of the newer clips out there, it really doesn't add much time to the operation. So I think this is really an important paper that will change what we do as surgeons.
Dr. James de Lemos:
Can I just comment that I think the trial has indirect implications well beyond surgery, because the demonstration of combined benefit for oral anticoagulation with left atrial appendage occlusion really suggests that, even for patients not going for cardiac surgery, at some point in the future, we may be thinking about not and either/or between the devices and anticoagulation, but maybe both.
Dr. James de Lemos:
Mike, let me come back to you. There's a really fascinating paper by DeCarlo evaluating penetrating aortic ulcers that really change my thinking on this. Can you talk a little bit about this paper and your thoughts?
Dr. Michael Fischbein:
Thanks very much, James. I think this is really an important paper that's going to change what we do as surgeons. As you know, symptomatic penetrating aortic ulcers are grouped with dissections in tremula hematoma where we treat those patients immediately. None of us know what to do though with the asymptomatic aortic ulcer, which is actually more common. A lot of us are basing our reports on some observational studies. Many of these studies are mixed, symptomatic and asymptomatic. And so the treatment really varies, from watching them conservatively to treating them with open or endovascular approaches.
Dr. Michael Fischbein:
However, this paper by DeCarlo's really excellent. They followed 273 asymptomatic penetrating ulcer patients over time following their CT scans. And they really had two key important findings. One that these ulcers really didn't change much over time, and two, the risk of some complication occurring, whether that's rupture, symptoms or progression of disease was very low at 6.5% over 10 years. And so I think this is really going to be important, because we know that these asymptomatic penetrating ulcers, we can watch them conservatively. They do have to be still followed, but we don't have to go immediately to perform some surgical procedure.
Dr. James de Lemos:
Marc, any thoughts from you on this paper? Does this change what you guys will be doing in Ottawa?
Dr. Marc Ruel:
Absolutely. Yeah, I think this is, as Mike was saying, a very germane finding that's very helpful. I think the key word here, as Mike was alluding to, is really the word asymptomatic and how do you define that? Right? I mean, many of these findings are incidental findings. Someone comes in with a bit of shortness of breath or this or that, gets a PE protocol CT scan and then a penetrating aortic ulcer is found.
Dr. Marc Ruel:
So where do you draw the line between symptoms that may be a small left lateral effusion or a bit of shortness of breath. And it's also, I think that nuance will have to be determined going forward, what is truly asymptomatic versus a few symptoms that may be less specific and perhaps not relate to the penetrating aortic ulcer. But I think it's tremendously helpful in guiding practice going forward.
Dr. James de Lemos:
Fantastic. Thank you both. Mike, I want to come back to you on another really important paper from the vascular surgery standpoint, which is the paper from the Voyager investigators on the combination of rivaroxaban and aspirin for patients with surgical treatment of peripheral arterial disease.
Dr. Michael Fischbein:
Yeah, no, I think this is another or provocative paper. And as you know, peripheral arterial disease is a really highly-significant clinical problem. We say that affects 200 million people globally. And this includes patients with claudication, arrest pain, limb threat ischemia. And currently, the treatment for this is to either a open surgical or endovascular revascularization of the lower extremity. And the problem is while these patients, they have immediate symptomatic relief where you can save their limb, we say that one out of five will develop some sort of symptom or limb ischemia by three years.
Dr. Michael Fischbein:
And so the field is really looking for some sort of adjuvant therapy to help prevent these occurrences later on. And so the Voyager trial randomized over 6,000 patients who underwent surgery, whether it was open or endovascular, and then they randomized to either receiving rivaroxaban plus aspirin, versus aspirin and a placebo. And they showed that if you received riva, that those patients had a significant reduction in the instance of their primary endpoint, which included ischemia, limb loss or symptoms. And importantly, there was not an increase in major bleeding risk in these individuals.
Dr. James de Lemos:
So fascinating. I mean, this does this change practice and is this now the standard for surgically-treated peripheral arterial disease?
Dr. Michael Fischbein:
Yeah, I think there's still some questions that we have to answer. Yeah, I think definitely this, I think will be used after the bypass surgery, but some of the things in the trial that we would have to figure out is how applicable is this to everyone. In the trial, the open surgical arm had patients with less risks. Also, some patients received vein conduit versus a prosthetic conduit. And so, I think we'll have to look at some of the sub-analysis to see who we can apply this to.
Dr. James de Lemos:
Fantastic. Marc, any thoughts from your perspective on this one?
Dr. Marc Ruel:
Yeah. Mike provided a great summary. I think one other take-home message to me is that, really, these patients should be viewed as having panvascular disease, a little bit like our CABG patients. And essentially rivaroxaban or DOACs in general have a role, like in the COMPASS trial, in preventing other complications. So here, part of the composite endpoint was myocardial infarction, right? And we know that these peripheral vascular disease patients are very much at risk of it. So it may have an effect locally, but it really, probably, has most of its effect with regards to the panvascular disease that these patients present.
Dr. James de Lemos:
Excellent. And I'll just point out that just today, the FDA released news that they've granted an indication for this combination therapy for patients with peripheral arterial disease. Let me come back to Marc for a really interesting randomized controlled trial, from China, evaluating no-touch vein graft interventions for cardiac surgery. Marc, can you talk to us about this trial and your impressions on this?
Dr. Marc Ruel:
Absolutely. Thank you, James. So this is a trial from seven hospitals in China that randomized 2,600 patients between April, 2017 and June, 2019. And patients were randomized with the use of saphenous vein grafts between a no-touch technique and a conventional saphenous vein graft harvest technique. And I'll explain a little bit what this no-touch technique is. It actually consists of two things. You take the vein by a complete incision. Often, in fact, it's more invasive, and you take the actual saphenous vein with a surrounding layer of fat and connective tissue around it. And because of that, it's not easily amenable to endoscopic vein harvest or even using small incisions.
Dr. Marc Ruel:
The other component of no touch of vein harvesting is to really preserve the anterior layer by not using any syringe inflation and letting the conduit be rinsed, but flow naturally and not be distended at all. So the trial was positive, and the trial already showed a lesser incidence of saphenous vein graft closure at both three months and 12 months on CT scan. So to give you an example, the three months saphenous vein closure was 4.8% in the conventional harvest group, versus 2.8% in the no-touch group.
Dr. Marc Ruel:
Now what's interesting to here is twofold. There may be a couple of aspects in the benefits of the therapy, and one may relate, in fact, to the lack of pressure syringe dilatation. So it's hard to tease out, is it really the surrounding layer of fat or is it the fact that the syringe dilatation procedure is not being performed in the no-touch group? The second issue is the technique is definitely more invasive. The authors found in the trial more local complications, about 50 to a hundred percent increase in terms of a local numbness, exudation, et cetera, delayed wound healing. Because you have to make bigger incisions and you have to take more tissue around where the vein that you're harvesting.
Dr. Marc Ruel:
So it is a very intriguing trial. Obviously, graph patency is something that's tremendously important around the CABG operation. But unfortunately, it steers us towards a more invasive approach. In a nutshell, it is a positive trial, but it does require the surgery to be slightly more invasive, albeit, in most cases, with addressable issues with regards to delayed wound healing and exudation. But it would be ideal if we could combine the benefits of a no-touch technique with a less invasive approach to harvesting.
Dr. James de Lemos:
Mike, this is fascinating to me because you've got a procedure that probably improves the long-term outcomes of the operation, but is associated with a longer surgical time and more local complications. Mike, I'm wondering, what are your surgeon's going to do at Stanford? Are they going to adopt this or is this too difficult and associated with too much inconvenience for the patient to become something that's done routinely?
Dr. Michael Fischbein:
Brilliant, great question, James. Because I think, often, our patients, previous to endoscopic vein harvesting, they often complained more issues with their leg incisions than their actual sternotomy. And I always tell my patients now, though, one of the incredible things is that we can take their vein endoscopically. And now, we're talking about, while we do have improvement in graft patency for the vein, we're going to go backwards and maybe have some of these wound issues again. And I'd be curious what Marc thinks, though. We are trying to do more and more arterial grafts. And so, if we're just using one vein, is it worth accepting these higher wound complications?
Dr. Marc Ruel:
It's a great point, Mike, and perhaps exactly, as you say, perhaps an increased use of arterial grafts can be combined with lack of a pressure syringe dilatation of the vein after harvest, right? And there's already some data suggesting, as provided in the excellent editorial by Vidal, that this may be mechanistically important to enhance patency. So the study is very intriguing and still remains to completely unfold.
Dr. James de Lemos:
Excellent. Really important contribution to the surgical science. Marc, I want to come back to you with another important randomized control trial, this with a really novel therapeutic compound designed to address kidney injury after cardiac surgery. Marc, can you talk about the trial with the small interfering mRNA for renal protection?
Dr. Marc Ruel:
Absolutely. Thank you, James. This is an important trial, in my opinion. It's a Phase II study of a compound named, teprasiran, which is a interfering RNA, which modifies the p53 mediated cell death response in the renal tubal cells. So what does that do, essentially, is that the thought is that it may prevent acute renal injury after cardiac surgery. We know that's a tremendous problem. Most busy cardiosurgical ICUs would have at least between 15 to 25% of the patients requiring dialysis postop, depending on the level of risk acuity that your unit is presenting.
Dr. Marc Ruel:
And it's no different whether you're in Stanford or Ottawa or Germany, in my opinion. So we need solutions here. And this is a relatively simple compound, which is administered within four hours of completion of surgery. So for instance, if the surgery was performed on pump, it was given within four hours of completion of surgery. So, for instance, if the surgery was on-pump, it was given within four of hours completion of CPB, cardiopulmonary bypass. If it had been performed off-pump, it was within four hours of the last anastomosis.
Dr. Marc Ruel:
It's a two-minute infusion, 10 milligrams per kilo, and essentially in the trial, it was not associated with any safety concerns. And quite conversely, it was actually associated with the benefit, with regards to the development of early acute kidney injury, which was 50% prevalence in the patients who were treated with placebo, versus 37% in patients who received the compound, again, named teprasiran. So I think this is quite important. It has led to a Phase III which is currently ongoing, and I think this is a very instrumental finding in the field.
Dr. James de Lemos:
Fantastic. I mean really a testament to the progress in clinical science for cardiac surgery, that we've got these randomized controlled trials moving through a development phase that may be actionable in years to come. Let's finish the discussion of the original research articles, Mike, with a review of the Yang paper, really, which also, I think, is in Circulation's real sweet spot, where we're highlighting the very best of basic and translational science coming from Surgeon Laboratories. Can you talk about that paper for us?
Dr. Michael Fischbein:
Thanks very much, James. I think this is really an exciting paper. Qiong Yang's lab at University of Michigan, they're studying Loeys-Dietz syndrome. As you know, Loeys-Dietz syndrome is one of the connective tissue disorders. There's five subtypes, and these individuals form aortic root aneurysms. Importantly, it's specific to the aortic root that these aneurysms primarily develop. Although later on, you can see them in other locations, including intracranial and some of the branch vessels.
Dr. Michael Fischbein:
But these root aneurysms can dissect and this is life threatening. Currently, the only treatment strategy for these individuals is surgical, where you perform a prophylactic replacement of the aortic root. Unfortunately, there are no real medical therapies, primarily because we don't understand the mechanisms why these aneurysms form. So Dr. Yang's lab, they model this disease using a induced pluripotent stem cell model, where cells are differentiated into the different embryologic origins of the aorta.
Dr. Michael Fischbein:
The aortic group comes primarily from the second heart field. And so, when they studied these smooth muscle cells, they were able to show that there is lineage-specific smooth muscle cell defects, and they discovered some interesting pathways that might explain why aneurysms form specifically in the root in these in individuals. They also came up with some potential pharmacologic strategies to block some of these mechanisms.
Dr. Michael Fischbein:
And so, I think this is really exciting because this is using pluripotent stem cells more as a model to study disease states. And I could see the potential, also, for precision medicine, where you take an individual cells, make their iPSCs and study that individual's mechanisms, and perhaps come up with unique medical strategies for that individual.
Dr. James de Lemos:
So let's, Marc, finish, that's really all of the original research articles we covered. Really, an amazing spectrum of clinical translational and basic science that is a Testament, both to what you all have done to recruit content, but the tremendous growth in science and the surgical specialties. Marc, let's talk a little bit about the two terrific in-depth reviews that you picked for this issue and what their contributions are.
Dr. Marc Ruel:
Thank you again, James. We have two excellent reviews in this themed issue of Circulation. One is a frontiers piece about cardiac surgery in women in the current era, going over what are the gaps in care. And this is spearheaded by Leslie Cho, from the Cleveland Clinic, and it really goes over, very comprehensively, many of the issues around not only clinical trial enrollment of women, but specific issues pertaining to the care, and which goes back even to basic science of the sex and gender of animals being used in research for reasons that I said, that are very comprehensively, again, I want to emphasize highlighted by the authors.
Dr. Marc Ruel:
And I'll give you an example, for instance. In off-pump surgery, there are some discrepancies with regards to the use of off-pump versus on-pump surgery between males and females. And we off-pump surgeons know that there are really two very different ways from the surgery. Women, for instance, have a smaller heart which is easier to expose, for instance, for lateral and inferior territories. But in the same token, the coronary targets can be smaller. So there's really a number of discrepancies here, which can be anatomic, it can be sometimes due to the disease presentations.
Dr. Marc Ruel:
For instance, women have more tricuspid valve disease, and at a certain age start having an increased incidence of aortic problems versus males. And there's also some what I would call logistical issues with regards, for instance, to clinical trial recruitments from VA centers that typically have very, very few women being eligible for enrollment there. So these issues, again, are comprehensively addressed by Dr. Cho and her colleagues. And it's a very interesting read.
Dr. Marc Ruel:
The other piece you were referring to is a state-of-the-art paper around the use of transit time flow measurements during coronary bypass. And I think our cardiology colleagues and everyone in the cardiovascular field will be very interested to learn a bit more about this. Because essentially, when we perform bypass surgery, we don't have a validated easy way to ascertain whether the grafts that we just built are doing their job. And you may say, "Well, the surgeon's great at cutting and doing anastomosis," but as I like to tell my trainees, there's much more than suturing that might be happening.
Dr. Marc Ruel:
An anastomosis may have an unforeseen flap into it. There could be a small clot that's blocking something. There could be a kink or a twist in the graft that's not readily recognized. So I think it's very important to have a thorough assessment in everybody. I'm the last author of this piece, so I'm obviously somewhat partial to it. But I think it is important for the field to have quality checking of all grafts that are performed at something, especially something as invasive as bypass surgery. The patient should come out with functional grafts and that should be validated and objectively verified.
Dr. James de Lemos:
Fantastic. Marc, and we also have two research letters in this issue of Circulation. These are small pieces, but they pack a really powerful punch. Do you want to just briefly tell us about those two?
Dr. Marc Ruel:
Absolutely. Thank you, James. As a surgeon, I love research letters. I think they are a great venue. They're under a thousand words. Certain, sometimes we're busy, we don't want to always read a 5,000-word manuscript. And they're really, they are well-suited to what I would say are surgical follow-up studies. Once a technique has been described and you want to look at what are the late outcomes of this technique, I think they're an excellent format for that. And precisely, this corresponds to the two research letters that we have in the 2021-themed issue.
Dr. Marc Ruel:
One is a long-term, 10 year analysis of the SAVE RITA trial by Kim and Kim in South Korea. The SAVE RITA trial is a fairly famous trial in our specialty, which essentially, randomized patients to have a Y graft on the left internal thoracic artery, using either a saphenous vein conduit or the right internal thoracic itself. And essentially the early results were neutral. So the two groups were comparable, which is naturally neutral. I would say non-inferior for the saphenous vein graft.
Dr. Marc Ruel:
Now we have 10-year data in over 200 patients, equally randomized between receiving a saphenous vein graft versus the right internal thoracic artery. And the results are 10 years are equally excellent between the saphenous vein graft and the right internal thoracic artery. So this is quite non-intuitive to many. Essentially, what we're showing here is that a vein graft at 10 years has amazing patency. We're talking 90%-plus in those patients who received an angiogram. So I think there's a couple of messages to remember here.
Dr. Marc Ruel:
There may be a biologic role of connecting a saphenous vein graft onto the left internal thoracic artery with regards to nitric oxide dilution. Also, technically, the authors have readily acknowledged that the harvest the vein, again, back to this saphenous vein harvest issue, they harvest it from the lower leg. Therefore, the diameter of the vein is more suited to a Y graft. And, in fact, using a vein over right internal thoracic artery may have technical advantages, because the diameter is a little bit more facile to use with regards to complex composite grafting. So it may actually be something that, if you can maintain it with patency based on say, nitric oxide dilution, is a little bit easier to maneuver and build at the time of surgery.
Dr. James de Lemos:
Marc, can I ask a question here? Does this change your practice with regard to how often you're using Y graphs, in general, and the vein on artery Y? Because, Mike, outsiders experiences that these graphs aren't used and do these data suggest that we should be using why Y graphs, in general, and this particular type of Y more often in surgery?
Dr. Marc Ruel:
Absolutely. I think these data suggest precisely that. Whether the adoption will follow is another story. There's not a lot of groups, much to your point, that are using this configuration, but it's used commonly as a bailout strategy. Let's say, one of the arteries has been injured or is not available, or you have a porcelain aorta, I think based on these important data, you can now know that you can, if well-constructed, use a saphenous vein graft as a Y graft onto the LITA with relative impunity. In fact, excellent results, if done in the way that Kim and Kim are reporting.
Dr. Marc Ruel:
Our second research letter is actually a follow-up of hybrid palliation for hypoplastic left heart syndrome. This comes from the UK, where a number of centers had used several years ago the concept of a hybrid palliation in patients who were mostly high risk for hypoplastic left heart. So here, again, much to the research letter format, we have a follow-up series with regards to following all these children who had received either a initial Norwood approach or a hybrid approach progressing to a Norwood stage two. And essentially, the overall survival, which is about, between two thirds to 75% of children at three, four years, is no different between an initial Norwood stage one approach versus hybrid palliation.
Dr. Marc Ruel:
So I think this is obviously very intriguing data. It's used to be that a hybrid palliation would only be used in very high-risk cases. I think this would provide credence to using it in a more liberal fashion. There's still the possible caveat that the centers that use hybrid palliation have a little bit of a "expertise bias," if you will, because they have both modalities being available. But I think this is a very important and very intriguing data for this extremely challenging condition.
Dr. James de Lemos:
Well, thank you. And I'd like to thank both you, Marc, and Mike for just tremendous insight. I think for somebody that doesn't live in the cardiac surgery world, having the privilege, not just to hear you explain these terrific studies, but also provide your insights in pearls about cardiac surgery and vascular surgery care in 2021 has been invaluable. And I think our listeners will feel the same way. I'd like to turn it over to you, Marc, as our leader in cardiovascular surgery to close us out today from a wonderful podcast.
Dr. Marc Ruel:
Well, thank you very much, James. Again, I want to reiterate, I think this is really a tremendous issue. It's our best ever. And I want to thank you, James and Joe Hill, as well, our Editor-in-Chief, for your support of surgery within Circulation. I also want to thank Sarah, Molly, Nick, and Augie, really, for their in their indefatigable support of our issue. I want to, again, extend our gratitude to Tim Gardner and to Mike for their tremendous help with this issue. I think this is, again, very important. Do send your best work, and I'm speaking to our readership community and all surgeons to Circulation.
Dr. Marc Ruel:
Circulation is our premier journal and surgery's tremendously important. And the interface together is a strong one, because Circulation realizes that surgery provides, and I'm a bit biased when I say this, but I think it is true. It provides the most robust and durable treatment for advanced heart disease, so it is very important to be featured prominently in Circulation. And I think this is what our current leadership and staff at Circulation are supporting, and I'm tremendously thankful on behalf of all surgeons.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features a panel discussion. Please join author Harmony Reynolds, editorialist David Newby, and Associate Editors Nicholas Mills and Sandeep Das as they discuss the articles "Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study, "Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity," and editorial "Forget ischemia, it's all about the plaque."
Dr. Greg Hundley:
Welcome listeners to this week's, September 28th, issue of Circulation on the Run. And I'm Dr. Greg Hundley, Director of the Poly Heart Center at VCU Health in Richmond, Virginia, and associate editor at Circulation. And this week, listeners, we have an outstanding feature discussion. It's actually forum where we're going to discuss from Dr. Reynolds two papers pertaining to the ischemia trial. One looking really at the functional importance of stress testing, the other looking at the anatomical importance of cardiac CT scanning. We're going to have two of the associate editors along with Dr. Reynolds, each that handled the two papers and also a guest editorialist that will help put the entire paper together. Well, before we get to that, we're going to start and review some of the other papers in this issue. And let's grab a cup of coffee and get started.
Dr. Greg Hundley:
The first comes to us from Dr. Maliheh Nazari-Jahantigh from Ludwig Maximilian University in Munich, Germany, and it pertains to atherosclerotic plaque rupture. So the necrotic core of an atherosclerotic plaque is partly formed by ineffective efferocytosis, which increases the risk of an atherosclerotic plaque rupture. And in cell biology, efferocytosis comes from the Latin word effero, which means to take to the grave or to bury. And it's really the process by which apoptotic cells are removed by phagocytic cells. And so therefore, it can be regarded as the burying of "dead cells." Now MicroRNAs contribute to necrotic core formation by regulating efferocytosis as well as macrophage apoptosis. We also know that atherosclerotic plaque rupture occurs at an increased frequency in the early morning, indicating that diurnal changes occur in plaque vulnerability. Now all those circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear.
Dr. Greg Hundley:
And so these authors investigated this phenomenon. And what they found, interestingly, their results suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mer 21 expression in macrophages that is not matched by efferocytosis, and thereby increasing the size of the necrotic core of these plaques. So clinically, the implications are that a macrophage death clock controlled by mer 21 may enhance lesion growth and susceptibility to plaque rupture indicating that the molecular clock can have detrimental effects under pathologic conditions. And additionally, the molecular clock in lesional macrophages may contribute to the circadian pattern of myocardial infarction, which could be a target for preventive measures to limit the mismatch between apoptosis and efferocytosis and thus reduce plaque vulnerability in the early morning.
Dr. Greg Hundley:
Well, our second paper comes to us also from the world of preclinical science, and it's from Professor Thomas Braun from the Max Planck Institute for heart and lung research. And this particular paper pertains to pulmonary hypertension. And as we know, pulmonary hypertension and chronic obstructive pulmonary disease, or COPD, originate from a complex interplay of environmental factors in genetic predispositions and little is known about developmental abnormalities or epigenetic dysregulation that might predisposed individuals to develop pulmonary hypertension or COPD in adults. So these authors screen a cohort of human pulmonary hypertension in COPD patients for changes of histone modifications by immunofluorescent staining. And also, they developed knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types.
Dr. Greg Hundley:
Now molecular, cellular and biochemical techniques were applied to analyze the function of SUV420H1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Well, what did they find? So the investigators found that loss of SUV420H1 in cardiopulmonary progenitor cells caused a COPD-like pulmonary hypertension phenotype in mice, including formation of perivascular tertiary lymphoid tissue, and goblet cell hyperplasia, hyperproliferation of smooth muscle cells and myofibroblast, impaired alveolarization and maturation of defects of the microvasculature leading to massive ripe ventricular dilation and premature death.
Dr. Greg Hundley:
Now mechanistically SUV420H1 bound directly to the five prime upstream in regulatory element of Superoxide Dismutase 3 gene to repress its expression and increased levels of the extracellular Superoxide Dismutase 3 enzyme in SUV420H1 mutants increased hydrogen peroxide concentration causing vascular defects and impairing alveolarization. So what can we take away, listeners, from this clinically? Well, the author's findings reveal a pivotal role of histone modifier SUV420H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. And now these results suggest that this study will facilitate the understanding of pathogenic events causing pulmonary hypertension in COPD and aid the development of epigenetic drugs for treatment of other cardiopulmonary diseases.
Dr. Greg Hundley:
Well, listeners, what else is in, we call it, the mail bag, but some of the other articles in the issue? Well, doctors Varricchi and Wang exchanged letters regarding the prior article, the role of IgE FcεRI in pathological cardiac remodeling and dysfunction. And our own Sara O'Brien highlights articles from our circulation family of journals. Professor Ross has a Research Letter regarding the effects of walnut consumption for two years on lipoprotein subclasses among healthy elders findings from the WAHA randomized controlled trial. And then finally, Dr. Maurer has a really nice On My Mind piece that raises concerns pertaining to the use of cardiac scintigraphy and screening for transthyretin cardiac amyloidosis. And now listeners, we're going to turn to that forum discussion where we have an author, our associate editors and an editorialist discussing two really important papers from the ischemia trial.
Dr. Greg Hundley:
Well, listeners, we are very excited today to discuss in sort of the forum feature, two papers pertaining to the ischemia trial. And with us this day, we have Dr. Harmony Reynolds from New York University Grossman School of Medicine in New York city; two of our associate editors, Dr. Nick Mills from university of Edinburgh in Scotland; and Dr. Sandeep Das from UT Southwestern; and then also an editorialist, Dr. David Newby, who's also University of Edinburgh in Scotland. Welcome to everyone.
Dr. Greg Hundley:
Harmony, we're going to start with you. And in the first paper, the natural history of ischemia and no obstructive coronary artery disease, can you describe for us a little bit of the context of what shaped this question for you, what hypothesis did you want to test? And then describe for us a little bit your study population and your study design.
Dr. Harmony Reynolds:
Sure. Thanks so much for having me here to discuss these papers. I'm really appreciative of the attention from circulation, and I'm excited for this discussion today. So in this first natural history paper, we were looking at ischemia with non-obstructive corona arteries, INOCA, the kind of thing that used to be called cardiac syndrome X. And we know this is an extremely common problem. It's defined by having signs or symptoms of ischemia and no 50% or greater lesion on coronary imaging. And we also know from prior invasive studies that the mechanisms of this are overwhelmingly microvascular coronary disease and provokable coronary spasm. Some patients prove to be normal and invasive testing, but most will have some objective abnormality.
Dr. Harmony Reynolds:
We know this problem is associated with a higher risk of cardiovascular events and with high costs, but what we didn't know was whether the symptoms and ischemia on stress testing are tracking together in these patients. So if we're trying to treat these patients, should we be doing serial stress testing and targeting the medical therapy to ischemia abrogation or should we just be making their symptoms go away? And would this provide any long range insights for us into when we can figure out the symptom are truly ischemic in nature?
Dr. Harmony Reynolds:
So we decided to use the ischemia trial, and we had a fantastic platform for that in ischemia because, as you know, patients were screened in part for randomization using coronary CT angiography. And even though these patients had moderate or severe ischemia, some had no obstructive coronary disease on that CT coronary angiogram. And those are the patients that we enrolled in CIAO-ISCHEMIA. They had an assessment of angina at baseline, and they had to be symptomatic at some point. They didn't have to be symptomatic at the moment. They were enrolled in CIAO, but they had their stress test generally to evaluate ischemic symptoms. And they had their stress echocardiogram read by a core lab. Importantly, that core lab did not know the result of that CT scan. So they read them like all the other ischemia stress echoes. And then these patients had an angina and ischemia assessment with a repeat stress echo at one year.
Dr. Greg Hundley:
And what did you find?
Dr. Harmony Reynolds:
There were a number of interesting findings from this study. The first thing was that the severity of ischemia in the CIAO patients with INOCA was very similar to the ischemia patients who had obstructive coronary disease. So that tells us that the INOCA problem can happen with quite a lot of ischemia, and that had not been as well delineated before. Another finding expected, but we did find that is that there were many more women in the INOCA group, two thirds of our child population was female. And in ischemia, overall, it was closer to a quarter. We found that the symptoms and the ischemia were quite changeable. So at one year, the stress echocardiogram was normal in half of the child participant and only 23% still had moderate or severe ischemia. Angina had improved in 43%, and it worsened in 14%. There was an awful lot of change over one year, but the change in angina and the change in ischemia did not track together. And that was a bit of a surprise to me.
Dr. Greg Hundley:
Very nice. Well, Nick, I know serving it as an associate editor, you see many papers come across your desk. What attracted you to pushing this paper forward for publication?
Dr. Nicholas Mills:
Thanks, Greg, and congratulations. Harmony, we love the papers you've been sending from ischemia trial, which genuinely is changing clinical practice all over the world. And it's been great to see the secondary analysis and follow-up papers. So this paper attracted me because it addresses an area where I still don't fully understand in clinical practice, what recommendations to make for my patients and what tests to arrange. As you say, INOCA is more common in women. I think these patients have largely been understudied over many decades, and there remains a lot of uncertainty. I liked it because you had a core lab, blinded core lab analysis with systematic follow up and it was a really well-done study. It reassured me in many ways because it told me that actually a lot of these patients, their symptoms get better, sort of irrespective of what we do. The treatments didn't seem to track within improvements of symptom, nor did the severity of ischemia, and that I think provides a lot of reassurance to our patients who are in this situation.
Dr. Nicholas Mills:
Of course, there is a group there who continue to have moderate to severe ischemia a year later. And I think this trial helps us understand maybe how we should study this group more, understand the heterogeneity that you've observed in this population in order to really try and resolve that and resolve their ongoing symptoms. But for the majority, four in five patients, they're going to do well and they're going to get better over time. And I think that's an important message from this study.
Dr. Greg Hundley:
Thank you so much, Nick. Well, Harmony, we're going to come back to you. You have a second paper, the outcomes in the ischemia trial really based on coronary artery disease and ischemia severity. Can you describe for us, again, working us back through, what were some of the constructs that you really wanted to address here? What was your hypothesis? And again, how did this study population maybe differ a little bit in this second paper?
Dr. Harmony Reynolds:
Thanks so much. So this paper tracked outcomes based on the severity of ischemia and the severity of coronary artery disease on the CT coronary angiogram now in randomized patients in the ischemia trial. So all of these had obstructive coronary disease and they were selected for randomization. And the premise of the ischemia trial was partly that we would be able to select patients who might benefit from revascularization and from an invasive strategy really based on how much ischemia they had on the stress test. Moderate or severe ischemia was required for randomization and for entry into the trial, but a core lab read those stress tests independently and independently assessed ischemia. And in some cases, when the site thought there was moderate or severe ischemia, the core lab did not agree. And the core lab independently decided whether it was moderate or severe. So we wanted to understand whether the ischemia severity at the time of trial entry influenced outcomes and influenced the outcomes by randomization treatment assignment.
Dr. Harmony Reynolds:
Similarly, about half of the patient had a CT that was interpretable for the number of vessels disease. And we wanted to understand in the context of all those prior stable ischemic heart disease trials, showing a lot of heterogeneity by the amount of coronary disease, whether in ischemia as well, there would be heterogeneity of the treatment effect based on how much coronary disease you started with. So the ischemia population, and this is almost the entire randomized cohort, but it's important to recognize for the CT analysis that only about three quarters of the patients had CT. They didn't get a CT, if your GFR was too low or if you had known coronary anatomy. And among those Cts, not every CT is perfectly interpretable for the number of vessels disease. These are sicker patients. These are not the super stable patients who have a low prevalence of disease. These were pretty sick, multi-vessel coronary disease patients, and they couldn't always hold their breast all that well. There was a lot of calcification in these.
Dr. Harmony Reynolds:
So for example, if there was motion artifact in the right coronary artery, we wouldn't be able to quantify the number of vessels disease. And that left us with a cohort of about half of our ischemia population, but that's still a giant cohort of several thousand patients. So that's how our study.
Dr. Greg Hundley:
Very good. And what did you find here?
Dr. Harmony Reynolds:
Here, we found that more severe ischemia was not associated with outcomes. Now that does go along with the COURAGE study in which after you adjust for clinical characteristics, ischemia was not associated with outcomes. But still it came as something of a surprise that even severe ischemia was not associated with a higher risk of outcomes than moderate or mild ischemia. We also found that in the coronary disease group, no matter how you measure the severity of coronary disease, the Duke prognostic index, the number of vessels disease, the segment involvement score, the segment stenosis score, all of these measures were very strongly associated with our outcomes, whether it was all cause mortality MI or our composite.
Dr. Harmony Reynolds:
When it came to treatment effect, we found that the ischemia severity were no relationship to treatment effect. There was no ischemia subgroup in which there appeared to be an advantage with an invasive strategy. But in the coronary disease group, and again taking into account the caveats of not everybody had a CT interpretable for the number of vessels disease, in those with the most severe coronary disease, that's the Duke 6 subgroup. And they had multi-vessel severe disease, either two vessel including the proximal LAD at 70% or three vessels with 70% stenosis. There was no benefit on mortality. But if we looked at the composite endpoint of cardiovascular death or MI, there appeared to be some advantage to the invasive strategy.
Dr. Greg Hundley:
Very good. Well, Sandeep, similar to Nick, working as an associate editor and meeting weekly, what attracted you to this particular paper? And why did you want to really see it come forward to be published?
Dr. Sandeep Das:
So first of all, I want to echo Nick's comments that these are great papers, and thanks very much for sending those our way and letting us have sort of first crack at them before they're released to the world. And I also want to comment on the side that Harmony and her team were just absolutely fantastic to work with in this process. From having been on the other side when you get 300 different comments from the editors and reviewers and you respond to them thoroughly and with grace, that's a feat in and of itself. So I want to shout out Harmony and her team for just being fantastic partners, because really we see ourselves as sort of the author's partners in kind of making the paper as good as it can be as the best it can be.
Dr. Sandeep Das:
So I'll admit upfront, I think it's kind of fashionable for people to say, well, I knew that this was going to show this, I knew this all from COURAGE, and this is not surprising to me. But I'll admit that I was surprised. And so this has been practice-changing for me, so this whole evolution post ischemia. And I really feel like a little bit of an existential crisis because I'm not sure I understand what ischemia means anymore. You ask me five years ago, I would've been very confident that I knew the answer to that. So you know what, really, as soon as this paper crossed our desk, I thought, wow, this is something we want to keep, this is something that's going to be really important to practice of cardiology. It's going to be really important to our readers. It's a great paper from a great group. This is something we want. So really it was never a question of, well, am I interested or am I not? I was interested from reading the abstract.
Dr. Sandeep Das:
So the question then became what are the real important questions that we need to sort of tease out and help elucidate for the clinician for the reader? And really for me, the question has always been, is there a subset of people where... So in my heart of hearts, I always kind of thought that burden of ischemia, if there was enough burden of ischemia, that it probably did help to revascularize that, right? I definitely practiced that way, right? There was some sort of number where I would start to say, that's a lot of ischemic myocardium and maybe we need to do something about that. Even though I know my intellectual brain says, no, there's no data that supports this, I really kind of thought it was true. And so Harmony and her team put another nail in that coffin here because it doesn't seem to be true, which to me was interesting and different and practice-changing.
Dr. Sandeep Das:
So the real questions here were sort of to tease out the interaction between anatomic severity, and we've all known that sort of anatomic burden of disease is proportional to adverse outcomes. That's not surprising. But the question then is, can we tease out a group where there may be benefit to revascularization? So there's a real interesting sort of interplay here between degree of ischemia and anatomic burden of disease. And is there a subset with enough of an anatomic burden of disease where you really may be interested in going after that to improve heart outcomes? So that's what I thought this was really fascinating paper.
Dr. Greg Hundley:
Very good. Well, David, we're going to turn to you next as the editorialist and asking you to sort of put the results of each of these two studies together. One, kind of highlighting for us how functional imaging might be useful to identify whether ischemia is present or not. And then the second study, really defining for us an association between anatomy and outcomes. So putting these all together, could you share your thoughts with us regarding these two papers?
Dr. David Newby:
Yes. Thank you. So I think that the CIAO-ISCHEMIA is very interesting, isn't it? And those clinicians were often challenged with symptoms versus our objective tests and trying to work out exactly what's going on, and it is. And such an important group as Harmony says, I can't agree more. We have a lot of morbidity here. As Nick said, I think the short term, a lot of the patients do seem to get better with just conservative management is good, but there's a core group that clearly are a problem. And as Harmony highlighted, you've got people with terrible regional wall-motion abnormalities on stress echo and yet no angina, others with no angina with no apparent difficulty on repeat testing. And then you've got a core group that has both, and it is fascinating to try and unpick that. And clearly, the symptoms are not correlating with our tests, and that's not the patient's fault.
Dr. David Newby:
And very often, no, no, you're wrong, can we say that to the patient? No, no, the patient is right and our tests are wrong, and we've got to work out how best to manage them. And I have a bit of analogy with Takotsubo cardiomyopathy as well, I think is at play here. I mean, here, you've got people with stable pain. We're not coming in as an acute emergency, but they're having regional wall motion abnormalities at times. They're getting a lot of symptoms. And we see similar things with Takotsubo, which is, I suppose, a much more flurry thing. I know that's something close to Harmony's his heart too. Excuse the pun. But this ischemia relationship, these regional wall motion abnormalities with chest pain, particularly in women, is something we really need to get our heads around and understand what's going on. It just reflects our ignorance, I think, of knowing exactly how to manage these patients.
Dr. David Newby:
And so for me, ischemia testing is about symptoms. It's about working out what's going on with the patient. It doesn't always give us the answer, but I certainly think that the role of ischemia testing is more about the symptoms.
Dr. David Newby:
And then when it comes to the second paper and outcomes with the ischemia trial, I absolutely was delighted to see those findings. I have to say place to what my prejudice is, I suppose, as someone that's been working with CT. And I suppose the slightly obvious thing is that the more disease you have, the more you will benefit from an intervention. And plaque and the burden of plaque is critical to that because how do you have a heart attack? Well, you have to have plaque, right? And it has to rupture. So the more plaque you have, the more likely you are. And I think that the analysis is again reinforcing what we've learned from some of the imaging trials with PROMIS and SCOT-HEART. Actually, the more plaque you have, the worse you are.
Dr. David Newby:
And yes, ischemia predicts risk, but ischemia predicts risk through its association with plaque burden, not through ischemia itself. And what I think we're seeing very nicely being played out in ischemia trial is the risk is definitely much stronger for CT than it is for imaging. And that's very clear, and that's exactly what PROMIS found exactly what SCOT-HEART found as well, and it's a rise robust finding. The interaction with the treatment effect that I find also fascinating and again plays to some of the bypass surgery trials that we've seen, bypass surgery tends to prevent spontaneous MIs and, even in some cases, mortality. And we're seeing trends in ischemia for mortality, can't over call them. I'd love to see what happens in 10 years. But I think in terms of the prevention of MIs, I'm putting all my money in one basket, which is the bypass surgery, 25% of course of patients revascularized that way. I don't believe that PCI is going to prevent the myocardial infarction. So I think all my money is in that box.
Dr. David Newby:
But it's absolutely fascinating data. It is all about the plaque if you're talking about prevention of clinical events downstream. And I think that's where the dichotomy is, scheme is about symptoms and understanding the patient's problems in terms of symptomatic improvement. If you want to improve their long term outcome, it's all about the plaque, understanding the burden of plaque and what you can do to hopefully prevent downstream event.
Dr. Greg Hundley:
Great. Thank you so much. And so listeners, we're going to ask each of our speakers today in really 20 or 30 seconds to go through and identify what do they think is the next study really to be performed in this space? So Harmony, we're going to start with you and then Nick, Sandeep and then finish up with David. Harmony?
Dr. Harmony Reynolds:
Thanks. Well, when it comes to INOCA, I would like to see more studies in the vein of CorMicA. So I'd like to see routine invasive testing to define the underlying pathophysiology problem and then targeted medical therapy interventions, and I'd like to see outcome trials. There's one outcome trial going on. It's a challenge because the event rate, though very important and higher than in the general population for sure, is low enough that these trials have to be quite large, and we look at ischemia with a relatively high event rate. And even so it's a stable population and that had to be large, this would have to be even larger. So we're going to need more mechanistic studies in order to lead to the treatment trials that will really influence practice.
Dr. Harmony Reynolds:
And in terms of the severity of coronary disease, this is a tough one. We felt like ischemia was a lift, and I'm not sure that there will be another huge stable ischemic heart disease trial. But sure, I'd love to see in people selected by CT for their advanced severity of coronary disease, whether an invasive management strategy makes a difference compared to medical therapy. I don't know that we'll see that one come to pass, but you never know.
Dr. Greg Hundley:
Nick?
Dr. Nicholas Mills:
Yeah. I agree. We need more mechanistic research, but I'd like to see more non-invasive methods to understand the mechanistic basis of this condition because CorMicA has caught an invasive protocol for a condition, which we know is benign and who most patients get better without any treatment. I would also like to see randomized blinded studies of treatment effects and because there are too many observational on blinded studies here. And I think the outcome has to be patient-focused and symptoms.
Dr. Greg Hundley:
Sandeep?
Dr. Sandeep Das:
Yeah. So everything that's been raised so far are fantastic comments and really on point. For me, I think if we can tease out the population that may benefit to get back to Dave's earlier comment that there's possibly not going to be a little humble here, there's possibly a population that has extensive, extensive CVD that could benefit from bypass surgery. And I think that that hasn't really been firmly demonstrated yet, although it's been suggested strongly. So that I think is an interesting study, and I hope that that gets done as a trial, but I can understand that it'd be a giant undertaking. And then the other thing I think is just algorithmic approaches that are driven by anatomical studies like SCOT-HEART and things like that, where we really try to make decisions based on the anatomical approach and pretend like the last 15 years never happened and that we kind are starting fresh with our best approach to how to treat these patients.
Dr. Greg Hundley:
And finally, David.
Dr. David Newby:
Yeah. I'm actually going to agree with everybody there, and I'm rooting for this trial actually because that's the one I want to do is look at advanced coronary disease on noninvasive imaging, irrespective of symptoms. And that's the big call actually if you've got no symptoms to put yourself through a bypass, because it's bypass, it's not standing. Bypass, we need. I'd also love to see some substudy coming out of ischemia. I think you're doing them. I hope you are looking at plaque burden and plaque characteristics because I think that's another level of complexity. We're so obsessed with stenosis, actually. And again, even anatomical and ischemia testing plays to that, it's not just about stenosis, stenotic arteries have big plaque burdens, et cetera. And it's not bypassing them, it's bypassing all the nonobstructive plaque and the obstructive plaque that has given you the benefit of revascularization with surgery. So I think you need to think about a really nice cool trial where we can do that trial even in the presence of nonobstructive disease, but big plaque burden, adverse plaque characteristics, and think about bypass.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Harmony Reynolds for bringing us these two really informative studies from the ischemia trial, and also our associate editors, Dr. Nick Mills and Dr. Sandeep Das for providing their perspective and our editorialist, Dr. David Newby, who really helped us organize our thoughts and put both of these two studies into great perspective highlighting in the first that functional testing can really help us identify the presence or absence of ischemia. And then our second study highlighting the association between CT coronary angiography and the identification of the anatomic severity of disease with cardiac outcomes.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speaker in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features author Benjamin Levine and Guest Editor Walter Paulus as they discuss the article "One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage-B HFpEF."
Dr. Greg Hundley:
Well, welcome listeners. This is the September 21st podcast for Circulation on the Run. Sadly, I'm without Carolyn today, but I am your host today, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Greg Hundley:
Our feature discussion today is really interesting. It's from Dr. Ben Levine, and he's evaluating the utility of exercise training and actually trying to reverse abnormal left ventricular myocardial stiffness in individuals that have stage B, it's a very early heart failure and preserved ejection fraction. But before we get to that, let's grab a cup of coffee and we're going to work through some of the other articles in this issue.
Dr. Greg Hundley:
So the first one comes to us from Göran Bergström from University of Gothenburg in Sweden. He and his team used coronary computed tomography angiography or CCTA to determine the prevalence, severity and characteristics of coronary atherosclerosis and its association to coronary artery calcification scores in a general population of greater than 25,000 individuals all aged 50 to 64 years and without known coronary heart disease. It really comes to us from the Swedish CArdioPulmonary BioImage Study or SCAPIS. Well, Carolyn would ask me that is a really large study, and what did they find? Well, let's get to the results.
Dr. Greg Hundley:
So using CCTA to detect silent coronary atherosclerosis, the investigators showed that any coronary atherosclerosis was actually quite common, 42% of individuals and significant stenosis of greater than 50% was less common, only 5% of individuals. More severe forms were rarely found, only 1.9% in this very large, random sample of middle-aged individuals.
Dr. Greg Hundley:
Now disease onset was delayed by 10 years in women and a higher prevalence of coronary atherosclerosis was observed with higher age and accumulation of risk factors. Interestingly, CCTA detected atherosclerosis increased with an increasing coronary artery calcium score. All those with a high CAC score of greater than 400 had atherosclerosis and 45% had significant stenosis. 5.5% of those with no coronary artery calcification had atherosclerosis and 0.4% had significant stenosis. So although there was a strong association with high coronary artery calcium scores and significant stenosis, atherosclerosis was not excluded in those with zero coronary artery calcification especially in those with high baseline risk.
Dr. Greg Hundley:
Well, our second article comes to us from the world of preclinical science and it's from Dr. Nathan Palpant from the University of Queensland. So the article pertains to ischemia reperfusion injury, and it's one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. Now during cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6 to 6.5, and the resulting tissue acidosis exacerbates ischemia injury and significantly impacts cardiac function.
Dr. Greg Hundley:
So the authors today use genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a or ASIC1a, we'll call it from now, in cardiac ischemia reperfusion injury at the cellular and whole organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of ischemia reperfusion injury were used to test the efficacy of ASIC1a inhibitors as pre-imposed conditioning therapeutic agents.
Dr. Greg Hundley:
So what did the authors find in this study? Well, they demonstrated for the first time that acid-sensing ion channel 1a or that ASIC1a mediates cardiac ischemia reperfusion injury. The authors identify that ASIC1a inhibition is a novel therapeutic strategy for preventing acute injury response to myocardial ischemia reperfusion injury.
Dr. Greg Hundley:
So what are the clinical implications of this research? Well, first there are currently no drugs in clinical use that prevent acute injury response to myocardial ischemia, despite many promising candidates identified over decades of research, all of which ultimately failed in subsequent clinical trials. Second, the identification of new therapeutic targets for preventing the injury response to myocardial ischemia reperfusion injury would therefore have profound implications in cardiovascular medicine. Therefore, the results of this study reveal that ASIC1a inhibiting drugs, they're safe and they have potential applications in heart transplant and myocardial infarction with potential use in other clinical scenarios where myocardial ischemia reperfusion injury is a risk such as those that undergo cardiac surgery.
Dr. Greg Hundley:
Well, our next article comes from Robin Choudhury from the University of Oxford. Have you ever wondered why cardiovascular risk and diabetes remains elevated despite glucose-lowering therapies? Well, these authors hypothesized that trained immunity in response to elevated glucose accounts for diabetic hyperglycemic "memory", we'll call it, in relation to atherosclerosis. So accordingly, the author sought to determine if hyperglycemia-induced disease relevant changes in monocyte and macrophage function and whether these changes persisted after restoration of normal glucose, thereby implying fundamental reprogramming. So the team combined studies of cellular function, metabolomics, transcriptomics and epigenomics to define how hyperglycemia altered metabolism to modulate long-term activation through epigenetic modifications.
Dr. Greg Hundley:
Well, what did they find? First, hyperglycemia induced a trained immunity in bone marrow progenitor cells by inducing persistent epigenetic modifications. Second, hyperglycemia-induced trained immunity persisted after differentiation into those macrophages. Finally, hematopoetic stem cells transplanted from mice with diabetes to euglycemic mice promoted exaggerated atherosclerosis. So therefore, the findings of this study may explain the resistance of macrovascular complications of diabetes to conventional glucose-lowering treatments.
Dr. Greg Hundley:
Well, in the mailbag this week, there are some other articles. Professor Huang has a Research Letter entitled, “Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity.” Dr. De Caterina has an In Depth article on coronary artery anomalies. Finally, Professor Merid has a Perspective piece entitled, “Digital Redlining and Cardiovascular Innovation.”
Dr. Greg Hundley:
Well, listeners, what a great group of articles, and now we're going to turn to that feature discussion with Dr. Ben Levine.
Dr. Greg Hundley:
Welcome listeners to our feature discussion today and we're very fortunate. We have with us, Dr. Ben Levine from UT Southwestern in Dallas, Texas and also Dr. Walter Paulus from Amsterdam. Welcome gentlemen.
Dr. Greg Hundley:
Ben, we'd like to start with you. Could you describe for us a little bit of the background related to your study and what was the hypothesis that you wanted to test?
Professor Benjamin Levine:
Sure. Oh, nice to talk with you, Greg. As you know, our lab has been very interested in the effects of both aging and physical activity on cardiac mechanics. To cut a very long story short, what we know is that sedentary aging leads to stiffening of the heart. We also know that HFpEF, heart failure with preserved ejection fraction, is a disorder predominantly of the aged. I don't know about you, Walter, but I've never seen any lead masters athlete HFpEF.
Professor Benjamin Levine:
What we've shown is that if you regularly exercise over a lifetime that the heart can preserve its youthful compliance and flexibility. But if you wait until somebody is older, meaning over 65, 70, regardless of how hard or intense we train, the heart seems to lose its plasticity. It can't actually get that much better. But if we start in late middle age, it turns out that you can actually reverse some of the adverse effects of sedentary aging. So we said, "Okay, we know what the dose is, how much exercise you need to do. We know what the sweet spot in time. Now how do we find those people who are most likely to go on to develop HFpEF in whom getting them on a regular exercise program might help forestall this very challenging syndrome."
Professor Benjamin Levine:
So as part of an AHA-funded strategically focused research network and prevention, we identified a group of patients who had left ventricular hypertrophy, but evidence that they were on the wrong path. Their biomarkers were elevated. They have an elevated NT-BNP or a high sensitivity troponin. We did a right heart catheterization and we looked at their cardiac stiffness using a technique that we've done now for the past 25 years or so, and showed that indeed those patients' hearts are clearly stiffer than healthy, but otherwise sedentary middle-aged individuals.
Professor Benjamin Levine:
So our key question was what happens if we put them on a long sustained high intensity exercise program? Can we reverse the effects of sedentary aging superimposed with hypertension, left ventricle hypertrophy and elevated biomarkers?
Dr. Greg Hundley:
Really interesting, Ben. So describe your study design for us. How are you going to set up? It sounds like a very elaborate experimental setup here. Then also, maybe just define for us your study population. Did you have men and women or-
Professor Benjamin Levine:
Yeah, we started by going to the Dallas Heart Study. We're blessed here in Dallas by having this room access to our remarkable population where we know a lot about them. So we picked people in late middle age of all races, both sexes, and we reached out to the members of the Dallas Heart Study if they had left ventricular hypertrophy by echo or MRI and were of the right age range. We enriched that database by going to an EKG database and looking at the Ecolab database, trying to find people who did not have heart disease already. That was important. They couldn't have had a heart attack. They couldn't have had heart failure. They couldn't have had infiltrative disease. They had to be generally healthy except had left ventricular hypertrophy.
Professor Benjamin Levine:
We screened a lot of patients to get there, I have to acknowledge that, almost 4,000 of them or so to get the small number who were interested in doing a one-year exercise training program. But as we eventually got a good solid number that because we use such high resolution techniques, we were able to define the key outcome variable, which is cardiac stiffness.
Professor Benjamin Levine:
Briefly in our lab, we put a right heart catheter in to measure wedge pressure. We use 3D-echo to measure volume and then we use something called lower body negative pressure to unload the heart. It's almost like standing up progressively or tilting upright and then we give them a rapid saline infusion, 200 mls a minute. So a lot of saline, 15 and 30 mls/kg. We can get the left atrial pressure from about three or four up until about 18 to 20 and define the entire physiologic range of left ventricular filling. We look not just at the wedge pressure of course, but the transmural pressure.
Professor Benjamin Levine:
John Tyberg and his colleagues in Canada have shown clearly that the pericardial pressure is pretty close to right atrial pressure. So transmural pressure, which is the distending pressure of the heart, is left atrial minus right atrial pressure. We use that as the input into a pressure volume relationship.
Dr. Greg Hundley:
Very nice, and then what did you find?
Professor Benjamin Levine:
Well, what we found is after demonstrating that these patients with LVH and elevated biomarkers have increased stiffness, what we found quite remarkably actually was that we were able to reverse that by a year of training.
Professor Benjamin Levine:
Now when I say training, I mean, we do use the optimal approach to training that we've demonstrated in our lab. We didn't just pick one thing, get on a bike, do that for 30 minutes three times a week, right? These were sedentary people so we built them up slowly over about seven months. We added frequency, we added duration, we added intensity.
Professor Benjamin Levine:
I am enamored by the four by four in old Norwegian ski team workout, which is four minutes at 95% of max followed by three minutes of recovery repeated four times. We added interval training and long slow distance battle lasting about an hour on the weekends and a little bit of strength training, too.
Professor Benjamin Levine:
So what we consider the ideal prescription for life, four to five days a week, one long session, one high intensity session, two or three moderate intensity sessions and a little bit of strength. We did it for a year. It took a lot of effort. We had dedicated trainers. We gave them all heart rate monitors. Each person had a trainer to follow them.
Professor Benjamin Levine:
We did have a control group. We randomly assign them to a group that did stretching and yoga and mindfulness and a little bit of strength training, which makes people feel better. But we know from experience, it doesn't make them fitter and doesn't change their cardiac compliance.
Dr. Greg Hundley:
What happened with the treatment group?
Professor Benjamin Levine:
Oh, they got much more compliant. They got as compliant as if they had been training most of their lives. It was quite remarkable, actually, frankly, better than we expected it to be. We check the data multiple times by multiple people to make sure that this was a real finding. We really reversed much of the effects of the adverse effects of sedentary aging plus LVH. We hope that if that would be sustained over more than a year, years of long training study, there are very few training studies that go that long. But it's not a lifetime and at least we've set the stage for the concept that if this were to be sustained over a lifetime that we think it could forestall HFpEF.
Dr. Greg Hundley:
Very nice. Well, Walter, I know serving as a guest editor for us at Circulation and we're most appreciative for you doing that task. What struck you about this particular article and really enticed you to want to help us move it toward publication?
Professor Walter Paulus:
Well, I felt that the article was very visionary. Of course, as it comes from Ben, I didn't expect anything else. But what struck me were two points.
Professor Walter Paulus:
First of all, he looks at patients which we would label type B HFpEF. Most of our efforts have always been focusing on sick people, stage C HFpEF, stage D HFpEF. Now Ben was so clever to go to an early stage, and I believe that many of the so-called neutral outcomes in therapy for HFpEF are related to the fact that we actually address patients population who is quite far out on its natural history. So I think this was the first point to me. He, Ben, was addressing a population at the early stages of HFpEF.
Professor Walter Paulus:
The second point that struck me was that the variable he was looking at is in my opinion the key variable in HFpEF. It's the main reason I appreciated that this is the disease of myocardial compliance of left ventricle stiffness, and then very nicely addressed the stiffness of the heart as its primary outcome. This is something what we miss in all the pharmacological trials. I have always been curious when are we going to see the pharmacological trial whereby somebody is going to evaluate a compound in terms of its effects on left ventricular stiffness on myocardial compliance.
Professor Walter Paulus:
So these were for me two very salient features and very visionary in terms of treatment of a HFpEF population. Also, a couple of things that need to be clarified for me and I did. The patient's entry criteria were very demanding, has been also already said. I have the feeling that if you have LVH and then you will try NT-proBNP to be elevated and all your required troponins to be elevated, it's probably be very hard to get such a patient population and that may be then the only remark that could come up toward an extent in such a patient population still reflective of everyday health.
Dr. Greg Hundley:
Very good. Well, Ben, coming back to you, what's your next study?
Professor Benjamin Levine:
Well, we have a large program project grant, Greg, funded by the NIH, looking at the mechanisms of dyspnea and HFpEF. We're now just entered our third year. We're looking at a strategy to try to lower cardiac filling pressures acutely to see if that improves exercise tolerance and reduce dyspnea. We're looking at peripheral mechanisms of oxygen uptake and utilization and vascular control. We're looking at autonomic function, sympathetic nerve recordings, regulation of the sympathetic nervous system. We have a group focused on pulmonary mechanics, particularly on the effects of obesity.
Professor Benjamin Levine:
Our team with Tom Sarma is our recruitment core expert and one of the Circulation editors and is really the lifeblood of our study and leads our effort. We have Paul Fidel from UT Arlington who's leading our peripheral function studies, Qi Fu from UT Southwestern leading our autonomic group, and Tony Babb also from Southwestern in the pulmonary division leading our pulmonary mechanics.
Professor Benjamin Levine:
So we're entering this phase where we're trying to say, "Are there other components?" We know myocardial stiffness is a key factor, but what else in patients with the already manifest HFpEF is causing them to be so short of breath and can we change that?
Professor Benjamin Levine:
So that's what we're doing next, Greg. I think that if you ask what is the next step from this study, I think it has to be population-based and pushing the concept that exercise is medicine. When you find patients who have hypertension in general, and most of these had hypertension or diabetes, I mean, Walter has led this field and in emphasizing these comorbidities and what they do to the heart and the vasculature and the rest of the body, we have to catch people early. We can't wait until they have full-blown manifest HFpEF. We have to get them to include exercise as part of their personal hygiene.
Professor Benjamin Levine:
I know that that's a major effort from the American Heart Association. But I think that for the long-term health of our population and preventing this disease that is so difficult to treat when it's firmly established, we have to as cardiologists and as a healthcare system, we have to start by including incentives for reducing healthcare costs to get people to use exercise as part of their personal hygiene and daily life.
Dr. Greg Hundley:
Very nice. Walter, from your perspective, what do you see are the next studies that need to be performed in this sphere of research?
Professor Walter Paulus:
Well, I will be very curious to see how many patients would actually go on to develop HFpEF in their life. It should be as if Ben's hypothesis holds, then the control group probably would have an access development of HFpEF compared to his exercise training group. I think that would really extend to study from above, from a mechanical observation to a clinically, epidemiologically more relevant endpoint. So I think that to me would be the first question, how many patients will evolve to clinical HFpEF.
Professor Walter Paulus:
Second point I would be very intrigued in is, are there SIP groups in the patients who have a positive response to exercise? For instance, what happens with the different ejection fractions? Because we are very intrigued at present in HFpEF that at high ejection fractions nothing seems to work. Sacubitril was notable at high ejection fractions. Empagliflozin was also neutral to ejection fractions. What would happen with exercise? Do the patients who present with the 70% ejection fraction at the angio study, do they still have a positive response? This would be a game change because this would then be the only intervention that is able to cure the HFpEF with high ejection fraction. These are some future projects that come into my mind.
Professor Benjamin Levine:
Let me just add that we have studied and put patients with HFpEF on a yearlong exercise program with not as much effect as we would like. I think that's one of the things that pushed us to getting earlier into the course of HFpEF, as Walter said earlier.
Professor Benjamin Levine:
Ambarish Pandey and Jarett Berry, also from UT Southwestern, of course are very interested in this effect of fitness at different points in the lifespan, our fitness test, for example, measured in mid-life and what means for heart failure later. I think it's hard to do the kind of studies that we do and follow patients for 20 years to see if they're going to develop heart failure, and that's where I think being creative and looking at the studies that incorporate an assessment of fitness and that follow people over time will be very informative. I hope with me, Walter's hope and hypothesis that these patients are less likely to develop HFpEF. We've got to get in there early.
Dr. Greg Hundley:
Very good. Well, listeners, we want to thank Professor Benjamin Levine from UT Southwestern in Dallas and also Dr. Walter Paulus from Amsterdam for bringing us this really interesting study, indicating that in patients with LVH and elevated cardiac biomarkers, sort of the stage B HFpEF that one year of exercise training reduces left ventricular myocardial stiffness.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Miriam Cortese-Krott and Associate Editor Charles Lowenstein as they discuss the article "Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-host I'm Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, today's feature paper is one of those really, really landmark papers that really advance our understanding of Nitric oxide signaling. And it's about red blood cell and Endothelial eNOS, and how they independently regulate circulating nitric oxide, metabolites, and blood pressure. A real, real must, but let's go on and look at the other papers in this issue first. Greg, you want to go first?
Dr. Greg Hundley:
You bet, Carolyn. Better grab a cup of coffee. And my first paper is from professor Nathan Mewton from Hôpital Louis Pradel Hospices Civils de Lyon. Carolyn, these authors hypothesized that Colchicine a potent anti-inflammatory agent may reduce infarct size in left ventricular remodeling at the acute phase of STEMI. And so to address this hypothesis, they performed a double-blind multi-center trial and randomly assigned patients admitted for a first episode of STEMI referred for primary PTCA to receive oral Colchicine two-milligram loading dose followed by 0.5 milligrams twice a day, or matching placebo from admission to day five and the primary efficacy outcome was infarct size determined by cardiovascular magnetic resonance imaging at five days. And the relative left ventricular end-diastolic volume change at three months and infarct size at three months was also assessed by cardiac MRI. And these were secondary outcomes.
Dr. Carolyn Lam:
Nice. Okay. So what were the results?
Dr. Greg Hundley:
Right, Carolyn. So 192 patients were enrolled. 101 in the Colchicine group and 91 in the controls. And as a result of this trial, the oral administration of high dose Colchicine at the time of Reperfusion. And for five days thereafter did not reduce infarct size assessed by cardiac MRI. And so Carolyn, the clinical implications of these results suggest that other studies exploring the timing, pharma kinetics, and dose-response of Colchicine, as well as other anti-inflammatory agents are needed to identify an effective method to reduce infarct size and limit remodeling in this group of patients.
Dr. Carolyn Lam:
Wow, it's just such a rich field done with all this about Colchicine. Well, our next paper is a pre-specified sub-analysis of the randomized EAST-AFNET 4 Trial and the sub-analysis assess the effect of systematic early rhythm control therapy that is using Antiarrhythmic drugs or catheter ablation compared to usual care, which means allowing rhythm control therapy to improve symptoms in patients with heart failure. And this was defined in the sub-analysis as the presence of heart failure symptoms of New York Heart Association status two to three or a left ventricular ejection fraction of less than 50%.
Dr. Carolyn Lam:
Now, the authors led by Dr. Kirchhof at University Heart and Vascular Center UKE in Hamburg, Germany included 798 patients in this sub-analysis of whom 442 had HFpEF, 211 had heart failure with mid-range ejection fraction and 132 had HF-rEF over a median of 5.1 years of follow-up the composite primary outcome of cardiovascular death stroke or hospitalization for worsening heart failure, or for acute coronary syndrome occurred less often in patients randomized to early rhythm control therapy compared with patients randomized to usual care. And this was not altered by heart failure status with an interaction P-value of 0.6. Left ventricular function, symptoms, and quality of life improved equally in both treatment strategies.
Dr. Greg Hundley:
Wow, Carolyn, a lot of information here. So what can we take away from this?
Dr. Carolyn Lam:
Well, let's remember that this is a sub-analysis, albeit pre-specified of that randomized trial of the EAST-AFNET 4 Trial, but nonetheless, the data supports a treatment strategy of rhythm control therapy with Antiarrhythmic drugs or ablation within a year of diagnosing atrial fibrillation in patients with signs and symptoms of heart failure to reduce cardiovascular outcomes.
Dr. Greg Hundley:
Very nice, Carolyn. So, Carolyn, my next paper pertains to Alarmin Interleukin-1 Alpha, and it comes to us from Dr. Thimoteus Speer at Saarland University. So, Carolyn, Alarmin Interleukin-1 Alpha is expressed in a variety of cell types, promoting sterile systemic inflammation. And the aim of the present study was to examine the role of Alarmin Interleukin-1 Alpha in mediating inflammation in the setting of acute myocardial infarction and chronic kidney disease.
Dr. Carolyn Lam:
Wow, sterile inflammation. It's a really hot topic now. So what did these authors find?
Dr. Greg Hundley:
Right, Carolyn. So we're going to call Alarmin Interleukin-1 Alpha. Let's just call it IL-1 Alpha and so increased IL-1 Alpha surface expression on monocytes from patients with acute myocardial infarction in patients with chronic kidney disease was found to be associated with cardiovascular events. Next, IL-1 Alphas itself served as an adhesion molecule, mediating leukocyte-endothelial adhesion, and finally, abrogation of IL-1 alpha prevented inflammation after myocardial infarction and ameliorated chronic kidney disease in Vivo.
Dr. Carolyn Lam:
Wow. So what does this mean clinically?
Dr. Greg Hundley:
Right, Carolyn, so perhaps targeted therapeutic inhibition of IL-1 Alpha might represent a novel anti-inflammatory treatment strategy in patients with myocardial infarction and in patients with chronic kidney disease.
Dr. Carolyn Lam:
Amazing. Thanks, Greg. Well, in today's issue, there's also an exchange of letters between doctors Lother and Filippatos on Finerenone and risk of hyperkalemia in CKD and type two diabetes. There's an On My Mind paper by Dr. Sattler on the single-cell immunology and cardiovascular METs in, do we know yet what we don't know?
Dr. Greg Hundley:
And then Carolyn, from the mailbag, a Research Letter from Professor Wehrens entitled “Atrial Specific LK Beta One Knockdown Represents a Novel Mouse Model of Atrial Cardiomyopathy with Spontaneous Atrial Fibrillation.” Well, Carolyn, how about we turn our attention to those red blood cells and endothelial nitric oxide synthase.
Dr. Carolyn Lam:
Yeah. Can't wait.
Dr. Mercedes Carnethon:
Well, welcome to this episode of Circulation on the Run. Our podcasts, where we have an opportunity to speak with authors of important papers that are appearing in the journal of circulation. I'm pleased to introduce myself. My name is Mercedes Carnethon, professor and vice-chair of preventive medicine at the Northwestern University Feinberg School of Medicine. And I'm pleased today to invite our guest author, Miriam Cortese-Krott, who is the faculty of the University of Duesseldorf, and a guest professor at the Karolinska Institute in Stockholm. And we have with us as well the other associate editor who handled the piece for circulation, Dr. Charlie Lowenstein from Johns Hopkins University. So welcome to each of you this morning.
Miriam Cortese-krott:
Thank you.
Dr. Charles Lowenstein :
Thanks for having me.
Dr. Mercedes Carnethon:
Well, thank you. I'm really excited to jump right into this piece, Miriam, can you tell me a little bit about the rationale for carrying out the study, why you pursued it?
Professor Miriam Cortese-Krott:
The reason is because when I was working as a post-doc, I had to isolate an enzyme from red blood cells, which is a very, very difficult. And if you know, this enzyme is endothelial nitric oxide synthase, which produce nitric oxide, and actually, the red blood cell is full of the worst enemy of nitric oxide, which is hemoglobin. So actually, when I was talking about my project, everybody was asking, "Why are you doing that?" And I was actually able to isolate the enzyme and look at activity and be sure that the enzyme was fine, but the function of this enzyme was absolutely unknown.
Professor Miriam Cortese-Krott:
And the only way to study proteins in red blood cells is to make modification in the bone marrow of the mice. So in the Erythroid cells, because you can not, of course, if there are cells without nucleus you don't have any chance to modify them in culture, something like that. So the only way was to generate mice with modification specifically in the red blood cells. And I had the chance to create, to generate red cell-specific eNOS knockout mice. And of course, as a control endothelial-specific eNOS knockout mice by using the Cre-loxP technology. And with this technology, I could really understand what's happening to the physiology of the mouse if you remove this protein from the red blood cells. And so this was the whole idea.
Dr. Mercedes Carnethon:
Thank you so much. It was really exciting for me to read this piece. We are on opposite ends of the scientific inquiry spread as I'm an epidemiologist who does things at the population level, and you're identifying things at the basic science level. I thought the paper was extremely well-written and that encouraged people to dig in, even if you're unfamiliar, and in part that's because you provided such a great explanation of how your findings are used and how they're relevant to the process. Do you mind sharing a little bit about your findings and how you expect that they will be used by our scientific community?
Professor Miriam Cortese-Krott:
I think the main finding of this paper is that if you remove eNOS from the red blood cells if the mice are hypertensive, have hypertension, and this is completely something that you actually will not expect, as I told you that indeed red cells are full of the enemy of nitric oxide that remove it immediately. So you can ask yourself how it is possible. But I think the key finding here in this paper was that I also generated the opposite model. So I created the model a conditional eNOS Knockout model where you can decide in which tissue you want to have your enzyme. And of course, I applied for red blood cells. And what you see in this model is that you start from a global knockout mouse with hypertension, you reintroduce the eNOS just in the red blood cells, you have normal tension. So this means, this is the main finding. You have a switch in the red blood cells, which is the enzyme eNOS, which it's behaving in a completely different way clearly as compared to the vessel wall eNOS and still regulating blood pressure.
Dr. Mercedes Carnethon:
Well, thank you so much. I think this is the point at which I like to turn to the associate editor who handled the piece. Charlie, you and I don't get to talk as often given the diversity of work that we each pursue, but Charlie, tell me a little bit about what excited you about this piece?
Dr. Charles Lowenstein:
Thanks, Mercedes. So I love this piece. I thought Miriam, your article is so great. So a couple of thoughts. One is nitric oxide and nitric oxide synthase are so important in biology and medicine, nitric oxide regulates blood pressure. It regulates neurotransmission. It regulates inflammation. And this is true, not only in the lab, looking at cells in mice, but also in the human. So genetic variance in the endothelial nitric oxide synthase gene or NOS3 are associated with risks for diseases like coronary artery disease. So eNOS is just so important in biology and medicine. And now some ancient history. When I was a cardiology fellow, about a hundred years ago, I worked in the lab that first purified nitric oxide synthase proteins, and we cloned two of the nitric oxide synthase genes that was in the lab of Dr. Solomon Snyder at Johns Hopkins back in the 1700s.
Dr. Charles Lowenstein:
So when we cloned the nitric oxide synthase genes, when we and others did, we made a huge mistake. We chose the names for these isoforms from the tissue where they were first isolated. So we called the brain nitric oxide synthase nNOS, because it's a neurons, macrophages MCnos we called it MCnos and in endothelial cells, we called it the nitric oxide synthase eNOS or endothelial NOS. But in the last 20 years, lots of investigators have found these isoforms are in other cells, not just the original cells at discovery. And so Miriam's question is just so important, which cells make endothelial NOS also called NOS3. That's the history. Now what Miriam has discovered is just so important. I was so fascinated by her work because as she just said, she made two amazing discoveries. One, red blood cells make endothelial nitric oxide synthase.
Dr. Charles Lowenstein:
And that's been a controversy for a long time. Some people have said, "Yes." Some, "No." And Miriam made the definitive answer. Yes, red blood cells make eNOS, and secondly, she has discovered so much about the physiology of ENO coming from red blood cells, the nitric oxide that's made inside red blood cells regulates blood pressure. What a magical, interesting, and important finding. That's a little bit about the history. Nitric oxide and NOS are important in medicine. The people who originally cloned and purified the nitric oxide synthase isoforms named them after the tissue in which they discovered. And Miriam has made a major discovery that it's not only endothelial cells that make nitric oxide but also red blood cells.
Dr. Mercedes Carnethon:
Thank you so much for that summary. And I guess, I would have thought perhaps this was something of an Elixir of youth because if you've been working in this area for 200 plus years and Miriam, you started working on this as part of your dissertation work, you both have a lot of insight and background on where we've been and what the advances are. Miriam, can you tell me a little bit about how you'd like to see these findings used by the scientific community?
Professor Miriam Cortese-Krott:
I think I would like that the scientific community would use my mice first because I think, as Charles has said, it's not only red cells that express eNOS and it's not only endothelial cells. There are other cells producing eNOS and the function in the other cells is not known even in leukocytes, even when they have iNOS of course, but also have eNOS. So you can use my mice since it's a flux model. You can choose whatever you want, what cell you want, and then knock it in and knock it out. So this is one thing that I think the community could really do. I cannot do everything. So I'm happy to give my mice away.
Professor Miriam Cortese-Krott:
And the second thing is I would like too that in particular, the clinical community would see this link between Emathology and cardiovascular disease. This is something that was started, of course, there are studies looking at anemia and cardiovascular disease, but these studies have sometimes some issues I of course cannot speak as a basic scientist. I cannot speak about huge clinical trials, but I think this link exists and exists at the molecular level and it can be a target for pharmacological therapy. So I think this is what I would like to transport with this study to the clinical community and the basic science community.
Dr. Mercedes Carnethon:
Yeah. I think this is the point at which Charlie, I turn it to you because you really stand at the intersection of both of those communities. What questions do you have for Miriam going forward, as you think about spreading the word on this important work?
Dr. Charles Lowenstein:
So Miriam's discovery is just so important and she now has the tools to help answer really, really important questions. How is nitric oxide made in red blood cells? How is it stored in red blood cells? How is it transported throughout the body in red blood cells? What is the chemistry of nitric oxide, when it is stored, when it combines with oxygen when it forms nitrite and nitrate, how is it released from red blood cells? How is it targeted from a red blood cell to the vasculature? So there're these great basic science questions that Miriam and her colleagues are now poised to answer. So there's the science part of it. Then there's the medicine part of it because Miriam's mice and her great discovery have really huge implications for medicine. And so the question is, how can we use ENO? How can we deliver it? How can we target ENO to human tissues?
Dr. Charles Lowenstein:
How can we turn on erythrocyte, nitric oxide synthase? How can we turn it off? Because there are all these medical diseases where too much nitric oxide is bad, like in sepsis or inadequate amounts, don't protect the vasculature like atherosclerosis. Then there are all these other interesting questions. When we transfuse red blood cells, sometimes if you transfuse aged red blood cells, it's not good. You can harm people. Maybe we can load up or activate eNOS in stored red blood cells and then help deliver more ENO to patients who need red blood cells. So there are all these fascinating medical questions that we can look at based on Miriam's really important discovery.
Dr. Mercedes Carnethon:
Well, thank you so much. We're coming to the end of this wonderful and informative podcast. And I guess, I'd just ask Miriam, do you have anything else you'd like our listeners to know about your work and about the findings from this study?
Professor Miriam Cortese-Krott:
I would like people know that hard work help a lot, and that you have to believe in what you are doing and the quality of your science at the end would bring their true discoveries. So I think it's important specifically, for the young women in science that having this message too. So the science per se must be excellent and to proceed, you need a lot of work, but then the work goes to a good end.
Dr. Mercedes Carnethon:
Miriam, thank you so much for that inspirational note. The hard work that scientists need, the persistence across one's career and building from earlier discoveries, and bringing those forward through one's career are always critically important. And so I hope everyone has really enjoyed this episode and this opportunity to hear from Dr. Cortese-Krott. Miriam, you've done such wonderful work, and thank you as well, Charlie, for your insights about the intersection of this work with clinical care and basic science.
Professor Miriam Cortese-Krott:
Thank you.
Dr. Charles Lowenstein:
Thank you.
Dr. Mercedes Carnethon:
Thank you all very much for joining us today in this episode of Circulation on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first?
Dr. Carolyn Lam:
All right. I got my coffee.
Dr. Greg Hundley:
So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown.
Dr. Carolyn Lam:
Wow. Okay. And what did the current paper do and find?
Dr. Greg Hundley:
Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke.
Dr. Carolyn Lam:
Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample.
Dr. Carolyn Lam:
However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm.
Dr. Greg Hundley:
Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear.
Dr. Carolyn Lam:
So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter.
Dr. Carolyn Lam:
And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use.
Dr. Greg Hundley:
Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1.
Dr. Greg Hundley:
Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations.
Dr. Carolyn Lam:
Oh, okay. And what did the authors find?
Dr. Greg Hundley:
Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling.
Dr Carolyn Lam:
Okay, Greg, that was super summarized but what are the clinical implications?
Dr. Greg Hundley:
Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias.
Dr. Carolyn Lam:
Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection.
Dr. Greg Hundley:
And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.”
Dr. Carolyn Lam:
Nice. Well, let's go on to our feature discussion. Can't wait.
Dr. Greg Hundley:
You bet.
Dr. Mercedes Carnethon:
Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it.
Dr. Mercedes Carnethon:
Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you?
Dr. Sung-Min Cho:
Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study.
Dr. Mercedes Carnethon:
Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you?
Dr. Sung-Min Cho:
Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3.
Dr. Mercedes Carnethon:
Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece.
Dr. Marc Ruel:
Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration.
Dr. Marc Ruel:
Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it?
Dr. Sung-Min Cho:
Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data.
Dr. Sung-Min Cho:
So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through.
Dr. Marc Ruel:
Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD.
Dr. Marc Ruel:
Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events.
Dr. Marc Ruel:
So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera.
Dr. Marc Ruel:
So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this?
Dr. Marc Ruel:
Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found.
Dr. Sung-Min Cho:
Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3.
Dr. Sung-Min Cho:
So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3.
Dr. Mercedes Carnethon:
Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more?
Sung-Min Cho:
Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market.
Sung-Min Cho:
So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah.
Dr. Marc Ruel:
Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team.
Dr. Marc Ruel:
If you still have a minute or two, I had a couple of more secondary questions?
Dr. Marc Ruel
In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this?
Dr. Sung-Min Cho:
Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript.
Dr. Sung-Min Cho:
And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke.
Dr. Sung-Min Cho:
There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications.
Dr. Marc Ruel:
Mercedes, if I'm so allowed, I do have one final comment and question.
Dr. Mercedes Carnethon:
Most definitely. This has been delightful, so yes.
Dr. Marc Ruel:
Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that.
Dr. Marc Ruel:
And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question.
Dr. Sung-Min Cho:
Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not.
Dr. Sung-Min Cho:
We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients.
Dr. Sung-Min Cho:
But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into.
Dr. Sung-Min Cho:
Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent.
Dr. Mercedes Carnethon:
Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it.
Dr. Mercedes Carnethon:
I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Kypros Nicolaides and Associate Editor Karol Watson as they discuss the article "Pravastatin versus Placebo in Pregnancies at High Risk of Term Preeclampsia."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley associate editor, director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
We have a really important feature discussion today. It's on pravastatin versus placebo in pregnancies at high risk of term preeclampsia. Very important condition. And I'm just so glad that we will be discussing this issue, coming right up. But first, I want to start on the other papers in this issue. And this first study, which is the first study to assess the effects of aerobic exercise training with and without caloric restriction on changes in the proximal aortic stiffness using cardiovascular magnetic resonance imaging. Now the corresponding author is Dr. Brinkley from the Sticht Center of Healthy Aging and Alzheimer's Prevention in Wake Forest School of Medicine. But guess what? Our very own Dr. Greg Huntley is a co-author. So whether you know it or not, Greg, we're going to do a mini feature, right now. So Dr. Huntley, could you please give us some background to your study, it's so cool?
Dr. Greg Hundley:
Oh, Carolyn, thank you so much. It's quite a privilege to be, actually being interviewed by you. So about the paper. Aortic stiffness is really a prominent manifestation, as we know, of vascular aging. And it's an independent predictor of cardiovascular events and mortality. And risk factors such as hypertension, diabetes, obesity, they can promote vascular changes that lead to accelerated vascular aging. Now, on the other hand, lifestyle factors such as healthy diet, regular physical activity, they may attenuate age related increases and aortic stiffness.
Dr. Greg Hundley:
And both cross-sectional and longitudinal studies indicate that exercise is associated with lower aortic stiffness. However, some data suggests exercise alone may not be sufficient to improve aortic stiffness in certain subpopulations of older adults. And so what Tina did, she worked in combination with all the co-authors and determined the effects of aerobic exercise training, with and without moderate to high caloric restriction on the structure and function of the proximal aorta in a 160 older, so 65 to 79 year old men and women with obesity that had a body mass index of 30 to 45 kilograms per meter square.
Dr. Carolyn Lam:
Wow. Okay, cool. But how do you assess this by MRI? Isn't that part of the novelty of the study, right?
Dr. Greg Hundley:
Right, Carolyn. So kind of two ways magnetic resonance imaging assesses aortic stiffness. First is to look at the distensibility. What is this distensibility? That's the change in the area of the aorta, relative to the distending pressure. And you can't measure that distending pressure noninvasively. So what we do is use a surrogate, your cuff pressure at your brachial artery. So that's one measure. Area change divided by basically the pulse pressure indexed for the resting area. And the second is pulse wave velocity. And for the listeners, remember pulse wave velocity, the faster the blood moves around through the aorta, the stiffer the artery is. And so we measured both aortic distensibility and pulse wave velocity.
Dr. Carolyn Lam:
I love it. You're such a good decentral educator. Okay. So what are the results real quick?
Dr. Greg Hundley:
Thanks Carolyn. So there were significant treatment effects for descending aortic distensibility and strain. And aortic arch pulse wave velocity with the aerobic exercise training plus the moderate caloric restriction group, having a 21% increase in distensibility, and an 8% decrease in pulse wave velocity. And none of the aortic stiffness measures changed significantly in the aerobic exercise training. Only, or in the aerobic exercise training plus very intensive caloric restriction.
Dr. Carolyn Lam:
So how do you put that all together? What does this mean for us clinically?
Dr. Greg Hundley:
Right, Carolyn. So I think the findings that Tina and everyone here in this group are showing, they suggest that exercise alone, that is in the absence of significant weight loss, has minimal effects on proximal aortic stiffness in older adults with obesity. Second, although obesity likely blunts the beneficial effects of regular aerobic exercise on aortic stiffness in older adults, these data support a growing number of studies indicating that intentional weight loss can be safe for older adults with obesity. And then finally, Carolyn, the addition of moderate caloric restriction appears to maximize improvement in aortic stiffness. Whereas higher intensity caloric restriction may not be necessary or even really advised. And that has important indications for weight loss recommendations to improve cardiovascular disease risk among older adults.
Dr. Carolyn Lam:
Oh, wow. Thanks Greg. And congratulations to you and your co-authors on this beautiful paper. Well, in the next paper, we switch to the preclinical world and I'm going to tell us about the WW domain containing E3 ubiquitin protein ligase 1. And I'm not going to be able to say that again. So I'll call it WWP1. We know that this is an important regulator of aging related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload induced cardiac remodeling and heart failure is yet to be determined. So this next paper looks at that with co-corresponding authors, Dr. Li and Ling from the State Key Laboratory of Space Meds and Fundamentals and Application, China Astronaut Research and Training Center in Haidian district in Beijing. Now the authors use WWP1 Knockout Mice, and adeno associated virus, serotype nine, carrying cardiac troponin T promoters driven by small hairpin RNA targeting WW1. And in these special mice, found that WW1 regulated cardiac hypertrophy induced pressure overload by stabilizing disheveled segment polarity proteins, or DVLs.
Dr. Greg Hundley:
Carolyn. So disheveled segment polarity proteins. So what are those?
Dr. Carolyn Lam:
Well, the DVLs, which include DVL one, two, and three are important cytoplasmic mediators, involved in canonical and non-canonical WNT signaling. And these are pivotal in cardiac remodeling. The authors demonstrated that WWP1 interacts with DVL2, and stabilizes it through an atypical ubiquitin type modification. And thus WWP1 has the potential as a therapeutic target for cardiac hypertrophy and heart failure.
Dr. Greg Hundley:
Excellent, Carolyn. Boy, what a fantastic summary. Well, my next paper comes from Dr. Zhao Wang from University of Texas Southwestern Medical Center. And Carolyn, as we know, metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. And the elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, it's role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully understood. And so these authors aim to dissect the role of cardiac pyruvate kinase muscle iso enzyme 1 in glucose metabolic regulation and cardiac response under pressure overload.
Dr. Carolyn Lam:
Oh. Wow. So what were the results?
Dr. Greg Hundley:
Right, Carolyn. So they found that pyruvate kinase muscle iso enzyme 1, so let's call that PKM1 expression, is reduced in failing human and mouse hearts. And importantly cardiomyocytes specific deletion of PKM1 exacerbated cardiac dysfunction and fibrosis in response to pressure overload. Now inducible over expression of PKM1 and cardiomyocytes protected the heart against TAC induced cardiomyopathy and heart failure. And at the mechanistic level PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration and ATP production under pressure overload. And furthermore deficiency of PKM1 caused a defect and cardiomyocytes growth and a decrease in pyruvate dehydrogenase complex activity at both the in vitro and in vivo levels. So, Carolyn, in summary, these findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.
Dr. Carolyn Lam:
Oh, nice, Greg. Well, let's go on to what else is in this issue? There's a Research Letter by Dr. Aguib on a new variant with a previously unrecognized mechanism of pathogenicity in hypertrophic cardiomyopathy.
Dr. Greg Hundley:
And, Carolyn, I've got three papers. First, there's an ECG Challenge from Professor Gunnaseelan [Rajendran], “Not All Waves Are Factual.” There's a nice On My Mind piece from one of our associate co-editors Torbjørn Omland entitled “Cardioprotective Therapy in Cardio-Oncology: Quo Vadis?” And finally, there's an In-Depth article from Dr. Brilakis entitled the “Saphenous Vein Graft failure From Pathophysiology to Prevention and Treatment Strategies.” Well, Carolyn, how about we head off to the feature discussion, and learn a little bit more about pravastatin versus placebo in pregnancies at high risk of term pre-eclampsia.
Dr. Carolyn Lam:
Let's go.
Dr. Mercedes Carnethon:
Well, welcome to Circulation On the Run. I'm pleased to be one of your hosts today. My name is Mercedes Carnethon. I'm an epidemiologist and professor at the Northwestern University's Feinberg School of Medicine, and one of the associate editors of the journal. I'm really excited to participate in the podcast today with our featured guests. We have a paper led by Dr. Nicolaides, Kypros Nicolaides, from the University of Exeter in the United Kingdom. And we have the associate editor, Dr. Karol Watson, who handled the piece for the journal.
Dr. Mercedes Carnethon:
So I'm really pleased to have each of you with me today and good morning.
Dr. Karol Watson:
Good morning. Thank you for having us.
Dr. Mercedes Carnethon:
Well, thank you. So why don't we jump right in? So the title of today's piece is pravastatin versus placebo in pregnancies at high risk of term preeclampsia. A really exciting read that I think provides important insights to us as well as emphasizes what we can learn from negative trials and negative studies. And so I'll jump right in and rather than me providing a summary, I'll turn it over to you. Kypros. Tell me a little bit about your inspiration for carrying out this work and why you pursued this topic.
Dr. Kypros Nicolaides:
Thank you. Well, preeclampsia is one of the major causes of death and handicap for the mother, and the fetus, and the baby. We have been trying for many decades to develop a method of identifying a high risk group of women that would develop preeclampsia. And we succeeded in doing so. And five years ago, we carried out a major trial at 12 weeks where we gave aspirin to the high risk group. And that study was very successful. We managed to reduce the rate of preterm pre-eclampsia by about 60%. And it was published in the New England Journal of Medicine.
Dr. Kypros Nicolaides:
However, screening at 12 weeks was not very effective in identifying women that deliver with pre-eclampsia term. And aspirin was not effective in preventing term preeclampsia and although preterm preeclampsia individually has more serious complications than term preeclampsia. Because three quarters of preeclampsia happen at term, the overall contribution of term preeclampsia is actually higher than that of preterm preeclampsia.
Dr. Kypros Nicolaides:
So that was the rationale, the background of having to do something to first identify the high risk group for term preeclampsia. And secondly, see whether we could do something to prevent it. So we, in this study involving about 30,000 women carried out in several hospitals in England, essentially, and Belgium, we screened at 35 to 56 weeks. We identified that 10% of the population at high risk. And then we randomized 1,120 women in trial with pravastatin 20 milligrams against placebo. Why pravastatin? Because a study from the United States by Constantine in a preliminary study, 10 women that were randomized to try the pravastatin or placebo starting from 12 weeks showed extremely promising results. So pravastatin studies are very commonly used for the treatment or prevention of hypertensive disease outside pregnancy preeclampsia and hypertensive disease are very closely related. So we felt that perhaps pravastatins given at this late stage would prevent the development of preeclampsia. Unfortunately, we found that that was not the case.
Dr. Mercedes Carnethon:
You know, your final point, there is one that we often lecture about and talk about with students. What do you do when you have a negative trial? I noticed that you said, unfortunately, you found that wasn't the case. But tell us about the value of the negative trial. I think part of the reason why this is so compelling and important is you may have ruled something out. So tell us a little bit about your findings. Did they surprise you? What do you make of them?
Dr. Kypros Nicolaides:
I can divide the findings into two, Mercedes. Firstly, the ability to screen in a multicenter study using our method, it was a method of validating our previous model. And we had found that we could identify 75% of the women that would develop term preeclampsia for a screen positive rate of about 10% and I think that that was very important. And I think that Karol Watson that was editing and dealing with the article identified that as being an important component of the article. And to me, that is very much so. We found, we have now a method of identifying a very high proportion of women that will develop term preeclampsia.
Dr. Kypros Nicolaides:
We failed. The drug, it was disappointing. But we have a background method with which we can identify the high risk group to try new methods of intervention that perhaps would be helpful. I think that I will have, in a sense, great success with aspirin in the first semester. And to a great extent, elimination of preterm preeclampsia forced us to move with optimism of preventing term preeclampsia. But perhaps giving pravastatin starting from 35, 36 weeks was perhaps too late. We should have perhaps started giving treatment before that. But we couldn't be because we did not have a good method of identifying the high risk group. So as far as I am concerned, we learned that pravastatin is unlikely to be beneficial, even if we try it every year, because we cannot identify the high risk group.
Dr. Karol Watson:
I'm so sorry for interrupting, but I just -
Dr. Kypros Nicolaides:
I'm glad you did.
Dr. Karol Watson:
This was such an important trial in so many respects. I think you under sell it a little bit. This was phenomenal to be able to identify this high risk group. As you say, just phenomenal. You know, 35,000 women screened, identifying this high risk group, and then to do a randomized trial of statin therapy in pregnancy. That is landmark. That was really very, very prescient, thoughtful, and really important to study. And I'm so grateful that you guys did.
Dr. Kypros Nicolaides:
Carol, thanks very much for your kind words and for accepting our paper for publication. Thank you.
Dr. Mercedes Carnethon:
You know, Kypros, this is really exciting. And I'm glad that you jumped in, Carol. You know, it stands out to me that part of why I will love having this as a potential paper to add to cases where we teach people, how to understand, how to carry out a study and how to respond when your primary hypothesis isn't born out. However, even if your primary hypothesis wasn't born out, you did learn something. And it sounds as though you learned a strategy to identify high risk individuals. And it is informing your next steps in your next study. Carol, you are obviously very involved. It was great to hear your feedback. What are your thoughts about what the lessons are for the practicing cardiologist?
Dr. Karol Watson:
Well, there are several that I took away from this. One is, I mean, I think building on your prior work with aspirin, that was landmark. As you know. And the first time we actually had a viable therapy for preventing preeclampsia. So we can prevent preeclampsia. That's the really important thing that we found out. And then there was a really good theoretic basis for thinking pravastatin might work. I mean, the rationale for this study was so solid and so important. I think the timing issue is, I think it's still an answered whether treating with pravastatin earlier might've helped. I don't know.
Dr. Karol Watson:
But again, we'd have to be able to identify people at risk, which is what your group is so good at doing. But I also think it was brave and very important that you guys decided to treat pregnant women with statin therapy. As you know, there was an FDA contra-indication to that until about a week ago when they removed, or a month ago when they removed it. So you guys had to say, we have the data, we know this seems to be safe, certainly in this time period, and we want to do this. And that was a really important thing to do. This is just such a rare and important trial. The randomized controlled trial of statin therapy in pregnancy. We just don't see that. You guys are groundbreaking
Dr. Kypros Nicolaides:
And, Carol, on that point for those that are still, I know that in the United States, people are planning new trials, starting from the first trimester. But as you said, they were stopped by the FDA. We provided further evidence of the potential safety of the drug. It was not published in the journal, but as part of the trial, we were collecting from some women cord blood. And it had shown that there were no adverse biochemical events. And also there were no significant differences in adverse events between the placebo and the pravastatin group. So in that respect, it is a good starting point to encourage those that want to do studies everywhere only in pregnancy.
Dr. Karol Watson:
So important, so important.
Dr. Mercedes Carnethon:
Thank you so much, Kypros. And I'm really excited that we're featuring this in Circulation On the Run because it means that we can get word out beyond our core audience of cardiologists. This is really an important piece as well for the obstetrician gynecology community to hear about given the steps that they will, how they'll consider using these data. Certainly, and you both touched on a really important point, which is that it isn't as common that we do intervention studies in vulnerable groups and protected groups. And pregnant women typically are. You enrolled 1,100 people into this trial. That is really impressive. Can you share with our audience a little bit, to the extent, a little bit about that process. How did you convince the team of the safety and were women enthusiastic and how did they respond? I look forward to using your responses to discuss with my trainees, how we go about carrying out this important work.
Dr. Kypros Nicolaides:
One of the issues about trials, Mercedes, is to have the background method of identifying a high risk group. In the United States, unfortunately, there is no method of routine screening in pregnancy during the first trimester. In very few cultures, if I take ultrasound scanning, for example, a few decades ago I was instrumental in introducing a 12 week scan. Because I have noticed that increased nuchal translucency is a marker of chromosomal abnormalities and so on. And that created a 12 week routine assessment in many countries of the world. It was at the back of that assessment that we introduced first trimester screening for preeclampsia. That led to the aspirin trial and the successful results of prevention. We have pioneered, in my hospital, the series of hospitals that I have under my influence, because they are run by ex research fellows of mine, a routine 36 weeks scan in pregnancy.
Dr. Kypros Nicolaides:
I call three scans in pregnancy important. One at 12 weeks, we find out whether the woman is truly pregnant or not, whether she carries one baby or not, whether the babies are generally all right. Whether we can screen at that point for chromosomal and other abnormalities, and now screening for preeclampsia. At 20 weeks scan, where we look for the fetal anatomy again, and then the development of the baby. In the third trimester scan, which I call it the delivery scan. At 36 weeks, we can tell whether the baby is developing normally or not. Whether the baby's in the right position cephalic or breach. And now whether the baby's too big or too small. And now whether you can identify they're high risk group for preeclampsia. So you need that background of routine screening of the whole population. And then of course we are quite experienced in recruiting women into our studies.
Dr. Kypros Nicolaides:
I deliberately call my center—although it is a routine, national health center institution—I call it an institute of research in fetal medicine. The ideology of the center is research. There are so many things that we do not know. And women have understood the value arriving in a research institute. They accept the ideology that if you participate in research, you will benefit or others will benefit or you will benefit your next pregnancy. So I think a successful recruitment into trials is the projection that you have a center that is actively being involved in research. And research is an integral part of providing a good clinical service. That's all I can say as a general point.
Dr. Mercedes Carnethon:
That is wonderful. You know, Kypros, I've really appreciated the time you spent with us. And I just want to end by calling on my colleague, Carol. Any final words or comments as we wrap up today?
Dr. Kypros Nicolaides:
I just thought from soup to nuts, beginning to end, this study was so informative and illustrative. We were able to, thanks to you and your group, Kypros, to understand that you can identify this high risk group. That you can treat pregnant women with statin therapy, with safety. And that you can get information out of a neutral study. And I just think all of those are so important and I am really looking forward to your next step. Because I think your group has just been groundbreaking in so many levels.
Dr. Mercedes Carnethon:
Well, thank you so much, Kypros, Carol. I think we've had a really exciting discussion this morning and our listeners from the cardiology community, to even the more broad research community, and the OB GYN community have learned a great deal from your work. So this is Mercedes Carnethon, one of the associate editors at Circulation and the happy host of the Circulation On the Run podcast. So thank you very much.
Dr. Karol Watson:
Thanks so much.
Dr. Kypros Nicolaides:
Thank you.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also wish everyone a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.
This week's episode features special Guest Host Victoria Delgado, as she interviews author Qiang Zhang and Greg (who was the editorialist and handling editor) as they discuss the article "Towards Replacing Late Gadolinium Enhancement with Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohost. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. And Carolyn, this week's feature actually is a magnetic resonance imaging paper, which you know, of course, I'm very fond of. And these authors have come up with a new methodology to get information equivalent to a late gadolinium-enhanced exam without administering gadolinium. But before we get to that feature discussion, how about we start in with some of the other articles in this issue?
Dr. Carolyn Lam:
Yep.
Dr. Greg Hundley:
Well, how about if I go first? So Carolyn, the first paper I'm going to discuss is from Dr. Paul Welsh from the University of Glasgow, and it pertains to abdominal aortic aneurysms, which you know can occur in patients who are ineligible for routine ultrasound screening. A simple abdominal aortic aneurysm risk score was derived and compared to current guidelines used for ultrasound screening of abdominal aortic aneurysms.
Dr. Greg Hundley:
And so, this study comes to us from the UK Biobank, and they examined participants without previous, and let's just abbreviate this as AAA or AAA. So without previous AAA, we're split into a derivation cohort of 401,820 individuals, and a validation cohort of 83,000 individuals. An incident AAA was defined as a first hospital, inpatient diagnosis of AAA, death from AAA, or a AAA-related surgical procedure. And, of course, they used multivariable Cox models to develop the derivation cohort, and then apply that to the validation cohort.
Dr. Carolyn Lam:
Wow, Greg, that is a large number of people, the power of the UK Biobank, huh? So, what did they find?
Dr. Greg Hundley:
Right. So, Carolyn, components of the AAA risk score were age, stratified by smoking status, weight, stratified by smoking status, any hypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and then diabetes.
Dr. Greg Hundley:
So, Carolyn, in the validation cohort, over 10 years of follow-up, the C index, for the model for the USPSTF guidelines, was 0.705, whereas, the C index of the risk score as a continuous variable was 0.856. And in the validation cohort, the USPSTF model yielded a sensitivity of 63%, and a specificity of 71%.
Dr. Carolyn Lam:
Okay, Greg, but what's a take-home message?
Dr. Greg Hundley:
Right, Carolyn. So the take-home message is that in an asymptomatic general population, a risk score based on patient age, height, weight, and a medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. And also, these results highlight that further development and validation of risk scores to detect asymptomatic AAA are needed.
Dr. Carolyn Lam:
Wow, and that was a great summary with a lot more data in the article, huh? Let's refer the readers to it. But for my paper, it highlights the key role of histidine triad nucleotide-binding protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy.
Dr. Greg Hundley:
Wow. Carolyn, so tell me a little bit more about HINT 1.
Dr. Carolyn Lam:
I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton protein that belongs to the histidine triad super family. It was previously shown to play a role in diverse neuropsychiatric diseases. Loss of HINT 1 increased susceptibility to carcinogenesis in mice, suggesting, as well, a tumor suppressor role. So recently, HINT 1 has emerged as a tumor suppressor with multiple molecular mechanisms, involving regulation of apoptosis, gene transcription, and cell cycle control.
Dr. Carolyn Lam:
Now, with that as a background, today's paper from co-corresponding authors Drs. Ji, Xie and Han, from Nanjing Medical University, used animal models and cell models of hypertrophic growth, and found that HINT 1 deficiency aggravated overload-induced cardiac hypertrophy and fibrosis and deteriorated cardiac dysfunction in mice, whereas, cardiac-specific HINT 1 over-expression attenuated cardiac hypertrophy, and rescued cardiac dysfunction.
Dr. Carolyn Lam:
Furthermore, the more the authors uncovered Homeobox A5, or Hox A5, as a HINT 1 target gene, which contributed to hypertrophy through activating the TGF beta signal pathway. Combined, these findings demonstrate HINT 1 may be a prognostic biomarker, and this may establish a foundation for future investigation of its potential as a therapeutic target for cardiac hypertrophy and heart failure.
Greg Hundley:
Great, Carolyn. So, we get a hint for future cardiac hypertrophy.
Dr. Carolyn Lam:
Hahaha.
Dr. Greg Hundley:
Couldn't resist.
Dr. Carolyn Lam:
Bravo.
Dr. Greg Hundley:
Couldn't resist. So, Carolyn, my next paper comes to us from Dr. Mark Gladwin from the University of Pittsburgh. And, as you know, many patients with one of your faves, heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension. Now, increases in pulmonary vascular resistance, in patients with HFpEF portend a poor prognosis. This phenotype is referred to as combined pre- and post-capillary pulmonary hypertension.
Dr. Greg Hundley:
And therapeutic trials of exercise-induced pulmonary hypertension, and pre- and post-capillary pulmonary hypertension, have been disappointing, suggesting the need for strategies that target upstream mechanisms of the disease. And so, this work reports novel rat exercise-induced pulmonary hypertension models and mechanisms of pulmonary vascular dysfunction, centered around the transcriptional repression of the soluble guanylate cyclase enzyme in pulmonary artery smooth muscle cells.
Dr. Carolyn Lam:
Ooh, so much of this is of interest to me, from HFpEF to soluble guanylate cyclase. Ah, all right, so what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So, in the HFpEF and in the pre- and post-capillary pulmonary hypertension models, metabolic syndrome contributed to pulmonary vascular dysfunction and exercise-induced pulmonary hypertension through enhanced reactive oxygen species and MIR193B expression, which downregulates NFYA-dependent soluble guanylate cyclase beta-1 expression, and adenovirus mediated NFYA over-expression and SGLT-2 inhibition restored NFYA soluble guanylate cyclase beta-1 cyclic GMP signaling, and ameliorated exercise-induced pulmonary hypertension.
Dr. Greg Hundley:
So Carolyn, after all of that, these results uncover a molecular explanation for the unsolved clinical associations linking metabolic syndrome with exercise-induced pulmonary hypertension in patients with pre- and post-capillary pulmonary hypertension, as well as HFpEF.
Dr. Carolyn Lam:
Wow. That is super, Greg. Thanks. Now, other articles in today's issue include a research letter by Dr. Schunkert on identification of a functional PDE5A variant at the chromosome 4q27 coronary artery disease locus in an extended myocardial infarction family.
Dr. Carolyn Lam:
There is a policy front paper by Dr. Lackey on applying decision analysis to inform FDA's benefit risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke, based on the THEMIS trial. There's an exchange of letters between Drs. Olson and Reiffel regarding the article emulating randomized controlled trials with non-randomized real-world evidence studies, the first results of the RCT Duplicate Initiative.
Dr. Greg Hundley:
Great. Carolyn. Well, I've got two other papers. There's an ECG challenge from Professor Macherey entitled, Wide QRS complex bradycardia in a hemodynamically unstable young woman. And then, finally, one of our nice perspective pieces from Dr. Armstrong entitled, Extending the product label for ticagrelor: Looking under the FDA hood. Well, Carolyn, now we're going to learn a little bit more about that non-contrast method of MRI to get, maybe, the equivalent to late gadolinium enhancement in patients with hypertrophic cardiomyopathy.
Dr. Carolyn Lam:
And all by AI. Very, very cool. All right, let's go.
Dr. Victoria Delgado:
Hello, I'm Victoria Delgado, associate editor of Circulation, and working at the University Medical Center, and I have the privilege to welcome Dr. Zhang from the University of Oxford, division of cardiovascular medicine, and first author of the article published in Circulation, which presents a new technology that has the potential to change our clinical practice, and how do we assess myocardial tissue characteristics, particularly fibrosis with cardiac magnetic resonance.
Dr. Victoria Delgado:
With us, we have also Dr. Greg Hundley from VCU Pauley Heart Center, associate editor of Circulation, and host of Circulation on the Run and editorialist of this article. And Greg has handled this article in the review process and guided Dr. Zhang and coworkers to finally get a very impactful, in my opinion, and novel paper that has the potential to change clinical practice. He will help us to put in perspective the main message of this article. But first, Dr. Zhang, why don't you tell us briefly, what is this new technology for myocardial tissue characterization with cardiovascular magnetic resonance, and why did you develop it?
Dr. Qiang Zhang:
Well, first, I want to say thank you very much for the invitation. Well, as we know, CMR late-gadolinium enhancement, or LGE, has been the imaging gold standard for micro tissue catheterization. However, LGE requires the injection of a contrast agent, which prolongs the scan, increase the cost, and is cautioned in some patient groups. It is therefore desirable to develop a contrast-free technique to replace LGE. A native or pre-contrast CMR such as cine imaging, T1-mapping and the T2-mapping are alternative means for myocardial tissue characterization without the need for contrast.
Dr. Qiang Zhang:
And notably, T1-mapping can detect a wider range of pathology, but its clinical application is hindered by confounding factors and a lack of clear interpretation. So we thought that since MRI is inherently multimodal and multiparametric, with different modalities reflecting complimentary information about micro tissue, therefore can we use the ones of an AI method to combine the enhanced pre-contrast and modalities to produce a virtual LGE image without the need for contrast, and this leads to our concept of CMR virtual native enhancement.
Dr. Victoria Delgado:
Excellent. And in which population did you evaluate this technology? Why did you choose? So, can you tell us a little bit the characteristics of the population where you choose to assess the performance of this new technology?
Dr. Qiang Zhang:
Yes, so we validated this concept first on the hypertrophic cardiomyopathy patients using the image data from HCMR study, which is a larger multinational study. We trained the new network models on about 2,700 images, and then we tested independently on 124 patient materials.
Dr. Victoria Delgado:
And what were the results? Can you summarize them for us to understand what you found, how you evaluated the performance of this new technology compared to classical late gadolinium enhancement?
Dr. Qiang Zhang:
Yeah. So, we found that first, the VNE image had significantly better image quality than the traditional LGE, and the secondly, the VNE revealed characteristic HCM lesions in hypertrophic segment and added the anterior and the inferior right ventricular insertion point, and those VNE lesions were in high visual spatial agreement with the lesions detected by LGE. And thirdly, VNE correlated strongly with LGE in quantifying hyperintensity, micro lesions, but also more subtle intermediate-intensity lesions as often observed in the HCM patients.
Dr. Victoria Delgado:
Exciting. And now I would like to turn to Greg. You are a renowned expert on CMR. What did this article attract you? What were the main findings that you found interesting in this article?
Dr. Greg Hundley:
Yes. Thank you so much, Victoria. And just first, before I get started, I wanted to thank Zhang for sending us this work, and his entire team really spanning several institutions around the globe. Victoria, I want to thank you for leading this discussion. And Victoria, we work as a team looking at imaging, and what's very impressive is this caught multiple of us on the imaging team, but also the editorial board. So want to thank you Victoria. And then, finally, I want to thank Dr. Charlotte Manisty and Jennifer Jordan who helped with the editorial.
Dr. Greg Hundley:
So, just to take a little bit of a step back in the year 2000, Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern University, in Chicago, administered gadolinium contrast. It's an extra cellular agent and they were examining myocardial perfusion, and then they noticed if they took images 10 or so minutes after that administration, they appreciated this late enhancement of the myocardial tissue that was associated with two things, one myocardial injury, and then, also, scar formation.
Dr. Greg Hundley:
And for the last 21 years, that technique has been very valuable in assessing infarct size in those with ischemic cardiomyopathy, and then also recognizing extracellular fibrosis or forms of myocardial injury in a variety of non-ischemic cardiomyopathy processes. And one of those is hypertrophic cardiomyopathy. And so, Zhang and his group have been working on a technique that did not utilize gadolinium anymore. And they based this on, really, had two important features.
Dr. Greg Hundley:
One is, some examination of the T1 relaxation that's available when you acquire magnetic resonance images, and then also applying artificial intelligence to analysis of these images. Those two factors allowed this investigative team to produce images that are very similar to what we appreciate with gadolinium enhancement in patients with hypertrophic cardiomyopathy. And why is that significant? So administration of gadolinium, we think about two things, again, that are an issue with that.
Dr. Greg Hundley:
Well, one, we've got to give the contrast agent, and some patients are not well-suited. If you have renal dysfunction, you can develop nephrogenic systemic fibrosis, a scleroderma-like syndrome when the gadolinium is not cleared, and it's stays in your body a long time. The other thing we tend to worry about much more recently was accumulation of gadolinium in the brain stem. We don't know that that has an adverse effect, but we're certainly aware of it.
Dr. Greg Hundley:
And finally, I guess there is a third point. There are a few patients, one in 20 to 40,000 that have allergic reactions. So, for all those patients that really can't get gadolinium, this is another potential opportunity moving forward. The second point is time. So during an MRI scan time, or process, we administer the gadolinium. And remember what I said, we've got to wait about 10 minutes to then collect these images. Well, if you can have a technique where you don't have to administer gadolinium, you get the same administration and you don't have to wait that 10 minutes, we might be able to save a large amount of time. And you say, well, 10 minutes, what does that mean?
Dr. Greg Hundley:
But if you're doing many patients during the day, that really could equate to a big time-savings. So what attracted us to this article? A technical innovation that perhaps may obviate the need for the administration of gadolinium in many cases, and here in these patients with hypertrophic cardiomyopathy, I think the images were quite stunning in that they appreciated the extent of the fibrosis and scar in patients with hypertrophic cardiomyopathy to the same degree, and maybe even with higher image quality than we had in the gadolinium-enhanced comparitors.
Dr. Victoria Delgado:
Yeah. I agree with all those comments, indeed. For these 20 years, there have been other developments, in terms of assessing diffuse fibrosis with T1-mapping techniques after administration of gadolinium, but also before administration of gadolinium. And this technology Dr. Zhang and co-workers have shown actually reduces the time of acquisition because you only need 15 minutes to acquire the cine images and the T1 images. And the analysis is not very long in terms of post-processing, because it's also very short. As seen the paper was indicated.
Dr. Victoria Delgado:
And as you said, the administration of gadolinium enhancement is not free of potential risks. And in these patients, for example, we have hypertrophic cardiomyopathy that can undergo repetitive evaluations during follow-up. The use of this imaging technique can help to reduce the exposure to gadolinium enhancement.
Dr. Victoria Delgado:
Now, the question for you, Qiang, will be, what are the next steps for you and your team to further develop this technique, to further convince the community to implement this technique in clinical practice, and that can have an impact in our management of these patients with hypertrophic cardiomyopathy, or with other patients on whom we also evaluate the presence of myocardial fibrosis?
Dr. Qiang Zhang:
Thank you, Victoria. And thank you Greg, for the very insightful comments. So we think that the immediate future work would be to validate the VNE HCMR study clinical outcomes as a potential new contrast-free biomarker for HCM patients. And in the meantime, we are working on extending the method to other pathologies, particularly myocardial infarction, for viability assessment.
Dr. Qiang Zhang:
And we also think that the concept of AI virtual contrast agent maybe apply it to other post-contrast images, such as early gadolinium enhancement and extracellular volume refraction mapping, or even, maybe, first perfusion. And also in collaboration with MR vendors, we plan to implement VNE as inline sequence on the scanner to display lesions immediately after the pre-contrast cine and the T1-mapping acquisitions.
Dr. Victoria Delgado:
Very interesting. And Greg, another group of patients, for example, that I'm thinking of where this technology can be very helpful, and you have expertise on this, are patients undergoing treatment with chemotherapy, what we need to address, for example, or to evaluate the presence of cardiac toxicity. Would you see in this population the value of this technique, or how do you see the future of these technique in clinical practice?
Dr. Greg Hundley:
Yeah. Great questions, Victoria. I think probably five things and many of those Qiang has already just brought up. One, with the current study, it's going to be great to follow these patients over time and look at the outcomes. What did amount, presence, location of the findings with this new technique, how did they equate to outcomes in patients with hypertrophic cardiomyopathy? So we're going to anxiously await that.
Dr. Greg Hundley:
I think once we move out of the current study, thinking about other vendors, using this and acquiring images from General Electric and Phillips, and multiple vendors around the world and multiple field strengths, how do we going to understand the findings there? I think another particular issue will be different diseases as Qiang ha said, ischemic cardiomyopathy. Well, what about amyloid? Victoria, you've mentioned using the other possibility here is, can this technique help us produce something similar to extracellular volume fraction measures? And could that be used to identify interstitial disease processes?
Dr. Greg Hundley:
And, for example, as you mentioned, the fibrosis that's associated with the administration of certain chemotherapeutic agents or radiation therapy. I think another thing is, Qiang, can we go back and use retrospectively-collected data? Can your technique be modified so that many of the studies that have been performed in the past, large population studies, like Mesa or a Framingham or Jackson heart study, and could we use that to develop forecasting and algorithms moving forward?
Dr. Greg Hundley:
And then, lastly, I think as you mentioned, the artificial intelligence component of what you've described and how's that can compare when Victoria and I look at the images, and could we get into combining reads from one institution, reads from another, reads from another, tracking outcomes? And so, when a patient comes in and has a study performed, your artificial intelligence, not only does it read that study and highlights the increased signal in the myocardium, but then goes and looks at outcomes across multiple sites, and what would that mean for a given patient with a different condition? So, oh my goodness, the horizon is just so expansive here. The future is very bright. And just to congratulate you on, I really think this could be another landmark technical innovation, so fantastic work.
Dr. Victoria Delgado:
Indeed. Thank you very much, Greg, for all these insightful comments and these perspectives that we have in the future, particularly with the use of this technique in retrospective studies in large cities, that where we can develop these algorithms. And I would like also to thank Qiang for submitting your article to Circulation, for giving us the opportunity to present this new technology and make this article, like the landmark article, where there will be many other articles to follow. We hope that you also choose us.
Dr. Victoria Delgado:
But with this, I would like to thank both of you, Greg and Qiang, for the excellent discussion that we have had in this new technology, based on artificial intelligence, that can identify myocardial fibrosis without the use of gadolinium enhancement, that maybe by now will be obsolete in the future, and that can impact on how we do our clinical practice. Many thanks to all of you and happy to discuss in the future other articles.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also, wish everyone a great week. And we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features author Philippe Gabriel Steg and editorialist Gregg Stone as they discuss the article "International Observational Analysis of Evolution and Outcomes of Chronic Stable Angina: The Multinational Observational CLARIFY Study."
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore here with my other co-host, a little bird that you can hear I think in the background and then my real co-host, Greg.
Dr. Greg Hundley:
Thanks so much, Carolyn. Yes, I'm Dr. Greg Hundley. I'm not the bird this week. Associate editor, director of the Pauley Heart Center in Richmond, Virginia. Carolyn, so this week, our feature discussion is really going to be on the importance of stable angina and what that means prognostically. But before we get to that, how about we grab a cup of coffee, talk to our other bird friends and then we jump in and talk about the other papers in the issue. Would you like to go first?
Dr. Carolyn Lam:
Love it, Greg. Thank you so much. This first paper, very important question. We know that while the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It's still unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. And so today's paper is really important from Dr. Mills from the University Center for Cardiovascular Science Royal Infirmary of Edinburgh in the University of Edinburgh and colleagues.
Dr. Carolyn Lam:
What they did was a secondary analysis of the high stakes trial of more than 46,000 consecutive patients with suspected acute coronary syndrome. They evaluated the performance of the 99th percentile rule in threshold and thresholds of 64 ng/L and five times the upper reference limit for the diagnosis of type 1 myocardial infarction. They found that troponin concentrations at presentation have a low, positive predictive value for type 1 myocardial infarction and a threshold of 50 times the upper reference limit is required to achieve a positive predictive value of more than 70%. A change in troponin on serial testing only marginally improved positive predictive value for type 1 myocardial infarction over the presenting troponin alone.
Dr. Greg Hundley:
Interesting, Carolyn. Very important data. What's our take home message here.
Dr. Carolyn Lam:
Well, troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction and should not be used in isolation to guide management decisions in patients with suspected ACS. Consideration of other important clinical factors may be more helpful than any particular rule in threshold to guide initial triage and management.
Dr. Greg Hundley:
Wow, Carolyn, so really great new data and more data on the utility of these troponin concentrations.
Dr. Greg Hundley:
Well, my next paper comes from the world of preclinical science and it's from Professor Vladimir Kalinichenko from Cincinnati Children's Hospital Medical Center. Carolyn, as we know, pulmonary hypertension is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a severe congenital disorder associated with mutations in the Foxf1 gene. Now, while the loss of alveolar microvasculature causes pulmonary hypertension in, and we're going to abbreviate this ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent pulmonary hypertension and right ventricular hypertrophy in these subjects.
Dr. Carolyn Lam:
Wow. Wow. Okay. Let's repeat that. ACDMPV stands for alveolar capillary dysplasia and misalignment of pulmonary veins. Really cool stuff. What did they find, Greg? This sounds like a first of its kind study.
Dr. Greg Hundley:
Right, Carolyn. Thanks. The Foxf1 wild type, S52 mice developed pulmonary hypertension and RV hypertrophy after birth. The severity of pulmonary hypertension in these mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Second, increased fibrotic remodeling was found in the human ACDMPV lungs. Third, the mouse endothelial cells carrying the S52F Fox1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that the Foxf1 wild type S52F endothelial cells have a propensity to differentiate into pulmonary myofibroblasts. And then finally, intravascular delivery of nanoparticles carrying Stat3 copy DNA protected the Foxf1 wild type S52F mice from RV hypertrophy and pulmonary hypertension, improved their survival and decreased that fibrotic lung remodeling. Carolyn, nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent pulmonary hypertension in alveolar capillary dysplasia with misalignment of pulmonary veins.
Dr. Carolyn Lam:
Wow, thank you, Greg. Such incredibly hopeful papers here. The next paper identified a key role of a particular amino acid in cardiac aging.
Dr. Greg Hundley:
Ah, Carolyn, so you didn't ask me the quiz but I guess it's implied here. Okay, I give up. Which amino acid is it?
Dr. Carolyn Lam:
Spot on, Greg. Well, the answer is phenylalanine. This is an essential amino acid whose levels are regulated by the tetrahydrobiopterin or BH4 dependent rate limiting enzyme, phenylalanine hydroxylase and whose expression is physiologically restricted to the liver and the kidney. Well, co-corresponding authors Dr. Czibik and Derumeaux from Paris, France, hypothesized that phenylalanine plays a causal role in promoting cardiac senescence and dysfunction based on prior evidence from human metabolomics that shed light on a link between amino acids, aging and heart failure, as well as data showing that plasma levels of phenylalanine increase with age and inversely correlate with leukocyte telomere length. In addition, increased serum phenylalanine levels are associated with heart failure. Here, the authors tested their hypothesis in a series of elegant mouse experiments and showed for the first time that a decline in hepatic phenylalanine catabolism was a causal contributor to a rise in systemic levels, leading to cardiac ectopic phenylalanine hydroxylase activity and resultant cardiac aging.
Dr. Carolyn Lam:
They demonstrated that phenylalanine administration induced a remarkable premature cardiac deterioration in young mice, closely mimicking that of aged mice and leading to cellular senescence in vitro. They identified hepatic phenylalanine catabolism to decline with age in a p21 dependent manner, while demonstrating that p21 deficiency prevented age related cardiac dysfunction. Administration of phenylalanine hydroxylase cofactor BH4 or dietary phenylalanine restriction, both abrogated the age related rise in the plasma levels and reversed age associated cardiac alterations. This study really identifies phenylalanine and its hydroxylase modulation as a potential therapeutic strategy to promote cardiac health and prevent age related cardiac impairment. Amazing, isn't it?
Dr. Greg Hundley:
Yeah, Carolyn. Really interesting about phenylalanine and while it may impact cardiovascular health and the aging process.
Dr. Greg Hundley:
Well, I know we've got some other articles in this issue, so how about I'll go and dip into the mailbag first? The first is from Professors Wong and Finn and they're exchanging letters regarding the prior publication entitled, Microthrombi as a Major Cause of Cardiac Injury in COVID-19 and it's a pathologic study. There's a nice Research Letter from Dr. Zhu entitled, “Catheter Based Adrenal Ablation Remits Primary Aldosteronism: A Randomized Medication Control Trial.” There's a Perspective piece from Dr. Stehlik entitled, “The Long and Winding Road to an Effective Left Ventricular Assist Device: The Demise of Medtronic's HVAD.” And then finally a report from Dr. Mehta and colleagues, really Carolyn, thinking about clinicians' wellbeing and addressing global needs for improvements in the healthcare field. And it's a Joint Opinion representing the American College of Cardiology, the American Heart Association, the European Society of Cardiology and the World Heart Federation. Really a nice report on really addressing physician stress in the workplace.
Dr. Carolyn Lam:
Nice. Well, there's also an ECG Challenge by Dr. Shi entitled, “An Acutely Breathless Patient with Inferior St-Segment Elevation: A Diagnostic Trap.” In Cardiology News, Bridget Kuehn describe studies detailing heart risks for firefighters. Wow, what an interesting issue, but let's go on now to the feature discussion shall we, Greg?
Dr. Greg Hundley:
You bet.
Dr. Greg Hundley:
Welcome listeners to our feature discussion. And today we have with us Dr. Gabriel Steg from Paris, France, Universite de Paris. And also Dr. Gregg Stone, an editorialist from Mount Sinai in New York. Welcome gentlemen. And Gabriel, we'll start with you first. Could you describe for us some of the background related to your study and what was the hypothesis that you wanted to test?
Dr. Gabriel Steg:
Thank you, Greg. As you know, there have been tremendous changes in cardiology over the past 25 years with the advent of effective anti-anginal therapy, with the advent of myocardial revascularization and the dramatic changes produced by widespread availability of percutaneous coronary intervention and finally the availability of evidence based secondary prevention therapies. And there has been really a sea change in the presentation and treatment, management and outcomes of patients with coronary artery disease. And when we started off, we asked ourselves, is angina pectoris really prognostic in patients with stable coronary artery disease? Is the symptom of angina really prognostic? That was the question we tried to address.
Dr. Greg Hundley:
And Gabriel, what was your study population and your study design?
Dr. Gabriel Steg:
It was a very simple descriptive design. We use a large international registry of patients with stable coronary artery disease called the CLARIFY registry, which enrolled almost 35,000 patients with stable coronary artery disease and followed them up for five years. Now, how was stable coronary artery disease defined? It was defined as any of the following conditions, a prior MI, more than three months before enrollment, a prior PCI or a CBG, angina pectoris was a demonstration of myocardial ischemia on noninvasive stress testing or finally the presence of a fixed stenosis of the coronary arteries on an angiogram. And you could get any of these criteria. Of course you could have more than one at the same time. And the design was to describe the anginal status at baseline and every year based on investigator reports, not a formal angina questionnaire, as there are several, including the Seattle angina questionnaire. We had a very simple assessment of angina and angina severity based on presence or absence and then Canadian class of angina.
Dr. Greg Hundley:
Did you follow these individuals too? Did they experience specific events?
Dr. Gabriel Steg:
Yes. We collected all the cardiovascular hospitalizations events, revascularizations. We followed the medications and we collected the biological results, although there was no core lab but we collected the results of the tests that were done. We essentially aimed was that registry to describe the population, their management and their outcomes over five years. And this is over 40 plus countries. And fortunately does not include any patient from the United States but has a substantial contribution from Canada and Mexico.
Dr. Greg Hundley:
Very nice. And so what did you find, Gabriel?
Dr. Gabriel Steg:
Well, the first observation is the prevalence of angina at baseline and it's 22%. We found that in a patient population selected for having stable coronary artery disease, approximately a fifth to a quarter will have anginal symptoms. I don't think that's a major surprise but what was a big surprise to us is that angina resolved very, very substantially, 40% of the patients who had angina at baseline had no longer angina by one year. And what was even more surprising is what caused the resolution of angina. And it was rarely changes in anginal medications, rarely revascularization. It was largely spontaneous. Almost 80% of the patients had spontaneous resolution of angina. And so, yes, it's been known that angina can regress but we did not expect that it would regress that often and that much spontaneously without intervention or need for increasing medications.
Dr. Gabriel Steg:
And the other aspect is then we looked at what happened for those patients who had angina resolution at one year and what were the subsequent outcomes? And we found they were indistinguishable from those who had no angina at baseline. And then we looked at those patients who had persistent angina at one year or occurrence of angina at one year, despite not having angina at baseline. And again, we found that having angina at one year was detrimental to the longterm prognosis. It's really good that you either not have angina or that your angina resolve. That's really important.
Dr. Greg Hundley:
Did you find any differences, Gabriel, between men and women?
Dr. Gabriel Steg:
No. We looked at a variety of subgroups. We looked by criteria for enrollment. We looked across geographic locales. We looked according to the presence or absence of diabetes and sex and other variables and there were really no major differences. The results were remarkably consistent.
Dr. Greg Hundley:
Very nice. Well listeners, one of the advantages of some of the publications that we pursue at Circulation is the ability to bring in an editorialist. And with us today, we have Dr. Gregg Stone from Mount Sinai in New York. And Gregg, we want to turn to you. How do we put the results of this study in perspective with other studies that have been involved in this sphere of research?
Dr. Gregg Stone:
Well, thank you, Greg. First off, I'd like to congratulate Gabriel and his colleagues for a tremendous study and thank you and Circulation for offering David Waters and I, the chance to provide our perspectives. I think this study raises a lot of important issues. Angina is kind of like the common cold to cardiologists. We're always dealing with it but it can be very difficult to diagnose. There's typical angina, atypical angina, anginal equivalent disease, non-anginal chest pain, et cetera. And we've learned in the last several years or decade that the etiology of angina can be very complex. It's not just epicardial coronary disease. There can be microvascular disease, macro or microvascular spasm and other causes. I think that we have to, when we're thinking of angina, we have to try to understand the mechanism and know whether or not it's really due to at least epicardial coronary artery disease, which is the type of disease that may respond to revascularization.
Dr. Gregg Stone:
In this regard, both David and I were struck with the fact that the CLARIFY even though a very large population, is a very mature population of patients with coronary disease, who I believe were diagnosed at least approximately seven years ago, most had undergone a prior revascularization therapy, about 50% ahead of myocardial infarct and the minority interestingly had inducible ischemia. We wondered is this real angina? Is this true angina that these patients are having? Because they've been effectively revascularized. In contrast, I was one of the co-principal investigators of the ISCHEMIA trial, which was a very different population because we took only with exercise induced moderate or severe ischemia. And while we excluded most patients with class three or four angina because we know those patients basically don't tolerate medical therapy without frequent crossovers. We found that in our trial, angina was more persistent and was substantially reduced by revascularization, by an interventional approach. Much more so than in the medical therapy arm. I think that it really does depend on the patient population and the likelihood of which the angina is due to true inducible ischemia that may respond to a revascularization approach.
Dr. Greg Hundley:
Very nice. And so Gabriel, want to turn back to you, what do you think is the next study that really needs to be performed in this space?
Dr. Gabriel Steg:
Well, I think it's really in line with Dr. Stone's comments. I think that what we need to do is to have a much more formal prospective assessment of a broader population of patients with angina using formalized questionnaire, such as the Seattle angina questionnaire, which allow a much better and thorough characterization of the presence, type and severity of symptoms and to look across the whole spectrum of patients with and without myocardial ischemia and look at the prognostic importance of the symptoms. I think that teasing out the relationship between the anginal symptoms, their severity, myocardial ischemia and outcomes is really critical to our interpretation of the series of recent trials, the last of which being ISCHEMIA, which have revolutionized our thinking regarding management of coronary artery disease. And we're still somewhat in the dark as to how to incorporate that information relative to the symptoms and outcomes of our patients. And I think we still have a lot of work to do in that respect.
Dr. Greg Hundley:
Very Good. And Gregg, do you have anything to add to that?
Dr. Gregg Stone:
Yeah. I would certainly echo Gabriel's comments. In addition, I think we have to think of angina as a collection of different diseases. And we have to do a better job at trying to understand the mechanisms underlying angina. First, we have to be able to determine whether it's really cardiac in origin versus non-cardiac. And then second, we have to understand again, whether it's coming from epicardial coronary disease, microvascular disease or other mechanisms. We've just been struck in even many of our simple stent studies, how often patients redevelop angina after treatment with no re-stenosis whatsoever, suggesting that many of them may have other etiologies of angina. I think these studies to me are very important because they really highlight, yes how much we've learned but how much more work there still is to do for us to be able to effectively diagnose and treat these patients.
Dr. Greg Hundley:
Well listeners, we want to thank both Dr. Gabriel Steg, the author of this paper and also Dr. Gregg Stone, who provided his editorial expertise, in bringing us information from these 32,000 plus individuals from the CLARIFY registry, of patients with stable coronary artery disease and helping us answer really two questions regarding the presence of angina. One, both that angina may resolve spontaneously and then second, persistent angina is associated with future cardiovascular events.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I want to thank our speakers and then also wish everyone a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features a panel discussion in regard to Covid-19. Please join authors Kathryn Larson, Christopher deFilippi, James de Lemos, and Biykem Bozkurt as they discuss their articles regarding temporary myocarditis and Covid-19 vaccination.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Greg Hundley:
Carolyn, this week, oh my goodness. It's a forum, almost a triple or quadruple feature, and you know what we're going to be discussing? COVID-19 vaccinations and their relationship potentially to myocarditis. We're going to have our associate editors and our deputy editor involved, be really interesting. But before we get to that, how about we start in with the papers in the issue. Would you like to go first?
Dr. Carolyn Lam:
Absolutely. And my first paper is so interesting. It identified a novel underlying mechanism of graft arteriopathy, or otherwise known as coronary allograft vasculopathy, a devastating development of heart transplant in which arterial intimal thickening limits coronary blood flow and could lead to transplant failure.
Dr. Greg Hundley:
Oh wow, Carolyn. So, what did they find?
Dr. Carolyn Lam:
Well, this was Dr. Martin from Yale Cardiovascular Research Center and colleagues. What they did is they used both human coronary allograft vasculopathy and renal transplant samples as well as murine models, basically, and found that TET methylcytosine dioxygenase 2, or TET2, is a critical negative regulator of vascular smooth muscle cell apoptosis in graft arteriopathy and vascular injury. Enhancing smooth muscle TET2 activity with a high dose of ascorbic acid rescued donor vascular smooth muscle cells apoptosis and intimal thickening in murine transplant vasculopathy. Furthermore, TET2 expression and activity were repressed in arterial vascular smooth muscle cells in human and mouse graft arteriopathy compared to controls.
Dr. Carolyn Lam:
Interferon gamma signaling in vascular smooth muscle cells resulted in TET2 repression. Preventing donor vascular smooth muscle cell apoptosis with high dose ascorbic acid may therefore represent a safe and cost-effective therapeutic strategy for limiting graft arteriopathy in patients undergoing solid organ transplant. Neat, huh?
Dr. Greg Hundley:
You bet, Carolyn. Really an interesting article on limiting graft arteriopathy.
Dr. Greg Hundley:
Well, Carolyn, my next paper comes to us from Dr. Greg Stone and colleagues at the Cardiovascular Research Foundation. It involves the randomized COAPT trial. Remember that in the COAPT trial, there were 614 heart failure patients with 3+ or 4+ secondary mitral regurgitation and had trans-catheter mitral valve repair with the MitraClip, reduced mitral regurgitation, heart failure hospitalizations and mortality as well as improving quality of life compared with guideline directed medical therapy alone. So the authors here, Carolyn, sought to examine the prognostic relationship between mitral regurgitation reduction and outcomes in trans-catheter mitral valve repair versus guideline directed medical therapy alone.
Dr. Carolyn Lam:
Wow, okay. So, what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So, among patients with heart failure and severe, grade 3+ or 4+ secondary mitral regurgitation randomized to trans-catheter mitral valve repair with the MitraClip versus guideline directed medical therapy, the reduction of MR to 2+ was strongly associated with subsequent two year freedom from death and heart failure hospitalization and improved quality of life regardless of whether this reduction to 2+ MR was achieved by trans-catheter clip or guideline directed medical therapy alone. And the improvement in long term prognosis was similar after this mitral regurgitation reduction to grade 2+ compared with grade 0 or 1+ in both arms, although the mitral regurgitation reduction was a little more durable over time after the trans-catheter mitral clip.
Dr. Greg Hundley:
So Carolyn, the take-home message is that substantial benefits are realized even if mitral regurgitation is reduced to only 2+.
Dr. Carolyn Lam:
Nice, Greg. Thanks.
Dr. Carolyn Lam:
Now, this next paper, oh, close to my heart. We know that individuals of South Asian ancestry actually represent 23% of the global population, corresponding to 1.8 billion people, and that they have a substantially higher risk of atherosclerotic cardiovascular disease compared with most other ethnicities. However, what is the magnitude of that enhanced risk, the extent to which it is captured by existing risk estimators, and what are its potential mechanisms?
Dr. Carolyn Lam:
This was studied in this beautiful paper. Dr. Khera from Massachusetts General Hospital and colleagues used data from the large UK Biobank prospective cohort study to investigate the relationship between South Asian ancestry and incident atherosclerotic cardiovascular disease within the context of contemporary medical care. Their findings confirmed an approximate doubling of atherosclerotic cardiovascular disease risk among South Asian compared with European individuals that was not captured by the pooled cohort equations. The higher risk of atherosclerotic cardiovascular disease persisted despite adjustment for a broad range of potential clinical, anthropometric, and lifestyle mediators. Hypertension, diabetes, and central adiposity explain a greater proportion of risk of atherosclerotic cardiovascular disease in South Asian compared with European individuals.
Dr. Greg Hundley:
Wow, Carolyn. So, a lot of data here. How do we take all this and put it together clinically?
Dr. Carolyn Lam:
Well, the results confirm and extend the current guidelines that consider South Asian ancestry a risk-enhancing factor in assessing future risk for atherosclerotic cardiovascular disease. Residual risks that persisted after accounting for a range of potential mediators may relate to differences in social determinants of health, unmeasured risk factors and genetics and so on, that this warrants further investigation. Whether a targeted intervention can attenuate the outsized impact of diabetes or central adiposity among South Asian individuals also warrants further attention.
Dr. Carolyn Lam:
This is accompanied by a beautiful editorial entitled The South Asian Enigma: Solving a Puzzle of Global Importance, love that, from Drs. Kandula from Northwestern University Medical Center and Kanaya from University of California San Francisco.
Dr. Greg Hundley:
Very nice, Carolyn. I just want you to know, after being quizzed last week on phospholamban, I went and did a little bit of studying, okay? So I get to bring to you, Carolyn, this week, a paper on phospholamban. But I'm going to spare you from the quiz.
Dr. Greg Hundley:
All right.
Dr. Carolyn Lam:
Yay!
Dr. Greg Hundley:
This comes to us from Professor Fadi Akar from Yale University. Carolyn, arginine 14 deletion is the calcium regulatory protein phospholamban, so hPLN R14 deletion. It has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy, and mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling really remain unclear.
Dr. Carolyn Lam:
Interesting, Greg. So, what did they find?
Dr. Greg Hundley:
Right, Carolyn. Adverse electrophysiological remodeling was evident in the absence of significant structural hemodynamic changes, and the R14 deletion hearts exhibited increased arrhythmia susceptibility compared to their wild-type counterparts. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to beta-adrenergic stimulation. A steep repolarization gradient at the LV/RV interface provided the substrate for inter-ventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. And then once sustained, these circuits evolved into high frequency rotors, which in their majority were pinned to the right ventricle. Importantly, these rotors exhibited unique spatio-temporal dynamics that promoted their increased stability in the R14 deletion compared to the wild-type hearts.
Dr. Greg Hundley:
So Carolyn, in summary, this research found the crucial role of primary electrical remodeling caused by the hPLN R14 deletion mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of the PLN R14 deletion induced a cardiomyopathy.
Dr. Carolyn Lam:
Oh, and ties up very nicely about how we mentioned that this dilated cardiomyopathy is associated with lots of ventricular arrhythmias that we discussed last week. Really cool.
Dr. Carolyn Lam:
Well, let's do a little tour around what else there is in today's issue. Tracy Hampton presents from the literature discussing how excessive exercise may damage mitochondria and impair glucose control in a publication from Cell Metabolism. Data on an oral antisense oligonucleotide for PCSK9 inhibition was published in Science Translational Medicine.
Dr. Carolyn Lam:
And there's a paper on structuring clinical text with AI. How very interesting, published in Patterns. There's an On My Mind paper by Dr. Berger on summoning strength to question the placebo in reducing.
Dr. Greg Hundley:
Right, Carolyn. Also in the mail bag, there is a reply to the Quintao and Cazita from Professor Brunham entitled High-Density Lipoprotein Cholesteryl Ester Transfer Protein and Sepsis. And then finally, from Dr. Goldstein, an ECG challenge. Does this ischemia pattern look right?
Dr. Greg Hundley:
Well, Carolyn, this is going to be a really interesting feature forum discussion today on COVID-19 vaccinations and myocarditis. How about we get on to that discussion?
Dr. Carolyn Lam:
Yep. A really important issue now. Yup, let's go.
Dr. Greg Hundley:
Welcome, listeners. We have a very exciting, really series, of feature discussions. We're going to call it a forum, and focusing on COVID-19 vaccine associated myocarditis. We really have four manuscripts to discuss today. We have Dr. Kathryn Larson from the Mayo Clinic in Rochester. We have another author, Dr. Chris deFilippi from Inova Health, really in the Washington DC metro area. We have our executive editor, Dr. James deLemos from UT Southwestern in Dallas, Texas. And then also one of our senior associate editors, Dr. Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Welcome to everyone.
Dr. Greg Hundley:
Well, first, listeners, we're going to start with Dr. Larson. So, Kathryn, can you tell us a little bit about the background and the hypothesis that you were testing in your research project, and then a little bit about your study design and what were the results of your study?
Dr. Kathryn Larson:
Absolutely. Well, first off, thank you so much for having me, Greg. It's a pleasure to be here and in such good company. My study really grew out of a clinical interest in a number of patients that had presented to our institution and other institutions that we had been in discussion with of really young male patients with no significant past medical history who were coming in two to three days after receiving their COVID vaccines, most often the second dose, and presenting with laboratory and clinical findings consistent with myocarditis. I think in a lot of arteriosity and what the course of their illness may be and what the best course of treatment may be, that really drove our hypothesis to try and describe other cases that were coming up and that we had heard about from a lot of our colleagues around the country and around the world.
Dr. Kathryn Larson:
Our paper really grew out of a case series of eight patients, and they're from the United States and from Italy, and they're of eight patients who were diagnosed with laboratory and clinical and imaging findings consistent with myocarditis after receiving their COVID-19 vaccines. Our patients had received either the Pfizer BioNTech or the Moderna vaccines, the mRNA vaccines. Really, only two of our patients had previously been infected with COVID at all, and so most of these patients were coming in with really no relevant medical history. They were really young in age, between 21 and 56 years old, and basically all patients except for one developed their symptoms after receiving the second dose of the vaccine.
Dr. Kathryn Larson:
The timeline was generally about two to three days after that dose and was often accompanied by other symptoms which we have seen and heard about things like myalgias, subjective fevers, chills, and kind of a general malaise. They presented really with very typical features of myocarditis, chest pain, one of the patients had a more pleuritic type of chest pain, and had ECG changes, troponin elevations, elevated inflammatory markers, and most importantly cardiac MRI findings that were significant and really diagnostic of myocarditis.
Dr. Kathryn Larson:
There was a good amount of investigation into other potential causes and none other identified in any of those eight patients. All thankfully had a relatively unremarkable course clinically and all are currently doing very well. There was mild reductions in LV function, no clinically significant heart failure, and at last known contact, those patients really had recovery of LV function and are essentially back to baseline.
Dr. Greg Hundley:
Excellent. Well, listeners, we're going to move to another part of the country, and again, Dr. Chris deFilippi is in the Washington metro area. Chris, you also have a case series. Can you describe for us what you were looking at with your study, and then what were your study results?
Dr. Chris deFilippi:
Greg, first, thank you for having me here today. As a regular listener to Circulation on the Run, it's really a privilege to actually be able to participate and contribute to it. First, I would have to say was a little bit of serendipity. We recognized one case out of the ordinary with respect to suspected myocarditis in early March, and given our location around Washington DC, some of our faculty were former active military and serve in the reserves and one returned and said, "The military is beginning to find a small series of cases."
Dr. Chris deFilippi:
We've worked hard within our academically oriented independent health system to develop a research clinical trials network, and we called upon our cardiologists and cases started coming forward actually fairly rapidly, drawing upon five hospitals in our network. Combining our efforts with UT Southwestern, we identified seven individuals. They were all men or young adults in their 20s and 30s. Six out of seven had received the mRNA vaccines. Most of them had developed symptoms between three to seven days after their second vaccination.
Dr. Chris deFilippi:
Very similar to Kathryn's presentation, we did an extensive evaluation, of course including advanced imaging with MRI using the Lake Louise criteria, but also did a lot of serologic measurements. I think it was remarkable that troponin values using still a conventional assay ranged from mild elevations, 0.34 to as high as 44 milligrams per milliliter.
Dr. Chris deFilippi:
All patients fortunately had resolution of symptoms within several days and returned back to normal life and then all return follow-ups seemed to remain symptom-free. Again, we looked for multiple other etiologies including autoimmune disease, other respiratory infections, and these were all effectively negative.
Dr. Greg Hundley:
Very nice. Well now, listeners, we're going to head south, down to Dallas, Texas and bring in Dr. James deLemos. James, you also have a case report and did some extensive study, I believe, in your patient in terms of investigating perhaps mechanisms. Could you share with us your study and some of your findings?
Dr. James deLemos:
Yeah. Thanks, Greg. Ours was like Kathryn and Chris's experience, purely serendipitous. I was on service in late January at our university hospital and we had a case that came in three days after receiving the Moderna vaccine with what appeared to be clearly myocarditis in temporal association with the vaccine. At that time, we reported it to the CDC, but there was really not much, if anything, and so what we decided to do was pull together a translational team. We brought together clinical pathologists, immunologists, infectious disease experts, and a panel of folks to think about how we might get at a potential mechanism, obviously in a highly exploratory fashion because this was one case and at this point we really didn't know whether this was a true causal association or just circumstance.
Dr. James deLemos:
What we did was really a broad exploratory analysis, comparing our index case with a number of vaccinated controls, COVID infected controls, and normal controls. We did autoantibody panels, cytokine panels. We looked at flow cytometry for cell fractions, and really tried to see if there was a signature for our case that distinguished it from these other control groups.
Dr. James deLemos:
I think one important thing we didn't see was an exuberant or over exuberant response in terms of the spike antibody. That was also not seen in several other cases from Chris and Kathryn. The antibody response seemed to be in the normal range of what would be expected after the vaccine. We also didn't see broad spread inflammation in our case compared to controls. There were several cytokines that were upregulated, some of which have been reported in myocarditis, and there were some natural killer cell subsets that would seem to be upregulated, and then several autoantibodies as well that have been reported in myocarditis. But interestingly, none of the poor prognosis autoantibodies that had been reported, which may in part, we think, explain why these cases seem to be doing quite well.
Dr. James deLemos:
I'd emphasize it's one case, so we recognize this is purely exploratory and hopefully will set the stage for other people as they try to investigate this in more depth.
Dr. Greg Hundley:
Thank you, James. Well, Biykem, you've been spending a large segment of time, the last year, really year and a half, trying to put together for us at the American Heart Association what may be operative in these patients receiving these vaccines, and also really studying COVID-19. It sounds like what we're hearing amongst all three of these, young men, really a myocarditis that develops after the second vaccine. We have typically elevated troponins, there's MRI findings. You've put together a review. Maybe you could start to share with us what have you learned over this past year and a half?
Dr. Biykem Bozkurt:
Thank you, Greg. As my colleagues have alluded to, the characterization of the presentation is pretty concordant. What I did in the review was to review all the case reports and case series published to date, which summed up to 61 cases. Additionally, I looked at what has been reported by the Vaccine Adverse Event Reporting System by the CDC and their internal analyses, and also looked at the reports that came from Israel as well as the US military, which is a large cohort and population base reporting.
Dr. Biykem Bozkurt:
The messages for the clinicians, number one, the presentation in most of these reports have been pretty unified in the sense that most patients presented day two or day three after the second dose of mRNA vaccination. Secondly, most if not all had cardiac troponin elevation along with chest pain on presentation. The majority of the patients, more than 90, 95 in the case series, had EKG abnormality, usually with ST elevation. When we're to examine the echo findings, about two thirds or sometimes in the case series about 40% of abnormalities and only a small percentage had LV systolic dysfunction with EF less than 50.
Dr. Biykem Bozkurt:
When done as was the case in all the case series and case reports, cardiac MRI was always abnormal. They were very self-limited. Important concepts are, these were very self-limited cases. All of them recovered and were discharged and had resolution of their symptoms, biomarker findings as well as imaging findings.
Dr. Biykem Bozkurt:
Now, let's look at the benefits versus risk concept that was examined at the CDC level. The current reporting in the VAERS system, the Vaccine Adverse Event Reporting System, is about 12.6 cases per million doses of vaccination. This is after 300 million doses being given in the US and about 170 million individuals being vaccinated in the US. Of those, when compared to what we have been expecting in the population, there appears to be a temporal association that the CDC has confirmed. If we were to look at the risk versus benefits ratios, it's very clear that COVID-19 is a deadly disease. It results in mortality even amongst the younger population, somewhere at the order of 0.1 to 1% per 100,000 people being infected. So for 12 to 39 years old, where the myocarditis risk is felt to be higher, still we need to keep in mind, that risk is very low. 12 per million doses, compared to about 0.1 to 1 death for about 100,000 infections.
Dr. Biykem Bozkurt:
And of course, if we were to add the number of hospitalizations, ICU stays, cardiac involvement, which we know is seen in about 12 to 20% of hospitalized patients by cardiac troponin elevation, as well as multisystem inflammatory syndrome that is seen in young populations, the benefits significantly outweigh the risks. In terms of mechanisms which James has alluded to, the things that are coming as potential signals or hypothesized mechanisms include the following. There could be molecular mimicry between the spike protein and the self-antigens. Currently, that experimental data, antibodies against spike protein have been reported to cross react with human proteins including alpha myogen. Other mechanisms could be vaccine and it making a response triggering a pre-existing dysregulated immunopathological pathway in predisposed patients. But mind you, we don't right now have a pattern of who's predisposed to myocarditis. It doesn't look like comorbidities as we have seen with COVID-19 infection.
Dr. Biykem Bozkurt:
And in James' case, there was no predisposition to cardiomyopathy identified by a gene variant that are known to be associated, so those were negative in the case reports that James had mentioned. There was increased frequency of autoantibodies in that case report that James had published. Again, this may be in reaction to the inflammation or injury rather than being the cause. It may be the outcome, but still it raises a concern whether autoantibody formation is one of the mechanisms.
Dr. Biykem Bozkurt:
Male predisposition is a known risk for myocarditis. We've known this even before the vaccine related myocarditis cases. In the experimental as well as population based studies in the past, young males have a higher predisposition than females or older age, and it's thought to be due to the differences related to sex hormones, especially testosterone, being pro-inflammatory. But of course, in the passive vaccine adverse event reporting, we also do know that the chest pain presentation did not appear to be as different among males compared to females and the imaging and studies were done in less frequency in females, so there may be also a bias toward work-up in females which needs to be further examined.
Dr. Biykem Bozkurt:
The most important message we'd like to put out there is the benefits highly outweigh the risks, but there needs to be recognition that there is such a risk for clinicians, and definitely do an appropriate work-up for patients presenting with chest pain to the emergency room or to the clinical setting for an appropriate work-up to be carried out including EKG, cardiac troponin in all patients, followed by imaging, such as cardiac MRI and/or other imaging as necessary depending on the symptomatology, the age, as well as the findings on the troponin and EKG. And cardiology moment is essential for those ones who are diagnosed with myocarditis. The treatment strategies in the case reports range all the way from non-steroidal colchicine to IV steroids to intravenous immunoglobulin. Probably the way to approach these cases is if it's very self-limited with resolution of symptoms and biomarkers within two or three days, they may not need to resort to very intensive therapy, but if the case is with unrelenting symptoms, persistent biomarker abnormality, an imaging finding higher level of intense geo-treatment with intravenous steroids or IV immunoglobulin may be considered.
Dr. Biykem Bozkurt:
So far in the published reports, there have not been any bad outcomes such as death and/or requirement for mechanical circulatory support, but again, further research is needed.
Dr. Greg Hundley:
Very nice, Biykem. Well, listeners, we're going to go back through our authors and just really quickly, Kathryn, Chris, James, Biykem, what study, maybe in 15 seconds, do you think might need to be performed next in this sphere of research? And then second, what's the one point that you think we ought to emphasize as we close out going forward? So, both questions for each author. Kathryn, we'll start with you.
Dr. Kathryn Larson:
Okay, cool. I think I'll bring a little bit of an imaging bias as that's my personal interest. I'd really like to see a lot of the data that's already out there from these patients both at their baseline studies, and I'd really like to see their follow-up studies in terms of what happens to things like LV function and in terms of their MRI findings. I think that could be really helpful given the amount of weight that imaging has in the diagnosis of these patients.
Dr. Kathryn Larson:
I think the biggest take-away for me in a lot of these discussions that we were having is, these are very rare issues and incidents when patients are presenting with these, and I think the vast majority of the information we have at hand is that these are self limited, there's good recovery of any decline in LV function, and that I think overall the clinical course is favorable.
Dr. Greg Hundley:
Very nice. Chris?
Dr. Chris deFilippi:
First, I shouldn't be promoting my colleague's work, but I've got to say that Biykem's review was terrific. I know I did a lot of background reading in this case presentation. I've gone through that review a couple times and it's clearly, I think, helped my thinking on this topic. As Biykem mentions in that review, the recording of myocarditis can have a number of biases either under or over reporting, basically what's available in the public and what sort of people are thinking about. I think looking at it from a population health standpoint, the risk benefits are so favorable for the benefits of vaccination. We knew that even a month ago, we know that even more today. But I think it would be great to get an understanding, recognizing that there may be cases of unrecognized myocarditis, myocardial fibrosis, at a population level in what we would assume would generally be very healthy, young adult males, do we see more cardiac related hospitalizations over time? Do we see more sudden death? I think we should just affirm that, hopefully we can affirm that isn't the case and keep moving forward.
Dr. Chris deFilippi:
That being said, I'm still really a big advocate for vaccination and the benefits of vaccination combined with these very small risks.
Dr. Greg Hundley:
Very nice. James?
Dr. James deLemos:
I'd say really two avenues for research. I'd echo Kathryn's point that we need longer term follow-up data for patients that have this syndrome. To do that we're going to have to collaborate, because each of us individually see very few cases, because fortunately this is rare, and we're going to need registries that look at longer term follow-up of patients with vaccine associated myocarditis. And then really getting to Chris' point on the front end, I think that's what's needed are prospective studies measuring high sensitivity troponin and cardiac MRI in younger individuals who get vaccinated, so we study them not once they get the disease, but trying to determine whether there might be even less severe versions of myocardial injury that are occurring after the vaccine and try to understand why that's the case, because mRNA vaccines are here to stay. They're remarkable advances. And let's understand what this apparently self limited myocarditis is all about.
Dr. James deLemos:
The take-home message I'd echo is that this is important and all of us even had angst about recording and talking about this, because we don't want this ever to be misconstrued to suggest that these vaccines, which are absolutely remarkable, don't have a favorable risk benefit, even for our cardiac patients. These data in no way affect the safety and efficacy of the vaccine, even in people with underlying cardiac disease, who are some of the ones that have the greatest priority to get vaccinated.
Dr. Greg Hundley:
And finally, Biykem.
Dr. Biykem Bozkurt:
I think I echo all my colleagues' sentiments in the necessity for prospective and imaging and biomarker. The way to do that, as James alluded to, is we should right now develop a consortium for a registry, and we should have a bioregistry. I would urge us to not solely consider it for vaccine related entity, but also COVID-19. So I think we need to straddle the whole concept of COVID-19 itself, the infection plus the vaccinated individuals and follow them in a prospective manner with the known biomarkers, the cardiac biomarkers as well as imaging, but also the thing that is lacking right now is to characterize them with a specific immune cell populations as to what is rising, what kind of response we've seen, with the changes that we're seeing in males and others, and capture further mechanistics, perhaps signaling. Quite a few of this phenotyping is needed in these individuals as well as perhaps a genotyping characterization and maybe a tissue characterization.
Dr. Biykem Bozkurt:
I think the consortium will need to entail pathologies as well as immunopathology along with biomarkers and imaging. And of course, prospectively following these individuals. As was done in certain other vaccines in the past may give us a totally different signal and prevalence.
Dr. Biykem Bozkurt:
Take-home message, I fully agree. Being able to get a message of the risk is low compared to benefit. While we're calling for, the necessity for further research is a delicate balance of what the scientists have to straddle. Yes, the vaccine is very safe. It's been shown in numerous, several randomized clinical trials. Current data actually validates that because it's a few cases in millions of doses of the safest vaccine. But for those very few cases, for those very few cases we need to be on the alert and treat them appropriately and not miss those diagnoses.
Dr. Biykem Bozkurt:
One other message I'm going to share is the rapidly evolving conceptualization of myocarditis. The lymphocytic myocarditis concept that historically was the gold standard characterization of myocarditis with other viruses is, I think, rapidly changing now with the recognition of what we saw with COVID-19 itself, as well as now with the vaccine. It does not seem to be the classical characterization of myocarditis, so again, understanding of myocardial injury, cardiomyocyte injury is now a continuum beyond what we used to call the path to MI and injury, now straddling all the way to a concept of injury that is much different than the lymphocytic myocarditis we've seen with other viruses, which we need to embrace.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Kathryn Lawson, Dr. Chris deFilippi, Dr. James deLemos, Dr. Biykem Bozkurt, for this wonderful forum discussion on COVID-19 vaccine associated myocarditis.
Dr. Greg Hundley:
Well, thank you so much and on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021.
Dr. Greg Hundley:
The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAJournals.org.
This week's episode features author Shih-Chuan Chou and editorialist Alexander Sandhu discuss the article "Impact of High-Deductible Health Plans on Emergency Department Patients With Nonspecific Chest Pain and Their Subsequent Care."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart center at VCU health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I am so excited about today's feature discussion that's going to be about high deductible health plans and their impact on emergency department patients with chest pain and their subsequent care. Now, I can tell you as coming from outside of US, I learned so much from this discussion so everybody's going to want to hear it. But before we go there, let's discuss the other papers in today's issue. Greg, do you have a paper?
Dr. Greg Hundley:
You bet. Thanks Carolyn. So my paper is going to really evaluate a very interesting question about the role of measuring lipoproteins and their subfractions in patients, not with coronary disease, but peripheral arterial disease. And it comes to us from Dr. Scott Damrauer from the University of Pennsylvania School of Medicine. So Carolyn lipoprotein related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, just like we said. Largely based on their role in progression of coronary artery disease, but the relative contributions of these lipoproteins to those with peripheral arterial disease really haven't been as well defined. So these authors leveraged a large scale genetic association data to investigate the effects of circulating lipoprotein related traits on peripheral arterial disease risk.
Dr. Carolyn Lam:
Interesting. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So ApoB was prioritized as the major lipoprotein fraction usually or almost causally responsible for both peripheral and coronary artery disease risk. Extra small VLDL particle concentration, we'll call that excess VLDLP was identified as the most likely subfraction associated with peripheral arterial disease risk while large LDL particle concentration was most likely the sub fraction associated with coronary artery disease risk. And genes associated with excess VLDLP and large LDL particle concentration included canonical ApoB pathway components although gene specific effects were quite variable. And then finally Carolyn, lipoprotein A was associated with increased risk of peripheral arterial disease, independent of Apo protein B. So therefore Carolyn, I think the take home message from this study is that ApoB lowering drug targets and ApoB containing lipoprotein subfractions had really diverse associations with atherosclerotic cardiovascular disease and distinct subfraction associated genes suggested that possible differences in the role of these lipoproteins really are involved in the pathogenesis of peripheral arterial as opposed to coronary arterial disease.
Dr. Carolyn Lam:
Wow. Thanks Greg. Hey, it struck me that we haven't had a quiz in a long time. Okay, but we're not going to do it now. Don't choke because this one's kind of tough. I don't think I could even answer it. What is phospholamban?
Dr. Greg Hundley:
Well, let me guess. I remember having this, I think. Let's just... Carolyn I do not know what phospholamban is.
Dr. Carolyn Lam:
Let me just tell us all. Phospholamban is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in phosphate lanvin is associated with dilated cardiomyopathy and a high prevalence of ventricular arrhythmias. But how this deletion causes dilated cardiomyopathy is still poorly understood. And there are no disease specific therapies. And hence today's paper, which comes from Dr. Karakikes and colleagues from Stanford university school of medicine. What they did is they employed human induced pluripotent stem cells and CRISPR Cas9 gene editing technologies to create an in vitro model of dilated cardiomyopathy associated with this phosphate lanvin 14 deletion mutation. Single cell RNA sequencing revealed the activation of an unfolded protein response pathway, which was also evident by significant up-regulation of marker genes in the hearts of patients with the deletion. Pharmacological and molecular modulation of this unfolded protein response pathways suggest a compensatory role in this type of dilated cardiomyopathy. Augmentation of the unfolded protein response by the small molecule BIP protein inducer X Millia rated contractile dysfunction.
Dr. Greg Hundley:
So Carolyn, tell me what are the clinical implications?
Dr. Carolyn Lam:
Well, these findings suggest a mechanistic link between proteostasis and the phospholamban 14 deletion induce pathophysiology that could be exploited to develop a therapeutic strategy for this kind of cardiomyopathy. The study also highlights how human induced pluripotent stem cells and cardiomyocyte modeling could be combined with small molecule testing as a paradigm for studying genotype, phenotype associations in heart disease.
Dr. Greg Hundley:
Very nice Carolyn. Well, my next paper comes to us also from the world of preclinical science. And it's from Dr. Philip Marsden from the University of Toronto. And Carolyn endothelial nitric oxide synthase or eNOS is an endothelial cell specific gene predominantly expressed in medium to large size arteries where endothelial cells experience athero-protective laminar flow with high shear stress. Now disturbed flow with lower average shear stress decreases eNOS transcription, which leads to the development of atherosclerosis especially at bifurcations and in the curvatures of arteries. So the prototypical arterial endothelial cell gene contains two distinct flow responsive SIS DNA elements in the promoter. The shear stress response element and the Kruppel-like factor or KLF element. Previous in vitro studies suggested there're positive regulatory functions on flow induce transcription of the endothelial genes, including eNOS. However, the in-vivo function of these SIS DNA elements remains unknown.
Dr. Carolyn Lam:
Wow. So what did these investigators do, Greg?
Dr. Greg Hundley:
Right. So Carolyn the authors report for the first time that the shear stress response element and the KLF elements are critical flow sensors necessary for a transcriptionally permissive hypo methylated eNOS promoter in endothelial cells under chronic shear stress in vivo. Moreover endothelial nitric oxide synthase expression is regulated by flow dependent epigenetic mechanisms, which offers novel mechanistic insight on eNOS gene regulation in atherogenesis.
Dr. Carolyn Lam:
Nice. Thanks Greg. Well, let's go through what else is in this week's issue. In a cardiovascular case series, Dr. Ribeiro discusses the Platypnea-Orthodeoxia Syndrome, a case of persistent hypoxemia in an elderly patient. In ECG challenge, Dr. Challenge shows a case of diffuse St. Segment elevation with idiopathic malignant ventricular arrhythmias. There's an exchange of letters between doctors Wang and Sattler regarding the article cross priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart. And there's an On My Mind article by Dr. Mullasari Sankardas on of occlusions, inclusions and exclusions time to reclassify infarctions. So interesting.
Dr. Greg Hundley:
Very nice, Carolyn. So I've got a couple of things in the mail bag. There is from Professor Kunfu a Research Letter entitled PTP MT-1 is required for embryonic cardio lipid biosynthesis to regulate mitochondrial morphogenesis and heart development. And then finally our own Bridget Kuhn has a cardiology news entitled vegan diets that are culturally aligned with traditional soul food gained popularity among black individuals. Well Carolyn, I can't wait to get to your feature discussion today.
Dr. Carolyn Lam:
Me too. Today's feature paper is about the impact of high deductible health plans on emergency department patients with non-specific chest pain and their subsequent care. I'm so pleased to have with us the first author Dr. Andrew Chou from Brigham and Women's hospital, as well as the editorialist Dr. Alexander Sandhu from Stanford university. Welcome gentlemen, please tell us about your current study.
Dr. Andrew Chou:
Yeah, so I think the reason we did this study was really obviously aware of the context, but also me working as an emergency decision. So anybody in the ED will now that, there's all kinds of versions of chest discomfort that comes through the ED and they always are worried about heart attack. And we do this testing kind of day in day out, it gets kind of inundated. So a lot of people have put thought into what we should do in the emergency room. We should get ECG, we should care cardiac enzymes when we're worried about it. But what really quite remains uncertain is really what to do afterwards. We get this patient, we test them, we didn't really find heart attacks, but there's a lot of uncertainty about what to do after. Do we do stress test, do we hospitalize them to get the stress test or other testing.
Dr. Andrew Chou:
As a result, there's a lot of variation in care. And I think partly because of that, they're kind of the shared decision making came out of that. As a part of the solution was to involve patient via, Hey, here are your risks. Let's talk about whether or not this would make sense for you to stay, get testing among other decisions. But what's always interesting to me is that even though we have this push towards having patients have kind of needing to make these decisions because of money, we don't really talk about costs and even their sort of sense of pride about, oh, we don't want to talk about costs. We just want to be the best medical treatment for you, but cost is such a reality for the patients. So, that's kind of the motivation behind getting this study done. So the way we wanted to test it was to set it up as closely as possible to run my trial but knowing that it's not really possible in the real world to do something like that.
Dr. Andrew Chou:
So we had to be pretty selective about who we include as a study population. So the first thing we did was we took essentially a large national insurer and their claims database. We look at only the people who enrolled in insurance products through their employer. So employers in the US can choose what type of plan they want to offer patients. And we only chose employers that offer only one type of insurance at a time within each year of a plan. So what we did is we chose people who had essentially two years of enrollment. And in the first year, they all have to have loaded up full plans.
Dr. Andrew Chou:
Meaning deductibles are less than $500. It's still a lot of money, but it's less compared to... The second year either they still have low deductible plan or the experimental group is going to be a group of people who employer only offer high deductible plan, which we define as having deductible greater than $1,000. So that sort of set up a control and experimental group with a similar baseline and then a different followup period of a year. And then we also did additional matching by employer characteristics and their own, the member characteristics to kind of make them as close as possible in terms of compabilities, age, as well as employer size, which we find to be a really big factor. Because large employers tend to have lower deductibles because they can risk care a lot better among their employees where a small employers like companies with five, 10 employees tend to have high deductible plans. So we use that population to compare essentially what happens after a certain company switch to kind of calculate the effect of the high deductible plan.
Dr. Carolyn Lam:
Great. Very novel design. But could you please tell us your results?
Dr. Andrew Chou:
Yeah, so we found is that once the employees from the companies that switch, there were less ED visits that ended up with a diagnosis of chest pain. This is important to bring in also the nuance here, which is that these are ED visits that effectively are not have been seen and test it. And they don't have a severe diagnosis like a heart attack or other significant cardiac issues that were found at least during the initial ED stay. And that decreased, which sort of makes the question whether or not these decreased visits or either where they just another chest visit without really other diagnoses or are they visits that actually have diagnosis. The other thing we found was also that there's a decrease in admissions from these ED visits actually. And majority of it, even though when we did our study, we actually were looking at admissions through the 30 days after these ED visits.
Dr. Andrew Chou:
But we found that the majority of difference is actually the admissions directly from these initial ED visits with time is just horrible. Two more things we found was that the amount of testing that was done after the ED visits, or not really consistently decreased because of high deductible, some tests really didn't have a difference and some more invasive and expensive tests did have some differences. But if you account for the decrease in the chest pain ED visits, then they're not really that notable. But the last finding, which perhaps is the most interesting of which is that there seems to be an increase in heart attack diagnosis and admissions after these visits for chest pain and our statistics for the entire study population actually wasn't significant. But we decided to look at the subgroup patients from poor communities who presumably have lower income and found that the same findings in this group was actually statistically consistent and so we felt comfortable reporting that. So I think that was probably the most interesting finding from our study.
Dr. Carolyn Lam:
Right. Thanks Andrew. Alex, I have to bring you in here. I really love the editorial love that you said to go or not to go as the title. But could you put these findings in context, please?
Dr. Alexander Sandhu:
Yes. Happy to and thank you for having me. I think studies like this study by Andrew and colleagues are incredibly important as we make health policy decisions that have large impacts on clinical decision-making for both patients and clinicians. It's important that we study them to understand how they impact patient decision-making clinical outcomes and costs, because obviously that can have important ramifications for future design at the end detecting unintended consequences. I think this study adds to a large body of work done by Andrew and his colleagues, really helping us to understand the implications of high deductible health plans on patient decision-making and subsequent outcomes. This is an incredibly important topic because of the proliferation of high deductible health plans over time and then potentially since the advent of the Affordable Care Act with fixed premiums leading to more and more cost sharing for patients. And it's really critical that we understand how that cost sharing impacts patients.
Dr. Alexander Sandhu:
And I think that chest pain is a wonderful test because chest pain can be something very serious. It's almost universal that when patients have acute onset chest pain, that a clinician asks them to go to the emergency department for further evaluation. However, we also have a large body of evidence that suggests that the large majority of chest pain episodes are not serious and don't end up needing additional treatment. So it's an area that I think both you could imagine decreased utilization once you applied cost sharing to patients. But what were you very much worried about the unintended consequences of people not going to the emergency department, if it's a serious condition. I think this was a well-designed quasi experimental analysis to look at the lower risk, but majority of episodes of chest pain where they're non-specific and not resulting in acute coronary syndrome and to try to demonstrate it that the high deductible health plans do lead to reductions in those episodes.
Dr. Alexander Sandhu:
I think as Andrew said, one of the most fascinating findings was this increase in acute MI's it was consistently significant amongst the low-income patients, but was not related to patients that were discharged because of potentially the effects of the high deductible and then came back in with acute MI's but were actually acute MI's during the initial admission. I was wondering if Andrew could maybe both explain that nuance a little bit more, which you get into the discussion of that paper, and then also walk us through maybe some thoughts that you and your study team had for causes for that potential finding.
Dr. Andrew Chou:
Yeah, absolutely. Thanks for raising that. So I think going into it initially, our hypothesis was really that, but when we first saw it, our initial thought was that, oh, maybe perhaps after they're discharged, they're supposed to get testing and patients or then follow up with their doctors. So they have increased poor outcomes. And so after that thought, that's when we did the kind of subgroup analysis looking at just patients who were discharged versus those who were admitted when they were diagnosed with chest pain at their initial ED visits. And exactly what we found is that the difference is really among people who were admitted initially, which is surprising to us. So I think what that signals to us is that our initial thought was not correct in the sense that this is not really a result of lack of followup or didn't intend to the testing that they were scheduled or didn't go see their doctor afterwards. But really like patients who are showing up in the ED already are more prone to perhaps having a heart attack.
Dr. Andrew Chou:
And so it really points to which is what you mentioned at your program, which we totally agree as well, that more upstream factors is affecting this. Could it be that they don't tend to take their medications as they should, or they didn't go to their doctors for checkups as they should, or they could have had earlier identification of heart problems if they have more perhaps milder symptoms beforehand until before the ED visits that could have presented certain things. So, that's hard to say. I do think that there is a... One of my mentors in this paper, Dr. Wareham, who has done a ton of work in the space of high deductible plan with kind of chronic disease management, they have definitely shown a lot of differences when patients have higher cost sharing. They'd certainly defer a lot of carriers, especially in diabetics have more complications and it might be a similar scenario here that which would make the most sense and fits the best with our findings here.
Dr. Carolyn Lam:
So that's a great question Alex and great insight Andrew. I think at this point, I need to ask you both. So what overall do you think is the clinical implication or there'd be any practical next step that you think should follow from this? Maybe I'll let Andrew start and then Alex finish?
Dr. Andrew Chou:
Sure. Thank you. I think there's kind of... I think two aspects to this one is really broader policy changes. I think if anything, it's quite uncertain whether or not the reduction in ED visits for chest pain is something detrimental. It's unsure whether or not the reduce admission is detrimental. But what is certain is that especially in lower income population certainly feels the higher out-of-pocket costs a lot more. And if there is an unintended consequence, it will certainly be magnified in this population. And in fact, I think a couple of past studies who having compared really high income versus low income population has found that really, high income patients tend to do okay and they're able to pick and choose appropriately of type of care they need. Whereas low-income patients tend to have really unanticipated changes. So, really trying to minimize the impact for low-income patients is going to be important policy direction.
Dr. Andrew Chou:
And there are a number of ways of doing it. I think there certainly is an increasing trend for companies to fund the health savings account, which is actually a tax deferred almost like investment accounts or certain fund to help them offset some of their healthcare out-of-pocket costs. But the other aspect of it, which I think is all a bit harder to push for is really for employers and insurance to just keeping their account patient's income when they're kind of pushing forward products for a high deductible plan. So low-income patients should just not have quite as big of a deductible as the high income earners do. But a different aspect it's really clinically for clinicians. It's tough because I think insurance put this forward because they want to influence patient decisions before they even see the clinician. But after they decide to come visit clinician, I think the clinician should be aware of the financial reality for the patient when making these decisions.
Dr. Andrew Chou:
But it's really hard for me to think about whether or not this is going to be a good thing for the patient or not. And one of the biggest concerns for really my colleagues in the department is really whether or not if we are really talking poor patients out of certain care by reviewing their financial reality with them and by through that are we essentially discriminating against other patients. So that's really a big unknown. I think that's definitely an area that we should definitely heavily invest in research because we're just pushing forward with price discussion for care to encourage price discussion at the clinic here without really knowing what's going to happen.
Dr. Carolyn Lam:
Yeah. Wow. Alex?
Dr. Alexander Sandhu:
Yeah, I definitely agree with Andrew. I think if we want to make decisions based on cost and we want patients to make those decisions and we as clinicians, obviously should be helping them. We need more transparency around costs, current deductible status, and that has to be available at the point of care so it actually can be integrated in decision-making. But I think that's likely not enough. I mean, even for clinicians, it's hard to determine how clinically necessary it is to get emergency evaluation before you see the patient when you get a phone call. So I think, if it's hard for clinicians with all of our years of experience, it's hard to understand how we can really expect that from our patients.
Dr. Alexander Sandhu:
I wholly agree with Andrew that I think a critical step is it's going to be important to reduce the risk of cost sharing for low-income patients with a number of potential interventions to do that, which I think are the real policy implications here. And then more generally, I think we should make sure that deductibles aren't discouraging utilization of high value cost effective intervention. There are currently safeguards in the Affordable Care Act about that. But I think we need to think about those closely and probably expand that so we don't see high deductible health plans leading to lower stat rates or worse diabetes prevention.
Dr. Carolyn Lam:
Wow. Words of wisdom. I just cannot thank you both enough for publishing such a beautiful paper, important findings, as well as just a very lovely editorial in Circulation. Thank you. Learned a lot. I'm sure the audience did too. Please remember you're listening to Circulation on the Run. Please tune in again next week with Greg and I.
Dr. Greg Hundley:
This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more visit ahajournals.org.
This week's episode features author Aaron Baggish and Associate Editor & Editorialist Satyam "Tom" Sarma as they discuss the article "SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts ... I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center from VCU health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, this feature discussion is just so relevant to our current times. It talks about SARS-CoV-2 cardiac involvement in young competitive athletes. Oh, one that I'm sure we're all dying to get to. Very important. But first, let's tell you what's in this week's issue. Greg, you want to go first?
Dr. Greg Hundley:
You bet, Carolyn. I'm going to grab a cup of coffee, and we're going to dive into the world of preclinical science. Our first paper comes to us from Professor Naftali Kaminski from Yale University. Carolyn, these investigators reprocessed human control single-cell RNA-sequencing, or scRNA sequence data from six datasets to provide a reference atlas of human lung endothelial cells to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium. Also, the signaling network between different lung cell types was studied.
Dr. Carolyn Lam:
Wow. Okay. So what did they find, Greg?
Dr. Greg Hundley:
Six lung single-cell RNA-sequencing datasets were reanalyzed and annotated to identify over 15,000 vascular endothelial cells from 73 individuals. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous endothelial cells, the co-authors found two previously indistinguishable populations. Pulmonary venous endothelial cells, called COL15A1neg localized to the lung parenchyma and systemic venous endothelial cells, COL1581positive localized to the airways and visceral pleura.
Dr. Greg Hundley:
Now, among capillary endothelium cells, the authors confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1, and TBXX2 and general capillary endothelial cells. The authors confirmed that all six endothelial cell types, including the systemic venous endothelial cells and aerocytes, are present in mice and identified endothelial marker genes conserved in both humans and mice.
Dr. Greg Hundley:
So Carolyn, I'm going to take a question I bet you're getting ready to ask. What are the clinical implications of this research? Well, mainly that understanding the lung endothelial diversity is crucially important to identify new therapeutic approaches for vascular diseases such as pulmonary hypertension.
Dr. Carolyn Lam:
Wow. That was interesting, Greg. Thank you. I've got another one from basic science world as well, and this one talks about the initial functional characterization of an exercise-induced cardiac physiological hypertrophy associated novel long non-coding RNA or LncRNA.
Dr. Greg Hundley:
Okay, Carolyn. Quick quiz. Can you remind us what these long-coding RNAs are?
Dr. Carolyn Lam:
Ha. Sure. So long non-coding RNAs or LncRNA refers to RNAs that are longer than 200 nucleotides and lack the potential to encode proteins, but have still been closely related to the occurrence and development of many diseases.
Dr. Carolyn Lam:
The current paper comes from co-corresponding authors, Dr. Li from the First Affiliated Hospital of Nanjing Medical University and Dr. Xiao from Shanghai University. They identified a LncRNA in the heart named cardiac physiological hypertrophy associated regulator, or CPhar. This was increased following exercise training and was necessary for exercise-induced cardiac growth. In neonatal mouse cardiomyocytes, over expression of this LncRNA induced an increase in these cardiomyocytes' size and expression of proliferation markers while inhibition of the LncRNA reduced these neonatal mouse cardiomyocytes' size and the expression of proliferative markers. Over expression of the LncRNA led to a reduction in oxygen glucose deprivation reperfusion-induced cardiomyocyte apoptosis, while LncRNA knockdown aggravated the apoptosis.
Dr. Carolyn Lam:
In vivo over expression of that LncRNA prevented myocardial ischemia reperfusion injury and improved cardiac function. So mechanistically though, the transcription factor, ATF7, acted as the functional downstream effector of this cardiac physiological hypertrophy associated regulator, the LncRNA.
Dr. Carolyn Lam:
Now Greg, following your example, I'm going to ask what are the clinical implications and tell you. So these results provide new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of this LncRNA known as cardiac physiological hypertrophy associated regulator in the heart. It also expanded our knowledge and understanding of the functions and fundamental mechanisms of LncRNAs in general.
Dr. Greg Hundley:
Wow, Carolyn. Beautifully described. Well, my next paper comes to us from the world of clinical science and really it's kind of something that's going to get into spending. It comes to us from Dr. Brandon Bellows from Columbia University.
Dr. Greg Hundley:
So Carolyn, spending on cardiovascular disease and cardiovascular risk factors, in total cardiovascular spending, accounts for a significant portion of overall US healthcare spending. The author's objective was to describe US adult cardiovascular spending patterns in 2016 and changes from 1996 to 2016, and look at the factors associated with these changes over time.
Dr. Carolyn Lam:
Wow. Okay. So were the authors are viewing time-dependent changes in cardiovascular spending. Is that it? What did they find?
Dr. Greg Hundley:
Absolutely Carolyn. So a bunch of data. Just kind of some interesting facts here. So let's work through them. Adult cardiovascular spending increased from 212 billion in 1996 to 320 billion in 2016, a period when the US population increased by over 52 million people and the median age increased from 33 to 36.9 years.
Dr. Greg Hundley:
Next, over this period, public insurance was responsible for the majority of cardiovascular spending at 54% followed by private insurance at 37% and out-of-pocket spending at 9%.
Dr. Greg Hundley:
Next, health services for ischemic heart disease at about 80 billion and hypertension, 71 billion, led to the most spending in 2016.
Dr. Greg Hundley:
Next, increased spending between 1996 and 2016 was primarily driven by treatment of hypertension, hyperlipidemia, and atrial fibrillation flutter on which spending rose by $42 billion, $18 billion and $16 billion respectively. Increasing service price and intensity alone were associated with 51% or 88 billion, and cardiovascular spending increased from 1996 through 2016. Whereas, changes in disease prevalence was associated with a 37% or $36 billion spending reduction over the same period after taking into account population growth and population aging.
Dr. Greg Hundley:
So in summary, Carolyn, US adult cardiovascular spending increased by about $100 billion from 1996 to 2016. Maybe policies tailored to control service price and intensity and preferentially reimburse higher quality care, perhaps that could help counteract future spending increases due to population aging and growth.
Dr. Carolyn Lam:
Oh, wow. Those are staggering numbers. Thanks Greg. Now let's go through what else is in this week's issue. There's an exchange of letters between doctors Mehmood and Houser regarding the article, Cardiac Remodeling During Pregnancy with Metabolic Syndrome: A Prologue of Pathological Remodeling. There's an ECG challenge by Dr. Real on an unusual call from the urology ward. There's also a Research Letter from Dr. Molkentin on cardiac cell therapy failing to rejuvenate the chronically scarred rodent heart. And finally a Special Report by Dr. Althouse on Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report from the American Heart Association.
Dr. Greg Hundley:
Great, Carolyn, and I've got a Perspective piece entitled, Intravenous Iron Therapy in Heart Failure with Reduced Ejection Fraction: Tackling the Deficiency. It's from Professor Ardehali.
Dr. Greg Hundley:
Well, Carolyn, how about we get on to that feature discussion and learn more about SARS-CoV-2 in young competitive athletes.
Dr. Carolyn Lam:
Ooh, let's go. In our current COVID-19 pandemic a huge question is, does cardiac involvement in athletes with COVID-19 preclude their further participation in sports? What is their involvement after they've recovered from COVID-19? Guess what? Today's feature discussion is really hitting the spot with this question. So pleased to have with us the corresponding author of the feature paper, Dr. Aaron Baggish from Massachusetts General Hospital, as well as Dr. Satyam Sarma also known as Tom Sarma, our dear Associate Editor from UT Southwestern, who is also an editorialist for today's paper. So welcome Aaron and Tom. Aaron, could you start us off by describing your study and what you found?
Dr. Aaron Baggish:
Sure. So just very briefly, some historical context. As everyone is quite aware, when we first started seeing COVID-19 in the hospital, there was a lot of concern about what the virus did to the hearts in people that were sick enough to be hospitalized. Those of us in the sports cardiology community were quite concerned that when young athletes that developed COVID-19 infection got sick and then returned to sport, that we'd be seeing the adverse events associated with cardiac involvement. So that was the impetus to start the ORCCA Registry, which was really an opportunity to try to capture the large-scale experience with collegiate athletes returning to sport after COVID-19 infection. Indeed, with roughly 19,000 student athletes across 42 universities, there were approximately 3,000 that developed COVID-19 infection and then went through some form of cardiac screening prior to return to play. The registry was really about telling that story of what we found and what we think the implications are.
Dr. Carolyn Lam:
Aaron, I mean, first of all, more than 19,000 athletes recruited in just ... What was it? September 1st to December 31, 2020? How did you accomplish this amazing registry so quickly? That's amazing.
Dr. Aaron Baggish:
I need to acknowledge the fact that this was an incredible team effort. I was joined and continue to be joined in this by my co-PIs, Dr. Jon Drezner and Kim Harmon, who are sports medicine physicians out of the Seattle area, and the combination of cardiology, expertise and sports medicine expertise really able to pull in many of the large universities and colleges around the country, including most of the Power Five schools to participate in this registry.
Dr. Aaron Baggish:
In short order, team physicians from all these schools understood the importance of this work and agreed to partner with us to work very hard to enroll their student athletes and to provide us with the information we needed.
Dr. Carolyn Lam:
Incredible. But with the foresight, congratulations, this in and of itself is amazing. Now, could you please tell us what you found?
Dr. Aaron Baggish:
Sure. So we found that indeed, as we expected, that these student athletes were undergoing a fair bit of cardiac testing prior to being allowed to return to sport, and that there was variability in terms of what type of testing they were getting. The majority of schools were following what at that point were the recommendations, which were do, what we call the cardiac triad testing, which includes an echocardiogram, a high-sensitivity troponin, and an ECG and to use that information to either clear athletes or send them through further clinically indicated tests. A small number of early adopters had decided to do mandatory cardiac MRIs. So within that, we were able to understand what the prevalence, if you will, of cardiac involvement in these COVID-19 student athletes looked like, and it varied as a function of what type of tests people were doing.
Dr. Carolyn Lam:
And? Give us a sneak peek.
Dr. Aaron Baggish:
As people would expect, the more sensitive tests you do, the more abnormalities you detect. So among the schools that were using a mandatory cardiac MRI approach, there was a 3% prevalence, if you will, of either definitive, probable or possible COVID-19 cardiac involvement. When schools were following the triad testing first followed by clinically indicated CMR that prevalence was much less. It was approximately 0.5 or 0.6%. So I would emphasize that on the whole, regardless of which test was being used, that the involvement was at a much lower rate than we expected based on what we saw early in the hospitalized patient experience. So I think it's a very good news story.
Dr. Carolyn Lam:
Indeed. That's exactly, I think the title almost of Tom's editorial. Tom, could I bring you in here, please? Could you give us the context of this and then tell us what as editors we thought of the paper when it kind of reached out doors at Circulation?
Dr. Satyam “Tom” Sarma:
Sure. No, this was, I actually remember almost exactly when I was asked to handle this paper from an editorial standpoint. Joe texted me, Joe, our editor-in-chief texted me ... I think, the night, actually it was a Friday night I think ... That we had a really important paper, would you be able to take care of it on an expedited basis? I said, "Of course." So took a look at it over the weekend, and it's one of those papers when you're reading it, you almost wish you had a time machine because you realize if we had known this information eight, nine, 10, 11 months ago, it would have totally changed how we handle the pandemic from an athlete and young person standpoint. So from that aspect, I thought this is obviously a very high impact paper.
Dr. Satyam “Tom” Sarma:
Which then led me to the second challenge is finding the right reviewers for this paper because obviously this is a very controversial topic. We wanted to make sure we had the best reviewers we can get. The challenge, unfortunately, was that a lot of my usual go-to reviewers were actually members of the ORCCA Registry. So there were some issues with conflict of interest there, and so from a reviewer standpoint, I looked to sort of leaders in the field who had done something similar. The first thing that came to mind was really how the field has handled ECG screenings for our young athletes. I think there's, again, a perspective there that I think is very similar to how do you handle patients or young athletes with COVID and then how do you emphasize shared decision making? So from that standpoint, I had a narrow list of experts in shared decision making in sports cardiology, and really leaned on them to help guide us through the process because this is a complex paper.
Dr. Satyam “Tom” Sarma:
I think their feedback was instrumental in really helping to kind of distill the message, to kind of phrase things in a way that allowed the message to be easily digested by both the lay media, but more importantly, by sports trainers and athletic directors around the country. From that standpoint we really work hard and again, really thank you to Aaron and Jonathan on this manuscript because they worked so hard with our reviewers. They were incredibly responsive to almost every review comment. From that standpoint, I think the end result was amazing to really see it in final format.
Dr. Carolyn Lam:
I love that behind-the-scenes look. Thank you so much, Tom. What is the strong clinical implication of this? If you have questions for Aaron, please go ahead.
Dr. Satyam “Tom” Sarma:
Sure. No, I think the biggest thing for us as editors and sort of from the public health impact was, as Aaron mentioned, some schools have unlimited resources to really throw as much money as they can at the problem or what they think is the best approach to the problem. Again, when you have unlimited resources, you can get the "best tests." I think, unfortunately not every school in this country, both from a collegiate or high school level, has a capacity and more importantly, around the world. That's a really important limiting factor.
Dr. Satyam “Tom” Sarma:
Is there a way to distill the algorithm in a way that's both safe for the athletes, but more importantly is feasible for most schools? For us, that was the most important public health message was really to get that out there. The second of course, was that thinking back to last summer, just how many COVID myocarditis papers we handled in Circulation. Looking back with the again, in the heat of the battle, things are always challenging, but just to sort of see how the pendulum shifted in such a 180 degree sort of manner. So that also I think was important to get out there as well.
Dr. Carolyn Lam:
Yeah. And exactly why this paper is so important. So thank you once again for publishing it with Circulation. Tom though ... Okay. I mean, not to underestimate the MRI findings and so on. I think you had a question for Aaron in relation to that?
Dr. Satyam “Tom” Sarma:
I do. One of the challenges, again, being on the myocardial side is that we're not always experts in the papers we're assigned, and it's obviously been an incredible learning process. For me, I was hoping to pick your brain a little bit about the MRIs and sort of how you think the field will evolve from a sports cardiology standpoint. Especially as scanners get more powerful, as scanners get more sensitive, the challenges I think the field's going to have is really detecting the tiniest fleck of an abnormality.
Dr. Satyam “Tom” Sarma:
I think the context here is really the recent paper out of the Big 10 where they MRI'd, I believe, everyone in that registry ... I want to say it was over 2,000 athletes. Just out of curiosity, how was that handled, again, amongst your co-authors in deciding how best to present the MRI data? I like how you use the probabilistic language of it's either definite, probable or possible. How do you see that sort of progressing in terms of is that something practical that can be used by sports trainers and sports medicine staff to help restratify your athletes or athletes?
Dr. Aaron Baggish:
Tom, there's so much packed into that question. Let me try to unpack it piece by piece. So first off in our registry, there were a few schools that were early adopters in mandatory CMR screening, and so we wanted to very much responsibly report that. Again, there was about a 3% prevalence of something being abnormal with the myocardium based on the scans. We also realized that not all abnormalities were created equal, and that's why we did come up with that definitive, possible, probable nomenclature to really capture the fact that there were a few people that looked like they had overt myocarditis. But the vast majority had non-specific findings that those of us as clinicians pre-COVID would not have considered myocarditis.
Dr. Aaron Baggish:
The issue with MRI is a complicated one. The way I like to think about this as, as you mentioned earlier, is to go back to the historical experience we had with ECG screening in which doing that before we understood how to use it as a screening tool caused more problems than it solved.
Dr. Aaron Baggish:
It was really back in the mid-2000s when the Italians published their first ECG screening paper that the Americans got interested in it. What we learned is that if you used ECG, and this applies to MR too, without having good normative data, without understanding the cost implications, without having the experts prepared to interpret the test and deal with the downstream findings, that you're just not ready for prime time.
Dr. Aaron Baggish:
While I think the use of MRI as a screening technique during COVID was done with the best of intentions, I think the Big 10 paper, which is a very important dataset in this discussion, highlighted why MRI is just simply not a useful screening tool right now. If you look across their schools, they had tremendously variable rates of cardiac involvement, which is not a function of pathobiology. This virus is not different in Virginia than it is in Tennessee than it is in Wisconsin. It's just simply that people are using the tool in different ways and coming up with different findings. What we're now seeing clinically is that all these MRIs are finding a lot of stuff that either we don't want to care about or we don't want to know, and we're stuck dealing with it. So a challenge ahead of us, for sure.
Dr. Satyam “Tom” Sarma:
No, I think that's a really important point, Aaron. I think looking back even from a clinical standpoint in those, didn't not necessarily look at athletes, I think what you bring up is really important. The cognitive bias. Find something abnormal. I do wonder if you could talk a little bit about ... One of the other concerns we had behind the scenes was if you know an athlete, if you're an MRI reader and you know an athlete or the scan in front of you says 19-year-old athlete with COVID, can you talk a little bit about the cognitive biases that kind of go into sort of assuming either the worst case scenario, especially with athletes, because again, these are young, robust, healthy people who may or may not be on TV or in a very public format. How do you handle that as a sports cardiology in general, just kind of overcoming the cognitive bias, both from a public policy standpoint, but also from a lay public standpoint?
Dr. Aaron Baggish:
Yeah. So I think bias is such an interesting word to me because bias has a negative connotation, but bias actually also has some positive attributes associated with it. Bias really pushes people to be, in this situation, to be conservative and to try to do what they think is best.
Dr. Aaron Baggish:
But what I think it boils down to is going back to a very simple tenet and that's understanding the pre-test probability of disease. So when we interpret imaging data or exercise testing data, it always goes back to the question of why did this person get the test done in the first hand and what is our pre-test probability of finding something wrong? I think what we've learned through the COVID pandemic is that just simply having COVID does not equate with a high pre-test probability of having myocarditis in this young population. That it's really the kids that present, and these are the rare few and far between, that present with clinical findings that any doctor would think of as being consistent with myocarditis, where the scan is really helpful. The vast majority of time it's just simply not that case.
Dr. Satyam “Tom” Sarma:
No, I agree. I think that's always the challenge as well, too clinically as well too, with the diagnostic creep of you get one test that's kind of abnormal and the next thing you know, you're doing a cardiac biopsy and trying to figure out how you got to where you got to.
Dr. Satyam “Tom” Sarma:
I wanted to circle back to Carolyn's comment. I guess obviously COVID kind of really was the dominant health story over the last 12 to 14 months. Has there been a similar rash, in other words, I'm thinking back to H5N1 or some other pandemics in the past, was there a similar concern historically from the sports cardiology community with those viral outbreaks?
Dr. Aaron Baggish:
No. Not to my knowledge, and that's simply because there wasn't as much of an experience with hospitalized patients in the US in those prior pandemics. Again, our concern in sports cardiology world really stemmed from a very different population than the one we deal with on a daily basis. I think we learned that, although we thought that was a well-intending way to approach it, that it turned out to be an overreaction.
Dr. Aaron Baggish:
Before we end, I want to return to Tom's comments about the process and just share with the listeners what a satisfying process this was as an author. Having been through the peer review process, many hundreds of times with different journals, I don't remember one that was as satisfying nor one that led to as high quality of paper based on the feedback we got from the reviewers. So very much appreciative.
Dr. Aaron Baggish:
I also want to acknowledge the American Heart Association that has become a long-term partner in this effort. As we move out of the pandemic, the ORCCA Registry will be pivoting to really capture what happens to young athletes that are diagnosed with genetic and congenital forms of heart disease. We're very appreciative that the AHA has agreed to partner with us on this.
Dr. Carolyn Lam:
Aw, my goodness. Thank you so much, Aaron and Tom, for this incredible discussion. I really want to end with, if I may Tom, citing your editorial. I love the way you ended it by saying, "As Nelson Mandela said, 'Sports has the power to change the world. It has the power to inspire. It has the power to unite people in a way that little else does.'" We got seriously scared with COVID-19, but this paper is just so important in providing some reassurance that there has not been a single case of cardiac complication to date, documented to be clearly related to COVID-19 in this population. It's a real testament to the hard work that you've put in. So thank you. Thank you very much for this paper. For all the effort. Thank you both for being here to discuss this.
Dr. Carolyn Lam:
Well, audience, you've been listening to Circulation on the Run. Thanks for joining us today, and don't forget to join us again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's episode features author Kieran Docherty and Associate Editor Torbjørn Omland as they discuss the article "The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts: I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate, editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got an exciting feature this week involving Neprilysin license inhibition and left ventricular remodeling in patients with asymptomatic left ventricular systolic function after they've sustained myocardial infarction. But before we get to that feature discussion, how about we grab a cup of coffee and jump in on some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I'd love to, and I want to talk about transcatheter aortic valve replacement, or TAVR, that we all know is really transforming our management of aortic stenosis. Despite rapid improvements, however, serious complications remain relatively common and are not well-described by single outcome measures. So the purpose of this paper was to determine if there was site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. And this is from Dr. Desai and colleagues from Hospital of University of Pennsylvania. So they performed a retrospective cohort study using data from the STS/ACC TVT registry to develop a novel-ranked competent performance measure that incorporates mortality and serious complications. Based on the associations with one-year risk adjusted mortality and health status, they identified for peri-procedural complications to include in the composite risk model, in addition to mortality. And ranked empirically, according to severity, these were: stroke, major life-threatening or disabling bleeding, stage three acute kidney injury, and moderate or severe perivalvular regurgitation.
Dr. Carolyn Lam:
Now, based on these ranked outcomes, they found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better-than-expected site performance was observed in 8% of sites, whereas performance as-expected was observed in 80%, and worse-than-expected performance was observed in 11% of sites.
Dr. Greg Hundley:
Carolyn, really interesting comprehensive data. So how do we put this all together? And what's the take-home message for us, clinically?
Dr. Carolyn Lam:
Well, there are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine the structural, process-related, and technical factors associated with high- and low-performing sites. And all this is discussed in a beautifully, beautiful accompanying editorial by Drs. Dharam Kumbhani and Eric Peterson.
Dr. Greg Hundley:
Oh, fantastic. You know, Carolyn, those editorials are so helpful in helping us put these new data in perspective. Well, my next paper comes to us from the world of preclinical science, and it's from Professor Vincent Christoffels from Amsterdam in UMC. So genetic variants of SCN10A, encoding the neural voltage-gated sodium channel NaV1.8 are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. And these investigators studied the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, and coding the major essential cardiac sodium channel NaV1.5.
Dr. Carolyn Lam:
Wow, great. So what did they find, Greg? Sounds like a first-of-its-kind study.
Dr. Greg Hundley:
Right, Carolyn. So genetic variants in and around SCN10A modulate enhancer function and expression of the cardiac-specific NCN10A short transcript, and the authors propose that non-encoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV .8 and cardiomyocytes that impacts NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.
Dr. Carolyn Lam:
Wow, that was a lot. So what are the implications, Greg? Could you simplify it for us?
Dr. Greg Hundley:
Yes. Right, Carolyn. So three things. First, the authors uncovered a novel alternative mechanism for how the SCN10A locus regulates cardiac conduction. Second, their data implicate that genetic variation-sensitive regulation of expression of NCN10A short modulates conductivity of the heart, and can predispose to arrhythmia in the human population. And then finally, Carolyn, in deciphering the underlying mechanism of the increased NaV1.5 mediated current density by NaV1.8 short, the authors believe their findings could ultimately lead to the development of novel therapeutic strategies for particular conduction disorder.
Dr. Carolyn Lam:
Thanks, Greg. Well, this next paper is really interesting. It's the first validation of the enhanced potency of human-induced pluripotent stem cells-derived cardiomyocytes over-expressing Cyclin D2, or CCND2, under the control of myosin heavy chain promoter, and differentiated into cardiomyocytes. Now, that was a mouthful, but so interesting, because Dr. Zhang and colleagues from University of Alabama in Birmingham used infarcted pig hearts, and transplanted these amazing cardiomyocytes, and found that they were associated with proliferation of recipient heart cardiomyocytes, epithelial cells, and smooth muscle cells, all, at least partly, by paracrine activity.
Dr. Greg Hundley:
Well, Carolyn. Really an involved clinical design. So, what are the clinical implications of all this research?
Dr. Carolyn Lam:
Well, first, I think the paper validated a novel therapeutic strategy aimed at upregulating proliferation of recipient cardiac cells using human-induced pluripotent stem cells-derived cell or cell products. Furthermore, targeting the myocyte cell cycle regulators, such as Cyclin D2, holds a strategic potential for re-muscularization of an infarcted region.
Dr. Greg Hundley:
Very good, Carolyn. Well, how about we see what else is in this issue? So I'll start first. There's a Research Letter by Professor Marston, entitled 'Combining High-Sensitivity Troponin with the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'. Next, there's an ECG challenge from Dr. Feliciano, entitled 'An Ominous EKG'. And then finally, there's a very nice exchange of letters from Drs. Lang and Sattar regarding a prior publication: volume status is the key in heart failure.
Dr. Carolyn Lam:
And finally, a very important perspective piece by Dr. Catapano on omega-3 for cardiovascular disease: where do we stand after reduce it in strength? Wow, that was great, Greg. But let's move on now to our feature discussion.
Dr. Greg Hundley:
You bet.
Dr. Greg Hundley:
Well, listeners, we are on to our feature discussion today, on this July 20 issue. And we're very excited to have with us Dr. Kieran Docherty from University of Glasgow in Glasgow, Scotland, and our own associate editor, Dr. Torbjørn Omland from University of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's start with you. Could you describe some of the background related to your study, and what was the hypothesis that you wanted to address?
Dr. Kieran Docherty:
Well, firstly, thank you very much for the invitation to discuss our trial today on the podcast. The background of our trial was that we are all aware that the development of left ventricular systolic dysfunction following acute myocardial infarction places patients at a subsequent increased risk of the development of heart failure, and the process of progressive dilatation of the left ventricle and a reduction in stroke volume, known as adverse left ventricular remodeling, is the process which underlies this elevated risk of heart failure. And many of the treatments that have been shown to be beneficial following myocardial infarction, such as [inaudible 00:09:24] , and angiotensin receptor blockers and beta blockers, the benefit of these medications, in part, is due to their ability to attenuate this process of adverse remodeling. Now, our hypothesis was that it would be possible to further attenuate, prevent, or delay the process of adverse remodeling in patients at risk of heart failure following myocardial infarction, by the addition of a Neprilysin inhibitor to current standard of care.
Dr. Kieran Docherty:
Now, as we all know, a Neprilysin inhibitor in the form of sacubitril valsartan when combined with an angiotensin receptor blocker, has been shown to improve outcomes in patients with symptomatic heart failure, with reduced ejection fraction in the PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous levels of natriuretic peptides, amongst a range of other substrates for Neprilysin, including adrenomedullan, GLP-1, and bradykinin. And our hypothesis was that adding in a Neprilysin inhibitor, thereby increasing endogenous levels of these peptides with potentially beneficial effects, such as reducing fibrosis, reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have an additive beneficial effect on left ventricular remodeling in these high-risk patients with left ventricular systolic dysfunction following myocardial infarction.
Dr. Greg Hundley:
Very nice hypothesis. So, how did you set up, Kieran, your study design, and what study population, how many patients and whatnot, did you include in your study?
Dr. Kieran Docherty:
Well, the first consideration when designing the study was broadly, what group of patients should we involve? And the main limitation was the indication for the use of sacubitril valsartan in patients with symptomatic heart failure, so we did not feel that we could include these patients. Therefore, our study population included patients who had asymptomatic left ventricular systolic dysfunction following previous myocardial infarction. And specifically, we wanted patients who were at least three months following my cardiac infarction. And the reason for that was to try and exclude patients who had transient systolic dysfunction or left ventricular stunning. And we performed a screening transthoracic echo at this time point. And if patients had an ejection fraction of 40% or less on echo, and if they were tolerant of a minimum dose of an ACE inhibitor, 2.5 milligrams of ramipril BD or equivalent, and they were taking a beta blocker, unless contraindicated or not tolerated, then they were suitable for randomization.
Dr. Greg Hundley:
Very good. And what did you find?
Dr. Kieran Docherty:
So we find that in comparison with the ARB Valsartan, sacubitril valsartan did not have any beneficial effects on cardiac MRI-based measures of left ventricular remodeling. And the primary end point of our study was left ventricular end systolic volume index. There was also no improvements in biomarkers of myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high sensitivity to Troponin I.
Dr. Greg Hundley:
Very nice. And any pertinent issues relevant to, perhaps, some subgroups, regardless of age or perhaps gender?
Dr. Kieran Docherty:
So in a post-hoc analysis, we performed an analysis of the primary endpoint in patients who were below or at or above the median NT-proBNP level, which is 238 p-grams per mil. And we found, very interestingly, the suggestion of a benefit, in terms of left ventricular remodeling with a reduction and systolic volume index in patients who had higher levels of NT-proBNP compared to those who had lower levels.
Dr. Greg Hundley:
Very good. Well, listeners, let's turn now to our associate editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers come across your desk. What attracted you to this manuscript? And then how do you put the results of this study in the context with other studies that have been published, particularly recently, in patients with heart failure that have received sacubitril valsartan?
Dr. Torbjørn Omland:
So, Greg, there were many aspects of this trial that made it very attractive for circulation. I think the hypothesis was very interesting, and also it is a very well-conducted study using the reference methods for assessing left ventricular function, using that for assessing the primary endpoint. And they also have a broad array of secondary end points that also sort of provide insight in potential pathways or mechanisms that can explain the effect sacubitril Valsartan. So, that's also a very sort of hot topic within the cardiology research currently, and we know that the ACC, actually a much larger study, PARADISE-MI, was presented. And we knew that this study was also very interesting, because we knew when we received this manuscript, that another, bigger trial that's sort of related would be presented at the ACC at the late-breaking clinical trial sessions there the PARADISE-MI study. But this sort of provided insight that nicely complimented the results of that study.
Dr. Torbjørn Omland:
And I think as Kieran alluded to, we already have the very impressive results from PARADIGM-HF is showing a very substantial benefit in patients with chronic heart failure and reduced ejection fraction. And then we have sort of the borderline results from the Paragon trial, in those with preserved ejection fraction, where it actually was a gradient from those with mildly elevated, where there seemed to be a beneficial effect to those with more normal EF, where there was no effect. So, this study sort of provided new information, very relevant to the whole field, I think.
Dr. Greg Hundley:
Very nice. Well, gentlemen, I want to turn back to you and ask each of you, first Kieran, and then Torbjørn. Kieran, what do you think is the next study that needs to be performed in, really, this sphere of research?
Dr. Kieran Docherty:
As Torbjørn has already alluded to, PARADISE-MI kind of... It fills the gap across the spectrum of heart failure. So in patients who are at high risk of heart failure immediately following myocardial infarction, that that group of patients were studied in PARADISE-MI. And there is an echocardiographic sub-study of PARADISE-MI, which we await the results for. And I think that will be very interesting, because our patient population was distinct from the group studied in PARADISE-MI, namely the fact that the median time from MI was 3.6 years. So, these patients were not in the throes of the neural humoral activation at the time of acute myocardial infarction and prior to the development of established my cardio scar and fibrosis. And so, it may be that the addition of a Neprilysin inhibitor to patients immediately following myocardial infarction may have some benefits, in terms of attenuating or preventing ventricular dilatation reduction and injection fraction that is observed. So I think we await the echocardiographic results of PARADISE-MI with great interest.
Dr. Greg Hundley:
Very good. And Torbjørn , do you have anything to add?
Dr. Kieran Docherty:
Yes. I found observations that actually, in terminal proBNP measurements, could potentially identify a higher-risk group that actually could benefit from the intervention. It was very interesting. So I think we always speak about precision medicine and cardiology, and I think this is sort of one avenue that we should pursue and see whether we use biomarkers like NT-proBNP to identify those patients who will benefit most from interventions like sacubitril Valsartan
Dr. Greg Hundley:
Excellent. Well, listeners, we've heard a really interesting discussion today. Another study investigating Neprilysin inhibition in combination with angiotensin receptor blockers, and basically highlighting that in patients with asymptomatic left ventricular dysfunction following several years after myocardial infarction, that treatment with sacubitril Valsartan did not have a significant reverse remodeling effect just compared with valsartan alone. Well, on behalf of Carolyn and myself, we want to thank Dr. Kieran Docherty and his submission here to circulation, and also our own associate editor, Dr. Torbjørn Omland.
Dr. Greg Hundley:
And for all of you, we wish you a great week, and we hope to catch you next week on The Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.
This week is a Double Feature Circulation on the Run. Please join author Patrick Serruys, editorialist Shamir Mehta, and Associate Editor Emmanouil Brilakis as they discuss their article "Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study" and editorial "Achieving complete revascularization for multi-vessel coronary artery disease." Then, please join author G. Michael Felker, and Associate Editor Mark Link as they discuss the Research Letter "Implantable-Cardioverter-Defibrillator Eligibility after Initiation of Sacubitril/valsartan in Chronic Heart Failure: Insights from PROVE-HF."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
So guess what, Greg, we have another double feature this week. First, we need to talk about completeness of revascularization in patients with three-vessel disease or left main coronary artery disease. Always a question, and this time we've got insights from the SYNTAX Extended Survival Study. And then, the next feature talks about implantable cardioverter defibrillator eligibility after initiation of sacubitril/valsartan in heart failure, and these are insights from PROVE-HF. But before we get to that, I suggest, as I pick up my coffee, could you tell us what some of the papers you've spotted?
Dr. Greg Hundley:
Thanks so much, Carolyn. Sure. So I'm going to start from the world of preclinical science, and the paper comes to us from Dr. Vadim Fedorov from The Ohio State University Wexner Medical Center. Carolyn, up to 50% of the adult human sinoatrial node is composed of dense connective tissue, and cardiac diseases, including heart failure might further increase fibrosis within the sinoatrial node pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atrium. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inheritantly fibrotic sinoatrial node environment.
Dr. Carolyn Lam:
That's true. So what did these authors do?
Dr. Greg Hundley:
Right, Carolyn. So these authors found that increased sinoatrial node-specific fibrosis, with presence of myofibroblasts and CILP-1, and periostin-positive interstitial fibrosis only in heart failure versus non-heart failure human hearts. And comprehensive proteo-transcriptomic profiles of sinoatrial node fibroblasts identified up-regulation of genes and proteins promoting stiffer sinoatrial node extracellular matrix in heart failure hearts.
Dr. Greg Hundley:
And next, fibroblast specific profiles generated by the team's proteo-transcriptomic analyses of the human sinoatrial node provided a comprehensive framework for future studies to investigate the role of sinoatrial node-specific fibrosis in cardiac rhythm regulation and arrhythmias. So really very interesting preclinical science, Carolyn.
Dr. Carolyn Lam:
Yeah. Makes me think of arrhythmias and heart failure very differently, too. Thanks Greg. Well, for my next paper, we know that dietary high salt is bad for us. It's associated with mortality and morbidity. Serum sodium can accumulate at sites of inflammation and affect the function of both innate and adaptive immune cells. But how do changes in extracellular sodium actually affect mononuclear phagocytes?
Dr. Greg Hundley:
Ah. Carolyn, this is really an interesting question, but how would you even set this up or go about investigating this?
Dr. Carolyn Lam:
Ah, good question, Greg, and these investigators are really smart. So first, let me tell you about the co-corresponding authors, Dr. Kempa from Berlin Institute of Medical Systems Biology at Max Delbrück Center for Molecular Medicine in the Helmholtz Association, and Dr. Müller from the Experimental and Clinical Research Center in Berlin, Germany. Now, guess what they did? They used sea horse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays to characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under high salt, in vitro.
Dr. Carolyn Lam:
And what they found was a disturbance of mitochondrial respiration as the initial step by which high salt mechanistically influenced immune cell function. While these functional changes may help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory cardiovascular disease. A further potential implication is that mitochondrial functional analysis in monocytes and other immune cells upon a high-salt challenge, could serve as a test for salt sensitivity of immune cells in future.
Dr. Greg Hundley:
Oh wow, Carolyn. We don't often think about salt sensitivity in immune cells. Really informative research. Well, my next paper comes to us from the world of clinical science, and it's from Professor Derek Chew, from the school of medicine, at Flinders University, the Department of Cardiovascular Medicine at Flinders Medical Center.
Dr. Greg Hundley:
Carolyn, this paper reports results from a multicenter prospective, patient-level, randomized comparison of care informed by unmasked zero to one-hour, high-sensitivity troponin-T protocol, reported as less than five nanograms per liter versus standard-practice, masked high-sensitivity, cardiac troponin T-testing, reported at a value of less than 29 nanograms per liter, assessed at zero to three hours, and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. And the primary endpoint was timed to all-cause death or myocardial infarction.
Dr. Carolyn Lam:
Interesting experiment there. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So, while the use of the zero to one-hour, high-sensitivity, cardiac troponin T-protocol expedited discharge of patients presenting to the emergency department, with a low-event rate at 30 days, an increase in death or myocardial infarction was observed at one year in those with unmasked, high-sensitivity, cardiac troponin T-concentrations. Next, among those with intermediate cardiac troponin concentrations, where care was informed by zero to one-hour unmasked, high-sensitivity, cardiac troponin T-protocols, increases in revascularization and reductions in noninvasive cardiac investigation were observed.
Dr. Greg Hundley:
So these changes in practice that result from the use of rapid-discharge protocols, may be potentially associated with an increase in all-cause death or MI, by 12 months among those low-level troponin elevations. So in summary, Carolyn, this research found that unmasked, high-sensitivity, cardiac troponin T-reporting, deployed within a zero to one hour protocol, did not reduce ischemic events over a 12-month followup, and changes in practice associated with the implementation of this protocol may be associated with an increase in death in MI among those with newly-identified troponin elevations.
Dr. Carolyn Lam:
Wow, that's very, very interesting and clinically important. Thanks, Greg. Well, let's do a little bit of a tour around what else is available in this week's issue, shall we? I want to talk about a Special Report that I was so privileged to contribute to and was led by Dr. Gemma Figtree. And it's a Call to Action for new global approaches to cardiovascular disease drug solutions. There's also a Research Letter by Dr. Solomon on the prognostic value of natriuretic peptides and cardiac troponins in COVID-19.
Dr. Greg Hundley:
Great, Carolyn. So I'm going to tell you about an exchange of letters between Professors Correia and Chaitman regarding a prior published article, entitled “Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.” Also, there's a very nice Case Series from Professor Shapira entitled, “In the Heart of the Ancient Silk Road: Fever of Unknown Origin, Right Ventricular Mass, and Systemic Vasculitis. And then, finally, Dr. de Boer has a very nice On My Mind piece From Studying Heart Disease and Cancer Simultaneously to Reverse Cardio Oncology.
Dr. Carolyn Lam:
So interesting. Well, let's get onto our double feature, Greg.
Dr. Greg Hundley:
Absolutely. Well, listeners, we are here for our first feature discussion today and we have with us really, an very interesting panel. First, Dr. Patrick Serruys from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster University in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute. Welcome gentlemen. Patrick, we're going to start with you. Could you describe for us the hypothesis that you wanted to test.
Dr. Patrick Serruys:
Yeah. The hypothesis was that if the surgeon and the interventional cardiologist doesn't achieve a complete revascularization, there will be a penalty. The penalty is we look at the all-cause mortality because that's really a unbiased assessment.
Dr. Greg Hundley:
And then, tell us the design of your study for us.
Dr. Patrick Serruys:
So SYNTAXES, which is the extension of the SYNTAX study up to 10 years, had 1,800 patient, and then basically, we took a threshold of eight. If you have a residual SYNTAX for more than eight, you have an incomplete revascularization. We stratify for less than four, four to eight, and above eight. And clearly, the group above eight has a bad outcome, not only with PCI, but also with surgery. The score is a little bit more difficult to establish in surgery, because you don't have an angiography immediately after the procedure.
Dr. Patrick Serruys:
And then as I said, if you do a complete revascularization by PCI, and that's basically a residual SYNTAX score of zero, then you have an outcome which is comparable to the surgical outcome. What is interesting, if you have above eight, you have to think twice and maybe refer that patient to surgery. It's difficult to anticipate, but of course, bifurcation, total chronic occlusion, small vessel, is the three major reason to have a residual SYNTAX score.
Dr. Greg Hundley:
Very good. So Shamir, could you help us put these results in context with other studies that have been performed in this sphere of research?
Dr. Shamir Mehta:
Yeah, sure. I would be happy to. So the SYNTAX study was unique in that they were able to look at the degree of revascularization, and the key finding that PCI was comparable to CABG surgery in terms of outcomes, when complete revascularization was able to be achieved, is a very intriguing finding. In cases where PCI was not able to achieve complete revascularization, it was clear superiority of CABG surgery. And so the question is in this study, this comparison, which is a non-randomized comparison, whether or not there's any type of external validity for these findings.
Dr. Shamir Mehta:
And, in fact there is. It's a timely publication, because recently we had the 4,000-patient multinational COMPLETE trial, which looked at the issue of complete revascularization versus incomplete revascularization in patients with STEMI, and found that complete revascularization with multi-vessel PCI, in appropriately-chosen patients, reduced hard clinical outcomes, including the composite of cardiac mortality and/or current myocardial infarction. And it reduces it quite substantially, by about 26%, and it's a highly-significant benefit.
Dr. Shamir Mehta:
I think the caveats to this finding are important, though. Because in the COMPLETE trial, patients were not eligible for recruitment, unless the interventional cardiologists felt that all of the lesions were amenable to PCI. So complete revascularization had to be achieved in the trial. And in fact, over 90% of patients in the trial were able to achieve complete revascularization. So that's absolutely key, and that brings up the importance of having a heart team in evaluating these patients.
Dr. Shamir Mehta:
The second point is that the SYNTAX score, Patrick had referred to was relatively low in the trial, it was only 4.6. Meaning that the lesions that were attempted were relatively straightforward, meaning that there was a high probability of achieving complete revascularization. So again, I think we're starting to see from the randomized trials and from the observational studies, the types of patients that may be suitable for PCI versus suitable for CABG surgery.
Dr. Greg Hundley:
Very nice. Well, Manos, Shamir, what an outstanding description in helping us put this paper in context with other research in this space. Manos, I know you see a number of papers come across your desk. Also, for you, what attracted you to this particular study?
Dr. Emmanouil (Manos) Brilakis:
Yeah, thank you, Greg. And again, congratulations to Patrick for a phenomenal study. I think the main strength of this analysis is the clinical relevance. I think everyone is still debating this question, is complete revascularization the goal in every patient? And all of the data, as mentioned already, have several limitations. Nevertheless, they move us a little bit closer to understanding better on whom complete revascularization should be used.
Dr. Emmanouil (Manos) Brilakis:
So the clinical relevance is one key. I think this paper does set the stage well for a randomized trial. End of the day, we are still not hundred percent sure if COMPLETE is the best for everyone, because COMPLETE counts as a risk, and the risk is going to be higher in those patients who have more complex anatomy. But that study will give us the definitive answer about which is the best way to go for each individual base.
Dr. Greg Hundley:
Very nice, Manos. So that's a great segue. So I'll turn to both Shamir and Patrick, and ask them also, as well, what do you think is the next study to be performed in this particular space? Shamir, you first and then we'll finish with Patrick.
Dr. Shamir Mehta:
Well, I think the concept of complete revascularization has now essentially been proven in multiple trials. And don't forget, if you go back several decades, really the first proof was in the context of CABG surgery. So really, this should be the goal in patients with multi-vessel disease. The next large randomized trial that is going to be starting very soon is the COMPLETE 2 trial where we are actually looking at the lesions physiologically to see whether or not we need to revascularize lesions that are physiologically significant versus anatomically severe.
Dr. Shamir Mehta:
This is an important question because what it does is it has the potential to reduce the number of lesions that we perform PCI in, by about 50%. We are also looking at plaque composition in that trial with optical coherence tomography. A very, very large number of patients will be receiving that. So that will be trying to target PCI to the actual pathophysiology of the disease, by targeting unstable plaques to perform PCI on. I think this is the whole next era of coronary intervention, where we are now beginning to target our therapies to the actual pathophysiology of the disease, which is a very, very exciting idea.
Dr. Greg Hundley:
And Patrick, do you have anything to add?
Dr. Patrick Serruys:
Yeah. I think, that obviously, you have to convert the anatomical SYNTAX Score in a functional SYNTAX Score. You could do that with the pressure wire and hyperemia of diastolic resting gradient. You can also do that by QFR or FFR CT. So we are going in that direction since a few years. The second point is that we have been working on machine learning that, at some point, the segmentation of the coronary segment, the assessment of the narrowing is done. And then, the next step that we are doing right now to is to convert that to the multi-slice CT scan.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Patrick Serruys, from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster university in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute, really bringing to us this paper that, in patients with complex coronary artery disease, incomplete revascularization can be common after PCI. And the degree of incompleteness can be associated with 10-year mortality. And therefore, if it's unlikely that complete or nearly complete revascularization can be achieved with PCI in patient with three-vessel disease, maybe we should be considering coronary artery bypass grafting.
Dr. Greg Hundley:
Well, again, let's get on now to that second feature discussion. Well, listeners, we are now here for our second feature discussion today, and we have with us Dr. Michael Felker from Duke University, and our own associate editor, Dr. Mark Link, from UT Southwestern. Welcome, gentlemen. And Mike, we'll start with you. Tell us a little bit about the background pertaining to your study and what hypothesis did you want to address?
Dr. G. Michael Felker:
Great. Thanks, Greg. So I think everybody's very familiar with the concept of favorable ventricular remodeling in patients with heart failure, that we know is something that happens when we treat our patients with guideline-directed medical therapy, like beta blockers, ACE inhibitors, MRAs. Interestingly, with the introduction of sacubitril/valsartan and the landmark PARADIGM trial, we had a drug where we had clearly a major outcome benefit, but we actually had very little understanding about whether that was mediated by remodeling.
Dr. G. Michael Felker:
And those questions led us to design the PROVE trial, which was a single-arm trial of 794 patients, looking at whether or not patients with heart failure and reduced ejection fraction who met the FDA label for sacubitril/valsartan, the initiation of that therapy will be associated with favorable changes in ventricular structure and function, as well as favorable changes in natriuretic peptide. The current paper's really trying to put those results in a clinical context around some of the things that we make clinical decisions about, in taking care of heart failure patients in this case, whether and when patients qualify for a primary prevention ICD.
Dr. Greg Hundley:
Fantastic, Mike. And so you've told us a little bit about the study design, and did you have exactly the same number of patients, or what was the study population for this sort of substudy, if you will?
Dr. G. Michael Felker:
Yeah. So in PROVE, we enrolled people who had chronic heart failure in the EF, less than 40%, because that's the FDA label for sacubitril/valsartan. In this analysis, because we were interested in patients who qualified for ICD therapy, we limited our analysis to those who an EF plus or equal to 35%. Because, as you all know, the guideline for primary prevention ICD is people who have a EF less or equal to 35% after at least three months of optimized heart failure therapy.
Dr. G. Michael Felker:
And so, one of our questions was in some patients start on sacubitril/valsartan, what happens to their ventricle and how many patients might favorably remodel? This is, obviously, a question that comes up a lot clinically as more and more we're switching people from ACE inhibitors, or ARBs, to sacubitril/valsartan in line with the recommendation that's 1A from the AHA guidelines.
Dr. Greg Hundley:
Fantastic. ell, we're all listeners waiting to hear your results, Mike. This is very exciting. So what did you find?
Dr. G. Michael Felker:
I think our results were quite interesting. I mean, for one thing, the patients that were enrolled PROVE were incredibly well-treated at baseline, and they had had heart failure for quite some time, and a average median time of over six years. So this is not patients who are just recently diagnosed. A lot of these are people that you might think, clinically, we're unlikely to go on and have much favorable ventricular modeling, but that's not what we found. We actually found that after the initiation of sacubitril/valsartan, after six months, on average, we had a five point increase in injection faction.
Dr. G. Michael Felker:
And by 12 months, on average, that was almost 10 points. So quite a bit of favorable remodeling, even in these patients you might think were less likely to do that. And we put that in the context of ICD decision-making. By six months, 32% of the patients who would initially have been eligible based on the guidelines for primary prevention ICD, no longer met those criteria because their EF had risen to greater than 35, and by 12 months, it was up to 62% of those patients. So as we're thinking about decision-making around ICDs, I think these data have some pretty obvious direct clinical relevance to decisions we now make in the care of our patients.
Dr. Greg Hundley:
Really interesting. So Mark, I know you get several papers coming across your desk, and as associate editor, boy, I think I can see why this paper was attractive to you. Tell us a little bit, how do we put these results from this study into the context of how we decide whether a patient should receive an ICD?
Dr. Mark Link:
Yeah. The current guidelines are to wait three months after guideline-directed medical therapy, and then repeat the ECHO and see if they still qualify. I think what this study shows us is that patients can continue to improve after three months, and that improvement is somewhat continuous, actually. Because at six months, the improvement in EF was five percent, and at 12 months, it was 10%. So I think that's what this shows, the context is, if you have a patient who has a low EF and they are improving, but still haven't quite made it to 35, let's say when they went from 25 to 30 in three months, I'd probably hold off and wait another three months and repeat the ECHO again.
Dr. Greg Hundley:
Excellent. Well, Mike, Mark, I'm going to ask you question. And we'll start with you Mike, and then go to Mark. What study would you perform next in this space? Mike, you first.
Dr. G. Michael Felker:
So, I think it's important to recognize some of the limitations of any study you do, including this one. So this was not a randomized trial. PROVE was a single-arm trial, there wasn't a control group. And the question about the ICD per se was not pre-specified. It was really a post-hoc analysis. So as is often the case, I think these are intriguing and highly-suggestive results, but I think there's clearly an opportunity to confirm them in perspective studies designed to answer this specific question.
Dr. G. Michael Felker:
So you could imagine a trial where patients who are starting on sacubitril/valsartan who don't have ICDs, get randomized to waiting three months or waiting six months, or 12 months or whatever the interval would be. So I think these are intriguing, and that there definitely opportunities to develop confirmatory results.
Dr. Greg Hundley:
Excellent. Mark, do you have anything to add to that?
Dr. Mark Link:
I think the big thing we would really like to know are predictors, predictors of response and predictors of non-response. And that would take a larger trial perspective, and that would be very, very valuable. Because if you could have a predictor of a non-responder, they would get an ICD earlier, and predictors of responders, you might wait a while.
Dr. Greg Hundley:
Very nice. Well, listeners, we get rate studies here in circulation, and you'll find this one as a research letter, highlighting that in the substudy of the PROVE heart failure study, that in patients with an EF less than or equal to 35%, the introduction of sacubitril/valsartan improved EF to greater than 35%, at 62% of subjects at 12 months. Really an interesting finding, and perhaps further randomized clinical trials as suggested by both Mike and Mark here, are maybe warranted in the future.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to A, thank Dr. Mike Felker and also our associate editor, Mark Link, and wish you, as listeners, a great week, and we will catch you next week On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's show features a panel discussion between authors Adrian Wells and Hyeon Chang Kim as they discuss their articles "Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation PATHWAY—A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy" and "Associations of Ideal Cardiovascular Health and Its Change During Young Adulthood With Premature Cardiovascular Events: A Nationwide Cohort Study."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, also your co-host. And Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, we're starting off the month with double features, and these are just so interesting. The first paper talks about psychological interventions for depression and anxiety in cardiac rehabilitation. And the next talks about ideal cardiovascular health and its change during young adulthood and how that relates to premature cardiovascular events. Cool, huh?
Dr. Greg Hundley:
Absolutely. Well, Carolyn. How about we grab a cup of coffee and start discussing some of the other articles in the issue? And I could go first. Carolyn, the first article that I've got is from Mrs. Elizabeth Jordan from Ohio State University Wexner Medical Center. And it really pertains to cardiomyopathies. And remember, Carolyn, classically, we categorize hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathy. And each has a signature genetic theme. Hypertrophic cardiomyopathy and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins. But in contrast, there are over 250 genes spanning more than 10 gene ontologies that have been implicated in dilated cardiomyopathy. And therefore, it really represents a very complex and diverse genetic architecture. So to clarify this, a systematic curation of evidence to establish the relationship of genes with dilated cardiomyopathy was conducted by an international panel with clinical and scientific expertise in dilated cardiomyopathy genetics. And they evaluated evidence supporting monogenic relationships of genes with idiopathic dilated cardiomyopathy.
Dr. Carolyn Lam:
Oh, wow. That sounds like a lot of work. And what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So in the curation of 51 genes, 19 had high evidence. 12 are definitive strong, and seven moderate. And notably, these 19 genes only explain the minority of cases, leaving the remainder of dilated cardiomyopathy genetic architecture really incompletely addressed. And clinical genetic testing panels include most high evidence genes. However also, the panel noted that genes lacking robust evidence are very commonly observed clinically.
Dr. Greg Hundley:
So Carolyn, the take home message from this international panel is that while dilated cardiomyopathy genetic testing panels include an average of about 60 genes, when curating published evidence for dilated cardiomyopathy, only 19 have really emerged as high levels of evidence. And then in this study, 51 genes were evaluated. And the 19 genes appraised as high evidence were recommended to be routinely used in the genetic evaluation of dilated cardiomyopathy. And one more point. Rare variants from genes without moderate, strong, or definitive evidence should not be used in clinical practice to predict dilated cardiomyopathy risk most importantly when also you're screening at risk family members.
Dr. Carolyn Lam:
Wow. Very nice. Stunning numbers. Well, my paper is identifying a novel therapeutic target in pulmonary arterial hypertension. Do you want to know what that is?
Dr. Greg Hundley:
Ah, yes, Carolyn. Very interesting. So what is it?
Dr. Carolyn Lam:
It's switch-independent 3A. Which is an epigenetic modifier, which is drastically down-regulated in pulmonary arterial hypertension patients and rodent models of pulmonary arterial hypertension. And strongly associated with decreased bone morphogenic protein receptor type two, or BMPR2 expression. So this switch-independent 3A overexpression up-regulated BMPR2 expression by modulating critical epigenetic pathways and decreasing a specific transcription factor binding to the BMPR2 promoter in pulmonary vascular smooth muscle cells. Furthermore, aerosolized lung-targeted gene transfer of adeno-associated virus zero type one and containing switch-independent 3A reversed and prevented pulmonary arterial hypertension phenotype in preclinical animal models. So this beautiful study, from Dr. Hadri from Icahn School of Medicine at Mount Sinai in New York and colleagues, really suggests that switch-independent 3A can be a clinically relevant molecule for the treatment of pulmonary arterial hypertension.
Dr. Greg Hundley:
Wow, Carolyn. Really nice. Very intricate science for the study of pulmonary hypertension. Well, my next paper actually comes to us from Dr. Joe Hill and colleagues at UT Southwestern Medical Center. And Carolyn, as we know, cardiac hypertrophy is an independent risk factor for heart failure. Of course, the leading cause of morbidity and mortality globally. And the calcineurin NFAT, or nuclear factor of activated T-cells pathway, and the MAP kinase ERK, or extra cellular signal regulated kinase pathway, contributes to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. However, Carolyn, how these pathways interact really remains unclear. And so Dr. Hill and colleagues engineered a cardiomyocyte-specific ETS2, a member of the E26 transformation specific sequence or ETS domain family knockout mouse, and investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth.
Dr. Carolyn Lam:
Wow. Okay. So what were the results, Greg?
Dr. Greg Hundley:
Right, Carolyn. Three main findings. First, ETS2 is activated by ERK1/2, or extracellular signal-regulated kinase 1/2, in both hypertrophied murine hearts and in human dilated cardiomyopathy. Second, ETS2 is required for both pressure overload, and calcineurin induced cardiac hypertrophy responses involving signaling cascades distinct from, but interdependent with ERK1/2 signaling. And third, this group discovered that ETS2 synergizes with NFAT to transactivate RCAN1-4, an established downstream target of NFAT, or nuclear factor of activated T-cells. And they identified an MIR-223 as a novel transcriptional target of NFAT ETS2 in cardiomyocytes.
Dr. Carolyn Lam:
Wow. Wow. That sounds like a lot of detailed work. Could you tell us what the clinical implications are, Greg?
Dr. Greg Hundley:
You bet, Carolyn. So in aggregate, these findings unveil a previously unrecognized molecular interaction between two conical hypertrophic signaling pathways, MAP kinase-driven hypertrophy, and calcineurin driven hypertrophy. And therefore, as pathological cardiac hypertrophy is an established risk factor for heart failure development, this unveiling of novel signaling mechanisms really is of potential clinical relevance.
Dr. Carolyn Lam:
Thanks, Greg. Well, let's round up with what else there is in this week's issue. There's a Frontiers paper by Dr. Chris Granger. And it's a big call to action to the cardiology community, to incorporate SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular and kidney disease risk reduction. There's a Joint Opinion piece from the American Heart Association, World Heart Federation, American College of Cardiology, and European Society of Cardiology on, “The Tobacco Endgame: Eradicating a Worsening Epidemic,” by Dr. Elkind.
Dr. Greg Hundley:
Oh great, Carolyn. Well, I've got an On My Mind piece from Professor Bhatt. And it's entitled, “Does SGLT1 inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes Mellitus?” And next, Dr. Viskin has an ECG Challenge entitled, “Long QT Syndrome and Torsade de Pointes Ultimately Treated With Quinidine, The Concept of Pseudo Torsade de Pointes.” And then finally, there's a Letter to the Editor by Dr. Lu regarding the article, “Association of Body Mass Index and Age with Morbidity and Mortality in Patients Hospitalized with COVID-19, Results from the American Heart Association COVID-19 Cardiovascular Disease Registry.” Well, Carolyn, I can't wait to get on to this double feature.
Dr. Carolyn Lam:
Me too. Let's go.
Dr. Greg Hundley:
Welcome, listeners, to our feature discussion today. And again, we're going to create today a forum, because we have two very interesting papers to present during this timeframe. Our first is going to come to us from Dr. Adrian Wells from University of Manchester. And our second paper will come to us from Dr. Hyeon Chang Kim from Yonsei University. I want to welcome you both, gentlemen. And Adrian, I would like to start with you. Tell us a little bit about the background related to your study. And then what was the hypothesis that you wanted to address?
Dr. Adrian Wells:
Okay, well thank you for inviting me to take part in this podcast. Following cardiac events, around one in three individuals will develop significant anxiety and depression symptoms. And we know that anxiety and depression can have an impact on prognosis, quality of life, future outcomes. Psychological treatment isn't routinely offered in cardiac rehabilitation for anxiety and depression, despite the fact that we identified that many of our patients felt that they would benefit from a psychological intervention to address these issues. And they felt that their needs were not really being met. So our primary question was, can we improve psychological outcomes in patients with cardiovascular disease?
Dr. Greg Hundley:
Very nice. And Adrian, what was your study population? And also, what was your study design?
Dr. Adrian Wells:
So we selected patients who entered cardiac rehabilitation in the UK. So these are patients with acute coronary syndrome, revascularization, stable heart failure, heart transplantation, and so on. And so, a wide group of individuals. We recruited 332 patients, all of whom had had anxiety and depression scores of eight or more. So these were people showing mild to severe levels of psychological distress. We conducted a two arm single blind randomized controlled trial, with 332 patients who were randomly allocated to one of these two conditions. And we assessed anxiety and depression symptoms before treatment at four months and at 12 months.
Dr. Greg Hundley:
Describe a little bit some of the specifics of your intervention. And then what did you find?
Dr. Adrian Wells:
We use relatively recent new treatment called metacognitive therapy. And this was delivered in a group format over six sessions. And we trained cardiac rehabilitation staff, nurse consultants, physiotherapists, in the delivery of this intervention. Metacognitive therapy works on helping patients discover unhelpful patterns of thinking, such as worrying and ruminating ,and excessive threat monitoring. And to reduce those patterns of thinking that contribute to anxiety, depression, and poor adaptation following stressful life experiences.
Dr. Greg Hundley:
And what did you find?
Dr. Adrian Wells:
Well, what we found was that the addition of metacognitive therapy to treatment to usual cardiac rehabilitation, significantly improved outcomes at four months and 12 months. What was striking about this was that our effect sizes were modest and moderate to large. They seem to be larger than those obtained in other studies or psychological treatments. And of note, the treatment seemed to impact well on both anxiety and depression symptoms. Whereas other types of intervention evaluated in the past have tended to treat the depression, but not so much the anxiety.
Dr. Greg Hundley:
Very good. So it sounds like a group-based intervention. And I'm assuming maybe participants interacted not only with your staff, but with one another. How would you put your results really in the context with other research that's going on in this space?
Dr. Adrian Wells:
Well, there have been a number of studies in the past that have looked at individual and group-based treatments, and patient preference for different types of intervention. I think this is the first study to use a clear manualized intervention that's based on the psychological theory of mechanisms that contribute to the maintenance of psychological problems. Obviously, this tended to use more prescriptive interventions like anxiety management, stress management, taking techniques from a range of different sources. So I think there's a difference of conceptual basis to this kind of intervention. And it's something that is highly manualized and structured, and in fact can be delivered by a range of different healthcare professionals.
Dr. Greg Hundley:
Very nice. And also during cardiovascular rehab. Correct?
Dr. Adrian Wells:
Absolutely, yeah. During cardiac rehab. One interesting finding... And we were a little concerned that this might adversely affect attendance at cardiac rehab. But we found that the treatment was well tolerated, and it didn't have any negative impact on attendance at these other sessions.
Dr. Greg Hundley:
Excellent. Well, congratulations on this new finding. Well, listeners, we're next going to turn to Dr. Hyeon Chang Kim from Yonsei University in Korea. And Yong-Chan, could you describe for us also the background related to your study, and the hypothesis that your research wanted to test?
Dr. Hyeon Chang Kim:
Thank you for inviting me to this wonderful discussion. South Korea is among the countries with the lowest cardiovascular mortality in the world. And the rate is even decreasing. However, cardiovascular risk factor is worsening. Especially in younger generation in Korea. So these young people may not have a very high cardiovascular risk, but I wanted to know the potential impact of worsening cardiovascular risk profile in this younger Korean generation. And furthermore, I wanted to know how much we can lead youth cardiovascular risk by improving their cardiovascular health profile.
Dr. Greg Hundley:
Very nice. And so tell us about your study design and what was the study population, related to your study?
Dr. Hyeon Chang Kim:
My study is basically based on the national health checkup program and national health insurance claim database. In Korea, adults over the age of 20 and employed workers of all ages are required to take general health checkup every two years. The participation rate is between 70 and 80%. So we identified three and a half million adults, age 20 to 39 years, who complete the health checkup. And cardiovascular health scores was calculated as the number of ideal cardiovascular health component, which include non-smoking, moderate physical activity three times a week, body mass index below 2030, normal blood pressure, normal cholesterol and normal fasting glucose. So the score can range from zero to six. And higher score meaning better cardiovascular health. Our outcomes were myocardial infarction, stroke, heart failure, and cardiovascular deaths in about 16 years. In addition, we also evaluate the risk of cardiovascular disease. According to two year change in how the vascular health score using repeated health checkup data.
Dr. Greg Hundley:
Very nice. So evaluating a set of behavioral patterns and risk factors in younger individuals, and then predicting what their longer term adverse cardiovascular outcomes would be. So what did you find?
Dr. Hyeon Chang Kim:
So even in this relatively low risk population, better cardiovascular health score was associated with significantly lower cardiovascular risk. About 20% reduction per one point higher score. And more importantly, people with improving cardiovascular score over two years showed leading toward cardiovascular risk. Even if their baseline cardiovascular health score was very low.
Dr. Greg Hundley:
Really unique findings. Tell us about the impact of your results relative to other studies published in this space. And was this also.... This was unique, because it's an Asian population,
Dr. Hyeon Chang Kim:
Asian population. And we are among the very low risk population. And even in this low risk population, cardiovascular health score was... Fear can be a good predictor of cardiovascular risk. And compared to many Western countries, we have very low cardiovascular risk. And our population was younger than most other studies. So we can provide some evidence that even in the higher risk population, they can do much better, based on our study. Another important thing, we can check the impact of a changing cardiovascular score, even in the younger generation.
Dr. Greg Hundley:
Very good. And just as a frame of reference for our listeners. Give us some characteristics, if you wouldn't mind, on what really constitutes practically a low risk score, versus what would constitute a high risk score
Dr. Hyeon Chang Kim:
In this younger Korean population, their cigarette smoking, and their obesity, and physical inactivity are the most common causes of worsening cardiovascular profile. And the behavioral risk factor also can attack the blood glucose and cholesterol blood pressure. So in this younger generation, they're keeping the good behavior. Past behavior is very important and it's beneficial in the very long-term.
Dr. Greg Hundley:
Very nice, well listeners. We're going to turn to our experts here. Two very interesting studies. And ask them both, what do they think is the next study that needs to be performed in their respective areas of research? So Yong-Chan, we'll start with you. Since we just discussed your paper. What do you think is the next study to be performed really in this sphere of research.
Dr. Hyeon Chang Kim:
Korea is a relatively low cardiovascular risk, has a very small size, and no racial diversity. But even in this country, disparity and inequality in cardiovascular health is becoming an important issue. So I want to identify subcultural relatively poor cardiovascular health among younger population. And also I want to find ways to improve their cardiovascular score. The conventional approaches, such as education and mass campaign, are less effective oppose this younger adults have a poor socioeconomic status. So, we may need to develop newer target-specific strategies to improve their cardiovascular health.
Dr. Greg Hundley:
Good. And Dr. Wells, our agent will turn next to you. What do you see is the next area of investigation or research study that needs to be performed in your sphere of interests?
Dr. Adrian Wells:
Well, I think the next step is to look at rollout of this intervention. Is that feasible, and how acceptable is this to cardiac services? In fact, the National Institute of Health Research have just awarded us some funding to examine feasibility and barriers to implementation in the healthcare system. In addition to that, we're beginning to examine the effects of metacognitive therapy with other health conditions, such as cancer in children and adolescents.
Dr. Greg Hundley:
Nice. Well listeners, we have had just a wonderful discussion today from both Dr. Adrian Wells from University of Manchester. Who brought to us combining a group-mediated, psychological stress-reducing, anxiety-reducing, intervention to the cardiac rehab sphere. And how impactful that was in reducing both anxiety, and overall depressive symptoms. And then also exciting research from Dr. Hyeon Chang Kim from South Korea. Identifying for us that in Asian population, as well as what we know in other races, those individuals in their twenties to thirties with favorable lifestyle habits, have reduced cardiovascular risk much later in life.
Dr. Greg Hundley:
Well, on behalf of both Carolyn and myself, we want to wish you a great week. And we'll catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.
This week, we have a special podcast: the interviewers become the guests! Join Digital Strategies Editor Amit Khera as he interviews Carolyn Lam, Greg Hundley, and Managing Editor David "Augie" Rivera as they provide a behind-the-scenes look at how Circulation on the Run comes to you each and every week. Come meet your favorite podcast hosts!
Dr. Amit Khera:
Hi, this is Amit Khera. I'm digital strategies editor for Circulation, and boy, do I have a treat today? I get to step in for Carolyn Lam and Greg Hundley, but wait, I actually get to interview Carolyn Lam and Greg Hundley today. So we have a very special Circulation on the run. Well, the interviewer becomes the interviewee. These two you get to hear every week and hear this amazing back and forth and deep insight into Science and Circulation. But, who are these folks behind the Circulation on the Run podcast? And boy, what interesting life stories they have and how they work through this. And wait, we also have a third joining us today, and that is Augie Rivera, who is the managing editor of Circulation. So we get to see the mastermind behind how all this runs. Well, Carolyn, Greg, Augie, welcome you three.
Dr. Carolyn Lam:
Thanks, Amit. Feels weird.
Dr. Amit Khera:
Good. Then mission accomplished this week. Well, first let me start with you, Carolyn. I know you and I started this long ago, with help from so many folks. People hear you every week and I'm sure many people know you quite well. I will say you have one of the most interesting backgrounds, incredible scientific and personal accomplishments, professional accomplishments. So we're very fortunate to have you as leading this podcast in the beginning, but a lot of people may not know your background story about sort of your training and your day job, because you do have a day job outside of podcasting. So tell us a little bit about yourself, about how you got here in life.
Dr. Carolyn Lam:
Oh my gosh. Amit, I'm humbled by your question. My goodness. I feel just very lucky to be part of the Circulation editors. And I humbly did my med school in Singapore, and did cardiology here, and traveled and lived overseas for the first time. Guess where, in Rochester, Minnesota. Tropical Singapore island to refrigerator state. Other than that, it was absolutely the most pivotal moment of my life. Met my first female mentor and Dr. Margaret Redfield. Really, really just came into my own and got involved in population-based research. And then hopped on over to Boston where actually I was working at the Framingham Heart Study. So continuing sort of the epidemiologic work, but then I think another mentor I really have to call out too is Dr. Scott Solomon, who kind of took me under his wing a little bit and showed me a little bit of the world of clinical trials. And boy, all I can say is I haven't looked back. And so here I am.
Dr. Amit Khera:
I think you took a detour in the Netherlands too. Am I right to say that?
Dr. Carolyn Lam:
Oh yes, but that was quite a late detour in life. I was really, really fortunate meet Dr. Adrian Voris who supervised my own PhD. That was a really interesting thing because I come from a family of a pediatrician in my mom, and a scientist, a biologist really, specialized in fish, in my father. And I'm saying this because my father told me never ever follow his footsteps and do a PhD. Make sure I follow my mom's footsteps and be a clinician, and go into private practice.
Dr. Amit Khera:
Well, it looks like you followed both of their footsteps, maybe the best of both, so they're very proud of you for that. We recently had the privilege of having you give us grand rounds and get to hear your impressive work in clinical trials. And I have to say, the work you're doing in half half and really with some great clinical trial and cohort data involving Asian populations was quite inspiring and impressive. How did you sort of get things going? You've traveled around and moved back and how did you start getting your career going and the momentum you've had so far, incredible success?
Dr. Carolyn Lam:
Oh goodness. Thanks for letting me share. Amit, honestly, I don't know. And I can only look back and be on my knees and be grateful for being at the right place at the right time. I think it's a combination of taking what I had learned in Olmsted County and Framingham. Coming back to Singapore and realizing that there was a need for similar epidemiologic studies. I firmly believe if I didn't do it, someone else would. I'm not that brilliant. I just get things done. And so that's what I did. I started that. And one thing led to another. It's having really friends as well. And so I really, really want to say big thanks to my mentors who have become my friends and colleagues. And to people listening. This is really, really from the heart. You don't plan these things. You just go the next step that you see, and you go with all your heart. And you make sure that you've got your eyes open to see the next opportunity, and have the energy to seize that one when it comes by as well. I think that's how it all happened.
Dr. Amit Khera:
Well, that is a good pivot because one of the next opportunities that came up in Circulation on the Run after you'd done it for a while, was to bring in this gentleman, Greg Hundley. And so we're so glad that you two partnered. Now, Greg, you and I have a little bit of a shared background. You were at UT Southwestern for a period of time, where I am currently. Well, tell us your story, Greg. Tell us a little bit about your background and training and where you are currently.
Dr. Greg Hundley:
Sure. Thanks so much, Amit. Again, I think like Carolyn, we really feel this is an incredible opportunity. The journal is a wonderful blend of collecting impactful science, both clinically and pre-clinically. And trying to bring that to the forefront. It's just been a fantastic opportunity to participate on the editorial side, but then after that, share with the rest of the world, the findings that we really develop each week. And it is truly a team effort. All the way from identifying impactful science, discussing it, preparing it, and then sharing it. And so I think like Carolyn, I just feel very privileged to have this opportunity. Now, my path, listening to Carolyn, and for listeners, you kind of move with it a little bit, and follow along seeking, I don't know, new opportunities, but also being very humble. And as they approach you, and doing kind of the best that you can in the situation.
Dr. Greg Hundley:
So my career path started at what was Medical College of Virginia, but is now VCU in Richmond, Virginia, and medical school there. And then, at Southwestern, did my internship, residency, and cardiology fellowship. And I would say, probably my first strong mentors was really a mentor team. There was expertise there. Jim Willerson had brought Ron P Shock and Craig Malloy on the magnetic resonance imaging side. So for those that are listening, I'm more of an imager in cardiovascular medicine. But also a key fundamental pivotal figure or figures were David Hillis, and Rick Lang in the cath lab. And at the time, magnetic resonance imaging, we were trying to figure out, well, could this noninvasive methodology help us understand problems related to cardiovascular disease that came along maybe before, or we needed to go to an interventional situation, or how they would relate to an interventional situation.
Dr. Greg Hundley:
And then was briefly a faculty member at Southwestern, and then recruited back to the East Coast to Wake Forest. Another really pivotal figure for me was Dr. Bill Little at Wake Forest. Now, he's passed away, but bill had again, that great insight and excellence in science, and performing research and investigations, but also clinical expertise and emphasize the world... We haven't talked a lot about this, but education. How we take the information that we gather and educate others. Began working with the American Heart Association, with the American College of Cardiology in that realm. Then after 22 or three years, another opportunity came up actually to return back to VCU, and be the director of the heart center. And so now have that position here in Richmond, Virginia. Again, very excited to be working here with Circulation on the Run.
Dr. Amit Khera:
Well, I hear some amazing themes from both of you about mentoring and people along the way. It's a great story obviously for our younger listeners that are thinking about life and careers and opportunity sort of finding where life takes you. I think those are great themes for both of you. Now, we won't have as much time for this story, but Greg, you and I spoke recently. You told me this most amazing story of how you were going to be an interventional cardiologist, walked over to drop off something. A patient had an MRI machine and saw this MRI and fell in love.
Dr. Amit Khera:
I'll paraphrase about staying up all night, drinking soda and coding zeros and ones since that's the technology back then, but what an amazing story. We'll have to do that for our next podcast. All right. I'm going to bring in Augie Rivera. Now, he is the managing editor of Circulation. Meaning he really keeps everything going, and is the engine and brains behind the operation. And one of the many things he does, is the podcast. And we'll talk more about the logistics of that. But Augie, people never get to hear your voice. So tell us a little bit about how you got into this medical publishing and circulation in the pacific, sort of your background.
David “Augie” Rivera:
Well, thanks, Amit. Also thanks to Carolyn and Greg for inviting me as well to participate. This is going to be shocking and maybe scary, but I only have a couple of years of scientific journal publishing experience, and that's with the Circulation family. My background for my entire career has been in educational school publishing, specifically in mathematics. And mainly grade K to 12 mathematics. So making the jump over to scientific publishing seemed a bit daunting, but after like 20 plus years, I was looking to do something else. And I was grateful that I saw something on LinkedIn. I interviewed for the position and I was very fortunate the American Heart Association that ended up hiring me. In a sense I always say, "Taking a chance on the long shot." And so that's what brought me here. So a lot of this has been very, very new to me, but at the same time, all the Circulation editors have been so helpful, as well as my staff that I work with. They've been so beneficial to me in learning the side effects. So, that's a little bit about me.
Dr. Amit Khera:
We're very glad that the DHA found you, Augie, and you've been obviously this incredible resource for us. I'm glad you brought up the staff because there's so many people on Circulation that make it run and we're very grateful for all their efforts, including those who help us put on this podcast. Well, I want to dig into the podcast. Carolyn, we haven't told the story in a long, long time. I think you told it on the very first podcast, but Circulation on the Run. For those that missed in earlier days, remind us how you came up with that name.
Dr. Carolyn Lam:
Okay, very quickly. I'm a runner, and I know a lot of us are. It's just on one of my runs that I realized, "My goodness, wouldn't it be great to be able to just feed my mind at the time?" I was on a treadmill actually, and I was trying to read, and it occurred to me, "It is impossible. I'm getting a serious headache to try to read while you're trying to run." And so I thought, "Wow, wouldn't it be great if somebody just read that to me, so I could just read the journal while I was running?" Yeah, you can join the dots. So that was exactly the idea. That, "No, I'll do that for someone. I'll give them the nuts and bolts of that issue."
Dr. Carolyn Lam:
At least the main papers. The way it's grown since then, it's frankly thanks to Greg. I need to make a plug here. Greg has admitted that he's humble. And in fact, that's why I need to drag this out of him. I did not realize until I interviewed him on one of the podcasts, that he is totally gifted at interviewing. And then he tells me just, by the way, in the usual Greg way, he has a history and thick experience in this. He had done the interviews like... Greg, you have to tell me, but he had done several of these. He had a show, he had ideas. He used to do it. And I was like, "Why are you hiding all this? You got to come do this with me." But he hides it. So Greg, now you have to fess up.
Dr. Greg Hundley:
Oh gosh. And now Carolyn, she's too kind. So Carolyn, listeners as you can tell, just has a very warm, inviting personality. And she so couples that with just brilliance and interest in science. I mean, I can't take credit for the things, but she's also open to listening. And I think one of the really exciting things, this sort of team of three with Augie and Carolyn, we have great discussions behind the scenes on how we can bring the information in the journal to you as listeners, in a way that is inviting, engaging, and educational. It's really being part of a team, that has that common goal in mind and in thought. Carolyn and Augie, I just treasure the opportunities that we get to work together every several weeks and putting together the most exciting science that our journal really brings forth. So it's a team effort for the listeners. And just to maybe anticipate the next question, how do we do that?
Dr. Greg Hundley:
We do get the joy of reading the journal every week, and we spend some time each of us, on our weekends and late at nights reading thoroughly the journal. And Carolyn and I kind of divide up the articles. Both of us taking and becoming enthralled with areas of expertise that we may have. Again, we've talked about Carolyn in heart failure expertise and maybe me a little bit more on the imaging side and cardio oncology and the like. And then in any way we divide up the articles, we read them thoroughly, and then we produce a script. So one of the fun parts of this is working with Augie. We're producers as well as editors, as well as the spokespersons.
Dr. Greg Hundley:
So it's kind of all done in one shop and put together, and interactive, if you will. And then we are able to record that in sessions with Augie, coordinating them, and involving some of our authors, editorial experts. And then other experts that we gather from around the world that are also involved in the science. And the goal is to create discussions in addition to presenting the information that's in the journal, but to create meaningful, thoughtful discussions regarding this impactful science, so that we can actually take it in as practitioners or other researchers and scientists in the field quickly. And that's sort of the general concept.
Dr. Amit Khera:
You jumped right in there, Greg. And that's exactly what we want to dive into, which is sort of the behind the scenes, the mechanics about the why. Now, you two have an incredible chemistry. I will say since you two have been doing this together, it's really been a joy listening to you two. Carolyn, just maybe the dovetail on what Greg just talked about, about sort of the chemistry. That back and forth that you two do, the preparation behind that. Tell us a little bit about how that works out.
Dr. Greg Hundley:
Oh, absolutely. I've been dying to share. You should hear the bloopers. It's hilarious. So after a while, we just totally like... We have the fun doing this. And we realize it's very serious science that we're talking about. We're so solidly proud of circulation, but it's okay to have fun. It's okay by the way, to mispronounce some of these basic science words and to call Joe Hill, which I've done by the way, literally called him to ask him how to pronounce certain things. And you know what? And have fun at the same time. And so Greg starts these quizzes. Now, that is all Greg, okay. This Carolyn quizzes and... So after a while, we started to try to hide little quizzes inside our script with the answers given just in case. But it sometimes catches us unaware, and it's just really hilarious.
Dr. Greg Hundley:
And once or twice, I think Greg and I have tried to quiz Augie as well. But Augie never allows us to do that. So it's really great when we're having fun. And that is exactly what I'm so grateful for Greg to showing me that. He's the one who had the experience with the back and forth and gave us the idea. He's the one who push to say, "Look beyond the original articles, I really like as a listener, to have an overview of every single article." That was Greg. He's the one who initiated the sort of forum type discussions and double bill discussions, because he got feedback and acted on it, that people really, really enjoy listening to the authors too. And finally, we're really trying to make it even more useful for the audience based on feedback by seeing if we can get CME accreditation, seeing if we can be more responsive. I just want to let people know, even if we don't manage to achieve it, that we're listening, and we're trying, and we're constantly trying to improve. And that's what I really, really thank both Greg and Augie for.
Dr. Amit Khera:
Thanks for that. Listen, I want to just pick up on many things that you just said. First, I think what people may not appreciate is how much work goes into this. You read all of the articles and prepare with the featured articles. You create a script, and you have fun doing it, which is the most important thing. You record and have to coordinate. Takes a lot of time. I've seen this too, then people don't realize afterwards, you listen to the entire thing and edited again. This is impressive. And it shows, because it's a fantastic product. I want to talk a little bit about some of the deeper features. So you two obviously summarized in the beginning, the original research and we talked a little bit about the back and forth. I want to talk about the featured articles and the interviews of these different folks. Tell me a little bit about that and how that goes. What do you enjoy about the interview part of that. Greg, you want to start?
Dr. Greg Hundley:
Well, I thoroughly enjoy what we call the feature discussions, where we bring together the authors of the paper, editorial experts that... With Circulation, there's a team of associate editors that process the papers. And actually, when you as a listener submit an article, we review these in a discussion format. And one of the associate editors is leading that through a discussion group. And so we bring in that expert. And then oftentimes, we have an editorialist, or an expert from the world, and bringing together a discussion and focusing on the content, not only in that article, but how that article pertains to the world's literature, and then where we really want to go next with research.
Dr. Greg Hundley:
And I think that's sort of our objective, is to bring a living discussion for us as listeners, with authors, the active researchers, with the editorial team and the experts. Why of all the papers you get did this impactful science really come to the forefront for you? And then from the editorialists, how do we take this information and put it in the context of the world's research that's going on in cardiovascular medicine? So those are sort of the main insights and as listeners, just as Carolyn said, we really enjoy receiving feedback from you, and how we can perfect that further. One of the things we've started thinking about is, if we have a basic paper and a clinical paper on the same topic, is really having even a broader discussion, a forum discussion, where we talk about several papers at one time and really embrace a topic. And I love what Carolyn said about providing not only continuing medical education credits, but for those in the United States or maybe North America in particular, maintenance of certification credit, and something we're actively looking at, trying to work through right now.
Dr. Amit Khera:
Thank you for that. And Carolyn, do an add to the features and the interviewing these folks and some of the... what it is that's most interesting to you in doing that process and what you've learned.
Dr. Carolyn Lam:
Yeah. I certainly want to add, but probably in an angle you would not expect. And here, I really, really want to point out the tremendous work of coordinating this, that Augie takes care of. It is incredible. When we have an editor in Europe, a author in California, a me in Singapore, himself in another part of the US. I do not know how Augie does it. And not only does he do it super well, it's always with a smile. Augie, you truly are amazing. Your positivity has honestly kept me going many times, when I just came on the recording half dead. Kudos to you, truly.
Dr. Amit Khera:
Thank you, Carolyn, because I wanted to bring in Augie back again now. Augie, it must be amazing for you. I mean, first, the logistics. Maybe you can tell us about coordinating people from all over the world, different time zones, every single week and obviously people that are quite busy and show what a hard thing to do. And then maybe seeing the process. Boy, from seeing these papers come through our meeting, to the selection, to coordinating, to seeing the final product at the end, it must be a pretty satisfying process for you. Tell us a little bit about the mechanics and what this is from your vantage point.
David “Augie” Rivera:
Well, indeed, it is very interesting. It's something that I did a little bit of production back in college when I did college radio, way back in the day, but I never do. I would end up doing this again, but I think as far as the logistics are concerned, I'm not by myself in this at all. I mean, a big shout out to Sarah O'Brien who trained me when I took on this job because she was covering Circulation on the Run while there was a search for a managing editor. So she was the one who taught me all the tricks of the trade, on how to make some of this happen. But also it's the two assistants for Carolyn and Greg, Afshaan and Angela, who I contact and I go, "Please let me know what their availability is, when, and what can we fit here? And what can we fit there? And can we try to move a meeting?"
David “Augie” Rivera:
In fact, I get to tell Greg that we were successful in moving a meeting for tomorrow, and we have another one scheduled. So we made it work. So really Afshaan and Angela really help out with those logistics as well. We also have to thank you Ishara and her team over at Learner's Digest. They're the masters who put together all of our raw audio files, and cut them all together, to make the final product of the podcast. And not only does her team do that flawlessly, but it also coordinates with having those reviewed and approved by the editors as well. So there is no way that we would ever be able to get any of our podcasts out and delivered without their awesome help and support. So a big shout out to Ishara and team. And most importantly, and the viewers can't see this, but also to the authors and associate editors, editorialists.
Augie Rivera:
First of all, we're grateful that they've sent and submitted their articles to circulation for peer review, and then eventual publication, but their flexibility, because I know that they are very busy during their time too, and trying to make things work. I have had an author say, "Oh yeah, 12:30 in the morning, past midnight? Oh totally. I can totally do that. No problem." Or an associate editor who says, "Yeah, I can probably do that for 5:00 AM in the morning." So the flexibility of the authors, the editorialists and the associate editors is also what makes the logistics and everything work out. So it's not me, but it's completely a team effort. And it's also thanks to Carolyn and Greg for finding those pockets of time while they're doing their day job, to also take the time to be prepped and interview our authors and editorialists. So on that end, like I said, it's not me, it's a team of all of us that put this together.
Dr. Amit Khera:
Well, I appreciate everyone's humility, including yours, Augie. And you are right, there's a broader team and I appreciate you calling them out, but we certainly acknowledge you're at the center of that, and appreciate all your work to make this come to fruition. Well, we're winding down. I have maybe one last question for you two, Carolyn and Greg. Tell us about the future of Circulation on the Run. Where do we go from here? What's the future of this specifically? Or maybe podcasting and Circulation in general.
Dr. Carolyn Lam:
Well, what I can say is, it is continuously going to improve. You've heard us commit to that. We will and promise to try to make it as short and snappy as we can. So for those of you listening, who kind of don't get to the end, please hang in there with us. We're continuously getting better.
Dr. Greg Hundley:
Yeah. I would just want to echo that. If listeners have suggestions and there's a pathway to gather that information from you, we are all ears. We're listeners, and we would love to shape and mold this further based on your suggestions, because really, your suggestions have shaped a lot of where we are today.
Dr. Carolyn Lam:
And Amit, if I could, because the podcast is only one cog in the whole wheel of what you do as overall strategy for us, digital strategy. Could I ask you to give us that last word? I have to be the interviewer again.
Dr. Amit Khera:
You can't get it out of your system. This one is not about me. I'll give two seconds on my role specifically, but I have a neat role. We purposefully chose the term, digital strategies, because we appreciate there's so many different things behind getting medical literature out there, including website, working with traditional media, social media, podcast, and whatever else comes in the future.
Dr. Amit Khera:
So I'm very lucky because I get to work with you all plus a ton of other folks to really bring this material to life. And the coolest part is, you all are so easy to work with and so creative, and have done so many amazing things with this podcast. And it's been real privilege just to watch this grow and develop. What I love that you both said, and I hope the listeners heard this, that have hung on with this, you're appreciated for feedback and you always have been. Have made tweaks along the way to make this better and better. And so if anybody has any, feel free to email any one of us, and we welcome that feedback to make this even better. Listen, I want to say what a treat this has been to interview the interviewers. Amazing, and certainly did not disappoint learning about your backgrounds and a little bit more about all of you, and about what makes Circulation on the Run come to life.
Dr. Amit Khera:
So that's it. There's another rap. I'm Amit Khera, stepping in and interviewing Carolyn Lam and Greg Hundley, who will join you again next week. Thank you.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
First join author Marc Dweck and Associate Editor Victoria Delgado as they discuss the article "Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial." Then, join authors Torbjørn Omland and Geeta Gulati as they discuss the article "Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol."
Dr. Carolyn Lam:
Welcome to Circulation On The Run. Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Hooray, it's another double feature week! And guess what, these two papers are two randomized control trials. One looking at progression of aortic stenosis and the other, looking at a prevention of cardiac dysfunction following adjuvant breast cancer therapies.
Dr. Carolyn Lam:
So, very interesting two papers coming right up. But Greg, why don't you start by highlighting some of your favorite papers from today's issue.
Dr. Greg Hundley:
You bet Carolyn.
Dr. Greg Hundley:
So my first study was conducted by Dr. Gabriela Trifan and colleagues from University of Illinois who performed a meta analysis of major studies that compare the efficacy and safety of dual anti-platelet therapy versus monotherapy for secondary prevention of recurrent stroke or transient ischemic attack in those previously experiencing minor non cardioembolic stroke. And their primary outcomes were stroke and the composite of stroke, TIA, acute coronary syndrome and death of all cause. And the safety outcome was major hemorrhage.
Dr. Carolyn Lam:
Oh, okay. Very important study. What did they find?
Dr. Greg Hundley:
Right Carolyn. So the analysis included 27,358 patients. And compared with monotherapy, dual anti-platelet therapy reduced the risk of recurrent stroke and the composite outcome, but increased the risk of major bleeding. And in subgroup analysis at less than or equal to 30 days, dual anti-platelet therapy increased the risk of hemorrhage relative to monotherapy. In sensitivity analyses, the risk for hemorrhage with less than or equal to 30 days of dual anti-platelet therapy, after excluding the combination of aspirin plus Ticagrelor, was comparable to monotherapy. However, the risk of stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remained decreased compared to monotherapy.
Dr. Greg Hundley:
And so Carolyn, the take-home message from this paper is that dual anti-platelet therapy decreases the risk of recurrent stroke and composite events compared with monotherapy. But, dual anti-platelet therapy increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus Ticagrelor.
Dr. Carolyn Lam:
Ah, thanks for that last take home message. Thank you.
Dr. Carolyn Lam:
Well, the paper I'm going to tell you about is the first to examine the role of epicardial fat derived extracellular vesicles in the pathogenesis of atrial fibrillation. And this comes from Dr. Leor from Sheba Medical Center, Tel Aviv University in Israel and his colleagues who collected epicardial fat specimens from patients with and without atrial fibrillation during elective heart surgery.
Dr. Carolyn Lam:
Epicardial fat samples were grown as organ cultures and the culture medium was collected every two days. And the authors then isolated and purify these epicardial fat extracellular vesicles from the culture medium.
Dr. Carolyn Lam:
They found that epicardial fat extracellular vesicles of patients with atrial fibrillation had unique pro-inflammatory, profibrotic and proarrhythmic properties. Epicardial fat extracellular vesicles could in fact induce cellular, molecular and electrophysiological remodeling that could result in atrial fibrosis, myopathy and the development of atrial fibrillation.
Dr. Greg Hundley:
Wow Carolyn, so what are the clinical implications of epicardial fat extracellular vesicles?
Dr. Carolyn Lam:
Hmm, good question. Well, understanding their role in the pathogenesis of atrial fibrillation may for one lead to the discovery of new diagnostic markers or new targets for the prevention and treatment of atrial fibrillation. And that combined pro-inflammatory profibrotic and proarrhythmic effects of these epicardial fat and extracellular vesicles may in fact be relevant to the pathogenesis of other cardiovascular diseases associated with obesity and abnormal adipose tissue deposition.
Dr. Greg Hundley:
Very nice Carolyn.
Dr. Greg Hundley:
My next paper comes again to us from the world of preclinical science and these authors led by Dr. Masanori Aikawa from Harvard Medical School applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. They use global proteomics and high dimensional clustering on multiple vein graft tissues to identify potential pathogenic mechanisms. And experiments were conducted in both in vivo mouse models and in vitro human macrophages.
Dr. Carolyn Lam:
Oh wow. So what did they find?
Dr. Greg Hundley:
So Carolyn, peroxisomes proliferator activated receptors or PPAR alpha agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development.
Dr. Greg Hundley:
Now, metabolomics, lipidomics, functional metabolic assays and single cell analysis of cultured human macrophages revealed that PPAR alpha modulates macrophage glycolosis, citrate metabolism, mitochondrial membrane sphingolipid metabolism and heterogeneity.
Dr. Carolyn Lam:
Okay. So what is the take home message Greg?
Dr. Greg Hundley:
Right Carolyn, thought you would ask me that.
Dr. Greg Hundley:
So PPAR alpha activation suppresses the development of vein graft and arterial venous fistula lesions. And PPAR alpha reduces macrophage activation by influencing macrophage heterogeneity, mitochondrial integrity, and the metabolome. So Carolyn, given that peripheral arterial disease and chronic kidney disease prevalences are increasing, warranting needs for more vein grafts and arterial venous fistulas, this target discovery platform is applicable to investigating therapies for these diseases.
Dr. Greg Hundley:
And a really nice accompanying editorial is provided by doctors Reilly and Bornfeldt.
Dr. Greg Hundley:
Well Carolyn, how about we turn to look at what is in the mailbag this week?
Dr. Carolyn Lam:
Well let me tell you about it Greg. We've got a cardiovascular case series by Dr. Borlaug on things are not always as they seem, multimodality exercise assessment and evaluation of dyspnea. In cardiology news by Kuhn there's a discussion of Evinecumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag. A perspective piece by Dr. Watkins on time to think differently about sarcomere negative hypertrophic cardiomyopathy. And finally a research letter by Dr. Ahn on reduction in Kawasaki disease after non-pharmaceutical interventions in the COVID-19 era, a nationwide observational study in Korea.
Dr. Carolyn Lam:
Wow. That wraps it up for the summaries. Let's go on to the feature discussions shall we, Greg?
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
We are about to talk about the extended follow-up results of the PRADA trial. Oh, so interesting. So happy to have with us today, doctors Geeta Gulati and Dr. Torbjørn Omland, both from the Akershus University hospital in Norway, and you would probably recognize that Dr. Torbjørn Omland is also one of our associate editors, but both here are the co-corresponding authors of this beautiful paper.
Dr. Carolyn Lam:
Thank you so much for coming here today. Torbjørn, maybe you could start with what is the PRADA trial? Why did you decide to do an extended follow-up?
Dr. Torbjørn Omland:
Yeah so PRADA was a two times two factorial randomized double blind clinical trial that sought to evaluate the effects of intervention with receptor blocker Candesartan. And a beta blocker Metoprolol in patients with early breast cancer who received anthracycline therapy as part of their chemotherapy. And then we wanted to assess the effect of this sort of preventative therapy, left ventricular function and injury.
Dr. Torbjørn Omland:
So we reported the primary results of the trial a few years ago and showed that intervention with Candesartan most associated with a significant elevation of the reduction in left ventricular ejection fraction that these patients may experience, and also that treatment with the beta blocker Metoprolol was associated with an intimation of the increase in cardio proponents suggesting a beneficial effect on myocardial injury. However, whether these results were or these effects were sustained after termination of the study drugs was unknown. And that was what we really wanted to address with extended follow-up study.
Dr. Carolyn Lam:
Yeah, makes a lot of sense, especially because these injuries I suppose could still continue. And just to be very clear, the medications though were only taken during the adjuvant chemotherapy and therefore could be a variable duration from what I understand. Right? Great.
Dr. Carolyn Lam:
So Geeta then, could you tell us what did the extended analysis show?
Dr. Geeta Gulati:
The extended follow-up was interesting and it was something we really wanted to figure out because there are not many studies who have been done on the extended follow-up and you're not giving these study medications afterwards.
Dr. Geeta Gulati:
So very interestingly we saw that the decline in the ejection fraction was still there in the whole group. But this time there was no difference in the group who received Candesartan do those who didn't. And we show that there was a different in the primary results, but now in the extended follow-up there was no difference. And then also in the Metoprolol group that had previously shown that there was lesser rise in the troponins. Again, there was no difference in the groups now on the extended follow-up.
Dr. Geeta Gulati:
So this is very interesting because this shows that there is a small, modest decline in a left ventricular ejection fraction during and after the breast cancer therapy. But what does this really mean? It's a small decline and it's within the normal range and the cardioprotection is not working. So, are we perhaps looking at the wrong group? Perhaps we should look at patients who have the higher cardiovascular risk factors. Perhaps even we should look at more novel heart failure or cardiac drugs that may have a stronger effect on the ejection fraction.
Dr. Carolyn Lam:
Right. So Geeta though, can we unpack that a little bit? You see, the patients were not on the medication anymore at the time of follow-up. So you're saying that even though they were given adjuvant chemotherapy and covered with the drug, that even not having any more chemotherapy, their ejection fraction still fell. And if I'm not wrong, this was an MRI analysis. And so it was only by an ejection fraction of two percent on mean fall, right? How do we think about that clinically?
Dr. Geeta Gulati:
And that's the important question, isn't it? Because a decline in the ejection fraction of less than two percent within the normal range, what does it really mean? Well initially we thought that if there was a different in those who had cardioprotective medication compared to those that didn't, it may prevent development of further decline in the cardiac function and then heart failure in the future. But now, there is really no difference between the groups. So perhaps the clinical implication of giving cardio protection to all cancer patients is not really that useful. Perhaps they should look at those who are at higher risk because they would have a greater fall in ejection fraction and then more cardioprotective effect of these drugs.
Dr. Carolyn Lam:
Yeah, totally. And perhaps the metrics that we're used to seeing in the past with greater falls of ejection fraction, maybe it just doesn't apply currently or perhaps with the specific chemotherapeutic regimens perhaps that you're using now. Because with a very small fall, and I believe you only had one heart failure event, right? If I'm not wrong in this extended follow-up. So, just to let the audience know, it was very small fall, little number of events. It's hard to really tease apart what that clinically means. Now, could I ask though, does it mean we need actually a more sensitive marker? Because there was some interesting stuff about global longitudinal strain. Could you-
Dr. Geeta Gulati:
I would throw that question back to Torbjørn I think.
Dr. Torbjørn Omland:
Yes. So that's a very interesting question Carolyn. So we did observe what seemed to be a beneficial, but a sort of minor effect on global longitudinal strain. So we know that that is the more sensitive index of systolic function than left ventricular ejection fraction, that was the pre defined primary outcome. So that's raises of course questions whether a future trial should more focus on these more sensitive indices of cardiac function.
Dr. Carolyn Lam:
Yeah. Geeta, could I then really put it back to you? And the tough question I always get, how do we apply these results clinically then? I mean, you see these patients right? Now what? Do you give or do you don't give? And which one do you give? And how do you identify high risk patients? I don't know.
Dr. Geeta Gulati:
Again, I think all the patients are unique aren't they? So that's where we have to start. So in my clinic, if I have a high risk patient with hypertension, diabetes, hypercholesterolemia, yeah perhaps they even have had a cardiovascular disease before something like this. Then I will take more care of these patients and be more careful with the echo measurements I'm doing and if I find that they have a decline in their cardiac function, I may be more eager to start them on cardioprotective medication.
Dr. Geeta Gulati:
But then in R-Regen we follow all the HER two positive breast cancers with echo. If I don't have echoparamaties that clearly tells me that they have a decline in the cardiac function, then I may wait to start cardio protection because none of the studies has really so far show that all patients should have these cardioprotective medication or prevention.
Dr. Carolyn Lam:
Nice. Thank you. That was a tough one to get at. And I suppose Torbjørn I have to give you another tough one then. Because how to address the remaining unanswered questions, right? Because one of them on my mind too, is how to identify the high risk, do biomarkers play a role? And then the other is if we then start the preventive therapies like ERBs and beta blockers, should we actually continue it forever? And so on. But anyway Torbjørn please, please, what does the future hold?
Dr. Torbjørn Omland:
I think it's worthy of a recap or underscoring that these are really good news for many breast cancer patients that actually the risk of an important decline in ventricular function is lower than we thought. So that may be because of several things. I think in general, those whose used these cardiotoxic drugs are lower. And we also, I think that there's increased collaboration between oncologists and cardiologists. Also meaning that we are better to pick up the high-risk patients at an early stage.
Dr. Torbjørn Omland:
But of course, it's very important questions that you asked regarding how to identify the high risk patients. And I think that's where really future research should focus. So there we know that traditional risk factors are important. We are looking into whether biomarkers can be used, if there's more sensitive imaging in this can be used. But so far we haven't really succeeded in getting the risk model that really identifies it on the patient level. So that's work that remains to be done.
Dr. Torbjørn Omland:
And then we are also looking for new types of intervention, good exercise, good other drugs. We are doing now a PRADA two study where we look at the effects of Sacubitril Valsartan in this setting. And those are also very exciting, I think, and we look very much forward to present that in the future.
Dr. Carolyn Lam:
Oh wow thank you so much Torbjørn and Geeta. The PRADA two trial. I've got to ask you, why do you then call it the Chanel trial? But I think I'll save that for another day. So thank you. Thank you once again, this is fabulous and congratulations to you both.
Dr. Torbjørn Omland:
Thank you.
Dr. Geeta Gulati:
Thank you.
Dr. Greg Hundley:
Well listeners, welcome to our second feature discussion today. And we have with us Dr. Marc Dweck from University of Edinburgh in Scotland and our own associate editor, Victoria Delgado from Leiden in the Netherlands. Welcome to both of you.
Dr. Greg Hundley:
Marc, we're going to get started with you. Could you tell us a little bit about the background for your study and what was the hypothesis that you wanted to test?
Dr. Marc Dweck:
Thanks very much Greg for the invitation. So I guess aortic stenosis is perhaps the last major cardiovascular condition where we don't have a medical therapy. We're unable to treat these patients. We're unable to prevent progression. We're only left with a valve replacement. And so we, like a lot of groups around the world, want to develop a treatment for aortic stenosis. Our group did the first SALTIRE trial, where we looked at statins seeing if we could slow aortic stenosis progression. And that, like similar trials, was neutral. No effect on the valve progression.
Dr. Marc Dweck:
And so actually I've spent the last 10 years looking at some of the factors associated with aortic stenosis progression in particular. The answers that we've had from those trials have kind of come back telling us that really it's a process of calcification. If you look at what triggers progressive valve narrowness is this calcific process, that seems to be a self perpetuating disease.
Dr. Marc Dweck:
So the question is, how do you target this calcification process? How can you interrupt it? And how can you do that without compromising bone health in these elderly patients? So in trying to come up with a solution to that we thought about using osteopetrosis agents, which we hypothesized would maintain both bone health and reduce vascular calcification on the basis of observational data and also animal data suggesting that. And that was really where we came from in the design of the SALTIRE two trial.
Dr. Marc Dweck:
And doing a big trial with clinical endpoints wasn't felt to be feasible and instead we decided to look at imaging end points and see whether we could slow disease progression using these agents.
Dr. Greg Hundley:
Very nice Marc. And so you're really leading us into, tell us a little bit more about your study population and your study design.
Dr. Marc Dweck:
Yeah so we wanted to take patients from our outpatient clinic with mild, moderate and even early severe disease, asymptomatic patients crucially, patients that aren't scheduled for aortic valve replacement and see the effects of these drugs on disease progression.
Dr. Marc Dweck:
So we did a randomized control trial. There was three arms. Patients were randomized to Alendronate, Denosumab, these are the two osteopetrosis agents, or placebo. We then did a series of baseline imaging tests. So the primary end point was based on CT calcium scoring. So they had a baseline CT calcium score. They also had a baseline echocardiogram and they had a baseline fluoride PET scan. So this measures calcification activity in the valve. And then we essentially repeated those tests after a period of time on the drugs, or on placebo. We repeated the calcium score and the echo after two years and repeated the PET scan after one year.
Dr. Greg Hundley:
Very nice, and so before you tell us your results, a little bit, how many patients? And maybe their average age and the rough distribution of men versus women.
Dr. Marc Dweck:
Yeah so study recruited roughly 50 patients in each arm. The average age was 72 and there was 21% females in the study. So, like a lot of studies in aortic stenosis, a low female prevalence. Despite our best efforts, that's something we need to attend to in the future, but otherwise, a representative age group and patients with this disease.
Dr. Greg Hundley:
And what did you find?
Dr. Marc Dweck:
Well we found that the drugs didn't have an effect on any of these imaging assessments. So, there was no effect on the progression for CT calcium score at two years, no effects on any of the echocardiographic assessments of hemodynamic severity, and no effect on calcification activity as measured with the fluoride.
Dr. Marc Dweck:
So a very consistent result using multiple different imaging modalities, which I think gives us confidence that there isn't at least a dramatic effect of these drugs on disease activity or disease progression, in aortic stenosis.
Dr. Greg Hundley:
Very good. Well listeners, we're now going to turn to one of our associate editors, Dr. Victoria Delgado, and she is really a valvular heart disease expert member of our team.
Dr. Greg Hundley:
Victoria, I know you see a lot of papers that kind of come across your desk. What attracted you to this manuscript? And then how do you put the results in the context of other research that's going on to halt the progression of aortic stenosis.
Dr. Victoria Delgado:
Thank you Greg. So first the first thing that attracted my attention for this article is the question. We know that we don't have any medical therapy for halting the progression of aortic stenosis. And even if the previous studies have been negative or neutral, still there is the interest of trying to find a less invasive therapy for these patients, or even prevent that they arrive to surgical or transcatheter aortic valve replacement.
Dr. Victoria Delgado:
And the second is that these are very strong analysis because it's a randomized clinical trial and using as end points imaging. So that trial also in a way answers the question of which imaging technique we need to use in order to see the effects of specific therapies. Previous studies have used mainly echocardiography, but that only gave us information on the modynamic effects of the aortic stenosis. While in this study, we have the combination of CT and a combination of a PET that he give us also information on how the calcification is happening. So that makes the study very comprehensive and give us more insights into this pathophysiology, to this pathology particularly.
Dr. Greg Hundley:
Very nice. So it sounds like looking at aortic stenosis from multiple different angles, whether it be echocardiography or perhaps imaging processes that look at the progression of calcification.
Dr. Greg Hundley:
Well, Marc, I want to come back to you. What do you think is the next, sounds like you've been working in this area for an extended period of time. What do you see as the next research study that you and your group may undertake in this area?
Dr. Marc Dweck:
I Think we've got the study design about right. I think if in the future studies we want to do, I think we would adopt a similar design using these imaging end points.
Dr. Marc Dweck:
I have to say I'm very influenced by the recovery trial that has been conducted in the UK with COVID. I mean, here's a disease where we wanted to get a treatment as quickly as we can. And in doing that, developing a platform type trial where you potentially test multiple different promising agents simultaneously across multiple centers across the world or the UK, I think that would be the quickest way to developing a treatment. And so I'm encouraged that there are five or six very good targets where we could, for a new therapy in aortic stenosis. And I think a platform type design where we engage multiple groups using imaging as that initial end point. And then, the drugs that appear to have an effect on these imaging end points we can start to recruit more patients at those sites, into those centers, looking for clinical end points.
Dr. Marc Dweck:
I think that kind of discussion is happening around the world now between groups that are interested because we want to crack this problem quickly. We don't want to wait and do these different studies sequentially. We want to try and do them simultaneously. And I'm excited about that. I think if we do that, we've got a real shot at developing a treatment over the next five to 10 years say.
Dr. Greg Hundley:
Fantastic.
Dr. Greg Hundley:
And Victoria, I know you have interest in this particular area. Do you have anything you'd like to add?
Dr. Victoria Delgado:
Yeah. I think that those studies that Mark said are really welcome and I hope that they are positive. And give us a little bit of more to treat these patients. My main fear is that these patients are not as frequent, for example, as heart failure patients. Where we have several therapies where we have possibility to enroll patients in trials for new drugs, that we know that probably are going to be effective. But for valvular heart disease it has been always the end point to reach surgery or to reach an aortic valve replacement or indication of the mitral valve and mitral valve repair. So in early phase of the disease, my main concern is that maybe the patient is not going to be well-trained to understand what are the consequences. I want to always wait until maybe when is needed for the surgical or transcatheter procedure.
Dr. Victoria Delgado:
But I think that increasing the awareness of the prevalence of valvular heart disease and the consequences may help people to understand, to put more attention for an early diagnosis and develop new drugs that can help, like in this case, aortic stenosis one of the most frequent valvular heart disease, to prevent the proliferation and to prevent the replacement of the valve.
Dr. Greg Hundley:
Very nice. Well listeners, this has been a wonderful discussion and we greatly appreciate the input that we've been able to gather today from Dr. Marc Dweck from Edinburgh in Scotland and our own associate editor, Dr. Victoria Delgado. Bringing this information from a randomized trial, evaluating osteoporosis drugs, and really indicating they did not disrupt the progression of calcification in patients with aortic stenosis.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great rest of your week and we will catch you next week on The Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Join Mercedes Carnethon as she interviews authors Brendon Bellows, Dhruv Kazi, and Kirsten Bibbins-Domingo to discuss two articles published in the special issue: “Cost-effectiveness of Hypertension Treatment by Pharmacists in Black Barbershops” (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051683 ) and “Scaling Up Pharmacist led Blood Pressure Control Programs in Black Barbershops: Projected Population Health Impact and Value” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051782.
Dr. Joseph Hill:
Welcome to Circulation on the Run. My name is Joe Hill and I'm the editor-in-chief of Circulation. In recent months, we witnessed horrific acts of discrimination and violence against African-Americans. We are shocked and appalled, but yet we also recognize that this is in many ways nothing new. At Circulation, we are highly committed, longstanding commitment to shining a bright light on these pervasive inequities. And we are not willing to simply catalog the woefully longstanding racism that pocks our society, but rather we intend to shine a bright light on solutions. And with that, we are launching the first annual issue on disparities in cardiovascular medicine. This will be released in mid June corresponding to the date of Juneteenth, which is the date in the 19th century when a group of slaves in Galveston, Texas was apprised of the fact that they were no longer slaves now for two years.
Dr. Joseph Hill:
I'm honored to have our three editors who are running this podcast and this issue with us, they are Dr. Mercedes Carnethon from Northwestern University, Dr. Karol Watson from UCLA, both of whom are associate editors with the journal. And I'm pleased that Michelle Albert, who is one of our senior guest editors at UCSF will be joining us. These three professionals have led this initiative and I would like to spend a few minutes talking with them about this. First let's turn to Michelle if I may. Michelle, what do you think is required from a workforce perspective to make headway, to eliminate these disparities?
Dr. Michelle Albert:
Thank you, Dr. Hill. And I would first say that it is an honor to have been able to participate in this disparities issue focused on African-Americans and health. First, I think that it is important for our audience to understand that the metrics actually behind a workforce. In cardiovascular medicine, only 13% of fellows are underrepresented fellows, meaning black or African American, Hispanic, or Latinx, native Americans, Alaska natives, and Pacific Islanders. And only 9% of faculty are UIM in cardiovascular medicine. This stems from a pipeline or pathway issues that go all the way back to kindergarten and middle school. Indeed, over the last three decades only, although there's been a 50% increase in applications for blacks and Hispanics, the applications have only increased by 1.2% and there has been a drop in Alaska native and American Indian applications by 30%.
Dr. Michelle Albert:
So with regards to how improve these statistics, we have to have multifaceted approaches related to understanding pipeline barriers, which include things like lack of encouragement, lack of role models and paying attention to recruitment, but not just the only recruitment at the pre-medical level, immediate pre-medical level, but way prior to the pre-med level, we have to engage middle-aged and high school students in STEM and thereafter at the pre-medical level, we have to make sure that students get the appropriate advice to ensure successful careers in college that would then engender successful applications to medical school.
Dr. Michelle Albert:
Once we get into the actual medical institutional systems, we have to address structural barriers to discrimination that exist, that impede the progress through pathways in medicine. And these barriers exist at the medical school level, the residency level, fellowship level and faculty to leadership levels. I would say just a couple of examples at the medical school level to address would be actually paying attention to the fact that MCAT scores, we need to pay attention to a whole range of MCAT scores that focus on success in medical school and not just a specific hard cutoff. In residency we need to focus on evaluation disparities for UIM versus non UIM that then set the pathway again for a lack of progress into extremely competitive specialties like cardiovascular medicine. At the fellowship level we know that only 6% of program directors actually value diversity as one of the top three entities when ranking applicants. Duke School of Medicine actually had a really innovative process of holistic review and at all levels there should be holistic review that pays attention to distance, travel and metrics as well as attributes.
Dr. Michelle Albert:
And at Duke for example, what they did was they tripled actually their UIM enrollment in cardiology fellowship from 9% to 33% after employing a holistic review process that focus less on metrics and more on a combination of metrics, distance traveled, et cetera. Once folks are in the pipeline we have to set up systems of support to help trainees and faculty thrive in clinical learning and work environments because we noted small differences and assess clinical performance, amplify to large differences and evaluations, grades, and awards that have gone toward consequences for our workforce. And then I would say these are not my recommendations here or not all inclusive. But two other things I think that we really need to pay attention to besides the mentorship and sponsorship is actually stemming isolation for trainees and faculty within our structures and systems as well as ensuring that we all have implicit bias training and also the effect of implicit bias training is measured over time on the impact on healthcare outcomes and our pipeline outcomes. I know that was a mouthful, Joe, but this is a very complicated topic.
Dr. Joseph Hill:
Well, it certainly is Michelle. And I think all our listeners know that you have been and are a major leader on an international scale around these topics. Thank you for your leadership. My next question has to do with building trust with black patients in terms of their willingness to engage with their physician and also participate in research studies and trials. Karol, Dr. Watson from UCLA, maybe you can comment on that.
Dr. Karol Watson:
Yes, I would be happy to. And I have to piggy back on what Michelle just said. You start off talking about trust, there has to be a trust between the patient and the provider, the researcher and the participant, and that trust really it's multifactorial as Michelle states, but it really does rely on having a workforce that looks like the patient population, having principal investigators that look like the participants. We have an issue with trust in medicine in many areas, but one of them is lack of trust amongst African-Americans. When surveys are done and they ask patients to endorse or not endorse certain statements, the statement I trust my healthcare provider, it's less likely to be endorsed by African-American patients than others. And much of that mistrust is well earned. We're all aware of some horrific medical injustices that were meted out to certain communities, including African-American communities.
Dr. Karol Watson:
We're all aware of the Tuskegee syphilis study, but there are many others. So without trust, there really cannot be a healthy, collaborative care model that ensures optimal patient outcomes. So I think one of the most important things that we have to stop doing is thinking of blaming the patient for being, "Nonadherent, non-compliant, difficult," because many things go into that equation and much of it is on our backs. And as Michelle says, we have to diversify our workforce to start off. And I think there are so many other levels of Michelle really nicely laid out, but there are really so many other levels and including getting more African-Americans into clinical trials and we can't just do the same thing we've always done and expect to get different results. So we say, "Oh, African-Americans just won't up for research." Well, maybe we're not making that research relevant, appropriate, and easy for them.
Dr. Karol Watson:
If we ask people to come to our research centers between 8:00 and 5:00, Monday through Friday, when they're working three jobs and they have to watch their grandkids and they have no one to help. That's a very difficult ask, when you're asking people who are struggling for basic needs and basic survival to do extra things. It's a very difficult ask and we have to make it easier for them because I am of a firm belief that everyone wants to do the right thing. They want to help medical professionals get the research needed, do the right thing to care for their own health, but it has to be accessible and that's something we haven't done a great job doing.
Dr. Joseph Hill:
Well, thank you. What a challenge and that's why I think this issue that the three of you have spearheaded has helped move that needle around those sorts of questions. So my last question is a broad one and maybe even the hardest one that I will throw to Dr. Carnethon and that is what are the biggest remaining threats? What does the future look like when you put your headlights on high beam to solve these problems?
Dr. Mercedes Carnethon:
Well, thank you so much Dr. Hill, and it's great to follow my colleagues who've offered wonderful insights from multiple perspectives. When we think about the path forward, we have to really consider how we got here. And we didn't get here solely through faults in one system, for example, academic medicine, we got here because of the broader systemic and structural issues that have led to differences in access, that have led to the mistrust we're talking about and that have led to fewer opportunities for academic advancement for black adults within this country. And the path forward is going to have to be a collaborative path. It can't just be the researchers and clinicians within academic medicine making a change because we can't make those changes and reach out in isolation of the context in which the patients who were seeking to help live in. So it requires partnerships with individuals at the community level, so that we can think about how we roll out effective interventions.
Dr. Mercedes Carnethon:
So those interventions that work one-on-one how do we get those out to the people who need them the most? That requires partnerships with the community and even changing the environments in which people live, making them healthier. It requires partnerships with academic institutions building off of the point that Dr. Albert made about needing to start and bolster the pipeline early so that we can get researchers and clinicians who look like the patients that they're trying to serve. And ending as well with Carol's point, when we run a study and we don't have representation from across a range of socioeconomic status from multiple individuals, black individuals, white, other races and ethnicities, we don't know how well those therapies are going to work, or whether there are unique situations that are going to lead them to be less effective in one group versus another. So I think I would end really with the point that the path forward to promoting equity is one that's going to involve partnerships across multiple different domains. And I do feel very hopeful that we can get there, especially as we're calling attention to these important issues right now.
Dr. Joseph Hill:
Well, I will end by saluting the three of you because you are in fact pointing away to a path forward and concrete things to make a difference. And it is my pleasure and honor to work with the three of you leaders. And I'm so proud of this issue, which will be a recurring issue and in June of every year. And thank you again for what you've done, you're making an important difference in our world.
Dr. Karol Watson:
And thank you so much for Dr. Hill for spearheading and supporting this effort. It is so important.
Dr. Mercedes Carnethon:
Yes, thank you.
Dr. Joseph Hill:
My pleasure.
Dr. Michelle Albert:
It's indeed an honor. And we have to lead by example, and I hope that we do.
Dr. Mercedes Carnethon:
Thank you so much.
Dr. Mercedes Carnethon:
I'm really excited as we move past our discussion amongst the editors to have an opportunity in this podcast to also speak with a team of authors who submitted two papers to our very special issue we have with us today, Dr. Brandon Bellows, Dr. Kazi and Dr. Kirsten Bibbins-Domingo who are sharing their findings about pharmacist led interventions to manage blood pressure among black Americans in barbershops. So thank you so much for submitting your important work to Circulation. I'd like to start with questions for you, Dr. Bellows. So your particular manuscript is addressing the cost effectiveness of hypertension treatment by pharmacists in black barbershops. Thank you for working on this very important work, because it really extends some of what we talked about earlier, which is the need to scale up and disseminate what we know to be effective interventions in populations. So can you tell us a little more about what you studied and what was unique?
Dr. Brandon Bellows:
Yeah, thank you so much. So we studied the value of a program to bring clinical pharmacists into black owned barbershops as you mentioned, and have the pharmacist partner with the barbers to manage hypertension in black men. As we know, black men are disproportionately impacted by both hypertension and cardiovascular disease. So our work was based on a randomized trial that was performed in barbershops in Los Angeles County. And this was led by the late Dr. Ron Victor. So we're really building upon his great foundation. In that trial they found that the pharmacist-barber collaborations substantially reduced systolic blood pressure by over 20 millimeters of mercury, relative to Barber's providing education alone over one year. So given that having pharmacist drive around barbershops and Los Angeles is a very expensive proposition, but we wanted to know if the potential benefits long-term would outweigh some of those high upfront costs and would it be a cost-effective to do this in Los Angeles? So really focused on the trial.
Dr. Brandon Bellows:
So to do this, we combined the data from the randomized trial with our computer simulation model to try and project long-term clinical outcomes. So upto 10 years, so for both blood pressure, cardiovascular disease events, as well as the economic outcomes. So total healthcare costs, costs of the program and so on. So what we found was that having pharmacists work with barbers and these black owned barbershops was a cost-effective way to reduce blood pressure in black men. Over 10 years, we projected that the program would cost about $2,400 more, and that's total healthcare costs than barbers providing education alone so they enter the control arm in the trial, and we found that they would prevent about 30% of cardiovascular disease events over 10 years. So the incremental cost effectiveness ratio or ICER, which is how we define cost-effectiveness was $43,000 per quality adjusted life year gained.
Dr. Brandon Bellows:
And this is below the threshold recommended by the American Heart Association of $50,000 per quality adjusted life year gained to define something as highly cost-effective. So doing this with a highly cost effective way to improve blood pressure in black men. So one thing that makes our study unique is that our computer simulation model allows us to explore different designs of the program to see how that might impact the cost effectiveness. So for example, if we were to use only generic antihypertensive medications, or if we were to decrease the length of the intervention from one year to six months, the pharmacist barber program was even more cost effective. So given the long-standing disparities in cardiovascular disease that have been experienced by black men in the United States, we're really hoping that how our research can help motivate healthcare payers to adopt these kinds of non-traditional approach delivering hypertension care, because if nobody's paying for it, then there's not going to be uptake in the community.
Dr. Mercedes Carnethon:
Yeah. Brandon, thank you so much for sharing that and sharing the details about what you found. I love this line of work because quite often we've spent a lot of time discussing and describing disparities, but less attention considering ways in which we can reduce disparities by reaching people where they are. So that brings me to you Kazi. So your study uses the same population, but addresses a slightly different question that I think is very relevant to our audience as we seek to try to promote cardiovascular health equity. So tell us a little bit about what you did in the same population and what you found.
Dr. Dhruv Kazi:
I want to also start out by acknowledging that the study is anchored in the vision and genius of the late Dr. Ron Victor, who ran the barbershop based blood pressure controlled studies in Dallas, and then in Los Angeles. And kind of motivated by his pragmatic optimism, this idea that we have a problem where others high rates of uncontrolled blood pressure in black men, but it is a problem that can be addressed through a novel intervention that will then have to be contextualized. He was open-eyed about the need for contextualization that even though there's a large 20 millimeter mercury reduction in blood pressure, any intervention, when we go beyond Los Angeles would have to be contextualized for geography and for payer. Would treating blood pressure in Dallas, or San Francisco, or Detroit, or Atlanta would look different from both the economics and the practical aspects of delivering this care in Los Angeles?
Dr. Dhruv Kazi:
So we set out to ask the question that if we were to make these barbershop based pharmacists led blood pressure control programs more widely available across the country in urban areas, metropolitan areas, and were able to enroll black men with uncontrolled blood pressure into these programs, what would the clinical impact be and what would the economic constraints be for these programs to be sustainable? We estimated that about 950,000 black men could be enrolled in a program of this nature. So that's about a third of black men with uncontrolled hypertension and that doing so on an annual basis would reduce about 8,600 or 8,600 major adverse cardiovascular events. That's about including 1800 MIs and 5,500 strokes. So quite a large number of events, but 40% of events in enrolled populations. And we then set out to ask, "Well, that's great. If we could deploy these programs at scale, there's the potential for substantial clinical impact, what would the economic constraints have to be for this program to be sustainable?"
Dr. Dhruv Kazi:
So if we imagine that this were not a delivery program but rather a pill, and you were willing to pay $100,000 to reduce per quality adjusted life here for blood pressure control medication, how much would we be willing to pay for this barbershop based program? And we found that approximately it would have to be delivered at a cost of $1,400 per patient per year. Now, $1,400 per patient per year is a substantial amount of money when you scale it up across the entire eligible population, but at the same time would require innovation and delivery that goes beyond pharmacists driving from one barbershop to another. So what we hope is that our work will stimulate this conversation around how can we take this intervention that is highly effective, that is potentially scalable and adapted in a way that we can afford to deliver it nationwide without losing effectiveness that we saw in the Los Angeles trial?
Dr. Mercedes Carnethon:
Thank you so much Dr. Kazi. And this just generates a lot of discussion as we really think about how we can bring interventions to people and how we can have an impact. So Kirsten, I'm so pleased that you were also able to join us as one of the senior authors, senior members of these research teams, because we really value your perspectives as well about where do the findings from this study situate us in the field. How do we move forward to achieve our goals of achieving equity and particularly among black patients and black adults in this country who we know have experienced significantly higher rates of hypertension and hypertension related disorders, we have a significant need here. So tell us how do we use this important information in order to make a difference?
Dr. Kirsten Bibbins-Domingo:
Thank you so much for having us and congratulations on this really important issue.
Dr. Kirsten Bibbins-Domingo:
I think what we see here in why these papers and this work is important is that it is really trying to take the important science that we're producing, trying to aim that addressing disparities and put it in the context that we could ideally rapidly translate it to actually help and address this issue. And with hypertension, we have both the urgency of declining rates of blood pressure control in the US as well as the persistent disparities that we see. So we have this effective intervention marrying a care provided by clinical pharmacists with community-based venues and partnership with black barbershops that is highly effective. The detailed studies led by Brandon really suggest that even in LA, pharmacists driving around this is a cost-effective intervention and that if we were to scale it, it could actually reach a lot of black men in the US and even though $1400 per person per year is a lot of money, it's actually not out of context of other things that we do that are high priority for our healthcare systems.
Dr. Kirsten Bibbins-Domingo:
So what we hope is that these two papers together help us to start to bring more people to the table to how we can translate now an effective trial, a trial that can effectively scale in a cost-effective way to thinking about what we could actually do. So how might this look? We think this is something that we hope health systems start to engage in. When they see disparities in the care for their members, for their patients, how could they think more creatively?
Dr. Kirsten Bibbins-Domingo:
How could payers, how could Medicaid for example, think about incentivizing different ways of delivering hypertension care? How could we think in other contexts about departments of public health or cities that really want to have a population-based approach to improving cardiovascular health? And money isn't everything, but is an important thing that many of these entities are thinking about and understanding both that this is a cost-effective intervention and that the amount per person to actually achieve this important role in cardiovascular health is not out of scale for other things that we prioritize in terms of health I think is important and that's what we hope people will take away from these important studies.
Dr. Mercedes Carnethon:
Wow, I really appreciate the time and attention that your team put into designing these really high impact research studies that achieve what our goal is, is to really think about ways in which we can address and eliminate disparities. I've really loved hearing about this work, and I hope that a broad audience receives it and really thinks about some of what we talked about before, which are the multiple different parties and disciplines that are required to come to the table for us to effectively address disparities. So thank you so much for spending time with us at our Circulation on the Run podcast, Dr. Kirsten Bibbins-Domingo from University of California at San Francisco, Dr. Brandon Bellows from Columbia University College of Physicians and Surgeons and Dr. Kazi from Beth Israel Deaconess Medical Center. So thank you so much for spending time with us today.
Dr. Dhruv Kazi:
Thank you for having us.
Dr. Brandon Bellows:
Thank you. It's been a pleasure.
Dr. Mercedes Carnethon:
And finally, I'd like to end by thanking our listeners for spending time with us today. We hope that you enjoyed the podcast, and we hope that you will enjoy the issue even more.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week's podcast features author Nicholas Mills and Guest Editor Allan Jaffe as they discuss the article "High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial." (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.052380)
Dr. Carolyn Lam:
Welcome to Circulation On The Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke-National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor/Director of the Pauley Heart Center and VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to examine cardiac troponin, high-sensitive cardiac troponin, and its association with myocardial infarction. But first, before we get to that, how about we grab a cup of coffee and start in and review some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I would love that. The first paper brings up the problem of stroke, remaining a devastating complication of transcatheter aortic valve replacement or TAVR. Now, this stroke risk has persisted despite refinements and the technique and increased operator experience, while cerebral embolic protection devices have been developed to mitigate this risk data regarding their impact on stroke and other outcomes after TAVR are limited.
Dr. Carolyn Lam:
Dr. David Cohen from Cardiovascular Research Foundation in New York and colleagues performed an observational study using data from the STS-ACC TVT registry, including more than 123,000 patients from almost 600 sites who underwent elective or urgent transfemoral TAVR between January 2018 and December 2019.
Dr. Greg Hundley:
Wow, Carolyn, this sounds like a really good use of the registry. What were the results?
Dr. Carolyn Lam:
Indeed, in this nationally representative observational study, the authors did not find an association between embolic protection device use for TAVR and in-hospital stroke in their primary instrumental variable analysis. And that's a technique designed to support causal inference from observational data with site-level preference for embolic protection device use within the same quarter of the procedure as the instrument.
Dr. Carolyn Lam:
However, they found a modestly lower risk of in-hospital stroke in their secondary propensity weighted analysis. These findings provide a strong basis for large-scale randomized control trials to really test whether embolic protection devices provide meaningful clinical benefit for patients undergoing TAVR. And this is discussed in a nice accompanying editorial by Dr. Tam and with Wijeysundera from University of Toronto.
Dr. Greg Hundley:
Very nice Carolyn. Well, my first paper comes to us from Professor Hua Zhang from Shanghai Children's Medical Center. Cyanotic congenital heart disease is a complex pathophysiological condition involving systemic chronic hypoxia and some cyanotic congenital heart disease patients are chronically hypoxic throughout their lives which heightens their risk of heart failure as they age.
Dr. Greg Hundley:
Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-Alpha. And Carolyn, this study aims to determine the effect of chronic hypoxia on cardiac metabolism and function in cyanotic congenital heart disease patients and its association with age. The authors investigated the role of hypoxia-inducible factor 1-Alpha in this process, and the potential therapeutic targets for this were explored.
Dr. Carolyn Lam:
What did they find Greg?
Dr. Greg Hundley:
In cyanotic congenital heart disease patients maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. In cardiomyocytes, specific HIF1-Alpha knockout mice, chronic hypoxia failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF1-Alpha and was responsible for cardiac metabolic maladaptation in animals exposed to chronic hypoxia.
Dr. Greg Hundley:
Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal chronic hypoxia animals. And so, Carolyn, perhaps future studies could test whether pioglitazone administration during puberty might improve cardiac function in cyanotic congenital heart disease patients. And this article is nicely accompanied by an editorial from Professor Ghofrani.
Dr. Carolyn Lam:
That's really interesting. For the next paper we're going from cyanotic congenital heart disease to plain old hypertension asking the question, What is the association of blood pressure classification using the 2017 ACC/AHA blood pressure guideline with risk of heart failure and atrial fibrillation? Well, this question was addressed by Dr. Kaneko and colleagues from University of Tokyo who performed analysis using a nationwide health claims database collected in the JMDC claims database between 2005 and 2018. Now note, this was more than 2 million patients followed for a mean of more than a thousand days in whom more than 28,000 incident heart failure, and more than 7,700 incident atrial fibrillation events occurred.
Dr. Greg Hundley:
Carolyn, this is a really large cohort a lot of events. What did they find here?
Dr. Carolyn Lam:
Among adults not taking anti-hypertensive medications and with no prevalent history of cardiovascular disease, stage one and stage two hypertension, according to the 2017 ACC/AHA blood pressure guidelines was associated with a higher incidence of heart failure and atrial fibrillation. The population attributable fractions for heart failure associated with stage 1 and stage 2 hypertension were 23.2% and 51.2% respectively. The population attributable fractions for atrial fibrillation associated with stage 1 and 2 hypertension were 17.4% and 34.3% respectively. The categorization based on 2017, ATC/AHA blood pressure guidelines may improve risk stratification for identifying adults at high risk for heart failure and atrial fibrillation.
Dr. Greg Hundley:
Wow Carolyn. Really useful data and something I love about our journal, a transition from a large cohort study on hypertension, and now we're going to delve into the world of preclinical science and talk about myocardial hypertrophy. Carolyn, exercise can induce physiological myocardial hypertrophy and former athletes can live five to six years longer than non-athletic control suggesting a benefit after regression of physiological myocardial hypertrophy.
Dr. Greg Hundley:
Accordingly, these authors led by Professor Yulin Liao from Nanfang Hospital and Southern Medical University hypothesized that anti-hypertrophic memory exists after physiologic myocardial hypertrophy has regressed increasing myocardial resistance to subsequent pathological hypertrophic stress. In this study, C57BL, six mice were submitted to 21 days of swimming training to develop physiological myocardial hypertrophy. Then after termination of the swimming events and exercise, the physiological myocardial hypertrophy regressed within a week. And these physiological myocardial hypertrophy regression mice termed the exercise preconditioning group or HP, and then sedentary mice as a control group underwent transverse aortic constriction, or a sham operation and were observed for four weeks.
Dr. Greg Hundley:
Finally, in these two groups, cardiac remodeling and function were evaluated using echocardiography invasive left ventricular hemodynamic measurements and histological analysis.
Dr. Carolyn Lam:
Wow. Exercise induced and I hypertrophic memory in the heart. That is so cool. Greg, could you summarize what they found?
Dr. Greg Hundley:
Yeah. And how about that exercise stimulus? The mice were swimming. Carolyn, these authors found that exercise-induced physiological myocardial hypertrophy can produce cardioprotective effect. And this cardioprotective effect continues to exist after the physiological myocardial hypertrophy subsides. And it's termed a phenomenon exercise hypertrophy preconditioning.
Dr. Greg Hundley:
Now, mechanistically, the investigators found that exercise hypertrophy preconditioning up regulates the expression of the long noncoding RNA Mhrt779 by increasing the three methylation of histone 3 at the A4 promoter of Mhrt779.
Dr. Greg Hundley:
Carolyn, also cardiac overexpression are knocked down of Mhrt779 respectively enhanced or weakened the anti hypertrophy effect of exercise hypertrophy preconditioning. The clinical implications of this research are that these results will likely stimulate further research into the mechanisms of exercise hypertrophy preconditioning, and Mhrt779 may be a potential therapeutic target for myocardial heart hypertrophy and heart failure in clinical practice.
Dr. Carolyn Lam:
Wow. Thanks so much, Greg. That was an incredible summary.
Dr. Carolyn Lam:
Let me tell you what else is in today's issue. There's an exchange of letters amongst doctors Mehmood Donkor, and Westermann regarding the article “Left Ventricular Unloading is Associated with Lower Mortality in Cardiogenic Shock Patients Treated with Venal Arterial Extracorporeal Membrane Oxygenation.” There's an ECG Challenge by Dr. Bhasin regarding “A Young Woman with Palpitations. Is It a Poison or Is It a Reality?”
Dr. Carolyn Lam:
In Cardiology News by Tracy Hampton, she describes new research, revealing mechanisms behind exercise-induced heart damage, new details behind muscle injury repair, and new insights on plasma membrane rupture during cell death. Very interesting. A new section there. There's a Perspective piece by Dr. Passman on “’Pill in the Pocket?’ Anticoagulation for Atrial Fibrillation. Is That Fiction, Fact, or Foolish?”
Dr. Greg Hundley:
Great, Carolyn. Well also in the mailbag, there's a Frontiers and medicine piece from Professor Rohatgi entitled “HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.” And then finally, Carolyn, a Research Letter from Professor Felker, entitled Probabilistic Re-adjudication of Heart Failure Hospitalization: Events in the Paragon-HF Study.” Well, Carolyn, what a great group of articles summarized. How about now we proceed to that feature discussion?
Dr. Carolyn Lam:
Let's go Greg.
Dr. Greg Hundley:
Well, listeners. We are now to our featured discussion today and we have with us one of our associate editors who has submitted a paper, Dr. Nick Mills from Edinburgh, Scotland. And then we have a guest editor. Sometimes he's been a feature author, but now he's serving as a guest editor, Dr. Alan Jaffe from Rochester, Minnesota. Welcome gentlemen.
Dr. Greg Hundley:
Well, Nick, could you start us off first and describe for us the hypothesis that you wanted to test, and then maybe also provide a little bit of context or background around the study that you and your team have just performed.
Dr. Nicholas Mills:
Thanks, Greg. I've been working for about a decade trying to understand how we can get the value from high-sensitivity cardiac troponin in our clinical practice. We've tried a number of different approaches to implement them for the benefit of patient care that I'm particularly proud of this trial. What we'd recognized that I think with the rollout of these assays across Europe and more recently in America is that they're excellent tests, but they do generate some diagnostic uncertainty in clinical practice.
Dr. Nicholas Mills:
But as we've got used to using them, we've learned that actually their major strength is that the confidence that they bring in ruling out myocardial infarction rather than ruling it in. And they allow us to make really early decisions often with a single test at the point of arrival, where we can say with absolute confidence that a patient does not have acute coronary syndrome and it's unlikely to have a problem in the next 30 days or one year based on just how low that high sense of high-sensitivity cardiac troponin result is. And I've been a strong advocate for using these tests in that way for some time. But the limitation has been that much of the work in this field has been observational. And so the patients were actually managed accordingly because of uncertain pathways. And there's always been some uncertainty as just how effective they are when in clinical practice, whether using these approaches are safe. And so we designed the Historic Trial to address that definitively in our hospitals in Scotland.
Dr. Greg Hundley:
Very nice Nick. So what was the study population and what was the design for this
Dr. Nicholas Mills:
Thanks Greg. So we use an interesting study design set wage cluster, randomized controlled trial, where rather than randomizing individual patients and randomized hospitals in Scotland, in order to do a trial like this, you need very detailed infrastructure because we wanted to enroll every consecutive patient, attending our emergency departments with symptoms, suspicions of acute cardiac syndrome. We embed it so into our care path, which allows our clinicians to enroll patients for us. We were keen to enroll all consecutive patients because we wants to be confident that our findings were truly generalizable at any included patients with complex comorbidities presenting that of ours who were sick unwell, which is often not the case; they've been observational studies. We randomized hospitals and follow up patients with acute coronary syndrome up for a year in order to determine whether the implementation of already changed clinical care and that was safe and did not lead to recurrent and in the future.
Dr. Greg Hundley:
Very nice. So Nick, in this randomization of hospitals, how many total patients did you encounter and then what were your study results?
Dr. Nicholas Mills:
So we enrolled 31,492 consecutive patients. I've crossed all seven hospitals implementing our early relapse pathway, reduced length of stay overall in the hospital. By just over three hours, we increased the proportion of patients who are directly discharged home from the emergency department by more than 50%. So that overall 71% of patients attending hospital with possible acute coronary syndrome were able to be discharged from the emergency department rather than being admitted unnecessarily for further investigations. But the critical result was, was that major change in the care pathway safe. We had a non-inferiority design. We had a very small number of safety outcomes at 30 days, and it was difficult to prove non-inferiority, but the event rate favored the implementation there.
Dr. Nicholas Mills:
They will have pathway with the 0.4% of patients we attend within 30 days of heart attack or dying from heart disease for our implementing it and 0.3% in and crucially, we followed everyone up for a year and were able to demonstrate that the safety outcome was not increased in those that we are able to that pathway one year with absolute confidence. And furthermore, there was no difference in re attendance or an all-cause mortality. We the two different arms of the trial. So we concluded that the early relapse pathway was effective and safe, and that using this approach we'd have major benefits from patients who can avoid unnecessary for healthcare providers in terms of reducing actual cost limitations.
Dr. Greg Hundley:
Fantastic. Well listeners, we're now going to turn to our guest editor, Dr. Alan Jaffe, and Alan, could you help us put into perspective these new data regarding high sensitivity, proponent, and also comment what attracted you to this article so much so that you feel it's needs to be published and circulated worldwide in the literature?
Dr. Allan Jaffe:
One of the important areas in the field of biomarkers is the movement just finally occurring. And Nick has been the forefront of this, of starting to do randomized trials. Observational data is just that it's observational. The patients are not created based on the information that is by the biomarkers. Patients can be missed if you're missing a sample, you exclude those patients. In addition, most observational trials, try and get informed consent. And by getting informed consent often miss the sickest patients. So what's desperately needed by the field. And which is just now starting with two or three ongoing randomized trials is just that a randomized trial where the investigators are forced to use the data, to manage the patient. And by using the step wedge design that Nick and his group has used in other trials as well, they guarantee that they don't miss patients either.
Dr. Allan Jaffe:
So that it's comprehensive and takes all into account. This is terribly important to then validate things like in this instance, the rule-out pathway. And I think these data do substantially confirm the fact that a single sample rule-out strategy using the cutoff value that Nick had previously established as optimizing the percentage of the population that can be included works well. It is unfortunate that the way in which they design their trial mist and design their non-inferiority outcome for safety was such that they ended up not finding significance to that. But I agree with Dr. Mills in the sense that the outcome adverse effects were so low, that despite that I think there's very important and reasonable data that this strategy is also safe.
Dr. Greg Hundley:
Very good. Well, Nick, thinking forward, what do you feel is the next study that needs to really be performed in this area?
Dr. Nicholas Mills:
I completely agree with everything Alan said. I think there's lots of really interesting approaches to find a group diagnosis, risk stratification of this really common condition. We need trials that demonstrate these approaches actually influence care and outcomes. For me, the challenge remains how to really harness these great tests to route the ruler of my cognitive function. I run about ads of patients with elevated cardiac troponin added due to an underlying condition that is an acute coronary syndrome. And we're starting to think about ways in which we can individualize our decision-making a little bit moving to walk away from binary thresholds, because values are influenced by age, by sex, by comorbidities like renal disease and preexisting heart failure about heart disease.
Dr. Nicholas Mills:
And by incorporating some of these patient factors into the interpretation of cardiac troponin. I think we can give clinicians better guidance on who to treat early with antiplatelet therapies and who needs invasive investigation than just simply saying that the troponin concentration is all positive or negative. And it's our challenge, I think, is how to harness that information, make it workable in clinical practice, and then demonstrate that by doing so we actually target effective therapies better, and that it makes a difference for patient care. So this is where we're working on at the moment. And I hope that in due course, we'll be able to do randomized trials in this space and that will move things forward again.
Dr. Greg Hundley:
Alan, do you have anything you'd like to add to that?
Dr. Allan Jaffe:
Yes. I think we're in a new era. We are finally starting to see there are now two or three randomized trials. It is time that the biomarker diagnostic studies graduate to a higher level of evidence, meaning randomized controlled trials. Nick is leading the way in that regard and I suspect and hope that subsequent trials, although observational trials may help inform which ones we should do, but that subsequent trials will continue to be randomized and generate the more robust data that randomized trials are capable of generating.
Dr. Greg Hundley:
Well, thank you both. And Nick, thank you for bringing us this research and also Alan, for evaluating it and providing this commentary today. It's quite exciting to have really this new information produced from a randomized trial, which evaluated the utility of a low high sensitivity treponema value in patients presenting to hospitals with chest pain syndromes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.
In this week’s podcast, articles “The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin” by Light et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and “Metabolic effects of empagliflozin in heart failure: A randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic) by Jensen et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are discussed.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia,
Dr. Carolyn Lam:
Greg, it's double feature day. And guess what? Both papers that we're going to talk about are regarding the SGLT2 inhibitors, and really look at the mechanism of action of these amazing compounds, from both a pre-clinical and clinic point of view. That's all I want to say, because we've got to tune in, a very interesting discussion coming right up.
Dr. Carolyn Lam:
But first I'd like to ask you a question. What do you think is the association between health-related quality of life and mortality in heart failure around the world?
Dr. Greg Hundley:
Well, Carolyn, I would think that, actually, they might be linked.
Dr. Carolyn Lam:
That's a really clever answer. Thanks Greg. Well, the authors are actually going to tell you with this next paper. It's from Dr. Salim Yusuf from Population Health Research Institute and McMaster University in Hamilton, Canada, and colleagues, who looked at the global congestive heart failure, or GCHF study, which is the largest study that has systematically examined health-related quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, which is the largest study that has systematically examined health-related quality of life and its association with outcomes in heart failure, across eight major geographic regions, spanning five continents.
Dr. Greg Hundley:
Wow, Carolyn. So what did they find here?
Dr. Carolyn Lam:
Health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, or KCCQ, really differs considerably between geographic regions, with markedly lower quality of life related to heart failure in Africa compared to elsewhere. Health-related quality of life was also a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and with both preserved and reduced ejection fraction.
Dr. Carolyn Lam:
Indeed, this paper really highlighted a great need to address disparities that impact health-related quality of life in patients with heart failure in different regions of the world.
Dr. Greg Hundley:
Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn, and they're kind of similar, so we're going to do them back to back. The first study reports the results of the Sort Out X Trial, a large scale randomized multi-center, single-blind, two-arm, non-inferiority trial, with registry based follow-up designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34 positive antibody coated combo stent or DTS versus the Sirolimus-Eluting Orsiro Stent or SES.
Dr. Greg Hundley:
And the study comes to us from Dr. Lars Jakobson, from Arhus University Hospital. The primary endpoint target lesion failure, or TLF was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, all analyzed using intention to treat.
Dr. Carolyn Lam:
All right, Greg. So the DTS compared to the SES, what did they find?
Dr. Greg Hundley:
Thanks, Carolyn. So the DTS did not confirm non-inferiority to the SES stent for target lesion failure at 12 months. The SES was superior to the DTS, mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the two stent groups.
Dr. Greg Hundley:
Now Carolyn, in this same issue, we have another study evaluating endothelial function and implantation of intercoronary stents. And this second study comes to us from Professor Alexandra Lansky, from the Yale University School of Medicine and Yale Cardiovascular Research Group. And Carolyn, the study evaluated whether implantation of an intercoronary stent that facilitated endothelialization after the four to six weeks smooth muscle anti-proliferative effects post-stent implantation would be non-inferior to traditional drug-eluting stents.
Dr. Carolyn Lam:
Okay, another interesting study. And so, how did they do that? What did they find?
Dr. Greg Hundley:
Yeah, so Carolyn, a total of 1,629 patients were randomly assigned in a two to one fashion to the supreme DES stent, so 1,086 patients, or the DPDES stent, which was 543 patients. And there were no significant differences in rates of device success, clinically driven, target lesion revascularization, or stent thrombosis at 12 months.
Dr. Greg Hundley:
And the safety composite of cardiovascular death and target vessel revascularization or myocardial infarction was 3.5 versus 4.6% with the supreme DES stent compared to the DPDES stent. But target revascularization for this new stent was two and a half fold higher.
Dr. Greg Hundley:
So Carolyn looking at these two papers, what have we learned? So first, the Jakobsen, et al, tested whether the stainless steel COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive antibody could theoretically capture endothelial progenitor cells and regrow endothelium.
Dr. Greg Hundley:
And the investigators observed that this stent had higher, not lower or equivalent, target lesion revascularization relative to the current generation Cobalt-Chrome Stent that only eluted sirolimus.
Dr. Greg Hundley:
In the second study, Lansky and associates examined an approach which was touted as enhancing endothelial recovery, where the early erosion of material and release of drug was thought to allow earlier endothelial recovery enhancing vascular response. Non-inferiority of the rapid release was demonstrated, but rather than hints of superiority, there were signs of inferiority. Hereto, target lesion revascularization was problematic and was two and a half fold higher.
Dr. Greg Hundley:
And so, Carolyn, there's a wonderful editorial from Professor Elazer Edelman from the Massachusetts Institute of Technology entitled, “Karnovsky's Dictum that Endothelium is Good Looking and Smart,” where Dr. Edelman emphasizes that while some endothelial cells may have been present after deployment of these devices, perhaps a fully constituted functioning endothelium may not have been achieved.
Dr. Greg Hundley:
And as we know, it is a fully functioning endothelium with nitric oxide release, buried platelet adhesion that is most protective. It is a really provocative read that reflects on previous thoughts from Morris Karnovsky, who suggests preservation of endothelial function is optimized by minimizing injury to it. And so, Carolyn, these combined articles really highlight the current state of new developments within interventional cardiology to thwart re-stenosis and highly recommend them to our readers.
Dr. Carolyn Lam:
Wow, thank you, Greg. That was amazing. But you know what, so's this next paper, because it really provides novel insights into that enigma of the role that the epicardium plays in the pathogenesis of arrhythmogenic cardiomyopathy.
Dr. Carolyn Lam:
Now, to delineate the contributions of the epicardium to the pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian from University of Texas Health Science Center at Houston, Texas and colleagues performed a series of elegant mouse experiments using conditional deletion of the gene encoding desmoplakin in the epicardial cells of mice. Mutations in genes and coding desmosome proteins, including desmoplakin are known to be major causes of arrhythmogenic cardiomyopathy.
Dr. Greg Hundley:
Wow, Carolyn, very interesting. So what did they find here?
Dr. Carolyn Lam:
Epicardial derived cardiac fibroblasts and epithelial cells expressed paracrine factors, including TGF-β1 and fibroblasts growth factors, which mediated epithelial mesenchymal transition and contributed to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of arrhythmogenic cardiomyopathy. These findings really uncover contributions of the epicardial derived cells to the pathogenesis of arrhythmogenic cardiomyopathy.
Dr. Carolyn Lam:
Greg, there's a whole lot of other interesting stuff in today's series, as well. There's an exchange of letters among doctors Mehmood, doctors Moayedi and Dr. Birks regarding the article “Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Device.” There's an ECG challenge by Dr. Ezekowitz on a silent arrhythmia. How would you treat this patient? Go quiz yourself.
Dr. Carolyn Lam:
There is an AHA Update by Dr. Churchwell on how federal policy changes can advance the AHAs mission to achieve health equity. And finally, a Perspective by Dr. Talbert on rheumatic fever and the American Heart Association, The Nearly 100 hundred-Year War. Well, that wraps it up for the summaries. Let's go to the double feature, shall we?
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
Wow, today's feature discussion is really all about SGLT2 inhibitors, and that question that we're still asking, how do they work? And today, we are discussing two papers, very interestingly, looking at it from different aspects, one from a preclinical lens, finding a very novel target for SGLT2 inhibitors, and the other from a clinical lens, and really looking at the metabolic effects of the SGLT2 inhibitors in a way you've not seen before.
Dr. Carolyn Lam:
I'm very pleased to have with us the authors of these very exciting papers. We have Dr. Jesper Jensen from Herlev and Gentofte University Hospital in Denmark. We have Dr. Peter Light from University of Alberta, in Canada, and we have our associate editors, Dr. Thomas Eschenhagen from University Medical Center, Hamburg, and Dr. Justin Ezekowitz from University Alberta.
Dr. Carolyn Lam:
So, welcome gentlemen, thank you so much for joining us today. I suggest, let's start from the mice before we go to the men, and Peter, if you don't mind by starting us in, please tell us about this novel target you found, why you looked at it, how you found it, what it means.
Dr. Peter Light:
Hi, Carolyn, yeah, happy to discuss that. So, we all know that through numerous clinical trials, there's a very unexpected and exciting cardioprotective effect against heart failure with the SGLT2 inhibitors. And we decided to investigate some of the molecular mechanisms, which may underlie that protection. And in looking at the literature previously, and from my own lab's work, we're very interested in control of electrical excitability and ionic homeostasis in cells.
Dr. Peter Light:
So we investigated a known target or a known iron channel, which is involved in the etiology of heart failure as well as cardiac arrhythmias. And that would be the cardiac sodium channel. So, we investigated the effects specifically on a component of the cardiac sodium channel called the late sodium current, which is only induced in disease states, and they could be that during heart failure or ischemia, or can actually be in congenital conditions such as Long QT Syndrome Three, which involves certain mutations in this sodium channel.
Dr. Peter Light:
So we basically investigate the effects of empagliflozin, dapagliflozin and canagliflozin, in several different models of a sodium channel dysfunction, including mice with heart failure. And really what we've found is that this class of drug, and this is a class effect, it's not specific to just one of these SGLT2 inhibitors, what we found, they are very good inhibitors of this late current of the sodium channel. And in fact, they don't even affect the peak current at all.
Dr. Peter Light:
And when we did this and we analyzed the data, we found the IC 50s were in the low micromolar or even sub micromolar range for these drugs, which is exciting. And we extended those studies into cardiac myocytes and looked at calcium handling in those cardiac myocytes and saw that we get a very nice reduction in abnormal calcium handling in cardiac myocytes.
Dr. Peter Light:
We also used in silico molecular docking of these drugs to the cryo-EM structure of the NaV1.5, which is the cardiac sodium channel and identified that these drugs bind to a known region of that channel, which also binds the local anesthetics or anti-arrhythmic drug, Lidocaine, as well as the anti-anginal drug, Ranolazine.
Dr. Peter Light:
And finally, we showed that these drugs also reduce inflammation through the NLRP3 inflammasome in an isolated beating heart model. So collectively, we provide evidence that the late component of the sodium channel is a really important, or maybe a really important target for the molecular actions of this drug, and may underlie those observations received from the clinical trials relating both to heart failure, as well as sudden cardiac death.
Dr. Carolyn Lam:
Thomas, could you put this in context for us?
Dr. Thomas Eschenhagen:
Thanks, Carolyn. I mean, we immediately liked the story because as you said, and Peter as well, these drugs have amazing effects and every clinical paper and indeed some new ones, but it's really unclear how they do that. And what is, besides the established target, the SGL2 in the kidney, what could be the reason for all of this or some of this?
Dr. Thomas Eschenhagen:
And then, of course, other examples proposed, like the sodium hydrogen exchanger, but this story didn't go so far. So we saw now this data from Peter showing that, and this is, of course, for a pharmacologist, just like me, very important, it's very potent binding. It's not a binding which happens in a millimolar or high micromolar, but as Peter said in low micromolar range. So that makes it a very realistic effect, for example, much more potent than ranolazine.
Dr. Thomas Eschenhagen:
And, of course, now the question is, to which extent could this, now I would say, establish the effect on the late sodium current, explain some of the findings which came out of the clinical studies, and actually, a question I would have to Peter, now that I think most of you know, the late sodium current is a reason for the increased sodium for LQT3 syndrome, very rare.
Dr. Thomas Eschenhagen:
But, of course it would be tempting to say, okay, maybe that would be a very good drug, particularly for people with LQT3. Did you think about that, Peter? Is it something on your list, mexiletine has been tried.
Dr. Peter Light:
Yeah, so I think that it's a certainly intriguing possibility. In fact, in our study, we did test out several different Long QT3 mutations and saw a reduction in the late component as also sodium channel. It's tempting to speculate that, indeed, these could actually be a rather effective anti-arrhythmic drug in patients with these LQT3 mutations or specific ones. I would love to be able to test that in at least some of the genetic mouse models of Long QT3 and to see whether this concept holds water or not.
Dr. Carolyn Lam:
Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to now anti failure, and now anti-arrhythmic drugs? That's just amazing. Thank you, Peter. We should move on to this next paper, and this one all the way on the other spectrum, a clinical paper called Empire Heart Failure, Empire Heart Failure Metabolic, actually. Jesper, could you tell us about your trial and what you found?
Dr. Jesper Jensen:
Sure, thanks for the invitation to take part in the podcast, first of all. I'll tell you a little bit, we designed this study to try to get behind mechanisms, so the clinical benefits of the SGLT2 inhibitors in order to try to make a clinical outcome trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were competed very fast, demonstrating the clinical benefits in HFrEF patients.
Dr. Jesper Jensen:
So, the data of our study provides some detailed mechanistic insights to these findings. And from the literature, we know that SGLT2 inhibitors improve glucose metabolism in patients with diabetes, and these changes might not be surprising in the diabetes population, but moreover, alterations in glucose metabolism may not be the main mechanism for the early occurring clinical benefits.
Dr. Jesper Jensen:
However, we know that many of our heart failure patients without diabetes are insulin resistant as a metabolic feature of the heart failure, and the insulin resistance is associated with an increased risk of developing future diabetes, which in turn reduces the long-term survival and quality of life. So, the targeting insulin resistance in HFrEF patients is, therefore, of clinical relevance to our patients.
Dr. Jesper Jensen:
So, the population of the Empire HF Metabolic consisted of patients with chronic HFrEF, with or without type two diabetes, who are on a stable guideline directed heart failure therapy, and have also indicated on anti-diabetic therapy. And we randomized patients to receive empagliflozin 10 milligrams once daily, or matching placebo as an-add on for 12 weeks.
Dr. Jesper Jensen:
And this was a modest sized randomized control trial, including 120 patients. A very large proportion of patients received guideline directed heart failure therapy, and they generally consisted of the best one third of atypical HFrEF population, and only 10% had concomitant history of type two diabetes.
Dr. Jesper Jensen:
We then, at baseline and after 12 weeks, we formed an oral glucose tolerance test to assess the hepatic and a peripheral insulin sensitivity and performed a whole body DXA scan to investigate alterations in body composition. We know that patients lose weight when they get an SGLT2 inhibitor with and without diabetes, but we don't know what it consists of in a HFrEF population.
Dr. Carolyn Lam:
Tell us what you found after 12 weeks.
Dr. Jesper Jensen:
Yeah, so a large proportion, actually half of the patients without a history of diabetes, had a new onset diabetes, or impact glucose tolerance at baseline. So even though few have no diabetes, this population were at very high risk of developing future diabetes. And the main finding was that empagliflozin improved insulin sensitivity. So the hepatic insulin sensitivity was improved by 13% and the peripheral insulin resistance was improved by 20% compared to placebo.
Dr. Jesper Jensen:
And moreover, both fasting and postprandial glucose were significantly reduced. And regarding the body composition, patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly consisted of a loss in lean mass and no significant changes were observed in fatness, and this is from the DXA scan.
Dr. Carolyn Lam:
Hmm. Justin, could you shed some light on what the editors thought about this, and there's lots of questions still, huh?
Dr. Justin Ezekowitz:
Yeah, absolutely, Carolyn, and thanks Jesper for sharing this paper with Circulation. Thanks for summarizing it so well. I think the questions that come up and the reason why we liked it so much was we're all trying to understand mechanism of how these medications work so profoundly for our patients.
Dr. Justin Ezekowitz:
Now, in this predominantly non-diabetic population, the fact that the liver and the peripheral insulin sensitivity improves, how does that bear out for the fact that there is no fat loss in the early stages, yet that's all been linked to later improved exercise capacity and increased fat loss later on in life.
Dr. Justin Ezekowitz:
So, do you think those two are going to be linked if you went to say from 12 weeks beyond the 52 or two years down the road?
Dr. Jesper Jensen:
Yes, that is what we've seen from diabetes populations, at least. So you could imagine that the same would be the case also in the HFrEF primarily non-diabetic population, but again, we don't know. But early loss is the mass loss.
Dr. Justin Ezekowitz:
So Jesper, when you think about the peripheral insulin sensitivity improvement, is that largely indicating mostly muscle based insulin sensitivity improvement, and that would indicate that the muscles, perhaps, are functioning better in the short term with just a simple change in therapy.
Dr. Jesper Jensen:
Yeah, that could be a way to put it. I would agree upon that.
Dr. Justin Ezekowitz:
So thanks, Jesper, I think that may indicate the quality of life improvement that we may be seeing in the functional status there, Carolyn.
Dr. Carolyn Lam:
Yeah, but as you said, Justin, there just seems so many other questions. To Jesper, I want to know, what further might you want to do to find out what's happening with this? The loss of lean mass surprised me, frankly. I thought it would have been fat mass. So, what are you doing to look at that? And then to Peter, I want to go the other direction. What are you planning next that might bring this closer to humans and a clinical study? So maybe I'll ask Jesper to go first.
Dr. Jesper Jensen:
So, I definitely agree with you, Carolyn. We would also have to put our money on the fat from the beginning, before the study. So with respect to the weight loss, then a loss in lean mass is not preferable if it represents muscle. So however, the weight loss works to mediate the observed change in insulin resistance. And additionally, a significant loss in muscle would result in reduced insulin sensitivity. And we observed the opposite. Therefore, the observed loss in lean mass may be speculated to represent water and pointing towards the early diuretic effect SGLT2 inhibitors. So, the DXA scan is good at looking at body composition, but it has difficulties in separating lean mass from whether it's muscle or water, but combined with the findings on the insulin resistance, we speculate that the lean mass loss is more.
Dr. Carolyn Lam:
Thank you. And Peter, could you very quickly tell us what are next steps, in your view?
Dr. Peter Light:
Yeah, obviously we were studying mouse model of heart failure. We'd like to make a more of a translational step in the next experiments we do by studying human tissues. So getting access to ventricular tissue from ex-planted hearts, human hearts, too, and then measure electrical activity as well as some calcium imaging.
Dr. Peter Light:
Looking at some of these Long QT3 animal models would be another thing that we're going to do. And also start looking at to see whether we can get access to any electrophysiological data from electronic medical records to start looking for DCGs and measuring QT interval, for example, would be another nice step to that.
Dr. Peter Light:
And then, more of a drug development side of things, we are actively synthesizing new derivatives of these drugs and seeing whether we can enhance the cardio-protective effects on the late sodium current, but actually remove the ability to inhibit SGLT2. So we would no longer have a glucose-lowering drug, but we'd have a cardioprotective drug. So, it's all very exciting work going on right now.
Dr. Carolyn Lam:
You've been listening to Circulation on the Run. From Greg and I, don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Please join editorialist Padma Kaul and Associate Editor Karol Watson as they discuss the original research article "Preterm Delivery and Long-Term Risk of Stroke in Women: A National Cohort and Cosibling Study" and the editorial "Pregnancy as Oracle: What it Augurs for Women's Health."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Oh Greg, today's feature paper is really important. It's about preterm delivery and the long-term risk of stroke in women. A very, very important cardiovascular risk factor that we don't talk about. This is important data from the national cohort and co-sibling study. So hang on, look out for it. But first, how would you take us through some of your spotted original papers?
Dr. Greg Hundley:
So Carolyn, my first paper comes to us from Dr. Guido Claessen from University Hospitals in Leuven. Exertional intolerance, Carolyn, is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension, and traditionally, the etiology has been attributed to central factors, including ventilation, perfusion mismatch, increased pulmonary vascular resistance and right heart dysfunction and uncoupling. So pulmonary endarterectomy and balloon pulmonary angioplasty provides substantial improvement of functional status and hemodynamics. However, despite normalization of these pulmonary hemodynamics, exercise capacity often does not return to age-predicted values. So by systemically evaluating the oxygen pathway, these authors aim to elucidate the causes of functional limitations of chronic thromboembolic pulmonary hypertension patients before and after these pulmonary vascular interventional procedures.
Dr. Carolyn Lam:
So very interesting. Tell us more, what did they find, Greg?
Dr. Greg Hundley:
Yeah, well Carolyn, they utilize cardiovascular magnetic resonance, as you know, one of my big interests, but guess what? They also did it with exercise and simultaneous invasive hemodynamic monitoring. The authors in doing so, sought to quantify the steps of the oxygen transport cascade from the mouth to the mitochondria in patients with this pulmonary hypertension. So they had 20 subjects with pulmonary hypertension and they compared those to 10 healthy individuals. Furthermore Carolyn, the authors evaluated the effect of pulmonary vascular intervention procedures, both endarterectomy or balloon angioplasty, on the individual components of the cascade in 10 of those 20 individuals.
Dr. Greg Hundley:
So what did they find? They found that in this chronic thromboembolic pulmonary hypertension condition, these patients, they have significant impairments of all steps in the oxygen utilization cascade, resulting in markedly impaired exercise capacity, the thick equation uncoupled. And pulmonary vascular interventions increased, peak VO2, by partly correcting the oxygen delivery, but having no impact on abnormalities in peripheral oxygen extraction.
Dr. Greg Hundley:
So Carolyn, this suggests that the current interventions only partially address patient's limitations and that additional therapies may improve functional capacity, such as improvement in skeletal muscle function and metabolism. So maybe one of your faves, cardiac rehab, perhaps could work on some of those peripheral factors in these patients. So, really interesting, very well accomplished study.
Dr. Carolyn Lam:
Nice, elegant and clinically impactful. Very nice. Well, the next paper is the same. We know that prenatal detection has benefits for infants with hypoplastic left heart syndrome and transposition of the great arteries. Well, this next paper describes the largest multicenter study to evaluate whether social economic quartile, public insurance, race or ethnicity, rural residence and distance from the residence are associated with the prenatal detection of critical congenital heart diseases in North America. This study is from Dr. Krishnan from Children's National Medical Center in Washington, DC and colleagues. Basically, what they found was that lower socioeconomic position, Hispanic ethnicity, and rural residence were all associated with decrease prenatal detection rates of hypoplastic left heart syndrome and transposition of the great arteries.
Dr. Greg Hundley:
Wow Carolyn, so social determinants of health, interesting. So how do we, as clinicians, apply these results?
Dr. Carolyn Lam:
Well, clinicians can use the findings of the study to focus efforts on improving overall prenatal detection rates for congenital heart disease. They can specifically improve health equity in prenatal detection and timing of prenatal detection by improving linkages between tertiary care centers and these populations and regions that were identified in this study.
Dr. Greg Hundley:
Very nice Carolyn. Well, I'm going to turn to the world of aortic aneurysms and this next paper comes to us from Dr. Maria Mittelbrun from Centro de Biología Molecular Severo Ochoa. Carolyn, it involves Marfan syndrome, which you know, is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene, encoding a large glycoprotein in the extracellular called fibrillin one. The major complication, again as you know, of this connective disorder is the risk to develop thoracic aortic aneurysms. To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are surgery. So here, the authors studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm dilation, and mitochondrial boosting strategies as a potential treatment to manage these aneurysms.
Dr. Carolyn Lam:
Wow, that's really fascinating. So what did they find?
Dr. Greg Hundley:
So Carolyn, just like in circulation, these wonderful translational basic science studies, the research here by these authors was performed in both mice and in patient samples from Marfans patients. So mitochondrial function of vascular smooth muscle cells was found to be controlled by the extracellular matrix and drive the development of aortic aneurysm in the Marfan syndrome. Interestingly, restoring mitochondrial metabolism with the NAD precursors nicotinamide riboside rapidly reversed aortic aneurysm in the fibrillin positive mice. Thus Carolyn, the clinical implications are that by potentially targeting vascular metabolism, a new available therapeutic strategy for managing aortic aneurysms associated with these genetic disorders, such as Marfan syndrome, may become available. Really interesting new development in the world of managing aortic aneurysm dilation in patients with Marfan syndrome.
Dr. Carolyn Lam:
Oh my goodness, that would be paradigm shifting. Wow, hope that's going to be pursued further. Well, this next one is from the preclinical world and this study really uncovered a metabolic transcriptional axis that explains how dividing cells coordinate metabolism with gene regulation in pulmonary arterial hypertension. So this is from Dr. Rabinovitch and colleagues from Stanford University School of Medicine who applied RNA sequencing to pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension with and without a BMPR2 mutation compared to control pulmonary artery smooth muscle cells, basically to uncover genes required for their heightened proliferation and glycolytic metabolism. The assessment of differentially expressed genes establish metabolism as a major pathway. The most highly up-regulated metabolic gene was aldehyde dehydrogenase family 1 member 3, an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular smooth muscle cells, but now demonstrated in pulmonary arterial hypertension. Isn't that cool?
Dr. Carolyn Lam:
The findings were basically like this, an increase in this particular aldehyde dehydrogenase family 1 member 3, underlined the heightened proliferation and glycolysis of pulmonary artery smooth muscle cells in patients with both idiopathic and hereditary pulmonary artery hypertension, while promoting survival of their endothelial cells under stress. The authors further uncovered the way this molecule interacted with genetic factors in doing so and then finally demonstrated that transgenic mice with the deletion in smooth muscle cells did not develop chronic hypoxia-induced pulmonary hypertension.
Dr. Greg Hundley:
Wow Carolyn, really new, inventive material from the world of basic science. So what's the take-home message?
Dr. Carolyn Lam:
So these findings really suggest that selectively disrupting the pivotal role of aldehyde dehydrogenase family 1 member 3 in pulmonary artery hypertension smooth muscle cells, note that was smooth muscle cells, not the endothelial cells, may be a important therapeutic consideration in patients.
Dr. Greg Hundley:
Very nice.
Dr. Carolyn Lam:
So Greg, let me tell you about some other articles in today's issue. There's an exchange of letters between Drs. Pengo and Kario 00:10:36 regarding the article Nighttime Blood Pressure Phenotype And Cardiovascular Prognosis, A Practitioner-based Nationwide JAMP Study.
Dr. Greg Hundley:
Great Carolyn, well also in the mail bag, we have a perspective piece from Professor Chang entitled Trial By Wildfire, The Need To Expand The Framework Of Environmental Determinants Of Cardiovascular Health From Climate Change To Planetary Health. Also, there's a primer from Professor Miano entitled The Fate And State Of Smooth Muscle Cells And Atherosclerosis. Then lastly, we have another article from the world of basic science, a research letter from Dr. Ieda entitled Overexpression Of GATA4, MEF2C and TBX5 Generates Induced Cardiomyocytes Via Direct Reprogramming And Rare Fusion In The Heart. Well, Carolyn, how about we get to the world of preterm delivery and onto that feature article?
Dr. Carolyn Lam:
I'm there already, let's go.
Dr. Greg Hundley:
Well, listeners. Now we are turning to our feature discussion and we're so excited today to have with us our editorialist for this article, Dr. Padma Kaul and our own associate editor, Dr. Karol Watson and we'll be discussing today, a paper related to preterm delivery and long-term risk of stroke in women. Padma, I'd like to start with you. Describe for us a little bit, the context for this study, and then what were the authors' study population and study design?
Dr. Padma Kaul:
So Greg, this is a study, which is a retrospective cohort study from Sweden and they looked at women who had given birth over a pretty long period of time, from 1973 to 2015. In over two million women, they looked at the association between preterm birth and the long-term development of stroke in the mothers. It's a really interesting study. What they did find is that preterm birth was associated with a higher hazard ratio for stroke, over 48 million person years of follow-up. The authors also did an interesting co-sibling analysis to supplement what the overall primary analysis. This was by looking at a subset of women who had at least one sibling in the cohort. The point of that was to assure that the association between preterm birth and stroke risk remained, even after you account for familial or genetic environmental factors. They do find that it was demonstrated even in the subset.
Dr. Greg Hundley:
Very nice, just a couple quick clarifying points. Were these ischemic strokes, were they hemorrhagic strokes? And then give me a little bit of definition. How did they define preterm?
Dr. Padma Kaul:
So preterm was in less than 37 weeks of gestation, and they looked at both hemorrhagic as well as ischemic strokes in the women. So they did an overall stroke endpoint as well as looked at whether these two types of strokes, whether the relationship stayed.
Dr. Greg Hundley:
And was there any particular age at which these strokes occurred?
Dr. Padma Kaul:
That's an excellent point. As I told you, that the time period of the study is pretty long. So they did stratify the follow-up period into 10 year segments, and they found that higher risk in the early part of the 10 and the 10 to 20 time periods. It stayed in the latter periods as well, but it was more so associated with a higher hazard in the early time periods, the 10 and the 20.
Dr. Greg Hundley:
Thank you so much, Padma. Well now listeners, we're going to turn to our associate editor, Dr. Karol Watson from UCLA. Karol, I know working on the editorial board at Circulation, you see many papers come across your desk. What attracted you to this particular manuscript? And how would you put the results from this study in the context of other studies that have really evaluated women's health in this situation?
Dr. Karol Watson:
That's a fabulous question. I think really so many great manuscripts come in and there are important features of many of them, but this one caught my eye for a couple of reasons. It was so incredibly well done. This is a huge, huge cohort of over two million women and it's from Sweden, where they keep really exquisite records, so we had so much data on this population. So we really got to know all about these soliton deliveries in Sweden, over a 40 year period. So the great cohort that was really well characterized, the really long follow-up. I love the co-sibling analysis that they talked about, they really did control for so many things, shared familial factors, shared genetic factors, covariates. So they just did a fabulous study.
Dr. Karol Watson:
So, in the whole realm of women's health, we are understanding that pregnancy is a great window into a woman's vascular future. So we now know so many things, we know that preterm delivery is amongst those pregnancy outcomes that we have to look for. So we have to look for pregnancy-induced hypertension, gestational diabetes, but also preterm delivery and pregnancy loss. So all of these things are telling us that a woman's vascular system is under stress and we have to do things to make sure they have good outcomes, because we know they're at greater risk.
Dr. Greg Hundley:
Very nice. So as leading experts in the era, Padma first to you, and then I'll come back to Karol. Padma, tell us, what do you think is the next area of research that needs to be explored in this topic area?
Dr. Padma Kaul:
I think that this is an observational study. So one of the things we have to recognize is how do we add to the evidence that this study has provided us? That I think, is to see if in other cohorts, similar pregnancy birth cohorts with longitudinal data, whether we observe the same patterns that we ever observed in Sweden. Sweden is actually quite unique in terms of the makeup of the population and these are historical trends. We do know that the characteristics of the mothers who are giving birth are changing over time. Women are delaying childbirth, they are getting heavier, they may have preexisting conditions. So I think to keep monitoring the health of the mothers and pregnancy factors is what is needed to move the field forward.
Dr. Greg Hundley:
Very nice, and Karol? Karol, would you like to add anything?
Dr. Karol Watson:
Yeah, I agree completely with what Padma says. The beauty of the Swedish cohort is how well characterized it is, but one of the limitations is it's a fairly homogenous cohort. So I would love to see similar data in other racial or ethnic groups. We'd also like to see, again, as Padma said, this is observational cohort study, so we don't know truly the causal validy here, although this is a really good study to identify this trend. I would love to think of ways why this might be, we really don't have a good handle on the pathobiology. We can surmise some things endothelial dysfunction, et cetera, but we just don't know for sure. The other thing I'd like to think of is ways we might address mitigating risk. If this truly is a risk factor, how are we going to help these women have better vascular outcomes. But again, a great study to start all these questions.
Dr. Greg Hundley:
Well, thank you Karol and Padma and listeners. We certainly want to thank both Drs. Kaul and Watson for their time today and also the author group under the direction of Dr. Casey Crump for submitting this article to us at Circulation reporting on this large cohort of women from Sweden, identifying a preterm delivery and long-term risk of both ischemic and hemorrhagic stroke.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
This week, please join author Uwe Tietge and Associate Editor Anand Rohatgi as they discuss the article "High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events" (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050808)
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got a very interesting feature this week. It involves another paper in the line of the story of HDL, and looking at HDL and future cardiovascular events. But before we get to that, how about we grab a cup of coffee and jump in and review the other articles and the issue? And Carolyn, this week, maybe I'll go first.
Dr. Carolyn Lam:
Go, I've got my coffee.
Dr. Greg Hundley:
Very good. So Carolyn, this paper comes to us from Dr. Huso Hakala, from the University of Turku at Turku University Hospital, and the study pertains to cognition and cardiovascular disease. So Carolyn, as you know, cardiovascular risk factors such as high blood pressure, adverse serum lipids, and elevated body mass index, and midlife may harm cognitive performance. So importantly, perhaps the presence of cardiovascular risk factors since childhood, Carolyn, may impact cognition later in life. So these authors studied the associations of the cardiovascular risk factors from childhood to midlife, their accumulation and midlife cognitive performance. They gathered their data beginning in 1980 from a population-based cohort of 3,596 children who are aged three to 18 years that were repeatedly followed up for 31 years, and they assess blood pressure, serum lipids, body mass index, all in the follow-ups.
Dr. Carolyn Lam:
Wow. So accumulating risk, I suppose, Greg. So what did they find?
Dr. Greg Hundley:
Great. Carolyn, glad you asked. So consistently high systolic blood pressure or serum total cholesterol associated with worse midlife episodic memory and associated learning, compared to situations when blood pressure or cholesterol values were low. Obesity since childhood associated with worse visual processing and sustained attention compared to individuals or children that had normal weight. And an inverse trend association was observed for the cardiovascular risk factor accumulation with episodic memory and associated learning with visual processing and sustained attention and with reaction and movement time. So the take home Carolyn, is that, maybe we should be launching preventative strategies against some of these cardiovascular risk factors beginning in childhood, because perhaps they could benefit primordial promotion of cognitive health for those later in adulthood, maybe like you and me.
Dr. Carolyn Lam:
Oh, wow. Thinking back on my blood pressure, cholesterol and weight, I suppose, since childhood, yikes. Well, the next paper Greg is an important analysis from DAPA-HF. Now as a reminder in the DAPA-HF trial, the sodium glucose co-transporter two inhibitor dapagliflozin was shown to reduce the risk of cardiovascular death and a first episode of worsening heart failure, in patients with heart failure with reduced ejection fraction or HFpEF. In the current paper from Drs. Jhund and colleagues from University of Glasgow, they described the efficacy of dapagliflozin on the predefined secondary end point of total heart failure hospitalizations. That's the first and recurrent heart failure hospitalization and cardiovascular death. And this is so important because we know that patients with HFrEF are known to experience multiple episodes of heart failure during the course of the disease.
Dr. Greg Hundley:
So Carolyn, what did they find?
Dr. Carolyn Lam:
Well, they did this analysis by two methods in the first, which was the Lin, Wei, Ying and Yang or LWYY model the rate ratio for the effect dapagliflozin on recurrent heart failure, hospitalizations or cardiovascular death was 0.75.
Dr. Carolyn Lam:
And the second method, a joint frailty model, the rate ratio for total heart failure hospitalizations was 0.71 while for cardiovascular death, the hazard ratio was 0.81. The factors associated with more hospitalizations were, being a men, having a higher heart rate, NT-proBNP, New York Heart Association class type 2 diabetes, and a longer duration of heart failure with less hospitalization in those with higher systolic blood pressure and higher ejection fraction. So in summary, dapagliflozin in reduced the risk of total heart failure, hospitalizations and cardiovascular death. In fact, if you compare it to the time to first analysis, you can see that, that actually underestimated the benefit of dapagliflozin in HFpEF.
Dr. Greg Hundley:
Very nice Carolyn, well, my next paper comes to us from the world of basic science. And so Carolyn, neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocytes cell cycle exit and loss of the capacity for cardiac regeneration. Now the mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored.
Dr. Carolyn Lam:
Okay, Greg. So what did this current paper find?
Dr. Greg Hundley:
Right, Carolyn, so Dr. Ahmed Mahmoud from University of Wisconsin-Madison, they found that malonate, a competitive inhibitor of succinate dehydrogenase, promotes adult cardiomyocyte proliferation, revascularization of the infarct zone and myocardial regeneration following infarction. They also found that SDH inhibition by malonate is consistent with a metabolic shift from oxidative phosphorylation to glucose metabolism in the adult heart. So Carolyn, the clinical implications include the observation that transient inhibition of SDH may represent an important metabolic target to promote adult heart regeneration, following myocardial infarction.
Dr. Carolyn Lam:
Cool. Thanks Greg. Well, I've got another basic science paper. Let me try to tell you about la ribonucleoprotein domain family member seven. And I'm going to call that LARP7. Again, it's la ribonucleoprotein domain family members seven. Now LARP7 is a master regulator that governs the DNA damage response. The authors today, Dr. Zhang, from Xin Hua Hospital and Shanghai Jiao Tong University and colleagues aim to study its role in heart failure, pathogenesis by assessing LARP7 expression in human heart failure and in non-human primate and mouse heart failure models.
Dr. Greg Hundley:
Great, Carolyn. So what did they find?
Dr. Carolyn Lam:
LARP7 was essential for mitochondrial biogenesis energy production and cardiac function by modulating silent mating type information regulation to homolog-1, which is cert one, cert one homeostasis and activity. Now, reduction in LARP7 and diseased hearts due to activation of ataxia-telangiectasia mutated protein pathway contributed to the heart failure pathogenesis and conversely restoring LARP7 in the injured heart conferred myocardial protection. So in some, these results identified that this LARP pathway is a target or rather is a potential target for therapeutic intervention in heart failure.
Dr. Greg Hundley:
Great, Carolyn. One of the things I love about our journal is really the translational basic science that really could have future implications for how we manage patients with cardiovascular disease. So I, to follow, have another basic science article, and it comes to us from Dr. Florian Weinberger from the University Medical Center in Hamburg-Eppendorf. So Carolyn, human engineered heart tissue transplantation represents a potential regenerative strategy for our heart failure patients and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices and determination of the effective dose. So these authors performed studies in which cardiomyocytes were differentiated from three different human induced pluripotent STEM cell lines, including one reprogrammed under these GMP conditions. Protocols for human induced pluripotent STEM cell expansion, cardiomyocyte differentiation and engineered heart tissue generation were adapted to substances available in good manufacturing process quality. Engineered heart tissue geometry was modified and repair efficacy was evaluated at three doses in a cryo-injury Guinea pig model, human scale patches were epicardialy transplanted onto healthy hearts in pigs to assess the technical feasibility of this entire process.
Dr. Carolyn Lam:
Wow. And what did they find?
Dr. Greg Hundley:
Right, Carolyn? I mean, this is just so exciting, the practicality of how you implement some of these new strategies that we work on in the lab. So Carolyn, they found that human engineered heart tissue patch transplantation resulted in a partial re-muscularization of the injured heart and improved left ventricular function in a dose dependent manner in a Guinea pig injury model and human scale patches were successfully transplanted in pigs in a proof of principle study. So an exciting new front for engineered cardiac tissue transplantation. I mean, this is a really exciting article.
Dr. Carolyn Lam:
Wow, well, indeed. Thanks, Greg. Well, other than those wonderful papers in today's issue, we have an exchange of letters between Drs. Morgan and Lopes regarding initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure of left ventricular dysfunction and that's insights from the ischemia trial. Tracy Hampton does her wonderful review from the literature and it covers new research published in nature medicine, which indicates the impact of a Mediterranean diet on cardio-metabolic disease risks, which may be affected by an individual's gut microbes and goes all the way to network correcting therapeutic candidate for heart valve disease, which was published in science and even a newly discovered genetic arrhythmia syndrome, which was described in science translational medicine. That's a perspective piece by Dr. Kuwabara on the Japanese national plan for promotion of measures against cerebral vascular and cardiovascular disease.
Dr. Greg Hundley:
Great, Carolyn. Well, you've heard of mission accomplished. Well, Dr. Brooke has an On My Mind piece entitled mission unaccomplished, the optimal hyper, any hypertensive therapy. And then finally, Dr. Glembotski has a Research Letter entitled optimizing AAV9 for studies of cardiac chamber specific gene regulation. Well, Carolyn, what a great issue and integrating all the wonderful world of basic science in a translational fashion. Now, how about we get on and move toward our feature discussion?
Dr. Carolyn Lam:
Yep. HDL, here we come.
Dr. Greg Hundley:
Well, listeners, we are onto our feature discussion today and we're very excited to have with us today, professor Uwe Tietge from Stockholm, Sweden, and our own associate editor Anand Rohatgi from UT Southwestern. Welcome gentlemen. And Uwe, could you describe for us the hypothesis that you wanted to test and tell us a little bit about your study design?
Dr. Uwe Tietge
Okay. So thank you very much for inviting me and for having the opportunity to discuss this article with you today. So we've been for a long time interested in HDL function, and we have developed an HDL anti-inflammatory see, and we have tested it in some cross-sectional studies. And we have seen in this cross-sectional work, for example, in the acute mi or diabetes, are associated with significant reductions in HDL anti-inflammatory function. So we felt that the next important step would be to study this prospectively in the general population. So this is why we made use of the prevent cohort, which is a prospective general population study with white participants from Groningen, which is a city in the North of the Netherlands. Prevent stands for prevention of menial and stage disease, and prevent has a total number of participants of 8,592.
Dr. Uwe Tietge
So we first excluded all that had already experienced mi intrusion. And then we took all subjects, was the first cardiovascular disease events during follow up and matched controls for sex, age, smoking, and importantly also for HDL cholesterol levels. And we felt that such a design would allow us to truly identify changes in HDL function, independent of HDL cholesterol levels. So then finally we ended up with 340 match case control pairs.
Dr. Greg Hundley:
Uwe, sounds like a very interesting hypothesis. So what was your methodology and how did you perform your analysis? And then also describe for us, what did you find?
Dr. Uwe Tietge
The key method that we used was our essay determining the atrial anti-inflammatory capacity and the main outcome measured was incident cardiovascular disease. And in our case, that was deaths from cardiovascular disease, hospitalization from mi, PDCA, ischemic heart disease, or CABG. We did not have stroke in our study. So with respect to HDL function, we isolate HDL by means of PEG precipitation. And this is an established method that is widely used in larger cohort studies. We then take a primary industry that cells, humans, and we pre incubate them for 30 minutes with the individual engineer preparations. Then the agents removed and TNF alpha is added for another five hours. And after these five hours, we isolate RNA and determine BK1 and mRNA levels by quantitative real time PCR. Then we calculate the results relative to the [inaudible 00:16:09] or without the edit HDL. So when the empties data, we use statistical analysis to determine the perspective association in, based on HDL anti-inflammatory function and the outcome measure incident CVD.
Dr. Uwe Tietge
So to summarize the main findings of the study. So first of all, the anti inflammatory activity of HDL baselines intrusion in this study was significantly higher in controls than in cases. Next, the HDL anti-inflammatory activity was not correlated with any other CBD related biomarkers. Importantly also know it was HDL cholesterol at 8.1, but also not, for example, with triglycerides, or isolated CRP, and also not with [inaudible 00:16:58] capacity, which is another function metric of HDL.
Dr. Uwe Tietge
The further finding was that in conditional logistic regression analysis, we found that baseline HDL anti-inflammatory activity was significantly associated with future CV events, even in a fully adjusted model. Then finally, when we were adding this function of HDL to the premium, this form, or when we were replacing anti-inflammatory capacity in the score that improved risk prediction and interestingly adding cholesterol reflux and other HDL function, as said before, resulted in a further improvement.
Dr. Uwe Tietge
So the general conclusion was that of the HDL functional measures in the case of our actual study, this is the HDL anti-inflammatory activity has the potential to provide clinic information independent of conventional use biomark.
Dr. Greg Hundley:
Very nice who made. So we always think of HDL is the good cholesterol. And sounds like you're describing a whole nother process by which HDL could be beneficial. Well, Anand turning to you now. I know you see many papers come across your desk. What drew your attention to this particular manuscript and how does this new HDL anti-inflammatory capacity or activity impact the remaining science that we have that focuses on other beneficial effects of HDL?
Dr. Anand Rohatgi:
Thank you, Greg. And I would like to first start by thanking Dr. Tika to submitting his article to circulation and thinking about us for his studies. I will say when this came across my desk, I became extremely excited as HDL function is an area that is near and dear to my heart as well. And Dr. Tika is an international expert in this area. So we are quite excited. The reason why this really picked our attention at circulation is that this was really the first and large demonstration that this novel marker on anti-inflammatory capacity was linked to the incidents of cardiovascular events, so that it wasn't just the range and people who already had disease, but at baseline, in people who are otherwise healthy, it could predict those who would go on to be at higher risk of atherosclerotic events. So in this case, what we saw was a truly unique and novel cardiovascular marker.
Dr. Anand Rohatgi:
It was a significant translational study working in effort on the part of Dr. Tika and his research team to be able to do this, and so many participants, this is not an easy undertaking. So to be able to do this and show the results that they were able to show is really remarkable, which is really why it elevated to our interest at circulation. A couple of things in terms of the implications in science are that when they recorded this study, they intriguinly we found that there were really no other stablished risk factors, cholesterol levels, or other markers that are associated with this novel anti-inflammatory capacity, it really wasn't associated with high sensitivity CRP, a global marker of inflammation. And it wasn't associated with the only other HDL function that had been shown to be linked to cardiovascular events, cholesterol influx.
Dr. Anand Rohatgi:
So really what we have here is a truly novel marker that stands on its own. And it's not confounded by the usual things of obesity or other cardiovascular risk factors, and is clearly imparting different information than a global marker, like CRP. I'll extend that these observations to one or two concepts, when it comes to inflammation, there are a couple of things to think about. One is the timing of the inflammatory cascade. A lot of markers are studied at the time where people are in an acute disease state and pro-inflammatory already, and so that can actually have an effect itself on the markers. In this case, by self-report, the participants did not have any acute illness. And so the relationship we see here between anti-inflammatory capacity and cardiovascular events is presumably in the context of a healthy, low inflammatory state. So I think that's important. The other thing that's important, I think for our audience to know is that the inflammation can have tissue specific effects.
Dr. Anand Rohatgi:
So when you think of global markers like CRP or interleukin 6, those are flagged systemic levels of inflammation in your body, and they are also predictive. But when it comes to atherosclerosis, we think about specific tissue types, the endothelium, macrophages, dipocytes. And in this case, what this marker represents is specific activity at the level of the endothelium, which is a key player in the atherosclerotic process. So it really gives us new and novel insights into that process. And it highlights the potential to find maybe therapeutic targets that can be more precise in targeting the atherosclerotic process and improving outcomes. So those were some of the main things that we saw that were exciting.
Dr. Greg Hundley:
Very nice. Uwe, as an international expert. What do you see as the next study that needs to be performed that will perhaps use this new market?
Dr. Uwe Tietge
I think what we need here first would be validation in another cohort and ideally a cohort that involves different ethnicities because our participants were predominantly white. So in terms of generalization, I think this is the next step that we would need. In terms of making this essay applicable to clinical settings in the daily routine, so to speak, we need to simplify it. And this is another issue that we are currently working on, trying to have an easier essay that gives us quicker readouts and ideally, maybe not using primary industry, but something that is better standardizable. And I mean, when you think about next steps, then also identification of a certain biomarker, comes to mind. So something that would reflect the dimension, the activity component of the age that reflects its functioning. And can be used in daily routine and is applicable. It lies to take all the types of essays.
Dr. Greg Hundley:
Very good. Anand, do you have anything to add to that?
Dr. Anand Rohatgi:
Well, I agree completely. I think when you always see a novel marker, you want replication and validation, and I think extending this to other nonwhite cohorts is important. The prevent cohort with 70% men, and also add average out there were probably higher than contemporary populations, at least in the United States. So it'd be nice to see an extension of these observations and cohorts that reflect that diversity. Interestingly, cholesterol wheat blocks the other HDL functions that's been associated with events is not linked through vascular events, it's mostly linked to coronary events. So it would be really interesting to find out how the anti-inflammatory capacity relates to events related to other vascular beds outside of the coronary tree. And then I guess a question that I had for professor Tika is, do you think there might be certain groups of people either by disease or demographic that this might be more powerful formative? Or do you think you would have the same kind of information across the board?
Dr. Uwe Tietge
Yeah, that's a relevant question of course. When we divided our population by participant level characteristics, we saw that there are sex differences. So the predictive capacity seems to be a bit better in females are significantly better than females, which is in male. And also in participants with lower BMI, with ahigher BMI. And the third parameter was in participants with was lower for this one was higher this month. So yes, I expect that some parameters can play a role here and it would be very wise to explore these connections.
Dr. Greg Hundley:
Very good. Well listeners, what an excellent discussion. And we want to thank Dr. Uwe Tika and his team from Stockholm, Sweden, and also our associate editor, Dr. Anand Rohatgi for bringing to us this new research regarding this marker of anti-inflammatory capacity involving HDL, that demonstrates an inverse association with cardiovascular events.
Dr. Greg Hundley:
On behalf of both Carolyn and myself. We want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association, for more visit ahajournals.org.
This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis."
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up.
Dr. Carolyn Lam:
First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance.
Dr. Carolyn Lam:
What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen.
Dr. Greg Hundley:
Really interesting, Carolyn. Clinically, what are the implications today as we see these patients?
Dr. Carolyn Lam:
Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg?
Dr. Greg Hundley:
Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury.
Dr. Carolyn Lam:
Oh, wow. Interesting, Greg. what did they find?
Dr. Greg Hundley:
Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits.
Dr. Carolyn Lam:
Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic.
Dr. Greg Hundley:
Wow, Carolyn, really interesting. Can you summarize it for us?
Dr. Carolyn Lam:
Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy.
Dr. Carolyn Lam:
Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood.
Dr. Carolyn Lam:
Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find?
Dr. Greg Hundley:
Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production.
Dr. Carolyn Lam:
Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece.
Dr. Greg Hundley:
Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles?
Dr. Carolyn Lam:
Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation?
Dr. Carolyn Lam:
Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found?
Dr. Alexander Benz:
Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies.
Dr. Alexander Benz:
Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable.
Dr. Alexander Benz:
Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy.
Dr. Carolyn Lam:
Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation?
Dr. Lars Wallentin:
I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients.
Dr. Lars Wallentin:
This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments.
Dr. Carolyn Lam:
Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex?
Dr. Alexander Benz:
Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from.
Dr. Carolyn Lam:
Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable?
Dr. Lars Wallentin:
Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples.
Dr. Carolyn Lam:
Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish?
Dr. Alexander Benz:
Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this.
Dr. Lars Wallentin:
Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course.
Dr. Carolyn Lam:
Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion.
Dr. Carolyn Lam:
Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found?
Dr. Timothy McKinsey:
Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension.
Dr. Carolyn Lam:
You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found?
Dr. Timothy McKinsey:
Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction.
Dr. Timothy McKinsey:
We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction.
Dr. Carolyn Lam:
Very nice. If you could just give us a one-line on how will you find this hidden fibrosis?
Dr. Timothy McKinsey:
We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at extracellular matrix protein expression in the heart, there was really a profound increase in ECM protein expression in this mouse model, even though the staining for fibrosis was negative. That told us that there was this underlying hidden fibrosis.
Dr. Carolyn Lam:
Oh, that is really interesting. And so it is that form of fibrosis that was actually reversed, perhaps, by the HDAC inhibition, and that's what you showed. Would that be accurate to say?
Dr. Timothy McKinsey:
Yeah. So the HDAC inhibitor really had this profound ability to block that ECM remodeling, the hidden fibrosis, to the point where initially we thought it was an artifact. We thought maybe there was a mix-up of samples. It wasn't a mix up. It's just that the compound, this inhibitor of HDAC enzymatic activity, really has this amazing ability to block the formation of hidden fibrosis.
Dr. Carolyn Lam:
Oh, wow. Wow, Tom, I really, really loved your editorial where you put all of this in context and talked a little bit about the translational and clinical potential. Could you maybe share your thoughts here? I love the title by the way, Erasing Hidden Fibrosis.
Dr. Thomas Gillette:
Thanks. Thanks for that. Yeah, first of all, Tim, it was a really great piece of work, and it's actually really exciting because when we think of this diastolic dysfunction, and really it's the development of HFpEF, I think, that a lot of people are... It's the single most critical unmet need in cardiovascular medicine, is the treatment for HFpEF. That diastolic dysfunction, it's really that stiffness that Tim was measuring with his atomic force microscopy and those changes in ECM that really seemed to be critical, at least in that model.
Dr. Thomas Gillette:
And we know from other models as well that these underlying changes in fibrosis and stiffness, perhaps in the ECM, play a really important role, not only in the diastolic dysfunction, but also if you think about in strain as well, because I know in our models of HFpEF and this mouse model of HFpEF, we have the two-hit model published that Gabrielle, a Allie developed with Dr. Hale in Nature. It's that strain that we could measure that really seems to correlate well with the heart failure phenotype. And so it begs the question, has he caught a very early change in the ECM that's really critical to the development of this pathology? And is there a way that we could detect it early on in patients? Is there a way we could measure that in patients and really get a sense of who's progressing and how they're progressing?
Dr. Thomas Gillette:
Then there's a second point, and I mentioned a little bit in the editorial, I didn't go into it too deeply, and that is, it's really intriguing what this might mean for the development of the disease, because the matrix not only is involved in stiffness, but it's also a reservoir for growth factors, it helps recruit inflammatory cells, and inflammation plays a huge role in HFpEF. And so it begs the question, how many of those changes may proceed a lot of that pathology as well?
Dr. Carolyn Lam:
Wow, Tom, I really couldn't agree more. I made a big deal earlier about agreeing with Tim, calling this a diastolic dysfunction model rather than HFpEF, but I completely agree with you that the implications are for the development of HFpEF, and it needed the begs, the question of how many patients actually have this hidden fibrosis? And we know that in patients with HFpEF, there is a stage of advanced fibrosis where we feel patients don't respond to treatment as well. So have we caught an early phase that may be clinically applicable? I really loved the way you worded that. But finally, with Sergio, could you put it all together and what the editors thought of this paper? Why you invited Tom to write this editorial? And perhaps what next steps are?
Dr. Sergio Lavandero:
Okay, Tim, this is really a fascinating work. I have a long road, because in Italy, you develop the most important new concept. The new concept, the hidden fibrosis. The second important, originally, most of the HDAC inhibitors were developed for other diseases, originally for cancer. So now we have more data that, probably, this compound can apply to other diseases like cardiovascular disease. It was difficult to convince at the beginning some reviewers about the concept of hidden fibrosis, because it's not traditional. But finally, we asked to another expert to, "Okay, why don't you explain, please, this new technique?" For the future, Tim, what do you think? How can we evaluate hidden fibrosis in patients?
Dr. Timothy McKinsey:
Ideally, and you would have a non-invasive approach to assessing hidden fibrosis in patients. Obviously I know myocardial biopsies could be analyzed using the mass spec approach and atomic force microscopy, but not everyone is going to want to get a myocardial biopsy. So ultimately, we would like to correlate data that we obtain with biopsies, with circulating factors to see if there is a non-invasive surrogate circulating factor that correlates with the existence of hidden fibrosis. I think that would be very powerful clinically.
Dr. Sergio Lavandero:
What do you think the specificity of this research, because maybe it's too broad? What do you think?
Dr. Timothy McKinsey:
Yeah, that's a great point. There's a negative impression of general HDAC inhibition, because people just can't believe that you could inhibit a large number of HDAC enzymes throughout the body and not kill someone. But you can. And in our models you can use pretty low doses of these HDAC inhibitors and see efficacy. But obviously, the holy grail in this field would be to identify specific HDAC isoforms that regulate specific disease processes. So we have an active area of investigation where we're trying to tease apart the roles of different HDACs in the heart, with the ultimate goal of finding the HDAC or a subset of HDACs that regulate in fibrosis. Then you could selectively inhibit those and perhaps have a safer drug than a general HDAC inhibitor.
Dr. Carolyn Lam:
Thank you, once again. This is an amazing discussion and really, really an example of just the kind of papers we love publishing at Circulation. So novel and with such translational potential. Thank you, Tim, again, and Tom and Sergio. Thank you, audience, for joining us today. From Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, it's another double feature Tuesday and today we get to discuss two articles. One, some insights from the CREDENCE trial. And second, another article about left atrial appendage closure devices, some results from the PINNACLE FLX trial. But before we get to those, how about we grab a cup of coffee and dive into some of the other really interesting articles in this issue? Would you like to go first?
Dr. Carolyn Lam:
I would, because this next paper, right up your alley and I'm sure you'll like it. But first, we talk about mitral valve prolapse. Now, we know that's a frequent disease that can be complicated by mitral regurgitation, heart failure, arterial embolism, rhythm disorders, and death. Left ventricular replacement myocardial fibrosis is a marker of maladaptive remodeling and has been described in patients with mitral valve prolapse. However, the implications of this finding remain scarcely explored. So these authors, led by Dr. [Le] Tourneau from Hôpital Laennec in France, aimed at assessing the prevalence, pathophysiological and prognostic significance of left ventricular replacement myocardial fibrosis through late gadolinium enhancement by cardiac magnetic resonance in 400 patients with mitral valve products. I bet you like that, right Greg?
Dr. Greg Hundley:
Oh my gosh Carolyn, not only a favorite topic of cardiovascular magnetic resonance, but this is a really large patient population with mitral valve prolapse that underwent CMR. So tell us, what did they find?
Dr. Carolyn Lam:
So replacement myocardial fibrosis was observed in 110 patients, so that's 28% of the patients. It was associated with mitral valve apparatus alterations, left ventricular remodeling, and ventricular arrhythmia. The ventricular arrhythmias were more frequent in patients with replacement fibrosis, but were not associated with the grade of mitral regurgitation. In patients with trace or mild mitral regurgitation, the presence of replacement myocardial fibrosis was nonetheless associated with specific mitral valve apparatus alteration at normal left ventricular dilatation, not explained by volume overload and ventricular arrhythmias, suggesting the presence of a mitral valve prolapse-associated cardiomyopathy.
Dr. Greg Hundley:
Wow Carolyn, really interesting. So the late gadolinium enhancement and the evidence therefore of replacement myocardial fibrosis that was identified by CMR, maybe this particular study is suggesting that we might want to integrate that into the clinical workup of patients with mitral valve prolapse. Very interesting work, and great job on that fantastic CMR presentation. I must say, got to recruit you into the club.
Dr. Greg Hundley:
Well, my next paper is another wonderful paper from the world of basic science and it comes from Dr. Douglas Lewandowski at the Ohio State University College of Medicine. So Carolyn, the failing heart is energy starved with impaired oxidation of long chain fatty acids at the level of reduced carnitine palmitoyltransferase-1, or CPT-1, activity at the outer mitochondrial membrane. Recent work shows that elevated ketone oxidation and failing hearts as an alternate carbon source for oxidative ATP generation. So Carolyn, these authors hypothesized that another short chain carbon source, short chain fatty acids that bypass CPT-1, could similarly support energy production in failing hearts.
Dr. Carolyn Lam:
Wow. Okay, so what did they find?
Dr. Greg Hundley:
So Carolyn, the failing heart oxidizes short-chain fatty acids more readily than ketones, with short-chain fatty acids also displacing long-chain fatty acid oxidation to somewhat of a greater extent. So in particular, the short-chain fatty acid butyrate has a higher affinity for entry into mitochondrial oxidation at the enzyme, short-chain Acyl-CoA dehydrogenase than does the ketone 3-hydroxybutyrate at the hydroxy butyrate dehydrogenase and then also through the respective downstream metabolic pathways for each substrate. So Carolyn, failing hearts of rats and humans have increased levels of Acyl coenzyme A synthetase medium chain three enzyme, which can also oxidize short-chain fatty acids to enhance butyrate oxidation.
Dr. Carolyn Lam:
Wow, that really is interesting. I can't say that I would have predicted that result. So could you give us a clinical implication?
Dr. Greg Hundley:
You bet, Carolyn. A lot of basic science here. So here's I think what we can take home, and what we learned. So while ketones have been sought as a potential supplemental fuel to remedy the impaired oxidative metabolism of the failing heart, this study shows that failing hearts preferentially oxidize short-chain fatty acids over ketones and short-chain fatty acids may prove to be a more efficient energy source during pathological stress.
Dr. Greg Hundley:
Next, novel alterations in metabolic pathways, favoring short-chain fatty acid oxidation in the failing heart occur in patients with non-ischemic cardiomyopathy. Then finally, circulating ketones are not a unique, super fuel beyond the ability to bypass the inhibition of long-chain fatty oxidation in the failing heart, as do the short chain fatty acids.
Dr. Carolyn Lam:
Thanks, I like the way you broke down the clinical implications. Well, Greg, I've got a question for you. Have you ever thought that statins may do more than lower cholesterol, but depending on what you eat?
Dr. Greg Hundley:
Oh wow, Carolyn. We always hear about the pleiotropic effects of statins, but I never really thought that could depend on what you eat. Tell me, so what did these authors investigate?
Dr. Carolyn Lam:
Yeah, so this next paper is so interesting. It's from Dr. Hu from Huazhong University of Science and Technology in Wuhan, China and colleagues, who present a novel perspective on the story of the pleiotropic effects of statins, exactly like you said, Greg. They started with the premise that statins exert pleiotropic or cholesterol-independent effects by reducing geranylgeranyl pyrophosphate production. I'm not going to keep saying that, so geranylgeranyl pyrophosphate or GGPP, is how I'm going to refer to it.
Dr. Carolyn Lam:
So they developed a sensitive technique to quantify dietary GGPP, and conducted proteomics, RT-PCR screening, and western blot, to determine signaling cascades, gene expression, protein-protein interaction, and protein-membrane trafficking in wild-type and transgenic rats, focusing on models of pulmonary hypertension, given their interest in the potential therapeutic efficacy of statins in pulmonary arterial hypertension.
Dr. Greg Hundley:
Interesting, Carolyn. Really complex and sophisticated. So what did they find?
Dr. Carolyn Lam:
Okay, listen up. Red meat and soybean have a high content of GGPP and their ingestion increases GGPP plasma levels, but reduces the effects of statins in rat models of pulmonary hypertension. Ingestion of garlic extracts, rich in methyl-L-phenyl sulfonate, which is a natural inhibitor of GGPP production, decreases GGPP bioavailability, and rescues statin effects in pulmonary arterial hypertension models. So consequently, first of all, diet may influence the cholesterol-independent effects of statins and the data really raise a provocative question of whether populations in which the typical diet contains high amounts of soybeans of beef may benefit less from statins. All this is discussed in an elegant editorial by Dr. Thomas Eschenhagen from Germany, who really ends with saying the present study should be considered hypothesis-generating and stimulate retrospective analysis of clinical registries and existing large interventional trials to either validate or refute this hypothesis. Whatever the outcome, the study is a nice example of thorough scientific underpinning of the widely held maxim that we are what we eat.
Dr. Greg Hundley:
Oh, absolutely Carolyn. I think next time with my spaghetti, I'll have the-
Dr. Carolyn Lam:
Garlic.
Dr. Greg Hundley:
... sauce with the garlic, but I won't add the red meats. Especially if I'm taking a statin.
Dr. Carolyn Lam:
Oh, that's what I was afraid you might say. Oh well, let me tell you about other papers in this issue. There's an ECG challenge by Dr. Del-Carpio Munoz and entitled A Carousel ECG Confusion. There's an on my mind paper by Dr. Hammond, on the importance of shared decision making for return to play after COVID-19.
Dr. Greg Hundley:
Great, Carolyn. So, in the mailbag, there's a really nice research letter from Dr. Robert-Ebadi evaluating the impact of the age-adjusted D-dimer cutoff to exclude pulmonary embolism. It's from a multinational prospective real-life study or the RELAX-PE study. Well Carolyn, it's another double feature Tuesday. How about we get off to understand a little bit more about those insights from the CREDENCE trial, and then also left atrial appendage closure devices?
Dr. Carolyn Lam:
All right, come on with your garlic breath.
Dr. Greg Hundley:
Well listeners, we are onto our feature discussions and we are very fortunate, we're going to have two feature discussions. Our first feature really addresses high blood pressure. And we have with us today, Dr. Brendan Neuen from the George Institute of Global Health in Sydney, New South Wales, Australia. And our own associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern in Dallas, Texas. Welcome to you both. Brendan, we're going to start with you. Could you describe the hypothesis that you wanted to test and what was your study population and your study design?
Dr. Brendan Neuen:
Well, thanks Greg. In this study, what we wanted to assess was the blood pressure lowering effects of the SGLT-2 inhibitor canagliflozin in people with type two diabetes and chronic kidney disease. The reason we thought that this is important is because what we know about the blood pressure lowering effects of these drugs is largely based on people with normal kidney function, with relatively less data in people with chronic kidney disease. So we aim to assess both the blood pressure lowering effects of SGLT-2 inhibition in chronic kidney disease, as well as treatment effects by baseline blood pressure and other blood pressure defined variables. This was conducted in the CREDENCE trial, which was a large primary renal outcome trial of the SGLT-2 inhibitor, canagliflozin, which enrolled about 4,400 people with type two diabetes and chronic kidney disease with a urine albumin to creatinine ratio greater than 300 milligrams per gram and a GFR greater than 30 at enrollment. This was a high risk hypertension population, about 30% of patients had apparent treatment resistant hypertension, about 60% of people had a GFR less than 60 and about 20% of people were on four or more blood pressure lowering agents. So really high burden of hypertension in the CREDENCE trial.
Dr. Greg Hundley:
Very good. Tell us a little bit about that design. So is this a randomized trial?
Dr. Brendan Neuen:
So CREDENCE was an event-driven randomized, double blind, placebo controlled, international trial. It was the first primary renal outcome trial of an SGLT-2 inhibitor, the primary results of which were reported in the New England journal in 2019. What this trial did, was it randomized participants, as I mentioned, with a GFR of greater than 30 and significant albuminuria and type two diabetes to either canagliflozin 100 milligrams or matching placebo in a one-to-one ratio with primary outcome overall of doubling of serum creatinine, kidney failure, cardiovascular or renal death. The trial was conducted in several, I think, 20 or 30 countries overall and enrolled at approximately 4,400 people, with participants followed for a median of about two and a half years.
Dr. Greg Hundley:
Excellent. So Brendan, tell us, what did you find?
Dr. Brendan Neuen:
So we found a couple of important findings with regards to blood pressure. Firstly, what we found was that canagliflozin reduced systolic blood pressure by about three and a half millimeters of mercury in the overall trial population. But most importantly, this blood pressure lowering effect was consistent across the number of blood pressure defined subgroups, including in people on multiple numbers of blood pressure lowering agents. So irrespective of the number of blood pressure lowering agents at baseline, and also irrespective of a history of apparent treatment-resistant hypertension at baseline, that was important. We also, secondly, found that the blood pressure lowering effective SGLT-2 inhibition was present very early at the first trial visit at three weeks. This effect was sustained over the duration of the trial.
Dr. Brendan Neuen:
Thirdly, we also found that canagliflozin reduced the risk of kidney failure and cardiovascular events, regardless of the number of blood pressure lowering agents at baseline and regardless of blood pressure, history of resistant hypertension. Finally, there is this often important question of how do these drugs reduce the risk of kidney failure and heart failure. So we did a mediation analysis, looking at to what extent the blood pressure lowering effect of this drug explains the treatment effect on these important outcomes. We found that only about less than 10% of the treatment effect on kidney failure and cardiovascular events was explained by blood pressure lowering.
Dr. Greg Hundley:
Very interesting and strong, powerful results. Well, now we're going to turn listeners to our associate editor, Dr. Wanpen Vongpatanasin. Wanpen, I know you see a lot of papers come across your desk at circulation, really focused on blood pressure and its lowering. What struck you about this paper, and then how do you put into context the results that Brendan just describe for us with all the other results that you see in new blood pressure lowering strategies?
Dr. Wanpen Vongpatanasin:
Yes, so I think this is very important study and add to a body of literature showing that the canagliflozin, like many SGLT-2 inhibitors, inducing significant lowering of blood pressure. If anything, because CREDENCE is not designed to be hypertension study the effects of blood pressure lowering my even be underestimated because the backup ground therapy allowed to be changed throughout the trial, depending on physician judgment. Also, I think the effects of many studies start to look at effects of SGLT-2 inhibitor on out of office blood pressure, like home blood pressure, or 24 blood pressure. Some even that we have published over the years, show more pronounced blood pressure lowering effects when measure outside the office. So I think that it is very interesting study but it could be not just only the drug that we use cardiovascular and renal outcome, but maybe a new class of antihypertensive medication that we could use for that purpose, although it has to be tested.
Dr. Greg Hundley:
Very nice. Well, Brendan, I want to turn back to you and then we'll come to Wanpen. Brendan, what do you think as a followup study to yours, what do you think is the next study that needs to be performed in this space?
Dr. Brendan Neuen:
Thanks, Greg. I think there's so much we still need to know about the blood pressure lowering effects of these drugs in people with advanced CKD. It would be very interesting to look at the DAPA-CKD trial, to look at the blood pressure lowering effects in people with advanced CKD not due to diabetes, so nondiabetic kidney disease. These patients also have a high burden of hypertension and whether or not these effects are also present in this population would also be important to know, and study patients with even more advanced kidney disease. That is being done in the EMPA-KIDNEY study with empagliflozin. Those results should be known in the next 12 to 24 months.
Dr. Brendan Neuen:
So, I'm studying this further in people with kidney disease. And also as Wanpen mentioned, looking at effects on blood pressure phenotype, you know, 24 hour blood pressure dipping status would also be important though, blood pressure variability, all those things can add to our understanding of the effect of these agents on blood pressure.
Dr. Greg Hundley:
Excellent. And Wanpen, do you have anything to add?
Dr. Wanpen Vongpatanasin:
Yes. I think one also very important study that helps someone with carrying in the future is in the CREDENCE, the people who are already treated with a mineralocorticoid receptor antagonist were excluded. So whether among resistant hypertension group, adding canagliflozin will be beneficial in those groups already treated MRA and lower cardiovascular outcome in already treated with MRA will be very interesting to see.
Dr. Brendan Neuen:
Yeah, I think that's a really important point to point out about the design of the CREDENCE trial, that patients who were on MRAs were excluded from the trial initially. This was due to early concerns that canagliflozin might increase the risk of hyperkalemia. I think that risk has now been put to bed in the other SGLT-2 inhibitor trials. We've got more data looking at the effects on serine potassium coming out soon, hopefully, but the other trials in which enroll more patients on MRAs, it will be very important to look at the blood pressure lowering effects in these populations.
Dr. Greg Hundley:
Excellent. Well, listeners, we've heard a great discussion today and we want to thank Brendan Neuen for bringing this wonderful science to us through circulation at the American Heart Association. We also want to thank our associate editor, Wanpen Vongpatanasin for being present today and helping us discuss how, in patients with type two diabetes and chronic kidney disease, describing that the blood pressure lowering effect of canagliflozin occurs early and appears sustained over the long term and therefore perhaps canagliflozin and can be used or considered as an adjunct blood pressure lowering medicine in addition to perhaps its protective effects on the kidney and other cardiovascular-related issues. Well now listeners, we've got another feature to get onto. So we're going to get to that second feature discussion right now.
Dr. Greg Hundley:
Well listeners, we are now turning to our second feature discussion and we're so fortunate today to have with us Dr. Saibal Kar from the Los Robles Regional Medical Center in Los Angeles, California, and our own associate editor, Dr. Mark Link from UT Southwestern in Dallas, Texas. Welcome gentlemen. Saibal, let's start with you. Could you describe for us the hypothesis that you wanted to test and what was your study population and your study design?
Dr. Saibal Kar:
Dr. Hundley, or if I could allow to call you Greg, thank you very much for asking me this question. The hypothesis was that we do know that the WATCHMAN device does prevent ischemic strokes. We do know that the first generation device has a few limitations. So there were some modifications made to the new WATCHMAN device, which is now called the WATCHMAN FLX. We thought that these changes should translate into better safety and better efficacy. So, that was the hypothesis of the study. The study population was patients with nonvalvular atrial fibrillation with a CHADS-VASc score of three or more, who had high risk of bleeding or patients who cannot take long-term anticoagulants. The study design was a single arm, prospective multicenter study with endpoints, which were based on performance goals from previous clinical trials.
Dr. Greg Hundley:
Excellent. Before we get to your results, Saibal how many patients and how many centers participated in your trial?
Dr. Saibal Kar:
So as the national principal investigator, I've never seen a study which was enrolled so fast. So the intended population was 400 patients in 29 centers and before half those centers could be activated, the study was over in four months.
Dr. Greg Hundley:
Congratulations. I think all of us that have ... especially in this pandemic era for recruiting so well, and tell us, what did you find?
Dr. Saibal Kar:
So what we found is that there were two endpoints, a safety endpoint and the efficacy endpoint. So the first thing that we found is that of the 400 patients, we could actually implant in 395 patients, device actually, which made the primary success rate over 98%. regarding the safety endpoint, we had a safety margin around 4% based on a performance score and set about 2.5, but the actual safety event rate was 0.5%, which was only two minor ischemic events, peri-procedural. There were no pericardial effusions in the first seven days, and there was no device embolizations at any time period, so that was the primary safety endpoint. So we were actually clearly safer than the first-generation device.
Dr. Saibal Kar:
When it comes to efficacy, it was an anatomical efficacy and we set the primary goal for the previous generation to be 99%. We've made a delta to make it about 97% effective, but we actually achieved an effective closure in 100% of patients. When I say effective closure, I mean that anyone with a peri device leak of less than five millimeters. Going into a little bit of granular detail, we actually found out that 90% of the patients actually had no leak at all. So we did at least achieve both the anatomical as well as the safety endpoints.
Dr. Greg Hundley:
Excellent. Well, listeners, we're now going to turn to our associate editor, Dr. Mark Link and Mark, I know you have many papers that pass through your hands. What attracted you to this paper. Then, these results really sound significant. Can you describe what impressed you also with the results of this study and how do they relate to other studies pertinent to implantation of devices in patients with atrial fibrillation?
Dr. Mark Link:
Yeah, we were interested in this paper at CERT because it's the next generation of the WATCHMAN. The numbers of patients that are being implanted with this device to prevent strokes is dramatically going up, but it's not a perfect device. So we were, as the EP community, very interested in the next generation device. We're obviously also interested in other competitors' device, but it's clear that the WATCHMAN is probably the world's leader in this time. So we knew that many of our people reading this magazine, reading the circulation, would want to see how the next generation turned out, was it really safer. That was really the primary goal of this study, it's really a safety study more than an efficacy study because the efficacy was defined by echo criteria, not by clinical criteria of stroke, which is the ultimate criteria. It was a well done study and the results came out more positive than I think even the investigators thought it was going to come out. So we liked it and that's why we did our best to get it published in circulation.
Dr. Greg Hundley:
Very good. So it sounds like great new innovation and very, very safe, especially relative perhaps to the first-generation device. So Saibal, can you tell us in just a few words, what do you think is the next study to be performed in this space? After you answer, Mark, we'll turn to you and basically ask the same question.
Dr. Saibal Kar:
Thank you very much, Greg. Transcatheter left atrial appendage closure has been approved by the FDA, specifically the WATCHMAN device, for patients who are candidates for long anticoagulation, but have limitations to long-term anticoagulation and therefore not for all-comers and there's a reason for that. The time has now come to actually evaluate this device for all-comers. That means all patients with nonvalvular atrial fibrillations who are suitable for anticoagulants. Therefore, the next best study is the CHAMPION trial. This study is going to be a randomized trial of the WATCHMAN FLX versus NOACs, or more correctly DOACs, in all-comers, patients with nonvalvular atrial fibrillation who require long-term anticoagulants. It's a 3,000 patients clinical trial with a one-to-one randomization to WATCHMAN FLX or the continuation of DOACs and the primary endpoints will be estimated at three years with a follow-up up to five years. Our goal is to show that we are non-inferior in comparison to stroke and death, and superior respect to long-term bleeding.
Dr. Greg Hundley:
Very good, and Mark?
Dr. Mark Link:
Yeah, I agree. The CHAMPION trial is the obvious next trial that everyone wants to see the results of, comparing this device to DOACs. Another trial or data I'd like to see is the immediate post-procedural anticoagulation. It's still an area that we don't have enough data to know how to treat these patients. Traditionally, they've been treated with warfarin and anti-platelet agents, but many of the patients getting this WATCHMAN have a relative contraindication to anticoagulation. So I'd like to see some data on shorter term duration of anticoagulation post-implant.
Dr. Greg Hundley:
Very good. Well listeners, we've had a wonderful discussion here and we want to thank the lead author, Dr. Saibal Kar and also our own associate editor, Dr. Mark Link, for really providing us with new information that this left atrial appendage closure device met the primary safety outcome in 99.5% of all of those implanted within seven days, what a remarkable finding. So, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run. This program is copyright of the American Heart Association, 2021.
Dr Carolyn Lam:
Welcome to Circulation on the Run! Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr Carolyn Lam:
Greg, we got double features today. Now, the first one's all about fruit and vegetables. Now, before you switch off, this is a very important one, okay? So, listen on. And the second is on the EMBRACE heart failure trial. Now, this was a late breaker, very important, more data on empagliflozin, that SGLT2 inhibitor. So really, really fun discussions coming right up. But first, can I dig into one of the papers that I'm really dying to tell you about?
Dr. Greg Hundley:
Absolutely.
Dr Carolyn Lam:
Okay. This is all about the diagnostic performance of high-sensitivity cardiac troponin T strategies, that super hot topic. We know that European data support the use of low high sensitivity troponin measurements or a 0/1 hour algorithm for myocardial infarction or to exclude MACE among emergency department patients with possible acute coronary syndrome. However, there's really very modest U.S. data to validate these strategies. This study today from Dr. Allen and colleagues from University of Florida, really evaluated the diagnostic performance of an initial high sensitivity cardiac troponin T measure below the limit of quantification. And that is six nanograms per liter, a 0/1 hour algorithm, and their combination with heart scores for excluding MACE in a multi-site U.S. cohort. And this is the largest prospective multi-site U.S. study of high sensitivity troponin T strategies to date.
Dr. Greg Hundley:
Wow, Carolyn you've really piqued my interest. So what did they find?
Dr Carolyn Lam:
Okay. And initial high sensitivity, cardiac troponin T below that level of quantification of six nanograms per liter was associated with a negative predictive value of 98.3% for 30-day MACE. Okay. That was that value itself. Now the 0/1 hour algorithm rolled out 57.8% of patients with a negative predictive value of 97.2% for 30-day MACE. The addition of a low-risk heart score to that initial high sensitivity troponin T level below that six nanogram per liter and the 0/1 hour algorithm improved the negative predictive value for 30-day MACE to 99% and 98.4% respectively.
Dr. Greg Hundley:
Wow. Carolyn, it looks like a really comprehensive analysis of the high sensitivity troponin. So tell us what are the clinical implications of this study?
Dr Carolyn Lam:
So these data seem to imply that when used without a risk score and initial high sensitivity troponin T below six nanograms per liter, or a 0/1 one hour algorithm, may not have sufficient sensitivity or negative predictive value to exclude 30-day MACE in the U.S emergency department patients. But the addition of that low-risk heart score to those measures improves the negative predictive value, but rolls out fewer patients. And so in totality, these results suggest that in the U.S. Emergency departments, adding a risk score to either of these strategies really increases their safety.
Dr. Greg Hundley:
Boy, great new information in our journal. Well, Carolyn, I'm going to switch to the world of basic science and start to evaluate in this next paper, the regulation of cellular signatures in children with dilated cardiomyopathy, and the work comes to us from Dr. Stephanie Dimmeler from Goethe University in Frankfurt. So Carolyn, Stephanie's team performed single nuclei RNA sequencing with heart tissues from six children with dilated cardiomyopathy. One was age 0.5, 1.75 and another at 5, 6, 12, and then 13 years of age. And they did this to gain insight into age and disease-related pathophysiology, pathology, and molecular fingerprints. And the goal was to gain further insight into dilated cardiomyopathy, which is a leading cause of death in children with heart failure.
Dr Carolyn Lam:
Cool. So what did they find Greg?
Dr. Greg Hundley:
Right, Carolyn. So, the number of nuclei in fibroblast clusters increased with age in dilated cardiomyopathy patients, a finding that was consistent with an age-related increase in cardiac fibrosis quantified by cardiovascular magnetic resonance imaging.
Dr. Greg Hundley:
Now Carolyn, fibroblast of the dilated cardiomyopathy patients over six years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans and a switch in thrombospondin isoforms and signatures for fibroblast activation. Additionally, Carolyn, a population of cardiomyocytes with a high pro-regenerative profile was identified in infant dilated cardiomyopathy patients, but was absent in those children that were greater than six years old. And this cluster in these infants showed high expression of cell cycle activators, such cyclin D family members increased glycolytic metabolism and any oxidative genes and alterations in beta adrenergic signaling genes.
Dr Carolyn Lam:
Wow. That sounds like a magnificent and elegant study. Could you boil it down to the take home messages?
Dr. Greg Hundley:
You bet. Carolyn. Great question. So two points first, infants with a predominantly regenerative cardiomyocyte profile, may preferentially receive treatment strategies to support cardiac regeneration while patients with a pattern associable with cardiac fibrosis may benefit from an early anti-fibrotic therapy to avoid diastolic dysfunction. And second, despite the impracticality of performing these large cohort studies in children with dilated cardiomyopathies, tailored pharmacological treatment is possibly realistic. For example, based on the expression of beta adrenergic signaling genes.
Dr Carolyn Lam:
Oh wow. That is super cool. That's Circulation for you, publishing these amazing basic science papers with very big clinical implications. Well, I've got another basic science paper for you and this time I've learned a new word actually. It's called O-GlcNAcylation. I should get you to say it after me. I had to get our editor-in-chief Joe Hill to teach me to say that, O-GlcNAcylation. So, cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Now, in this paper, co-corresponding authors, Dr. Anderson and Umapathi from Johns Hopkins University provide a new genetic mouse model to control myocardial O-GlcNAcylation independent of pathological stress. Their data actually provided evidence that excessive O-GlcNAcylation caused cardiomyopathy, at least in part due to defective energetics. Enhanced O-GlcNAcase activity was well-tolerated. And conversely, attenuation of O-GlcNAcylation was beneficial against pressure overload induced pathological remodeling in heart failure.
Dr. Greg Hundley:
Interesting, Carolyn. So what are the clinical implications of these findings?
Dr Carolyn Lam:
Well, the data really provide new proof of concept that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy, and they also suggest that attenuation of this excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.
Dr Carolyn Lam:
Shall we go on and sort of wrap up on what else is in this issue? Because I'd like to talk about highlights from the Circulation family of journals that Sarah O’Brien really beautifully summarizes, talking about everything from Circulation: Arrhythmia & Electrophysiology, to [Circulation:] Cardiovascular Quality & Outcomes. It's just a beautiful piece where we get all the highlights. Must read. There's also a Perspective piece by Dr. Gillis on Rhythm Control in Atrial Fibrillation: Is Earlier the Better?, and that discusses the EAST-AFNET 4 and early AF trials.
Dr. Greg Hundley:
Very good, Carolyn. Well, from the mailbox, professors Pan and Liu exchange letters regarding a prior response to a letter regarding the article Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program. Also, Dr. Arbus-Redondo has an EKG challenge entitled, Dual Chamber Pacemaker after Sinus Node Dysfunction and an Enlarged Right Atrium. Is it what it seems?
Dr. Greg Hundley:
And then finally, Dr. Corrado has a very nice Research Letter, entitled, Serial versus Single Cardiovascular Screening of Adolescent Athletes.
Dr. Greg Hundley:
Well, Carolyn, I'm dying to hear about fruits and vegetables. How about we get onto those featured discussions?
Dr Carolyn Lam:
Cheeky, cheeky, Greg. Here we go.
Dr Carolyn Lam:
Oh, I'm so excited about today's featured discussion because it's about my favorite thing, fruits and vegetables. Okay, wait a minute, everybody. Before you start rolling your eyes, this is a really important one. Have you ever asked yourself, what is the optimal intake levels of fruit and vegetables for maintaining long-term health? Well, guess what? We're about to find out and I'm so pleased to have the first author of today's feature paper, Dr. Wang Dong, and he's from Harvard medical school and Brigham Women's Hospital. We also have our Associate Editor, Dr. Mercedes Carnethon from Northwestern University and our Associate Editor who is also the editorialist to this paper, Dr. Naveed Sattar from University of Glasgow. So welcome, everyone. Dr. Wang, please tell us what you did in this study and what were your main results?
Dr. Wang Dong:
Thank you, Carolyn. So, basically, in this study, we analyzed the data from two long running cohort study. That is the Nurses' Health Study and Health Professional Follow-Up Study. So these two study includes more than 100,000 participants who had been followed for up to 30 years. And we also include a meta-analysis that includes in total 26 studies and about two million participant from 29 countries, and had countries around the world. So, basically, the major finding from this study is, of course, the intake of fruits, vegetable is inversely associated with the risk of death from all cause and the different kinds of cause-specific mortality. And we have a very interesting finding that is intake of about five servings per day, that can be translated into two serving of fruits and three servings of vegetables per day, was associated with the lowest risk of total mortality. So that's an optimal intake level for fruits and vegetable.
Dr. Wang Dong:
And another important finding from this study is, not all foods that some people consider to be fruits and vegetables can offer the same health benefits. For example, in this study, we found that starch vegetables such as peas and corn, and some fruits juice and potatoes are actually not associated with any benefit in terms of longevity. On the other hand, if you look at green living vegetables such as spinach, kale, and fruits that's orange color fruits and vegetables, that's rich in beta-carotene and vitamin C such as citrus fruits and berries, carrots they're associated with a substantial reduction in the risk of total mortality. That's a major finding from this paper.
Dr Carolyn Lam:
Oh, I just love it. I mean, just like such wholesome, beautiful findings from a wonderful study. Now, if I could ask you, cause I think the first thing everyone's going to say is, okay, these are associations. I mean, what'd you do about the residual risks? Could you maybe describe how you try to address some of these things like, is taking in fruits and vegetables just a surrogate for people who, I don't know, exercise more, for example?
Dr. Wang Dong:
Yeah. So in original data analysis, we actually have extensive data collection of all kinds of foods, lifestyle, risk factors, medication use, any health-related variables. So we carefully adjust for a large number of confounding factors. So actually another thing I want to point out, most all of these health-related lifestyle factors actually are inverse confounding factors in this kind of analysis. So when you adjust for other confounding factors, it's tend to attenuated your inverse association. So the review from confounding actually wouldn't be a major explanation for this association.
Dr Carolyn Lam:
Oh, that's great. And by the way, I think I misspoke. I'm not sure if I said residual confounding or residual risk just now, but you absolutely read me right, that I meant residual confounding. So thanks. Now that we've got that out of the way, if I could ask Mercedes, please. I mean, ah, another fruits and vegetables paper, I mean, what made this one different that we said we have to have it at Circulation.
Dr Mercedes Carnethon:
Well, thanks so much, Carolyn. And thank you Dong, for your team's outstanding work. I know what excited me about it was the demonstration of something that we have adopted into our lexicon, that one needs five fruits and vegetables. So I was excited to see you quantify it. In particular, the question I have for you is, did you see that these patterns of association of fresh fruit and vegetable intake were consistent across the age range and in both sexes?
Dr. Wang Dong:
Yes, of course. In total, this acts as a stratification variable. So basically, in our original data analysis, we did the analysis in the Nurses' Health Study, which all the participants are women, and in the Health Professional Follow-Up study, in which all the participants are men, would be analyzed separately and we found very consistent results in both cohorts. Then will be the meta-analysis to meta-analyze the results from these two cohorts. It comes out age, actually if you look at the paper, I think in one of the supplemental table, with the age stratified analysis, to look at the a better association if it still holds in different age group. And we did found that the results is pretty consistent in different age groups. And also, I would point out this meta-analysis provides further support to show that this results is generalizable in different people with different social economic status, demographics status also from different background.
Dr Mercedes Carnethon:
Thank you so much, Dong. it brings me to what Naveed wrote about in his editorial, that food is medicine and I just really loved that and loved the implications of that. So, I don't know, Naveed, if you've got some comments to make? Questions?
Dr Naveed Sattar:
Yeah, thanks Mercedes. No, I really love this as well because clearly the cardiovascular community, we do lots of trials. Lots of us are nihilists and just look at trials, but actually it's hard to do trials in the food and the dietary area, but these data are very consistent. I think there are multiple potential mechanisms that may explain this. We all have to eat every day, so it's a big part of our lives. Increase fiber intake, increase potassium, micronutrients, food displacement, the more fruit and veggies you eat, the less you'll eat of other things that perhaps are not as protective. And actually, part of the motivation to write an editorial was to put all that into context in terms of mechanisms. And particularly fiber, I think we underestimate the importance of fiber, but then it was also to discuss, well, if this is true, how do we help people make the changes?
Dr Naveed Sattar:
And at the level of policy, at the level of high risk groups, and my own particular favorite is really communicating dietary change in the clinic. And one of the things I often try, and we put this in a kind of headline figure in the editorial, was actually getting people to try to undergo the palate test or the retraining their palates. I have lots of patients, who, would you believe, in the west of Scotland, never really eat fruit and veg, and I really pushed them to say, "Look, would you please try? And it might take a few weeks for you to retrain your palate". And lots of people come back saying, "Ah, you're correct. And my God, now I like banana and I now like salad."
Dr Naveed Sattar:
So actually, there's lots of tips that we can do to help people increase from their average of two to three intake, which is the vast majority of population, to four to five, but it's a gradual process and it requires good communication with our patients and to compel them that these changes might take time, but that if they make these changes, they can get to a point where they really enjoy eating fruit and veg and all the multiple health benefits that come, which this paper has now showed, Mercedes.
Dr Naveed Sattar:
I think for me, that was the real nub of this.
Dr Carolyn Lam:
Naveed, I just love the way you express it. And indeed, everyone take up that editorial and look at that beautiful figure. I love the colorful fruits and vegetables on top because it also reminds us, and this paper shows, we are not talking about potato chips, and was it those, corn and peas. But, you know, we're talking about nutrition and fiber and the good stuff. Oh, this is just amazing. I wish we could go on forever, but we have a double feature this issue. And I just want to end by saying, thank you, thank you all of you, for being on the show today. It was such an important topic and I really loved the discussion as I'm sure the audience did. Thank you.
Dr Mercedes Carnethon:
Thank You.
Dr Naveed Sattar:
Thanks very much.
Dr. Wang Dong:
Thank you so much.
Dr Carolyn Lam:
I am so pleased to have with us today, a friend, a deeply admired colleague and the corresponding author of today's feature discussion, Dr. Mikhail Kosiborod from Saint Luke's Mid America Heart Institute.
Dr Carolyn Lam:
Welcome, Mikhail. And thank you for publishing this beautiful paper on EMBRACE heart failure with us. I know that this was presented as a late-breaking trial at the Heart Failure Society of America meeting, and it's a very much anticipated paper, but maybe I could start with it's all about SGLT2 inhibitors these days. So please tell us how does EMBRACE add to this accumulating knowledge that we have on SGLT2 inhibitors and heart failure?
Dr. Mikhail Kosiborod:
Well, first of all, Carolyn, thanks so much for publishing our trial in Circulation. And you're right, SGLT2 inhibitors have been taking the world of cardiometabolic medicine and heart failure by storm over the past few years. EMBRACE is a very unique trial because it really, took this world of rapidly developing technology in heart failure and heart failure monitoring, and coupled it with one of the hottest topics in heart failure today in terms of drug management, which is the advent of SGLT2 inhibitors and the emergence SGLT2 inhibitors as a efficacious therapy, not just for prevention of heart failure, but also treatment of heart failure. Because as you know, pulmonary artery pressure and hemodynamic status are one of the strongest predictors of patient outcomes, both in terms of symptoms, hospitalizations, and deaths in heart failure. And we know actually that monitoring and intervening on elevated pulmonary pressure in this patient population may lead to hospitalizations and possibly even death.
Dr. Mikhail Kosiborod:
But up until recently, it's been very difficult to monitor pulmonary pressures and to use them as an outcome in heart failure trials, because you will have to use invasive monitoring, essentially a right heart catheterization to get that data. Well, now we can actually have this implanted sensors like CardioMEMS, which are the sensors that we use in EMBRACE-HF trial. So, the question we wanted to ask is, we know SGLT2 inhibitors in DAPA-HF and EMPEROR-Reduced trials, clearly reduce the risk of cardiovascular death and hospitalization for heart failure, worsening heart failure, but the mechanisms have been hotly debated. Is there a possibility these agents can actually have an impact on hemodynamic status and pulmonary pressures? And that's the key central question that we tried to address and EMBRACE-HF trial by using this novel technology at the time, now it's been around for a few years, to noninvasively measure pulmonary pressures and use it as a primary outcome in our trial.
Dr Carolyn Lam:
Mikhail, first of all, hats off, it was a very, very clever idea to look at these patient populations who already have CardioMEMS right, and then perform this randomized trial. I mean, when I saw this, I was like, "Aw, man, how come I didn't think of that? That's just like so clever, but it's just so Mikhail to be ahead of the curve." But I'd like to remind the audience, this was a prospective randomized trial, the pre-specified outcomes, right? So maybe you could describe that in a greater detail and then the results. Yeah.
Dr. Mikhail Kosiborod:
Absolutely. Well, Carolyn, first of all, once again, thank you very much. You're being very kind. We do think it was a very novel clever idea and that you're absolutely correct, as this was very rigorously designed, randomized, double blind placebo controlled investigating trial within this study and 10 sites in United States. And the patients had to have heart failure, either with reduced or preserved ejection fraction, about half-and-half actually, as it turned out to be once it's all said and done with the trial. Because they had to have implanted CardioMEMS for clinical indication previously, they were quite advanced in terms of their heart failure. So more than half of the patients were in NYHA class III or IV, they had elevated brain natriuretic peptide levels, they had hybrid symptoms as you would expect. And essentially the patients were screened, and if they were eligible, randomized to use a empagliflozin-placebo in a double-blind fashion.
Dr. Mikhail Kosiborod:
And they were monitored actually for a couple of weeks prior to randomization to get a baseline pulmonary artery diastolic pressure. They were then treated for 12 weeks with empagliflozin, 10 milligrams a day, or a matching placebo. And we were measuring pulmonary pressure twice a day, every day for the 12 week treatment period, and then at the end of the treatment period, the treatment was stopped, but we actually continued to measure pulmonary pressure for one additional week again, twice a day, every day. So we actually saw what happened for one week after the treatment was stopped. And, as I mentioned before, the patient population was quite advanced from a heart failure standpoint. These were patients that were adequately managed with guideline-directed medical therapy for heart failure. Of course, about half of those patients have, have HFpEF. Did I mention before was the standard of care is not a thoroughly defined?
Dr. Mikhail Kosiborod:
And essentially what we observed was quite remarkable, which is average pulmonary artery diastolic pressure at baseline was about 22 millimeters of mercury across the patient population, and in patients treated with empagliflozin, there was quite a rapid reduction in pulmonary artery diastolic pressure that we saw almost immediately within one week as compared with placebo. And that divergence of curves in terms of pulmonary artery diastolic pressure continued over the entire 12-week treatment period. And by the end of the treatment period, there was nearly two millimeter of mercury difference in favor of empagliflozin, with lower pulmonary artery diastolic pressure in patients with empagliflozin compared with placebo. And also interestingly, even after the treatment was stopped for an additional week, those curves continued to diverge, with even greater lowering of pulmonary artery diastolic pressure in patients that received empagliflozin. So, I think to our knowledge, this is the first evidence from a randomized clinical trial, randomized double blind placebo controlled clinical trial, that SGLT2 inhibitors, in this case, empagliflozin, have essentially direct the congestion effect towards a lower pulmonary artery pressure rapidly and with effect amplified over time.
Dr Carolyn Lam:
Yes. Congratulations and beautifully present it there. Now, if I could ask a few more questions now, because the things will come up there. What happened to the diuretic dose? Is this depend on diuretic dose? Are there any subgroups that appeared to benefit more?
Dr. Mikhail Kosiborod:
No, excellent question, Carolyn. So first of all, we monitored average daily furosemide equivalent dose continuously throughout the trial, and what we observed was that there was no difference in diuretic dose, essentially, between the two groups from a loop diuretic management standpoint. Now, remember this patients are getting frequent pulmonary pressures with diuretics being adjusted all the time. But if you look at what happens over time, that's one of the figures in the paper you see essentially the flat lines in both groups. And coupling that with the fact that pulmonary pressures continue to diverge for another week after the treatment was stopped, at least in my mind, suggests that this hemodynamic benefits as we observed with empagliflozin as compared with placebo was lowering of pulmonary pressures is likely not simply due to diuretic effect. It just cannot be explained only by diuretic effect. I think these findings are very much in line with the analysis that we had in DAPA-HF trial with the analysis that recently were published from EMPEROR-Reduced, showing that you just can't explain what you see with heart failure benefits with SGLT2 inhibitors simply by diuresis.
Dr Carolyn Lam:
Fascinating. Well, how about the question of diabetes?
Dr. Mikhail Kosiborod:
Yes. So in terms of subgroups, that you mentioned, we did do subgroup analysis. Now I will say that the subgroup analysis have to be interpreted with a great deal of caution in this trial, because the entire trial had about 65 patients, so it's a small trial. It was really powered to look at the entire patient population and look at the primary end point of the diastolic pressure. Nevertheless, as I mentioned before, we had half-and-half reduced and preserved EF and we did not see a statistically significant heterogeneity in the treatment effect when we look at patients with reduced to preserved EF, so that hopefully both for outcome trials in preserved EF heart failure, we'll see, of course, what happens with that. And in terms of diabetes we saw a bit greater effect in patients with diabetes as compared to patients without diabetes, in terms of pulmonary artery pressure reduction.
Dr. Mikhail Kosiborod:
But again, I would just strongly caution interpretation of those subgroups because certainly when we look at clinical outcomes in those DAPA-HF and EMPEROR-Reduced, we see no such difference. We see that the benefits, right, the hard clinical outcomes, benefits, are quite consistent regardless of diabetes status. I will say one other thing, which I think is really important. If you look at the pulmonary artery pressure trajectory in patients treated with placebo in EMBRACE-HF, you see that they actually go up over time. And this is in patients that have frequent monitoring of blood pressures, our own guideline-directed medical therapy are closely watched by predominantly heart failure cardiologists and their teams to make sure that they're well-managed. And despite that, you see this increase in pulmonary pressure over time, and that's just another reminder to us that heart failure is a progressive disease despite best available therapy.
Dr. Mikhail Kosiborod:
These patients deteriorate over time, which is why treatment, novel advancements, treatments like SGLT2 inhibitors and their effective implementation is just so important because we know the benefits occur very early. We saw one week here, when we start seeing separation of curves, certainly see a significant difference by 12 weeks with pulmonary pressure. But of course we know with clinical outcomes, we see within a few weeks of randomization, already a significant benefit in reducing CV death and hospitalization for heart failure, both in DAPA-HF and EMPEROR-Reduced trials. So I think that's a critical point for clinicians to keep in mind at the time of the death.
Dr Carolyn Lam:
Mikhail, those are just such important and practical take-home messages. Thank you again. In the last minute though, I just really, really have to go back to that very clever method. Could I just pick your brain? I mean, it's like a very clever population. This CardioMEMS population that maybe what's in the future plans? Give us a sneak peek!
Dr. Mikhail Kosiborod:
Well, Carolyn, very insightful as always. I really think of it as a novel platform for drug development and heart failure. I think this is the proof of concept. This is really the first time we did something in the heart failure space was with monitoring of pulmonary pressures that shows that drugs that work for hard clinical outcomes actually do something meaningful on hemodynamics. We've struggled for such a long time in heart failure to have a good surrogate endpoints that would be reflective of clinical outcomes. This may be it. It may be one of them. And I think EMBRACE-HF is a good concept proving study that can say, if you have a compound and you think that compound may be effective for heart failure. So of course the congestion is so important that we know correlates so well with clinical outcomes
Dr. Mikhail Kosiborod:
When we started to trial all the way back to late 2015, very few patients had this device. It's not lots of patients have this device. And testing novel treatments to try to understand will there promise in heart failure, and even making go-no-go decisions, in terms of drug development, I think is starting to become a potential future development, which we should at least seriously consider in the heart failure space.
Dr Carolyn Lam:
Wow, Bravo. And Mikhail, I mean. Okay, audience, listen, you heard it right here. This is amazing. Thank you once again for publishing with us and congratulations on the beautiful paper.
Dr Carolyn Lam:
And from Greg and I, thank you audience for joining us again today, you've been listening to Circulation on the run. Tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021.
For this week's Feature Discussion, please join author Marco Vinceti and Associate Editor Wanpen Vongpatanasin as they discuss the article "Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, co-host and Associates Editor, Director of the Pauley Heart Center, Richmond, Virginia, VCU Health
Dr. Carolyn Lam:
Dr. Greg, today's feature paper, super, super exciting. Everyone has to listen to it because it's about blood pressure and sodium intake. But you think you've heard it all? You haven't. You have to listen to this feature discussion, and I'm sure you'll learn a lot, just like I did. Seriously. But before that you got your copy, I got mine. Let me tell you all about microRNA. Shall I?
Dr. Greg Hundley:
Absolutely.
Dr. Carolyn Lam:
MicroRNA, we know, have a remarkable influence on the physiology of the heart and the remodeling of diseased hearts through canonical RNA interference mechanisms. Now, the authors of today's paper, co-corresponding authors, Dr. Fu and Deschênes from Ohio State University in Columbus, Ohio, investigated if microRNA one or mir-1 specifically binds with cardiac plasma membrane proteins, and they revealed an evolutionarily-conserved direct binding between this mir-1 and an inward rectifier potassium channel called cure 2.1. Now, this is endogenously existing in cardiomyocytes.
Dr. Carolyn Lam:
Now, the authors then used inside out and wholesale patch clamp recordings to show the biophysical modulation of cardiac electrophysiology by mir-1. They further studied the mechanism of this physical interaction and investigated its pathophysiologic relevance by using mir-1 deficient transgenic mice. In total, their study demonstrated a novel mechanism of microRNA ion channel biophysical modulation that regulates cardiac arrhythmia risk.
Dr. Greg Hundley:
Wow, Carolyn really sophisticated work involving the pathophysiology of some of these arrhythmias. What are the take home message?
Dr. Carolyn Lam:
Ah, I'm glad you asked. Let me circle back to what I said earlier. Cardiac electrophysiology is regulated by microRNAs. We knew about the canonical RNA interference mechanisms, but that needs hours to days to regulate gene expression. But now we have the newly discovered biophysical mechanism that quickly, and that is within seconds or minutes, modulates the function of the ion channels. These microRNAs could prevent or trigger arrhythmias through biophysical modulation of the ion channels, even before its RNA interference regulation of protein expression occurs in diseased hearts.
Dr. Greg Hundley:
Wow, Carolyn. Really interesting new basic science. Such an asset for our journal. Well, I'm going to switch and talk a little bit about really, really high coronary artery calcium scores, something that sometimes we see. The work comes from Dr. Michael Blaha from Johns Hopkins University in Baltimore, Maryland. Carolyn, as you know, there are limited data on the unique cardiovascular disease and non-cardiovascular disease and mortality risk of primary prevention individuals with very high coronary artery calcium scores. What do we mean by very high? These are scores greater than or equal to a thousand. That's especially true in comparison to rates observed in secondary prevention populations. In this study, the investigators compared the hazard ratios for coronary artery calcium scores greater than a thousand in comparison with calcium scores of zero, those from 400 to 999, and they looked at this for those with cardiovascular disease, non-cardiovascular disease, and also evaluated mortality outcomes.
Dr. Carolyn Lam:
Oh, wow. That's interesting and those are very high coronary artery calcium score. What did they find?
Dr. Greg Hundley:
Thanks, Carolyn. After full adjustment, coronary artery calcium scores greater than or equal to a thousand demonstrated a 4.7 to a seven and a half increase in the hazard ratio for outcomes compared to individuals with calcium scores of zero, a 1.6 to 1.3 four-fold increase compared to those with calcium scores in the 400 to 999 range. Carolyn, with increasing coronary artery calcium scores, the hazard ratios increased for all event types with no apparent upper coronary artery calcium threshold. For example, a coronary artery calcium of a thousand correspond to an annualized 3-point MACE rate of 3.4 per a hundred person years and that's similar to that of a for EA population of 3.3 and higher than lower risk for EA subgroups.
Dr. Greg Hundley:
Carolyn, these results raise the thought that as we're thinking and putting together future guideline statements, should we consider a less distinct stratification algorithm between primary and secondary prevention patients for these very high coronary calcium scores? The high scores in the primary prevention group for this study really mirrored those four EA scores that you see in patients that are undergoing secondary prevention. They've already had a heart attack. Should we start thinking about for these very high scores, really aggressive preventive pharmacotherapy, just like we would in a patient that was undergoing secondary prevention?
Dr. Carolyn Lam:
I like that explanation. Thanks, Greg. Well, this next one really speaks to my favorite topic, sex differences in cardiovascular physiology and disease outcomes. Greg, here's the quiz question. Do you think progesterone receptors in cardiac cells play a role in determining the difference between you and me? Co-corresponding authors Dr. Porrello from Murdoch Children's Research Institute in Melbourne, Australia and Dr. Hudson from the Berghofer Medical Research Institute in Brisbane, Australia, and their colleagues, hey performed single nucleus RNA sequencing to capture transcriptional changes across multiple cardiac cell populations during the human heart development from fetal stages to adulthood. Their data revealed six specific transcriptional mechanisms governing maturation of multiple cell types in the heart, including a previously unrecognized role for the progesterone receptor in human cardiomyocyte maturation. These data really provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.
Dr. Greg Hundley:
Oh, great, Carolyn. Very nice. Well, Carolyn, my next paper really involves an assessment of air pollution. As you know, many of the studies today have really focused on short-term exposures to air pollution. But this group headed by Dr. Yazdi at the Harvard T.H. Chan School of Public Health began to evaluate long-term or chronic exposure to air pollution. Carolyn, the study examined the relationship between the long-term exposure to find particulate matter with an aerodynamic diameter of less than 2.5. micrometers also from nitrogen dioxide and from ozone, and they evaluated all three of those relative to hospital admissions for four cardiovascular and respiratory outcomes: myocardial infarction, ischemic stroke, the development of atrial fibrillation or flutter, and the development of pneumonia. They looked at this in the Medicare population within the United States.
Dr. Carolyn Lam:
Hmm, interesting. What did they find?
Dr. Greg Hundley:
Okay, Carolyn, so a couple things. First, long-term exposure to that fine particulate matter was associated with an increased risk of all outcomes with the highest effect seen for those that incurred a stroke. The findings translated to 2,536 cases of hospital admissions with ischemic stroke per year, which can be attributed to each one unit increase in fine particulate matter levels among the study population. Also, the nitrogen dioxide was associated with an increase in the risk of admission for stroke and atrial fibrillation. Then, the ozone was associated with an increase in the risk of an emission for a pneumonia.
Dr. Greg Hundley:
Carolyn, what this study showed, at lower concentrations, a chronic exposure, long over time of all these pollutants, were consistently associated with an increased risk for all of the study-related cardiovascular and cardiopulmonary studied outcomes. New important information regarding long-term as opposed to short-term exposure of these pollutants.
Dr. Carolyn Lam:
Yikes, yikes. Important to pay attention to. Thanks, Greg. Let me now go to the other articles in today's issue. There is a beautiful Perspective piece by Dr. Shah titled Transcatheter Closure of the Patent Foramen Ovale: Not Always an Open or Shut Case. There is a Research Letter by Dr. Davis on engrafted human induced pluripotent stem cell derived cardiomyocytes undergoing clonal expansion in vivo.
Dr. Greg Hundley:
Great, Carolyn. I've got two publications to discuss. First, Dr. Ransom has an EKG challenge entitled Palpitations in the Clinic. Then, finally, our own editor in chief, Dr. Joe Hill has a wonderful in memoriam to Dr. Jim Willerson, a prior editor-in-chief of circulation, and really a guiding light for many of us in cardiovascular diseases for much of his life. Well, Carolyn, on that note, how about we now transfer to that feature discussion and learn a little bit more about sodium intake and high blood pressure.
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Carolyn Lam:
Now, most of us would agree that dietary sodium has a role in the modulation of blood pressure levels. That we've agreed on. However, we still debate over the magnitude of the effect, who it applies to, and the importance of sodium-driven blood pressure changes for global disease burden. Well, today's feature paper does a lot to address many of the remaining questions that are revolving around sodium intake and blood pressure. I'm so pleased to have with us the corresponding author of the feature paper, Dr. Marco Vinceti from University of Modena and Reggio Emilia in Italy, as well as our associate editor, Dr. Wanpen Vongpatanasin from UT Southwestern. Welcome both. Marco, if I may and begin with you, please, could you tell us the inspiration for your study and what you did?
Dr. Marco Vinceti:
Thank you by the way, for inviting me and good morning to everybody. Our inspiration was being aware that as you already say, there may be an association, there is an association between sodium intake and blood pressure, but that maybe not all the details about such relation are being explored and carefully investigated, also for the lack of adequate statistical tools. Also, because we know that health endpoints and exposures, both dietary and environmental factors, I mean, may have a relation that is not linear, that is, just has some kind of different shape, U-shaped curve, J-shaped curve, and so on. Our thought was to investigate better this relation between sodium intake and blood pressure, even in a category of people which is wide. Also, there isn't such a large consensus about the relation; that is, people without high blood pressure and to shape that association using new statistical tools in non-linear fashion, if appropriate.
Dr. Carolyn Lam:
Very nice. Could you tell us what was special about your study design? Because it is true that the methodology you used was very unique and then perhaps the top line of what you found.
Dr. Marco Vinceti:
We took advantage of from a recent, let's say, discovery. I don't know if the term is correct, but we consider it like a discovery, of a colleague of ours at the Karolinska Institute of Stockholm. He is a statistician named Nicola Orsini. He published it in 2019. A new tool, a new approach, call it a one stage dose response meta-analysis that is able to shape the relation between exposures, in this case, sodium intake, and health endpoints or outcomes. We're talking here of continuous endpoint such as blood pressure. We can maybe talk about an outcome, almost outcome hypertension, even in the whole range of exposure from very low intake up to a high intake.
Dr. Marco Vinceti:
Until recently the only meta-analysis that you could perform was just comparing high versus low sodium intake across trials or observational studies. But in each trial, the high exposure category is different from another trial so you are comparing across trials categories that are not the same categories, are not corresponding each other. This is a major limitation. So far, there are no publication able to shape the entire range of exposure, the result of experimental studies. For experimental studies, I mean the gold standard in medical research, in human medicine that are randomized controlled trials.
Dr. Carolyn Lam:
I love that. That is really spot on, I think, of what makes your meta-analysis so important. Could you maybe then now tell us about the results?
Dr. Marco Vinceti:
Well, yes, the results, if I go back to one last detail about our statistical approach, if I can add, in addition to what I said before, we also wanted to use extensively what in 2016, the American Statistical Association just declare it, that to avoid the systematic use of p-values and statistical significant testing, just a black and white approach or something which is statistically significant or not statistically significant, and to shape the relation in a smooth, in a different way, looking graphically their religion and not having a dichotomous black and white approach, exactly as recommended by the American Statistical Association in it's very important statement in 2016.
Dr. Marco Vinceti:
About the results. I think that the main results were that the relation was, unfortunately, I will say linear. Because we were looking at non-linear association and that we tried in any way to find out if there was some kind of non-linearity in the association and I'm saving unfortunately only because we used a tool that is suitable to test a non-linear association. But we found evidence confirming here at previous meta-analysis and previous studies that say that there is a linear association between intake, that is exposure to sodium, and blood pressure. But this association also holds for people without hypertension, participant in these trials without high blood pressure. This put there that this consensus is not exactly well established all over the world; that there are investigators claiming that in people without hypertension, there is no relation, particularly for diastolic blood pressure and sodium intake. Our analysis showed, in my opinion clearly, that such association exists also, even if it is slightly weak, let's say in terms of strength compared with people with hypertension, with at least a high blood pressure.
Dr. Marco Vinceti:
There is an association for people with and without high blood pressure for diastolic and systolic blood pressure, and it exists across the entire range of usual exposure in the Western world. Because we were talking about mainly Western population. Most studies were carried out in Europe, in Australia and North America. The large majority or the 85 trials, which is the largest amount of trials ever analyzed in meta-analysis so far, were carried out in Western population. In those populations, the relation exists and is really detectable across the entire range of association even at very low intakes.
Dr. Carolyn Lam:
Wow, thank you. Thank you so, so much, Marco. So indeed a large, extremely well done meta-analysis, 85 trials, basically showing a positive and approximately linear association between dietary sodium consumption and blood pressure. Wow!
Dr. Carolyn Lam:
Wanpen, please. I mean, Marco is so just delightful in sort of saying that we'd look really hard for that J and U shape that everyone else talks about. We didn't find it, but that's exactly, I think, why we editors found this paper so, so important. Wanpen, I know you can express this better than me, so please.
Dr. Wanpen Vongpatanasin:
Sure. I agree. This is a very important study for the precision in comparing different levels of sodium intake and what it means for blood pressure. Also, I liked the paper that examine the different cutoffs that for example, the paper has a project in blood pressure that recommend by the American Heart at different levels of 1,500 milligrams a day was just the usual American diet about 3.5 grams a day, and in some subgroups even more. We can get pretty good idea and what it's translate into a blood pressure reduction.
Dr. Wanpen Vongpatanasin:
The thing that I particularly like is there's no threshold. I think that's fascinating and I think that's really important. The data, at least part of, I think, inertia in the public too, at least for me as a physician, I saw many remarks saying, "Oh, if it's part of the problem we had before, without these type of techniques, we usually give a general blanket. Sodium restriction, lower blood pressure by a few millimeters. Why do we even bother? But here you can see a dose response relationship without plateau. It really tells us that the more you eat, the more you're going to get into this kind of problem. I think this is really important and perhaps we'll push the certain population that address and consume a lot of salt to rethink about it.
Dr. Carolyn Lam:
Wanpen that was just really, really nicely put. I know that Marco was just nodding and appreciating as well. I know you had some questions from Marco too. Would you like to ask them?
Dr. Wanpen Vongpatanasin:
Yes. Based on the information from your study, would you give a recommendation a little bit differently, or how would you ... you've changed your view in terms of preexisting guidelines from European or from the United States?
Dr. Marco Vinceti:
I think that our results are really strengthening the most recent guidelines from both the U.S. and in Europe. I'm talking about the American Health Association guideline of limiting sodium intake below or at least at 1.5 gram per day, about the national recent sodium dietary allowance reference values of coming not beyond the 2.3 gram, and the European Food Safety Authority it's not just a recommendation, it's a risk assessment of indicating 2 gram per day the ideal intake of sodium. I would say the AHA was absolutely right in pointing out the opportunity to reduce to 1.5 gram and even lower, I would say. It's not a general assessment that we're one of the sodium and the Human Health Association. It's not a general risk assessment of sodium, but we know that hypertension, high blood pressure is a major, probably the major driver of all cardiovascular diseases. In our opinion, keeping this threshold, let's say, and even attempting to go below, we know how difficult it is in public health. That is absolutely correct.
Dr. Carolyn Lam:
I completely agree. That's the amazing public health message of this very important paper. As you said, it supports the guidelines, but it also suggests, I mean, should we just be saying, go as low as you can? We don't see a threshold so that's really, really fascinating.
Dr. Carolyn Lam:
Oh, may I ask maybe, cheekily, I recall, you mentioned Marco, that you had a lot of press about this paper and the publication and circulation. We would love to hear about that. Could you share with the viewers?
Dr. Marco Vinceti:
I can tell you that this is not to use or to ask, to be able to publish in such a top journal and you are not only the according to Web of Science, number one journal in the world in the cardiovascular community, let's say, but everybody. Even in the journal of medicine. I mean, I'm a public health physician, and anybody in my world, in Italy, and of course, not only Italy, I'm talking about my country, well knows this journal and what is publishing in such a journal is like some kind of an endorsement of what you are telling.
Dr. Marco Vinceti:
We received a lot of attention not only in my medical school, in my university, but also for the local press. From the national press a lot of people call me and ask for interview and even from the media. This is something that, particularly in this period of what everybody, I'm a public health physician is talking about COVID-19 and this is the emergency of course. Having the capacity to look at usual traditional disease but so important, that probably haven't received enough attention during the last months, I think is very important because I hope we are not forgetting that these are the major health issues, even in this period that is so difficult for an effect of disease for the COVID-19 outbreak.
Dr. Carolyn Lam:
Thank you so much Marco. I mean, I wish the whole audience could see the smiles you have put on all of our faces. Really, the credit all goes to you and your team for fantastic work done. We are privileged to have published this very important paper in circulation. And so thank you very, very much once again, to both of you for being on the show and to the audience for listening in today.
Dr. Carolyn Lam:
From Greg and I, you've been listening to Circulation on the Run. Thank you for joining us today.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
For this week's Feature Discussion, please join authors Erik Näslund, Mehran Anvari, Editorialist Philip Schauer, and Associate Editor Ian Neeland as they discuss, in a panel forum, the articles: "Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Severe Obesity: A Nationwide Cohort Study," "Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease: A Population-Based Retrospective Cohort Study," and accompanying editorial "After 70 Years, Metabolic Surgery has Earned a Cardiovascular Outcome Trial."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Director of the Pauley Heart Center in Richmond, Virginia with VCU Health. Well, Carolyn, another double feature this week and investigating the world of metabolic, or as we also know, bariatric surgery and the impact of bariatric surgery on cardiovascular outcomes.
Dr. Greg Hundley:
But before we get to that double feature discussion today, how about we grab a cup of coffee and we jump into some of the other articles in the issue. I'll go first this week, Carolyn. The first article comes from Professor Andreas Schuster from University Medical Center in Göttingen. Carolyn, as you know, right heart catheterization using exercise stress represents a key method for the diagnosis of heart failure with preserved ejection fraction but carries the risk of that invasive procedure. These authors hypothesized that real time cardiovascular magnetic resonance exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary non-invasive alternative for diagnosing HFpEF.
Dr. Carolyn Lam:
Wow, Greg, you know how I love talking about HFpEF? I actually managed this paper. Could you just describe what they found? It's so exciting.
Dr. Greg Hundley:
Yeah, Carolyn. Even the methods are interesting here, where these authors created a situation where you're riding a bicycle and obtaining an MRI scan at the same time. Let's get to the results. The HFpEF stress trial, prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion with E to E primes greater than eight, New York Heart Association class greater than or equal to two. To then, undergo echocardiography, right heart catheterization and then this real time pedaling a bicycle CMR exam at rest and during exercise stress. And so what they found Carolyn, the real time CMR allowed a highly accurate identification of HFpEF during physiological exercise and qualifies, perhaps, as a suitable non-invasive diagnostic alternative to the invasive procedures. So Carolyn, I think these results will need to be confirmed in a multicenter prospective approach, but really interesting innovation here, in this particular study.
Dr. Carolyn Lam:
So Greg, the paper I want to talk about, actually, is the first indicative critical role of cardiac macrophages in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage micro RNA-21 as a key molecule for the pro-fibrotic role of cardiac macrophages. Now, this comes from Dr. Engelhardt from Munich, Germany, and colleagues who show that within the myocardium, micro RNA-21 has the strongest expression in cardiac macrophages. Where it is also the single strongest express micro RNA among all micro RNAs. Targeted genetic deletion of micro RNA-21 in macrophages of mice prevented their pro-inflammatory polarization and subsequent pressure overload-induced cardiac fibrosis and dysfunction. Analysis of intercellular communication using cell sequencing identified the cardiac fibroblasts as the primary recipient cell of intercellular signals that emanate from activated cardiac macrophages and that are controlled by micro RNA-21.
Dr. Greg Hundley:
Oh, Carolyn, really interesting findings. What are the clinical implications?
Dr. Carolyn Lam:
Ah, glad you asked? What this implies is that interference with the activation of cardiac macrophages represents a promising therapeutic strategy in myocardial remodeling and dysfunction. In fact, synthetic oligonucleotide inhibitors against micro RNA-21 are currently undergoing clinical testing against fibrotic disease. This is really, really fascinating.
Dr. Greg Hundley:
Well, Carolyn, my next paper also comes from the world of basic science and it's from Dr. Anke Tijsen from Amsterdam University Medical Center, University of Amsterdam. Carolyn, as you know, titin, the largest protein in human, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to cardiomyocytes. Mutations that disrupt the titin transcript are the most frequent cause of hereditary heart failure. These investigators evaluated the role of titin and specifically a class of circular RNAs for regulating splicing of key muscle genes in the heart.
Dr. Carolyn Lam:
Fascinating. Tell us what do they find.
Dr. Greg Hundley:
Yeah, Carolyn. In this study, the authors found that the back splice junction formed by circular RNAs creates a unique motif, which binds SRSF10, to enable it to regulate splicing. And furthermore, they show that one of these circular RNAs, cTTN1, distorts both localization of, and splicing of, RBM20. Carolyn, the authors demonstrate with this work that circular RNAs formed from the titin transcript are essential for normal splicing of key muscle genes by enabling splice regulators, RBM20 and SRSF10. This shows that the titin transcript also has regulatory roles besides its well-known signaling and structural function. So, really interesting new work involving titin.
Dr. Greg Hundley:
Well, Carolyn, as we transitioned to the other articles in the issue, I want to tell you about Dr. Maskoun. He has a cardiovascular case series entitled, A Plumbing and Electrical Problem: An Unusual Cause of Syncope.
Dr. Carolyn Lam:
I like that title. Well, there's also a perspective fees by Dr. Lindman on unloading the stenotic path to identifying medical therapy for calcific aortic valve disease, talking about its barriers and opportunities.
Dr. Carolyn Lam:
Tracy Hampton reviews the literature and fascinatingly highlights papers like how DNA base editing treats Hutchinson-Gilford progeria syndrome in mice, how some researchers have identified the protein involved in cardiac repair, which is the ZEB2 protein and more information on mapping early heart formation in the embryonic mouse heart.
Dr. Carolyn Lam:
We've got a research letter by Dr. Levine. This one is so fascinating. It's about the cardiac effects of repeated weightlessness during extreme duration swimming and how that compares with spaceflight. Is that cool?
Dr. Greg Hundley:
Yeah.
Dr. Carolyn Lam:
Anyways, this was just such a power-packed issue. Now, let's just go to our feature discussion. Shall we? I can't wait, Greg.
Dr. Greg Hundley:
You bet.
Dr. Greg Hundley:
Well listeners, we have got another exciting feature discussion today on this April 13th issue. We have with us Erik Naslünd from Karolinska Institute in Stockholm, Ari Doumouras from McMaster Institution in Ontario, Canada, Ian Neeland our own associate editor from Cleveland, Ohio, and Phil Schauer from Pennington Biomedical Research Center-LSU. Welcome gentlemen. Let's start with you today, Erik. Could you describe for us, what was the hypothesis that your study wanted to address and what were your study population and design?
Dr. Erik Naslünd:
Well, what we want to study was if metabolic surgery affects the outcome in patients with previous myocardial infarction. And in Sweden, we are lucky that every Swede has their personal identification number, which is connected to essentially anything that we do, including all healthcare and we then have several registries. One is in a metabolic surgery registry, and then we also have one for cardiovascular disease called SWEDEHEART. What we did was, we went into these registries and we found patients who had undergone metabolic surgery. And then, we went to the SWEDEHEART registry and we looked at those patients who'd had a previous myocardial infarction. And then, we were able to get a match cohort, the same BMI and so on, in the SWEDEHEART registry. We were able to compare these two. We got a cohort then of roughly 500 patients who'd had metabolic surgery without a prior myocardial infarction and 500 who'd had a myocardial infarction. We then, assessed to see what the outcome was.
Dr. Greg Hundley:
Very nice. And can you describe for us your results?
Dr. Erik Naslünd:
Yeah, what we found was... Our main outcome measure was in the major adverse cardiovascular event and we found that, that was lower in the group that underwent metabolic surgery. We also then looked at death, which was also lower. We also looked at the risk for new onset of heart failure, which was also reduced. We also then assessed the risk for a major complication of the surgery in the group that had undergone metabolic surgery. We compare that to our surgical registry and we found that that was essentially the same. There was not really difference in terms of outcomes in terms of severe complications after the surgery.
Dr. Greg Hundley:
Excellent. Now, Ari, you also have a study that is involving bariatric surgery or metabolic surgery. Could you describe for us your hypothesis and your study population and design?
Dr. Aristithes Doumouras:
Yes. Thanks, Greg. Our hypothesis, first and foremost, was very similar to Erik's that patients who underwent metabolic surgery, who already had a history of heart disease when compared to a group that didn't receive bariatrics or metabolic surgery would decrease the future cardiovascular risk through a MACE outcome. Our secondary hypothesis we had, that was that those with heart failure would actually have a greater effect of metabolic surgery because of the decrease in obesity compared to those without heart failure or patients with ischemic, just ischemic heart disease with no heart failure.
Dr. Aristithes Doumouras:
The setting of the study was Ontario, Canada, where we have a centralized bariatric surgery network called the Ontario Bariatric Network. Like Erik, in Ontario, we're able to have multiple databases that are connected. They have one unique identifier for each patient. And so we looked at all patients who underwent bariatric surgery in Ontario during a timeframe. To note, we have a very large private system. Most bariatric surgeries, more than 95%, happen in the public system so we're able to track a lot of our bariatric surgery patients and don't lose a lot. We tracked all of our bariatric patients and matched them, on a one-to-one ratio, with very similar patients who also had heart disease and access to cardiology care, access to family physician care and followed them over 10 years. And so the design was a retrospective matched cohort in this way, comparing these two groups.
Dr. Greg Hundley:
Thank you, Ari. And Ari, what did you find?
Dr. Aristithes Doumouras:
Once again, like Erik, we found that there was a lower rate of MACE outcomes in the patients who underwent metabolic surgery and the absolute values were actually quite high. The absolute risk difference between the two groups was 8% and actually that went up to almost 19% in patients with heart failure. There was no action causing interaction between ischemic heart disease and heart failure, so they were the same. And the risk was about 40% lower for future MACE events in the surgery group.
Dr. Greg Hundley:
Wow, a large difference. Ian, as an editorialist for Circulation, the American Heart Association, you see a lot of papers come across your desk, what attracted you to these two manuscripts?
Dr. Ian Neeland:
When I first read these excellent papers, I thought that first of all, it was globally diverse. One study was in Europe, the other one in North America. And nevertheless, they showed strikingly similar relative risk reductions in MACE. One of them showed between 40 to 50% and so did the other. That was one really striking thing, was the consistency of a risk reduction despite being globally diverse with different systems in each country. Second of all, the absolute risk reduction was astounding. Assuming you could translate the absolute risk reduction to a clinical trial, to real-world experience, you're looking at a number needed treat between five to 12 for MACE, which is astounding and much greater than many of the evidence-based therapies we have today. The magnitude of the findings were striking and the ability to generalize globally were really interesting.
Dr. Greg Hundley:
Thank you, Ian. Well listeners, we also have an editorialist that can help us put all of this in context of what we known previously about bariatric surgery or what we are calling metabolic surgery. So we're going to turn to Phil. Phil help us put the results of these two studies in the context of cardiovascular medicine specialists or even family practitioners, internists that are managing patients with cardiovascular disease that happened to be morbidly obese.
Dr. Phillip Schauer:
Yeah, Greg. Well, these are both outstanding observational studies. And congrats to Erik and Ari and their teams for putting these studies together. Now, what's unique about these studies, is that I think these are the first to actually look at metabolic surgery for secondary prevention. Now, there are nearly 30 studies looking at metabolic surgery as primary prevention. These are all observational. They're not prospective randomized trials, but they all show, nearly all of them, show mortality reduction and MACE event reductions. These two studies are the first to show that metabolic surgery is good for secondary prevention. This is really important because I think, up till now, cardiologists have been very reluctant to refer patients to metabolic surgery. Patients who've already had a heart attack because of the least perceived operative risk and surgeons have been reluctant to operate on these patients. And both Erik and Ari have showed that the perioperative risks were remarkably low for this population, operative mortality way below 1%.
Dr. Phillip Schauer:
And so within a very short period, within a year or two, the mortality reduction, by far, supersedes any perioperative risk. I think this is really very good news. We now have quite a large amount of observational data in the primary prevention side. These two studies, nearly identical, showing mortality, MACE event reductions, as Ian pointed out, 40 to 50%. That's a lot. That rivals almost anything else out there in terms of mortality reduction, whether it's an SGLT2 inhibitor, a GLP-1, or a statin, I mean, people dance in the street when you see a five and 10% reduction. With surgery, it looks like we're seeing 40 to 50%. So, this is remarkable news but we do have a little more work to do. Perhaps we can talk about that, your next question.
Dr. Greg Hundley:
What a great lead-in Phil. So listeners, striking results with this surgical intervention for patients with cardiovascular disease that have morbid obesity. Erik, let's start with you, but we'll go through all of our expert panelists here. Erik, what do you think is the next study that needs to be performed in this sort of area of research?
Dr. Erik Naslünd:
Well, I mean, the obvious answer to that is that we need to do a randomized control trial to verify these results. That's the number one. Number two, I think, we also need to tease out, if we can, which are the most suitable patients. And is there a difference between the most commonly performed metabolic surgery procedures. That's where I would suggest that you need to do next.
Dr. Greg Hundley:
Ari, how about you?
Dr. Aristithes Doumouras:
I agree with Erik. I think everyone's going to say the same thing. That I think a randomized trial is the next step when looking at bariatric surgery and the role of secondary prevention-based patients, as these are all observational studies. And they just need to be confirmed. We're starting on a pilot study for this exact randomized trial at our institution and obviously looking for more partners later on, but yeah, that's definitely the next step in the process for sure.
Dr. Greg Hundley:
Ian, what would you like to add?
Dr. Ian Neeland:
No, I definitely agree an RCT is needed. I think one that combines both primary and secondary prevention patients is important to try to understand that the difference. One could imagine that secondary patients may actually derive much greater benefit than prime prevention patients given their baseline risk. And if one can show that the operative morbidity, mortality is low in both populations, as both papers showed observationally, then I think there's a lot of benefit there. I also think it's important to try to randomize people to different procedures, to really try to understand is it the gastric sleeve? Is it the bypass? And which one has greater benefit in the setting of a RCT as well as how do the risks and safety outcomes differ between those two in the real-world RCT setting.
Dr. Greg Hundley:
Very nice. Well, Phil we've heard randomized trials, maybe also, do we need longer follow-up?
Dr. Phillip Schauer:
Yeah, Greg. In the title of my editorial, and I hope that the listeners actually do read it, is after 70 years, metabolic surgery has earned a prospective randomized trial, and it's true. This field is 70 years old, there's not a single prospective large randomized controlled trial. There are quite a few small studies that were powered for biomarkers, but not hard clinical end points. We need this and it is doable. For example, for coronary artery bypass surgery, there's over a hundred prospective randomized controlled trials. So we definitely need this type of study. It needs to be long follow-up, probably five years or more. As Erik and Ari pointed out, it should have a mixture of primary and secondary prevention.
Dr. Phillip Schauer:
I'll share with you right now, I'm working with a group in the US. Along with Steve Nissen, a very noted cardiologist, Bob Eckel, who's currently the president of the American Diabetes Association and a number of other experts. David Aterburn, Sonia Thomas, who are working together to try to develop a study. The question is who will fund this? And frankly, we've been talking to various funding organizations. And frankly, we need the help of the cardiology community to help us support this. This information is very important.
Dr. Phillip Schauer:
If I may say one more thing, it's interesting the entire field of obesity treatment, everybody who has obesity gets treatment to cause weight loss. Yet in 2021, we do not have data that shows that weight loss actually reduces morbidity and mortality. The closest thing we have is a look ahead trial, and it looked at weight loss via a lifestyle intervention. After 10 years, they got 6% weight loss, 6% weight loss is not enough. With metabolic surgery, we can get 25 to 30% weight loss. So we need to do this study, not just to show that metabolic surgery is effective, but to show that weight loss itself could actually reduce morbidity and mortality. And frankly, it's not just cardiovascular. The second most common cause of death in these studies is cancer. And that's the other interesting thing that should be looked at. Hopefully, we can get organizations like NCI to come in and support this initiative.
Dr. Greg Hundley:
Thank you. Well, listeners, what a wonderful discussion today, really a feature symposium. And we want to thank Erik Naslünd, Dr. Aristithes Doumouras, Ian Neeland and Phil Schauer for their time and expertise and sharing that with us today. Especially on this topic of bariatric, but now maybe more commonly called metabolic surgery, where these two studies have been demonstrating efficacy of these procedures now in patients with cardiovascular disease and even those post myocardial infarction.
Dr. Greg Hundley:
On behalf of Carolyn and myself, I want to wish you another great week ahead and we will catch you in that next week, on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
For this week's Feature Discussion, please join authors Igor Klem, Pasquale Santangeli, Mark N.A. Estes III, and Associate Editor Victoria Delgado as they discuss, in a panel forum, the articles: " The Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients with Non-Ischemic Cardiomyopathy," "Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias," and "Cardiac Magnetic Resonance Imaging in Nonischemic Cardiomyopathy: Prediction Without Prevention of Sudden Death."
Dr. Carolyn Lam:
Welcome to Circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate editor, Director of the Pauley Heart Center in Richmond, Virginia. Well Carolyn, this week we've got another sort of double feature with a forum and our focus is going to be on myocardial scar that's observed with late gadolinium enhancement during cardiovascular magnetic resonance and the two author groups we'll be discussing the impact of that scar on the development of ventricular arrhythmias. But before we get to that, how about we grab a cup of coffee and jump into the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I certainly would. Although I have to say, can't wait for the double feature. I love those, and this is right up your alley too. All right. But first, the first paper I want to talk about provides new randomized trial information regarding the benefits of catheter ablation in atrial fibrillation in patients who also have heart failure. Now, this is a sub-study of the CABANA trial.
Dr. Greg Hundley:
So Carolyn, remind us a little bit about the CABANA trial first.
Dr. Carolyn Lam:
I thought you might ask. Well, CABANA randomized 2,204 patients with atrial fibrillation who were 65 years or older or less than 65 with one or more risk factors for stroke at, it was huge at 126 sites, and they were randomized to ablation with pulmonary vein isolation or drug therapy. Now of these, 35% of 778 patients had New York Heart Association Class II or higher at baseline, and really formed the subject of the current paper. Although this sub-study was not specifically designed to evaluate patients with heart failure with preserved ejection fraction, about 91% of the patients with a clinical diagnosis of heart failure participating in CABANA for whom such data on injection fraction were available, really had an ejection fraction of above 40% and fully 79% had an ejection fraction above 50%. So excitingly, this is really majority talking about, have HFpEF. Now, what did they find well in patients with New York heart Association Class II or III heart failure at trial entry, most of whom did not have a reduced ejection fraction.
Dr. Carolyn Lam:
There was substantial clinical outcome benefits with the ablation over drug therapy with a 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding or cardiac arrest. Benefits were evident for both all-cause mortality and atrial fibrillation reduction. However, the effects on heart failure hospitalization were small and not significant. Authors also caution that these results should not be viewed as practice changing until they are reproduced in a confirmatory trial of ablation in the same population. And this is beautifully discussed in an editorial by Lynda Rosenfeld and Alan Enriquez from Yale University School of Medicine.
Dr. Greg Hundley:
Oh, wow. Thanks Carolyn. Well, my first paper comes from the world of basic science and it's from Professor Thomas Braun, from the Max Planck Institute for Heart and Lung Research. So Carolyn, vascular smooth muscle cells show a remarkable phenotypic plasticity allowing acquisition of contractile or synthetic states, but critical information is missing about the physiological signals that promote formation and maintenance of contractile vascular smooth muscle cells in vivo. So BMP-9 and BMP-10 are known to regulate endothelial quiescence after secretion from the liver and right atrium. And these investigators are studied the role of BMP-9 and 10 for controlling formation of contract, all vascular smooth muscle cells.
Dr. Carolyn Lam:
Greg, talking about vascular smooth muscle cells always reminds me of their role in pulmonary hypertension, am I right?
Dr. Greg Hundley:
Yes, Carolyn. So these investigators found that in mouse models, BMP-9 and BMP-10 act directly on vascular smooth muscle cells for induction and maintenance of their contractile state, and surprisingly the effects of BMP-9 and 10 in vascular smooth muscle cells are mediated by different combinations of BMP type 1 receptors in a vessel bed specific manner. And therefore, just as you suggest, Carolyn, these results may offer new opportunities to manipulate blood pressure in the pulmonary circulation.
Dr. Carolyn Lam:
Thank you, Greg. Well, my next paper provides the first proof of principle of gene therapy for complete correction of Type 1 Long QT syndrome.
Dr. Greg Hundley:
Ah, so tell us a little bit about Type 1 Long QT syndrome, Carolyn.
Dr. Carolyn Lam:
Okay. Well Type 1 long QT syndrome is caused by loss of function variants in the KCNQ1 and coded potassium channel alpha sub-unit. And that is essential for cardiac repolarization providing the slow delayed rectifier current. Now no current therapies target the molecular cause of this Type 1 long QT syndrome. Well, this study from Dr. Michael Ackerman colleagues from Mayo Clinic Rochester really established a novel dual component suppression and replacement KCNQ1 gene therapy approach for Type 1 long QT syndrome. And it's the type that contains the KCNQ1 short hairpin RNA to suppress endogenous expression and a codeine altered short hairpin RNA immune copy of this KCNQ1 for gene replacement.
Dr. Carolyn Lam:
So this very novel approach rescued the prolonged action potential duration in inducible pluripotent STEM cell cardiomyocytes derived from four patients with unique Type 1 Long QT syndrome, causative, KCNQ1 variants. So it's super cool. Just go have a look.
Dr. Greg Hundley:
Well, thanks Carolyn.
Dr. Carolyn Lam:
I want to also tell you about other things in the mail bag. We have ECG Challenge by Dr. Dai on “Severe Arrhythmia Caused by a Chinese Herbal Liqueur. What's the Diagnosis?” I'm not going to tell you. You have to go see. We have Dr. Karen Sliwa writing a beautiful Joint Opinion paper from the World Heart Federation and American College of Cardiology, American Heart Association, and European Society of Cardiology on "Taking a Stand Against Air Pollution, the Impact on Cardiovascular Disease."
Dr. Greg Hundley:
Well, thanks Carolyn. So I've got a couple other articles. First Professor Yacoub has a global rounds describing and working towards meeting the challenges of improving cardiovascular health in Egypt. Those are really interesting features to learn about cardiovascular care worldwide. Next there's an In Depth article by Professor Thum entitled, "Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases, Roadmap to the Clinic." And then finally, a Research Letter from Dr. Bottá entitled, "Risk of Coronary Artery Disease Conferred by Low Density Lipoprotein Cholesterol Depends on Apologetic Background." Well, Carolyn, what a great issue and how about now we proceed on to that double feature?
Dr. Carolyn Lam:
Oh, I can't wait. Thanks Greg.
Dr. Greg Hundley:
Well, listeners, we are here for a really exciting feature discussion today that's going to focus on imaging, in particular magnetic, resonance imaging, and some new findings in that era and how those findings may pertain to ventricular dysrhythmias. With us today, we have Dr. Igor Klem from Duke University who will be discussing a paper, Dr. Pasquale Santangeli from University of Pennsylvania, our own associate editor, Dr. Victoria Delgado from Leiden and an editorialist, Dr. Mark Estes from UPMC in Pittsburgh. Welcome to all of you. Well, Igor, we're going to start with you. Could you tell us what was the hypothesis for your study and what was your study population in study design?
Dr. Igor Klem:
Yes. Good morning, Greg and thanks for the invitation. We wanted to know if you have a patient who you diagnosed with non ischemic cardiomyopathy based on clinical grounds and you refer him for a cardiac MRI study with contrast, what is the additional information that you get from the MRI study? And so we wanted to compare, and that's primarily related to the findings on scar imaging with late gadolinium enhancement. And we wanted to compare that to one of the most robust clinical parameters in cardiology, which is left ventricular ejection fraction, and in particular using a cutoff of 35%, which somehow in our clinical management has sort of as established as a break point for many clinical decisions.
Dr. Igor Klem:
And so we created a registry among three centers of patients who undergo a cardiac MRI study, where we found an LVEF of less than 50% and we followed them for a number of outcomes. One is all caused death. And then we wanted to separate a little bit the events into those who have cardiac mortality to look at a little epidemiology because in those patients, we have two major adverse events: one as heart failure related mortality. One is arrhythmia related mortality.
Dr. Greg Hundley:
And how many subjects did you include?
Dr. Igor Klem:
We included about a thousand patients from three centers and coming to the major findings of our study, we found that both left ventricular ejection fraction, as we know, is a robust marker of all cause mortality and cardiac death. And so it was the presence of myocardial scar on cardiac MRI. But the major difference was in relation to the arrhythmic events. We founded left ventricular ejection fraction in particular, when we use the 35% cutoff actually had very little predictive power to inform us who is at risk of arrhythmic events. In contrast, there was a very strong and robust relationship or multiple statistical methods to stratify patients who are at risk for sudden cardiac death, appropriate ICD shock, as well as arrhythmic cardiac death.
Dr. Greg Hundley:
Very good. Well, Pasquale understand you also performed a research study utilizing cardiovascular magnetic resonance. Could you describe for us your hypothesis as well as what was your population and your study design?
Dr. Pasquale Santangeli:
Thank you, Greg. And of course, thanks to the editor for the interest in our paper. I need to thank also the first call authors Daniele Muser and Gaetano Nucifora for putting together a registry of 70 institutions throughout the U.S., Europe, and Japan and the our hypothesis came from a clinical need. We do know that patients with idiopathic ventricular re we ask, which includes not sustain a weakness like PVCs or non-sustained VT. Very few of them, but there is a group of them that have a higher risk of ending malignant and up comes in terms of your ethnic events over follow-up. And prior studies have shown that by doing an MRI and showings and the detecting scar related announcement, there is an increase with how we make events of a follow-up. However, if you do look at those studies late, an answer's been reported in up to 70% of these patients, which you never view is a highly practical way of re-stratifying these patients, because you have a risk factor that is present 70% of those, then it's hard to use it for clinical decision-making.
Dr. Pasquale Santangeli:
So in this registry, which you put it again at 686 patients with panel data idiopathic, not sustained ventricular arrhythmias, which were defined by a normal WBC gene status, a normal echocardiogram and a normal stress test. We looked at whether there is a specific pattern of late announcement. So how basically I believe lands, and it looks on the MRI, they may predict better or outcomes over follow-up. And again, we use a composite and Pauline the full cost mortality, but associated cardiac arrest due to ventricular fibrillation or a hemodynamically unstable BP, or in a subgroup of patients that underwent ICD therapy. We also looked at, I approve SED shocks.
Dr. Pasquale Santangeli:
The groups were divided in three different categories. The first one, which is a larger group of 85% of patients and no late announcement. The second group, the one with late announcement, which represents the remaining 50% of 15% of patients, we divided it into a ring light pattern, which was defined as that word says, as a ring like distribution of the lead announcement in the mid-market segments, which involves a three consecutive continuous segments in a short axis view. It looks like really at least half the ring or three-quarters of the ring.
Dr. Pasquale Santangeli:
And the other group is the one that had the leader announcement without a ring light pattern. And it's interesting that the third and the latest announcement was not that similar between the ring light and the one without ring light late announcement. What we did find though for our follow-up the patient with a ring light pattern, a significantly higher rate of the primary composite endpoint, which happened in the median follow-up about 61 months so it was quite long. And the composite outcome occurred in 50% of patients in the ring light group versus 19% in the no ring light a positive announcement group and a 0.3%. So really, really rare in patients. So then concluded that of course, late announcement does provide some information in general, particularly the type of announcement that increases the risk significantly. Probably although this has to be confirmed prospective fashion patient with a ring light pattern may benefit from other forms of interventions, including potentially defibrillator therapy in a prophylactic fashion.
Dr. Greg Hundley:
Very nice. So now listeners, we're going to turn to our associate editor. One of the imaging experts here at Circulation, Dr. Victoria Delgado. Victoria, you see a lot of papers come across your desk and as an imaging expert, what attracted you to these two papers? And what do you think are their significance?
Dr. Victoria Delgado:
Thank you, Greg. I think that these two papers are important because right now, if we follow the clinical guidelines, we decide implantation. For example, of an ICD based on the ejection fraction, and we see that in many patients based on ejection fraction, they may not benefit ever from an ICD because they don't have arrhythmias. What other patients who do not meet the criteria often injection fraction below 35%. They may have still arrhythmias. So the article by Igor highlights the relevance of the amount of burden of late government Huntsman with CMR, in patients with non ischemic cardiomyopathy, which are sometimes very challenging patients on how to decide when we implant an ICD or not. We need sometimes to base the decision on genetics.
Dr. Victoria Delgado:
If we have an on the other hand, the paper of Pasquale, these were patients with normal echocardiogram. So what patient, having arrhythmias where we don't see on echocardiogram, that is the first imaging technique that we usually use to evaluate these patients. We don't see anything, but CMR can give us more information in terms of structural abnormalities and particularly not only the burden of scar, but also the pattern of the scar. And we have seen in other studies that for example, not only for ICD implantation, but for ventricular tachycardia ablation. The characteristics of that scar and some areas where these are short of panel that can be targeted for that ventricular tachycardia ablation can lead to much more precise treatment if you want of these patients.
Dr. Greg Hundley:
Thank you, Victoria. So it sounds like listeners we're hearing late gadolinium enhancement, regardless of EF could be forecasting, future arrhythmic events. And then also the pattern of late gadolinium enhancement, where contiguous segments in a ring-like fashion may also offer additional prognostic information. Well, now we're going to turn to our editorialists and as you know, listeners at Circulation, we'll bring in an editorialist to really help put things together and uniquely here today, we have Dr. Mark Estes, who is really not an imager per se, but like many of us uses the information from imaging to make clinical decisions. Mark, how do you see this late gadolinium enhancement as perhaps a new consideration for placement of devices?
Dr. N.A. Mark Estes:
Greg, that's one of the key questions. There's no doubt, not only based on these two studies, which extend our prior information about LGE and patients with valid and non ischemic cardiomyopathies that scar burden is important in predicting not only total mortality, but arrhythmic events. All of the criteria that were used in the original ICD studies, which include the definite, the Skuid half Danish and made it our it trials use only ejection fraction and functional status, no imaging. These are legacy trials. Now, many of them, a decade or more older. And the treatment of advanced heart failure has progressed to the point that the total mortality is dramatically lower than it was at the time of these studies. In some instances down to 4 or 5% per year. The studies are important in that they identify a subgroup of patients with low ejection fractions, less than 35%, who might qualify for ICDs, who are unlikely to benefit.
Dr. N.A. Mark Estes:
They also identify a group of patients with preserved ejection fraction greater than 35%, less than 50 in whom the risk of sudden death may be substantial. And it extends prior observations about patchy, mid Meyer, cardio wall fibrosis, subendocardial, subepicardial and important ways. But the key issue here, and it was alluded to with Pasquale's comments about prospective validation, is that when one has a risk stratifier and identifies a high risk population that has to be linked to an unequivocal therapy, it improves survival. And we don't have that link quite yet.
Dr. N.A. Mark Estes:
Prospective randomized trials are unlikely to be done in the low ejection fraction because they would probably be considered unethical. Given the trials that have shown the benefit you can't randomize to defibrillator versus an implantable loop recorders. I think the future really lies in risk stratification for people with preserved ejection fractions greater than 35%, less than 50 using LG in that patient population. Currently, I think the best information we can give to clinicians is to stick with the AHA guidelines, which is PF less than 35% with dilated, nonischemic class II symptoms who have had optimal medical therapy for at least three months using perhaps in that patient population LGE for shared decision-making in patients about the magnitude of the risk. And I think that's as far as we can go pending future studies, and there is one which we can discuss later on the CMR study at just that preserved ejection fraction LGE randomizing to defibrillator versus ILR.
Dr. Greg Hundley:
Thank you, Mark. So listeners just really quickly, let's go back to each of our experts and ask them, you know, in 20 seconds, Igor, Pasquale, Victoria, and Mark, what's the next study that needs to be performed in this space? Igor, we'll start with you.
Dr. Igor Klem:
Well, number one, following on Mark's comment on the less than 35% population, I think that it's unlikely that they're randomized clinical trial is ethical in this population, but we may consider a wealth of registry data by now that shows that there is a subgroup of patients who have a lower risk or lower benefit from an ICD. I think in the preserved ejection fraction above 35%, maybe up to 45%, 50%. That's an interesting study that's coming up. Maybe there's more trials that can provide us that robust information that we need today in order to change the guidelines to risk stratify, not based on the LVF, but on the presence of scar or maybe subgroups of scar.
Dr. Greg Hundley:
Pasquale?
Dr. Pasquale Santangeli:
Yes. So I think of course, one of the major studies is the one already alluded by this, which is a prospective study that links as specific therapy like ICD or even additional risk factors like we've been using program's stimulation some of these patients to further risk for the five to see what they can benefit.
Dr. Pasquale Santangeli:
Based another one that I think is important for the study that we did is a mechanistic more study to understand why the ring light pattern was there, as opposed to other patterns. We do believe we think that some of these patients may have an initial form of lb dominant arrhythmogenic paramount. There wasn't really a detective before and ran. Now, if we actually extending our study and have a registry to try to screen also the family members or patients with ring light pattern to understand whether there is a familiar component to it, because really we do not see this type of pattern that commonly and it'd been associated with lb dominant. Magnetic kind of alpha in some others, small studies.
Dr. Pasquale Santangeli:
So that's the other part to dig in a little bit more into the field type for these patients to understand why one pattern versus another happens and whether that gets main to, to explain why there's a higher risk in one population versus another.
Dr. Greg Hundley:
Victoria.
Dr. Victoria Delgado:
Yeah. Following what has been said. I think that from the imaging point of view, we are always criticizing in a way that we increase the burden or the cost of healthcare. But I think that these studies or any randomized study where MRI or echo is used in order to design a therapy and show the value of using that imaging technique to optimize the health care costs is important. So I will not add much on which sort of populations, but probably patients within non ischemic cardiomyopathy with preserved ejection fraction that do not fulfill the recent scores, for example, in hypertrophic cardiomyopathy to be implanted with an ICD. But probably if we see a lot of scar on a AGE where specific patterns that can help to decide which are the patients that have benefited from an ICD implantation, for example.
Dr. Greg Hundley:
Thank you. And finally Mark.
Dr. N.A. Mark Estes:
But I think all the major points have been hit here. And unfortunately we have a bit of a dilemma. And that dilemma is that these legacy trials for ICDs, which selected based on low ejection fraction and functional class II were done at a time when contemporary heart failure treatment was not as good as it currently is pharmacologically. And it's been reflected with a lower total mortality. When the mortality in this patient population gets down to the 4 and 5% per year, it's unlikely that any intervention for prevention of sudden death is going to impact on that total mortality.
Dr. N.A. Mark Estes:
So I do think that the registries hold a lot of promise, giving us insights into the subgroup of patients that previously would have been selected for defibrillators who may not have as much benefit or who may benefit the most. And I think that they will play an important part in perhaps refining the risk stratification with greater sensitivity and specificity in the patient population, less than 35%. I think the CMR guide trial is going to be a critical trial and looking at ICDs in the patient population between 35 and 50%, but we need to be mindful of one thing. And that in the Danish trial, they get a sub study looking at about 240 patients using LGE. And they found that ICD in patients with LGE that was positive, did not make a difference in survival or total mortality. So again, we need to get the data. I think the best clinical practice has come out of the best clinical evidence. You'll clearly be limitations to what we can do, but I think in the future, we'll have much better data to make these judgment calls.
Dr. Greg Hundley:
Very good. Well listeners, we want to thank our panelists, Dr. Igor Clem, Pasquale, Santangeli, Victoria Delgado, and Dr. Mark Estes for this wonderful discussion related to magnetic resonance imaging, late gadolinium enhancement, and how it may be useful in identifying those at risk for future arrhythmic events. On behalf of both Carolyn and myself, want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
For this week's Feature Discussion, please join authors Michael Ackerman, Christopher Haggerty, editorialist Michael Rosenberg, and Associate Editor Nicholas Mills as they discuss the original research articles “Artificial Intelligence-Enabled Assessment of the Heart Rate Corrected QT Interval Using a Mobile Electrocardiogram Device,” “ Deep Neural Networks Can Predict New-Onset Atrial Fibrillation From the 12-Lead Electrocardiogram and Help Identify Those at Risk of AF-Related Stroke,” and “Trusting Magic: Interpretability of Predictions from Machine Learning Algorithms.”
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this week's feature, it's kind of a new thing for us. It's more than our double feature; it's actually a forum, where we're going to have two papers discussed, we'll have both authors represented from each of those two papers, we'll have an editorialist, and we'll have one of our associate editors. And the topic, Carolyn, just to keep you in suspense, is really on machine learning and actually how that can be applied to 12 lead electrocardiograms. But before we get to that, how about we grab a cup of coffee and start off on some of the other articles in this issue? Would you like to go first?
Dr. Carolyn Lam:
Yes, I would, but you're really keeping me in suspense. But first, let's focus on health related quality of life. We know that poor quality of life is common in heart failure, but there are few data on heart health related quality of life and its association with mortality outside of the Western countries. Well, until today's paper. And it's from the Global Congestive Heart Failure, or GCHF study, the largest study that has systematically examined health-related quality of life as measured by the Kansas City cardiomyopathy questionnaire 12, or KCCQ, and its association with outcomes in more than 23,000 patients with heart failure across 40 countries, in eight major geographic regions, spanning five continents.
Dr. Greg Hundley:
Wow, Carolyn. That KCCQ 12, that has been such an interesting tool for us to use in patients with heart failure. So what did they find in this study?
Dr. Carolyn Lam:
Really important. So the health-related quality of life differs considerably between geographic regions with markedly lower quality of life related to heart failure in Africa than elsewhere. Quality of life was a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and in both preserved and reduced ejection fraction. So there are some important clinical implications, namely that health-related quality of life is an inexpensive and simple prognostic marker that may be useful in characterizing symptom severity and prognosis in patients with heart failure. And there is certainly a need to address disparities that impact quality of life in patients with heart failure in different regions of the world.
Dr. Greg Hundley:
Very nice, Carolyn. Well, I'm going to turn to the world of basic science and bring us a paper from David Merryman from Vanderbilt University. So Carolyn, myocardial infarction induces an intense injury response, which ultimately generates a collagen dominated scar. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process post myocardial infarction. Now Carolyn, serotonin 2B receptor signaling has been shown to be harmful in a variety of cardiopulmonary pathologies, and could play an important role in mediating scar formation after MI. So Carolyn, these investigators employed two pharmacologic antagonists to explore the effect of serotonin 2B receptor inhibition on outcomes post myocardial infarction and characterized the histological and micro structural changes involved in tissue remodeling.
Dr. Carolyn Lam:
Oh, that's very interesting, Greg. What did they find?
Dr. Greg Hundley:
So Carolyn, serotonin 2B receptor antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated in their results by decreased scar thickness and decreased border zone area. Serotonin 2B receptor antagonism resulted in collagen fiber redistribution to a thinner collagen fiber. And they were more anisotropic. They enhanced left ventricular contractility and the fibrotic tissue stiffness was decreased, thereby limiting the hypertrophic response of the uninjured cardiomyocytes.
Dr. Carolyn Lam:
Wow. That is really fascinating, Greg. Summarize it for us.
Dr. Greg Hundley:
Yeah, sure. So this study, Carolyn, suggests that early inhibition of serotonin 2B receptor signaling after myocardial infarction is sufficient to optimize scar formation, resulting in a functional scar, which is less likely to expand beyond the initial infarct and cause long-term remodeling. The prolonged presence of the antagonist was not required to maintain the benefits observed in the early stages after injury, indicating that acute treatment can alter chronic remodeling. So Carolyn, it's really going to be interesting to see how this research question is pursued in studies of larger animals, including us, or human subjects.
Dr. Carolyn Lam:
Wow, that is really interesting. And so is this next paper. Well, we know that genetic variation in coding regions of genes are known to cause inherited cardiomyopathies and heart failure. For example, mutations in MYH7 are a common cause of hypertrophic cardiomyopathy, while mutations in LMNA are a common cause of dilated cardiomyopathy with arrhythmias. Now, to define the contribution of non-coding variations, though, today's authors, led by Dr. Elizabeth McNelly from Northwestern University Feinberg School of Medicine in Chicago and colleagues evaluated the regulatory regions for these two commonly mutated cardiomyopathy genes, namely MYH7 and LMNA.
Dr. Greg Hundley:
Wow, Carolyn. So this is really interesting. So how did they do this and what did they find?
Dr. Carolyn Lam:
You asked the top questions, because the method is just as interesting as the findings here. They used an integrative analysis that relied on more than 20 heart enhancer function and enhancer target datasets to identify MYH7 and LMNA left ventricular enhancer regions. They confirmed the activity of these regions using reporter assay and CRISPR mediated deletion of human cardiomyocytes derived from induced pluripotent STEM cells. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. Extending the strategy genome-wide, they identified an enhancer modifying variant upstream of MYH7. One specific genetic variant correlated with cardiomyopathy features derived from biobank and electronic health record information, including a more dilated left ventricle over time. So these findings really link non-coding enhancer variation to cardiomyopathy phenotypes, and provide direct evidence of the importance of genetic background. Beautiful paper.
Dr. Greg Hundley:
Very nice, Carolyn.
Dr. Carolyn Lam:
But let me quickly tell you what else is in this issue. We have an ECG Challenge by Dr. Lutz on flash pulmonary edema in a 70-year-old; there's an On My Mind paper by Dr. Halushka, entitled (An) Urgent Need for Studies of the Late Effects of SARS-CoV-2 on the Cardiovascular System.
Dr. Greg Hundley:
Ah, Carolyn. Well, in the mailbox, there are two Research Letters, one from Dr. Soman entitled (The) Prevalence of Atrial Fibrillation and Thromboembolic Risk in Wild-Type Transthyretin Amyloid Cardiomyopathy, and a second letter from Dr. Berger entitled Multiple Biomarker Approaches to Risk Stratification in COVID-19. Well Carolyn, now let's get on to that forum discussion and hear a little bit more about using machine learning in the interpretation of a 12 lead ECG.
Dr. Carolyn Lam:
Wow, can't wait. Thanks, Greg.
Dr. Greg Hundley:
Well listeners, we are here today for a double feature, but this double feature is somewhat unique, in that we are going to discuss together two papers that focus on machine learning applications as they relate to the interpretation of the electrocardiogram. With us today, we have Mike Ackerman from Mayo Clinic, Chris Haggerty from Geisinger, Mike Rosenberg as an editorialist from University of Colorado, and then our own Nick Mills, an associate editor with Circulation. Welcome, gentlemen. Well, Mike Ackerman, we will start with you first. Could you describe for us the hypothesis that you wanted to test, and what was your study population and your study design?
Dr. Michael Ackerman:
Thanks, Greg. The hypothesis was pretty simple, and that is could an artificial intelligence based approach, machine learning, deep neural network, could that solve the QT problem? Which is one of the big secrets among cardiologists, which, as you know, one of your associate editors, Sammy Biskin, published a sobering paper over a decade ago, showing and revealing the secret that cardiologists are not so hot at measuring the QT interval, and heart rhythm specialists sometimes don't get it right either. And we all know that the 12 lead ECG itself is vexed by its computer algorithms at getting the QTC just right, compared to those of us who would view ourselves as QT aficionados. And so we were hoping that a machine learning approach would solve this and help us glean, one, a very accurate QTC, as accurate as I can make it when I measure it, or core labs that do QT measuring for living.
Dr. Michael Ackerman:
And two, could we get that QTC from just a couple of leads to be as accurate as what the whole 12 lead ECG would be seeing so that we can move it to a mobile smartphone enabled solution? And so that was our hypothesis going forward, and we studied a lot of patients. And that's something that machine learning and the power of computation does, that in my world, I'm used to studying a hundred or a thousand patients with congenital long QT syndrome and thinking that I've assembled a large cohort, but for this study, we started with over two and a half million ECGs from over 650,000 people. And then ultimately, through training, testing, and validation of about 1.6 million ECGs from over a half a million individuals to sort of teach the computer or have the AI algorithm get the QT interval not too hot, not too cold, but just right. And as we'll discuss, I think we hit the mark.
Dr. Greg Hundley:
Thanks so much, Mike, what did you find?
Dr. Michael Ackerman:
Ultimately, we were able to show that with this drill, we could get the deep neural network derived QTC to be give or take two plus minus 20 milliseconds from what would the standard of care, and that being a technician over-read QTC. But then we took, I would say, pretty unique to AI studies, as many AI studies, just do training, testing, and validation for study number one. And then a future paper of a prospective study. But we did that prospective study within this single paper with a subsequent about two year enrollment of nearly 700 patients that I evaluated in our genetic heart rhythm clinic at Mayo Clinic. And half of those patients have congenital long QT syndrome, half did not. And what we showed was that the deep neural network derived QTC from a mobile ECG approximated the subsequent or the just prior 12 lead ECG within one millisecond, +/- 20 millisecond territory.
Dr. Michael Ackerman:
And it's ability to say is the QTC above or below 500, which we all know is sort of a warning sign, that's a very actionable ECG finding, do something about it, that that 500 millisecond cutoff by the deep neural network gave us an area under the curve of 0.97, which from a screening perspective, that AUC is far higher than a lot of AUCs for a lot of screening tests done in the cancer world and so forth. And so we think we are very close to what I've called a pivot point, where we will soon pivot from the way we've been doing the QTC since Eindhoven over a century ago to a fundamentally new way of deriving a QTC that's precise and accurate and mobile enabled.
Dr. Greg Hundley:
Very nice, Mike. So using machine learning to accurately assess the QTC from just two leads of an electrocardiogram. Well Chris, you also have a paper in this issue of circulation that pertains to another application of machine learning and looking at the electrocardiogram. Can you describe for us your study population, study design, and then also the question you were trying to address?
Dr. Christopher Haggerty:
Sure. Yeah, thanks Greg. Great to be here with you all today. Very similar to Mike's study, the motivation for us was we believe very strongly that there's opportunities with using deep learning applied to ECG data to uncover not only new knowledge latent in the ECG itself related to the current patient context, but also to try to predict future outcomes, future events. And that was really our motivation, was to take that paradigm of looking forward, in this case to predict new onset of atrial fibrillation within a year. We used our Geisinger patient cohort, which is a largely rural population in central Pennsylvania. We have very longitudinal data for a lot of our patients, which allows us to have this kind of design going back in our electronic health records, in this case, our ECG database to 30 plus years.
Dr. Christopher Haggerty:
Similar big numbers that Mike described, and in our case, 1.6 million ECGs over 430,000 patients used to train the model. And we had several different study designs that we employed. One just being a simple proof of concept, asking can we accurately predict new onset atrial fibrillation one year? And then a second study design that was intended to simulate a real world deployment scenario. Obviously the main rationale for trying to predict atrial fibrillation is to then be able to treat and try to prevent stroke. And so we tried to, as best we can in a retrospective fashion, simulate a scenario in which we might use this model to identify patients who went on to have a presumably AFib associated stroke.
Dr. Greg Hundley:
And what did you find, Chris?
Dr. Christopher Haggerty:
So I think there are three main findings that we highlighted here. So first, obviously we were building on the great work that Mike and some of his colleagues at the Mayo Clinic have done, showing that looking at AFib using deep neural networks needs to be feasible. We extended it in this case by looking out further than just an acute sense, looking at that one-year outcome. And we had an area under the curve for our proof of concept of 0.85. So area under the curve of 0.85 to identify patients with new onset of atrial fibrillation within one year in our millions of ECGs. Looking at it another way, the second main finding was that that one year prediction was shown to have prognostic significance beyond that one year, which is really interesting and warrants a lot of further study. Looking over 30 years of follow-up, patients predicted to be at high risk at baseline had a hazard ratio of 7.2 for developing atrial fibrillation, compared to those deemed to be low risk.
Dr. Christopher Haggerty:
And then really the third, and I think perhaps the most exciting finding that we had here, was this simulated stroke experiment that we had, where we identified patients from an internal stroke registry and identified patients who had new diagnosis of AFib at the time or up to a year after the stroke. So we can assume that they were an AFib associated stroke. And subsequently, or I should say previously, had an ECG that we could use to run through the algorithm to predict their atrial fibrillation risk. And we showed that the model performed well in this setting, that of the 375 strokes that we identified, for example, over a five-year period in our registry, we were able to identify 62% of them within three years based on that ECG. So a number needed to screen for an atrial fibrillation associated with stroke about 162, which compares favorably well to other screening techniques that are out there, obviously. So we took that as a great proof of concept that this type of AI technique might have benefits for screening for atrial fibrillation and preventing strokes.
Dr. Greg Hundley:
Well congratulations, Chris. Well, we're now going to turn to our associate editor, Dr. Nick Mills. And Nick, you have a lot of manuscripts come across your desk. What attracted you to these two papers, and what are the significance of the results as they apply to ECG applications as we move forward?
Nick Mills:
Thanks, Greg. Yeah, this is a rapidly growing field, where the availability of data scale with digital archiving and lots of really interesting new methodologies are available to our researchers. So we are receiving a lot of content in this area. What I loved about these two papers is not just the quality of the work, but also the really tangible benefits, potentially, for patients. So AI does not need to be complex, but it does need to solve a tangible problem. I guess what we look for in the journal, beyond the kind of innovation and methodology, is quality, and these studies used prospective validation, really reliable end points, ascertainments, transparency, reporting, all the things that we know are important for high quality clinical research. I think the idea that we can bring QT monitoring to the drug store on a portable device for our patients is potentially transformative. I also think that to take a technology, the electrocardiogram that we've been using for over a century, and provide new insights that go way beyond my ability to interpret the ECG, that might help us recommend a different course of action for our patients is also just really exciting.
Dr. Greg Hundley:
Very nice. Thank you, Nick. Well Mike ... we're going to turn to Mike Rosenberg now, listeners. And Mike wrote a wonderful editorial, and I would invite you to work through this. As you have an opportunity to read the journal and interact with it. Mike, there are two different types of machine learning, I think, that you described were used by the two respective investigative groups. Could you describe those for our cardiology listeners? What were the differences in those two approaches?
Dr. Michael Rosenberg:
Yeah, sure. And thank you for the opportunity to write the editorial. Two very fascinating papers. I should say that they both use the same approach of what's called supervised learning, where you basically have a set of data inputs, and you're trying to predict a labeled outcome. And what I talk about in the paper is that what we've learned is if you have enough data and enough computing power, you can predict almost anything highly accurately. What's interesting about the two papers, and what I sort of tried to contrast in the editorial, is that the one from the Mayo Group and Dr. Ackerman, was basically predicting what's already a known biomarker for sudden death, which is the QT interval. And essentially, almost trying to automate that process of predicting it accurately and in a way that, in essence, could allow a home monitoring of patients for QT prolongation, which obviously would be a huge benefit for clinicians, all those alerts and things, to be able to have patients taking drugs that are known to prolong the QT interval and feeling comfortable that if they have any prolongation, it could be detected accurately.
Dr. Michael Rosenberg:
The second one, which is sort of interesting, and in contrast is from the Geisinger Group and Dr. Haggerty, was the approach of ... where actually the prediction itself is actually the biomarker. And we don't actually know exactly what it's using, which I talk about a little bit of what that means and the implications clinically, but in essence, what they showed was that it actually is a very good biomarker and on par with what a lot of us would consider to be very strong predictors of agents. So I think it was two very interesting approaches to, again, applying the same type of machine learning, but really approaching it one from a more discovery side and another from sort of validated or almost automating something that we do on a daily basis.
Dr. Greg Hundley:
Thank you, Mike. So Mike, just coming back to you again, as we read the literature, and most of us are clinicians or researchers practicing, what should we look for when these new machine learning manuscripts and research studies come out as to gauge, "Ah, this is a really good study," or maybe not so much?
Dr. Michael Rosenberg:
Yeah. And it's a good question. I think one of the biggest challenges, as I talked about, is interpretability. I think in the clinical world, we're used to understanding the code for the variables that go into our risk prediction model. And so I think first and foremost is can I even understand what this is predicting or am I sort of expected to take the predictions as sort of a black box, it is what it is type of approach? I think that there's other things that I just look at when I'm reviewing these manuscripts. I mean, as I sort of mentioned, what these models are really doing, it's not anything magical. What they're doing is identifying patterns in the data and then using those to make predictions, again, toward whatever label that you've assigned them to.
Dr. Michael Rosenberg:
It's important that your data sets are split and that you're training at one data set and then testing it in one that's separate. And again, you can't ignore epidemiology. Is the data set that you're training it reflective of the population that you're going to be using those models in? And we know from outside of healthcare, there's issues with models that have been trained in one population where it's potentially biased or it's potentially offering predictions that are using information we may not necessarily want to use. Recidivism is a big example of that. So I think that that's, first and foremost, it's sort of taking a step back as a clinician and saying, "If this was a biomarker that someone was proposing to use to predict some new disease, what would I expect to use to evaluate that?" And that's probably what I would start with.
Dr. Greg Hundley:
Excellent. Well, I'm going to turn back and go back to our panelists here, listeners. And we're going to ask each of our panelists in about 20 seconds to describe for us what they think is the next most important aspect of research in their respective areas. So first I'll start with Mike Ackerman. Mike, can you tell us what's coming next in this area of assessment of QT prolongation or other aspects of the electrocardiogram?
Dr. Michael Ackerman:
I think next is implementing this in the real world. We are having our suite of the AI ECG as a hypertrophic cardiomyopathy detector. We've shown that as an ejection fraction detector, and now as a QT detector in AFib, from our work and Chris's work. And for the QT itself, I think where we are is we're really, really close to now having a mobile enabled digital QT meter. And a digital QT meter, once FDA cleared, then allows the QTC to truly emerge as the next vital sign. And it really deserves to be a vital sign. We use it as a vital sign. We know I want to know my patient's QTC every bit as I want to know his or her weight, blood pressure, saturation. It's an actionable finding, and we're now getting really close. We're just on the cusp of having a true digital QT meter.
Dr. Greg Hundley:
Excellent. Chris?
Dr. Christopher Haggerty:
I think for us to, in part address some of the comments that Mike brought up about the reproducibility of these types of models, we're very keen to demonstrate the prospective capabilities of our models to enroll patients in a prospective fashion, run their ECG through our predictor, and then screen them for AFib to determine how well we actually do moving forward, instead of just relying solely on our retrospective data. So we're very excited to do that. We're ramping up for that trial now and hope to be able to demonstrate similarly positive findings from our technique.
Dr. Greg Hundley:
Great. How about you, Nick?
Nick Mills:
I'd like to see the same quality and rigor applied to the implementation of these technologies as we have to other important areas in cardiovascular medicine. I think that's a really important step, not just to develop the tools, but to demonstrate their value. But I also think what we've done so far is relatively simplistic. We've taken an ECG and we've ignored almost all the other information that we have in front of us. And as these algorithms are trained and evolved, these and other vital clinical biomarkers and information, and integrating them into these neural networks will really enhance their performance for predicting things that are less tangible, like sudden death in the future or stroke.
Dr. Greg Hundley:
And then finally, Mike Rosenberg.
Dr. Michael Rosenberg:
Yeah, I actually see two challenging areas in this field. One is the access to data. And I think one of the things that a lot of companies are realizing is that even if they make hardware, that the data may be more valuable than the technology that they're getting the data from. So I think one is figuring out ways to get access to data so that people can reproduce findings from these studies. And the second is deliverable. A bottle like this is not like the CHADS-VASc score that I can calculate in my head in the clinic. I mean I need a way to actually run these models within an EHR, within a computer system like that. And I think it's going to be a big challenge to take a model like this and to deploy it at scale the way we would with the drug or any other innovation.
Dr. Greg Hundley:
Fantastic. Well listeners, we want to thank Mike Ackerman from Mayo Clinic, Chris Haggerty from Geisinger, Mike Rosenberg from University of Colorado, and Nick Mills from University of Edinburgh for really providing us with a wonderful discussion regarding the use of machine learning applications in one study to predict the QTC interval from two leads that may be applicable to wearable devices. And in the second study, predicting the future occurrence of atrial fibrillation and even stroke as an adverse event in people at risk.
Dr. Greg Hundley:
On behalf of both Carolyn and myself, I want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021.
For this week's Feature Discussion, join author author Hannah Valantine and Senior Associate Editor Biykem Bozkurt as they discuss the Original Research Article "Cell-Free DNA to Detect Heart Allograft Acute Rejection."
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, I think we've got an interesting feature this week.
Dr. Carolyn Lam:
Oh boy, we sure do. This one is one of those potentially practice changing landmark papers. I'll give you a clue. It's about using cell-free DNA to detect heart allograft acute rejection in transplantation. Huge, huge, but you got to wait. Listen to the summaries of this week's exciting issue first. Greg, you want to go first?
Dr. Greg Hundley:
Yes. And I can't wait for that feature discussion. I think that's going to be one of our top papers this year, but first onto some of the summaries. So my first article comes to us from Dr. Pilar Alcaide from Tufts University School of Medicine. So Carolyn, despite the well-established association between T-cell mediated inflammation and non ischemic heart failure, the specific mechanisms triggering T-cell activation during the progression of heart failure and the antigens involved are poorly understood. So Carolyn, these authors hypothesize that myocardial oxidative stress induces the formation of isolevuglandin modified proteins that function as cardiac neoantigens to elicit CD4 positive T-cell receptor activation, and then promote heart failure.
Dr. Carolyn Lam:
Oh, that's really interesting. Inflammation in heart failure is a hot topic. Tell me more.
Dr. Greg Hundley:
So Carolyn, these authors discovered that TCR antigen recognition increases in the left ventricle as cardiac dysfunction progresses, and they identified a limited repertoire of activated CD4 positive T-cell chronotypes in the left ventricle. Mechanistically, cardiac pressure overload resulted in reactive oxygen species dependent dendritic cell accumulation of isolevuglandin protein adducts, which induced robust CD4 positive T-cell proliferation.
Dr. Greg Hundley:
So collectively, Carolyn, these results demonstrate an important role of reactive oxygen species induced formation of isolevuglandin modify cardiac neoantigens that lead to TCR dependent CD4 positive T-cell activation within the heart. And therefore, these results help understand the relationship between T-cell mediated inflammation and heart failure.
Dr. Carolyn Lam:
Wow. Super. Thanks, Greg. I'm moving all the way from basic science now to talk about intensive lifestyle interventions, which we know are first line approaches to effectively treat obesity and manage the associated cardio-metabolic risk factors. However, to date, whether effective lifestyle based obesity treatment in primary care works, we need more data. And this is what this paper provides.
Dr. Carolyn Lam:
This comes from Dr. Katzmarzyk and colleagues from Pennington Biomedical Research Center in Los Angeles. And what they report is the PROPEL Trial, which randomly allocated 18 clinics equally to usual care or an intensive lifestyle intervention, and subsequently enrolled 803 adults with obesity from participating clinics. The usual care group continued to receive their normal primary care, while the intensive lifestyle intervention group received 24 months of high intensity lifestyle-based obesity treatment in a program, embedded in the clinic setting and delivered by health coaches in weekly sessions initially and monthly sessions from months seven through 24.
Dr. Greg Hundley:
Well, Carolyn, sounds like a really practical study here. So what were these results?
Dr. Carolyn Lam:
Yes, Greg, this was a pragmatic trial. And although pragmatic, this lifestyle intervention was consistent with national guidelines, and participants receiving the PROPEL intensive lifestyle intervention lost significantly more weight over 24 months than those receiving usual care. Results also demonstrated clinically relevant improvements in high density lipoprotein cholesterol, total to HDL cholesterol ratio, metabolic syndrome severity, and fasting glucose. The PROPEL model may therefore be a viable option to deliver effective obesity and cardio-metabolic risk factor treatment in primary care.
Dr. Greg Hundley:
Well, Carolyn, what an interesting article. A lot that we can take home from that. Well, I'm going to switch and talk to you about blood flow restoration and its effect on venous thrombosis and vein wall injury. And this article comes to us from Dr. Farouc Jaffer from the Massachusetts General Hospital at Harvard Medical School. So Carolyn, up to 50% of patients with proximal DVT will develop the post-thrombotic syndrome, which is characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. While catheter based interventions, enabling restoration of blood flow, have demonstrated little benefit on post-thrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. So here, these authors in experimental and studies, they examined whether restoration of blood flow has a restricted time window for improving DVT resolution.
Dr. Carolyn Lam:
Oh, very interesting, and potentially a significant clinical implications, huh? Tell us about it.
Dr. Greg Hundley:
Well, Carolyn, there were two types of studies performed in mice and those in human subjects in the ATTRACT pharmacomechanical Catheter-Directed Thrombosis trial. So in the series of experiments in mice, within a restricted therapeutic window, restoration of blood flow improved DVT resolution. And then in the human studies, the pharmacomechanical catheter directed thrombolysis did not improve the PTS scores for patients having a symptom onset to randomization or SOR time of less than four days or greater than eight days. So therefore, further studies are warranted to examine the value of time restricted restoration of blood flow strategies to reduce post-thrombotic syndrome in patients with deep venous thrombosis.
Dr. Carolyn Lam:
Interesting. Thanks. Greg. My next paper is related, also talking about anticoagulants. And this time, the authors led by Dr. Hijazi from Uppsala Clinical Research Center in Sweden evaluated the risk benefit balance of antithrombotic therapy according to kidney function in the AUGUSTUS Trial. As a reminder, in the AUGUSTUS Trial resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, whereas aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or PCI treated with a P2Y12 inhibitor.
Dr. Greg Hundley:
Carolyn, thanks for reviewing for us the AUGUSTUS Trial results. So what did they find in this study?
Dr. Carolyn Lam:
So what they did is they looked at patients with atrial fibrillation and ACS and/or a PCI, and found that apixaban, as compared to vitamin K antagonists, displayed a consistent safety and efficacy profile, irrespective of kidney function, without significant interaction and in accordance with the overall trial.
Dr. Carolyn Lam:
Next, they found that aspirin, relative to placebo, on top of oral anticoagulation and a P2Y12 inhibitor resulted in more bleeding, irrespective of kidney function again, and with an even greater increase among those with a GFR more than 80.
Dr. Carolyn Lam:
These findings can help clinicians perhaps make informed decisions on the antithrombotic therapy in patients with atrial fibrillation and kidney disfunction, with ACS and/or a PCI.
Dr. Greg Hundley:
Very nice.
Dr. Carolyn Lam:
All right, Greg. Well, tell you what, let's go onto the other papers in this issue. I would like to tell you about a letter to the editor from Dr. Saleh on carotid atherosclerosis thickness, a proxy for cardiovascular disease events. There's an ECG challenge by Dr. Liu entitled, intriguingly, A Noteworthy Electrocardiogram, and this really describes new SD segment elevation and its differential diagnosis. To refresh, look up the paper.
Dr. Greg Hundley:
Very nice, Carolyn. Well, I have a research letter to tell you about from Dr. Lanz entitled One Year Outcomes of a Randomized Trial, Comparing a Self-expanding to a Balloon Expandable Transcatheter Aortic Valve. And then finally, Dr. Maron has a very nice perspective piece entitled Exploring New and Old Therapies for Obstructive Hypertrophic Cardiomyopathy Mavacamten in Perspective. Well, Carolyn, I can't wait to get to this week's feature discussion. How about you lead us through that?
Dr. Carolyn Lam:
Me too. Let's go, let's go. I could not be more thrilled to be doing today's feature discussion. And I have to admit I'm feeling very star struck because I'm with two of the women I think are most at my own respect. And the first is Dr. Hannah Valantine, and she is professor from Stanford University now and also at NIH, and she's the corresponding author of today's incredible paper. And the next guest is of course, Dr. Biykem Bozkurt, senior associate editor of circulation from Baylor College of Medicine.
Dr. Carolyn Lam:
Welcome, ladies. On the topic today, it's really landmark. We could be talking about a new gold standard that may replace the endocardial myocardial biopsy. Wow. So if I could just start off, Dr. Valantine, could you please tell us about your study? What is cell-free DNA?
Dr. Hannah Valantine:
Yes. Thank you. It's a wonderful opportunity to be doing this podcast, and thank you for the interest on the technology. If you can imagine, when you put an organ transplant, essentially what you're doing is a genome transplant. You're transferring the genome of the donor into the recipient.
Dr. Hannah Valantine:
Now, we all have single nucleotide polymorphisms, otherwise known as SNPs, that are unique to the donor DNA, and that are unique to the recipient DNA. So that once we put that organ in and there is a teeny little bit of damage, little fragments of DNA come out of the donor organ into the recipient circulation, and we can pick that up, circulating in the plasma. And that's why we call it donor derived cell-free DNA.
Dr. Hannah Valantine:
So, you know the SNPs that belong to the donor, and you know the SNPs that belong to the recipient. You extract the DNA from the plasma of the recipient and you sequence it. And bingo, you can tell what the percentage of that cell-free DNA is coming from the donor, and that is the basis of the test.
Dr. Carolyn Lam:
Oh my goodness. I love that explanation. It's so lucid, and it's reminding me of what happened when I was pregnant. It's the same technology that's used, I think, in prenatal testing, in oncology in some cases, but this is the first time that you've shown it in a multicenter approach in cardiac transplantations. So could you please tell us about that?
Dr. Hannah Valantine:
Yes. Well, we first did this work in a single center when I was at Stanford, where we developed the technology, myself and a couple of colleagues in bio-engineering. But when you do a study, as you know, in one center, doesn't mean it's necessarily transferable or trans label into multicenter.
Dr. Hannah Valantine:
So when I went off to NIH, I transferred the technology there and did something else that was rather unique. I put together a consortium of the five local heart and lung transplant centers in the DC area. And we enrolled patients from each of those five centers into this study. And in the heart cohort, which is what is reported here, we were able to take blood samples on a serial basis. And there were 171 of them in the study. So, what happens is that we genotype the donor and the recipient of each of those 170 patients at the beginning, before the transplants, so that we could then know and monitor their cell-free DNA as they progress at serial time points after the transplant. And that's the way we were able to confirm the value of this test.
Dr. Hannah Valantine:
I can describe to you what the findings were. So what we found is that the cell-free DNA started to rise a lot earlier, before the heart biopsy showed a rejection. So it was just remarkable, because of the serial samples, we were able to look back and say, well, was there an elevation of the cell-free DNA before the positive biopsy? And that was definitively the case.
Dr. Hannah Valantine:
As you know, there are two types of rejection, antibody, mediated, rejection, and cellular driven rejection. And antibody mediator rejection, quite frankly, is the Achilles heel of organ transplantation because it's difficult to pick up and it occurs, that means it's diagnosed late, and it's really resistant to treat.
Dr. Hannah Valantine:
So what we found in this study is that the cell-free DNA was elevated for at least a couple of months before the heart biopsy actually showed the presence of antibody mediated rejection. And that has significant implications for the management of patients. And there are some other characteristics of the cell-free DNA that distinguish cellular and antibody mediated rejection. That is really important because the two types of rejection are treated differently. That's a great excitement of the results of this study.
Dr. Carolyn Lam:
Oh my gosh. I'm just tingling. My hairs are standing, just listening to you explain that. I really think we have a true liquid biopsy now for cardiac transplant rejection.
Dr. Carolyn Lam:
But Dr. Bozkurt, you're such an expert in heart transplantation. Could you frame it for us, just how significant these findings are?
Dr. Biykem Bozkurt:
This is transformative. So first, I would like to congratulate Dr. Valantine and her team for pioneering and leading this concept for such a long time. And now with this validations study, for providing the framework for the future studies for alternative strategies, implementation of how we're going to do this, as the liquid biopsy in lieu of endomyocardial biopsy.
Dr. Biykem Bozkurt:
So the findings that I think are truly practice changing are, yes, this study validates the ability to detect rejection. The second very interesting finding is predict the rejection almost three months before that we're able to detect it by histopathology. Third, for the first time, being able to detect antibody mediated rejection, as well as cellular. Fourth, being able to eliminate the necessity in approximately 81% of the patients with a very high negative predictive value.
Dr. Biykem Bozkurt:
Now, but I'm going to pose this question to Hannah. What is the gold standard now? Because in the historical past, we used to rely on histopathology to be diagnosed myocardial infarction. Now, we know that Troponin-I is a driver or Troponin-T or cardiac troponin. The profile of this is so, I would say, impressive, both for its negative predictive value. And I do realize the sensitivity and specificity is over 80%. And in the positive predictive, when we use the biopsy as the gold standard, the numbers are not as high as a negative predictive value, but if we add the clinical, those who've had the LV dysfunction, those who developed rejection subsequently, three months later, it is performing quite well.
Dr. Biykem Bozkurt:
So what now is going to be the gold standard? I'm thinking, shall we start calling things allograft injury and go and embrace the injury drum now with this profiling, and then trying to determine whether we can intervene early and prevent rejection? And I guess my question is, what's the next step?
Dr. Hannah Valantine:
Thank you for that lovely summary. This clearly, at this point, I would say the gold standard should be the cell-free DNA because in the study we switched it on its head. And we said, if the cell-free DNA is the gold standard, then how sensitive is the heart biopsy? And it wasn't very sensitive. And this is something that we've known for many years.
Dr. Hannah Valantine:
And I'll tell you a little anecdote that has driven my passion over the last 35 years to come up with a better diagnostic tool. When I was first an assistant professor and using echocardiography to study whether or not we could replace the biopsy, I had a patient who in whom I noticed had diastolic dysfunction. And my protocol was if we saw diastolic dysfunction, we actually did a biopsy. And to cut a long story short, I ordered these biopsies, and the biopsy was negative. And in retrospect, I think he had antibody mediated rejection. But the sad part of it is that after a few weeks I got a call from his wife to inform me that she found him dead in bed.
Dr. Hannah Valantine:
And so this has really motivated me to really find something better. And to your question, the cell-free DNA should be the gold standard. The problem is that physicians are human, and there is often takes a lot of time for adoption. So even though the data speaks for itself, that adoption piece is a social, psychological factor that to be overcome. But actually, we've had a really interesting experience in the context of COVID-19 when we were not able to do elective procedures, many centers have reverted to the cell-free DNA technology, and guess what? The patients are doing very well, as we documented in this study. So I think we're going to see a huge paradigm shift in the management of patients with cell-free DNA being the gold standard.
Dr. Hannah Valantine:
But I think that's not all because you asked the very important question about what's next and what's next about this research is to figure out, using the same technologies, why it is that black patients reject their organs so much more than white patients. And in this study, I hope you noticed that 44% of the cohort are African-American. And so it opens the door now to study this area. And then the third implication is that we can use cell-free DNA to actually look at other mechanisms and develop the technology. For example, DNA methylation profiles will come on board very shortly that can teach us more about where the damage is happening and add to the diagnostic tools.
Dr. Biykem Bozkurt:
I have another burning question. The peripheral gene expression profiles that also are available clinically to be able to characterize these patients. How do you see the difference in the cell-free DNA versus gene expression? And in this study, both the donors and the recipients were genotyped. Do you see the necessity of having to do so? Whether the current, you know, snip analysis will allow us not having to genotype patients, which may have an implication on the cost, as well as the practicality of how to implement this on the clinician bedside.
Dr. Hannah Valantine:
Absolutely. As you know, there are now several ways to get around having to genotype the donor by using an array of 260 or so SNPs known that are common in the population. And you can use that. And when you use that technology, it's equally sensitive. So that is what is going to move this forward in terms of clinical utility, so that we don't have to do that. So it's an extension of the technology. I like to do the recipient and donor genotyping because there's so much more research. So from the research perspective, it's useful to continue this technology. But for the application, yes, we're going to be able to do it without the genotyping, and rapidly.
Dr. Hannah Valantine:
And even beyond that, there are now new technologies coming up that we could use. For example, DVPCR, that could be translated into more rapid, an even more rapid test. Right now, the test takes about a day and a half to come back. My goal ultimately would be to have a point of contact test that we could actually use right there to make the diagnosis on a sample of the patient's plasma. So lots of new things coming out. This is just the beginning.
Dr. Biykem Bozkurt:
We're also excited about the possibility of the cell-free DNA, being able to predict coronary artery vasculopathy and/or other clinical events. So I'm sure your team is going to come up with results in regards to the future prognostication regarding the clinical events. So any, perhaps, prediction as to what we shall see those who don't decay, especially after 28 days? I'm very intrigued by those patients, which I think was a subgroup in your study.
Dr. Hannah Valantine:
Yeah. So that's absolutely right. What we are seeing is that those in whom the cell-free DNA remains relatively elevated, because what we find is that immediately after transplant, in the first 24 hours, the cell-free DNA diminishes and to a baseline low level. And then when there is rejection, we see these spikes, but when it's remains elevated, this might be a predictor of ongoing injury, an injury to the vascular dithulium that then sets up the familio for allograft vascular disease. And so we're chasing that hypothesis. The trouble is that the end point takes a while to develop, which is good for the patients. And so look out for future studies that where we will look at the correlation of the cell-free DNA as a predictor of allograft vasculopathy.
Dr. Hannah Valantine:
The other really interesting thing goes back to mechanism. You mentioned the question of consistently elevated cell-free DNA. And so I'm asking myself the question, whether this three floating cell-free DNA can actually act as a trigger of the immune response and therefore lead to damage and rejection. And that again is research that's ongoing, which will have significant implications for patient care. And it might actually help us in understanding why it is that African-American patients reject their organs. Because even those that are doing well in this study, they had relatively higher levels of cell-free DNA throughout the course, and did not decay as in the same pattern as the white patients. So lots of exciting work to come.
Dr. Carolyn Lam:
Oh my goodness, this is just a mind blowing discussion. So might not just be a marker, but even a target for rejection or anti-rejection therapy. And as a trialist, I'm already thinking ahead. Might we see future trials with raised cell-free DNA, but no evidence of rejection on biopsy, and whether or not treating these patients would actually improve outcomes?
Dr. Carolyn Lam:
So this is incredible. I wish we had all day to chat, and I think I really cannot let this end without at least saying something about Dr. Valantine, your work in diversity, and to just thank you on behalf of everybody for really forging this, and especially as part of Circulation. As you know, we have an issue focused on disparities, and we're just incredibly privileged to have you on the podcast today. Biykem, please would you add some last words?
Dr. Biykem Bozkurt:
I second those sentiments. We're grateful to Dr. Valantine for being a trailblazer for our transplant patients, for our community, to enhance the diversity, and for scientific excellence in all fronts. So thank you, Dr. Valantine.
Dr. Hannah Valantine:
Thank you very much. I'm humbled by your comments and very appreciative, and thank you for the support of this work.
Dr. Carolyn Lam:
Thank you, audience, for listening today. You've been listening to Circulation on the Run. Thank you for joining us, and don't forget to join us again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association 2021.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature involves interleukin-6 and a phenome-wide association study. So we have a lot to look forward to, but before we do that, how about we grab a cup of coffee and jump into the other articles in this issue? I could start first because I've got to tell you about some results from the ODYSSEY outcomes trial. And Carolyn, this comes to us from Professor Gregory Schwartz at the University of Colorado School of Medicine. Well, Carolyn, this study pertains to LDL lowering. As you know, recent international guidelines have lowered the recommended target levels of LDL cholesterol for patients at very high risk for major cardiovascular events or MACE.
Dr. Greg Hundley:
However, uncertainty persists as to whether additional benefit results from achieving LDL-c levels below some of these conventional targets. Now inferences from prior analyses are limited because patients who achieve lower versus higher LDL-c on lipid lowering therapy differ in other characteristics prognostic for MACE, and because few achieved very, very low LDL-c levels. So to overcome these limitations, these authors performed a propensity score matching analysis of the ODYSSEY outcomes trial, which compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving intensive or maximum tolerated statin treatment.
Dr. Carolyn Lam:
Sensible question, and what did they find?
Dr. Greg Hundley:
Well, Carolyn, the main finding of the study was that after accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-c levels less than 25 milligrams per deciliter did not appear to derive further reduction in the risk of MACE compared to those who achieved LDL-c levels of say 25 to 50 milligrams per deciliter. So, Carolyn, the take-home message is that recent international guidelines have lowered LDL-c goals for patients at very high risk for MACE to levels less than 55 milligrams per deciliter, and in some cases, maybe less than 40 milligrams per deciliter. However, any potential benefit of achieving LDL-c levels significantly below these goals to those very low, less than 25 really remains uncertain.
Dr. Carolyn Lam:
Very interesting. Thanks Greg. Well, my paper is about the HOST-REDUCE-POLYTECH-ACS trial. Got your attention? All right. I'll tell you what it is. It's an investigator-initiated, randomized, open-label, adjudicator-blinded, multicenter, non-inferiority trial, which compared the efficacy and safety of durable polymer versus biodegradable polymer, drug-eluting stents. And these investigators led by Kyung Woo Park from Seoul National University Hospital looked at 3,413 patients with acute coronary syndrome. At 12 months, the primary endpoint of patient oriented composite outcome, which was a composite of all-cause death, nonfatal myocardial infarction, and any repeat revascularization, occurred in 5.2% of the durable polymer group and 6.4% of the biodegradable polymer group. And so that met the non-inferiority P value of less than 0.01. the key secondary end points of device oriented composite outcome, which is a composite of cardiac death, target vessel MI, or target lesion revascularization occurred less frequency in the durable polymer versus biodegradable polymer groups, and this was mostly due to a reduction in target lesion revascularization. The spontaneous nonfatal MI and stent thrombosis rates were very low with no significant difference between the groups.
Dr. Greg Hundley:
Well, Carolyn, you know one of my favorite questions, so what's the take-home message here?
Dr. Carolyn Lam:
In patients with acute coronary syndrome receiving PCI durable polymer drug-eluting stents were non-inferior to biodegradable polymer drug alluding sense with regards to patient-oriented composite outcome at 12 months. I think that's the significant take-home message, and it's accompanied by an editorial where all this is discussed, and this editorial is by Doctors Byrne and Hanratty from Dublin.
Dr. Greg Hundley:
Very nice, Carolyn. Well, Carolyn, I am going to turn to the world of basic science and discuss phospho-lamin phosphorylation and how that may regulate vascular tone, blood pressure, and hypertension in both mice and men. And it comes to us from Dr. Michael Shattuck from King's College, London. So Carolyn, it's long been recognized that smooth muscle Na,K-ATPase modulates vascular tone and blood pressure. However, the role of its accessory protein phospho-lamin has not been characterized. So Carolyn, the aim of this study was to test the hypothesis that phospho-lamin phosphorylation regulates vascular tone in vitro, and this mechanism plays an important role in the modulation of vascular function and blood pressure in experimental models, both in vivo and in man.
Dr. Carolyn Lam:
Okay. So what did they find?
Dr. Greg Hundley:
Carolyn, these authors found that in aging wild type mice, phospho-lamin was hypo-phosphorylated, and this correlated with the development of aging induced essential hypertension. In human subjects, they identified a non-synonymous coding variant, a single nucleotide polymorphism RS-61753924, which causes the substitution of R-70 C and phospho-lamin. The R-70 C mutation prevented phospho-lamin phosphorylation at searing 68. This variance rare Alleo was associated with increased blood pressure in middle-aged men. So Carolyn, taking together these translational animal and human studies demonstrate the importance of phospho-lamin phosphorylation in the regulation of vascular tone and blood pressure and suggest a novel mechanism for aging-induced essential hypertension.
Dr. Carolyn Lam:
Interesting. And I suppose opening the door to translationally preventing this hypertension. Very interesting. Well from the next paper we switch to cardiac troponins, and you know these are the cornerstone of diagnosing acute myocardial infarction. But have you ever wondered, what is the duration of ischemia necessary to induce a measurable release of the cardiac troponins, or the very early release kinetics of cardiac troponins following an ischemic event? Well, this study is the first to report the early release kinetics of cardiac troponin concentrations, following different durations of experimental coronary balloon occlusion in humans.
Dr. Greg Hundley:
Ah, Carolyn. So how did they do this?
Dr. Carolyn Lam:
So 34 patients with N geographically normal coronary arteries were randomized into four groups with different durations of induced myocardial ischemia from zero to 30, 60, 90 seconds. Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected prior to balloon inflation and every 15 minutes for the first three hours and every 30 minutes for the next three hours. Cool, huh?
Dr. Greg Hundley:
Yeah. So did any of the patients suffer complications?
Dr. Carolyn Lam:
So the first thing to report is none of the patients had any complications, but what they found, and this was from authors, Dr. Iverson from Copenhagen, Denmark and colleagues. This is what they found increased cardiac troponin concentrations were detected by all three high sensitivity assays, be they high sensitivity troponin T by the Roche assay, high sensitivity troponin I by the Siemens essay, or high sensitivity troponin I by the Abbot essay. All assays detected a cardiac troponin increase after only 30 seconds of ischemia. High sensitivity troponin I by Siemens rose faster and reached a higher peak. Copeptin levels did not significantly change. So these interesting findings are accompanied by an editorial by Christopher deFilippi and Nicholas Mills discussing how the findings challenged some of our assumptions and may help shape future care pathways and the classification of ACS.
Dr. Greg Hundley:
Carolyn, so more in the evolution of high sensitivity troponins. Well, I'm going to shift to my last article of the day, and it focuses on eccentric remodeling and ischemic cardiomyopathy, and comes to us from Professor Konstantinos Drosatos at the Lewis Katz School of Medicine at Temple University. So Carolyn, these authors have shown that cardiomyocyte Krüppel-like factor or (KLF)-5 regulates cardiac fatty acid oxidation, and as heart failure has been associated with altered fatty acid oxidation, they now investigated the role of cardiomyocyte (KLF)-5 in lipid metabolism and the pathophysiology of ischemic heart failure.
Dr. Carolyn Lam:
Wow, Greg. What did they show?
Dr. Greg Hundley:
Well, Carolyn, they found that (KLF)-5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of (KLF)-5 in mice with myocardial infarction prevents ceramide accumulation, alleviates eccentric remodeling, and increases left ventricular ejection fraction. Thus, the authors suggest that (KLF)-5 may emerge as a novel therapeutic target for the treatment of ischemic heart failure. Well, Carolyn, we've got some other articles in the issue, and I'm just going to tell you quickly about an in-depth article entitled, “Cardiovascular Disease and Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options” that come to us From Dr. Marx, and then I'm going to turn it over to you.
Dr. Carolyn Lam:
Yes, we've got an exchange of letters between Doctors Grace and Mital regarding the article, “A Validated Model for A Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.” There's an ECG challenge by Dr. Peng on an irregular complex tachycardia. And there's this very interesting on-my-mind paper by Dr. Skolnik simply entitled, Gratitude. And I just have to tell you a bit about it, and I'm quoting from it now, “…having two surgeries for a large aortic aneurysm and aortic regurgitation, I am also left with an overwhelming sense of gratitude for living in the age in which I'm living. While some focus on what is wrong in the world, at least for today, my focus is on what is right.” Now, please read that paper. It's just such a beautiful piece. And, finally, there's a perspective piece by Dr. Sandhu entitled, “The Affordability of Guideline-Directed Medical Therapy, Cost Sharing, and How Cost Sharing is a Critical Barrier to Therapy Adoption.” Well, looks like it's a wrap. Greg, let's get on to our feature discussion, shall we?
Dr. Greg Hundley:
You bet. Well, listeners, we are now coming to our feature discussion today, and we're very fortunate to have with us today, Dr. Martin Dichgans and Dr. Marios Georgakis both from Munich, Germany. And we also have Dr. Svati Shah from Duke University, one of our associate editors. Welcome to you all. And I'll start with you Martin, could you explain to us a little bit of the background behind this study and what was the hypothesis that you wanted to test?
Dr. Martin Dichgans:
Yes, of course. We are interested in stroke, and more broadly, in cardiovascular disease, and inflammatory cytokines and inflammatory mechanisms in general play a major role in cardiovascular disease and particularly in arthrosclerosis, which connects a cardiac disease and stroke and also multiple other disorders. So that was our starting point. And we previously noted the importance of specific inflammatory cytokines in stroke, which is all primary area of research. We then quickly became aware of the central position of IL-6, which is downstream of IL-1β in the inflammatory cascade, and recognized not only that there's a lot of data on IL-6 in cardiovascular disease already, but that IL-6 actually is implicated in multiple inflammatory conditions, including autoimmune diseases, vascular, as I mentioned, and also metabolic disorders. And we noted that IL-6 receptor inhibition is already in use in some of these disorders, particularly in the treatment of autoimmune diseases, but not yet in use in cardiovascular disease.
Dr. Martin Dichgans:
So we asked ourselves whether there would be any repurposing potential, and also whether there would be an opportunity to explore the safety profile in its full width using genetic data because, and this I didn't mention, we have a background in genetics, a large interest in genetics, and you might have noticed that previously there has been a wealth of genetic data coming out, both on stroke, but also on cardiovascular disease in general. So also including other phenotypes, like for instance, and it has now become possible via a methodology called Mendelian randomization to utilize these genetic data and explore causal relationships between exposures such as IL-6 levels or specific cytokines and outcomes such as ordinary-after disease or stroke, and even go one further and explore the therapeutic potential, and also the full width phenotypes that could be relevant in such a scenario. So what we did is we took advantage of large scale genetic data from the UK biobank and data on specific outcomes available in the UK biobank to dive into the questions we were interested in.
Dr. Greg Hundley:
Martin, that was a wonderful explanation. So could you describe, what was the aim of your study?
Dr. Martin Dichgans:
In brief, the aim was to use large scale genetic data to explore the repurposing potential and safety profile of IL-6 receptor inhibition in the general population.
Dr. Greg Hundley:
Very nice. Describe your study design.
Dr. Martin Dichgans:
So the study population was the UK biobank, which is a population-based sample of, in this case, 340,000 unrelated individuals. And what we did is we performed the phenome-wide association study. So we looked across all available phenotypes that are systematically encoded in the UK biobank, and which included both clinical outcomes and biomarkers, in this case about 1,400 clinical outcomes and 360 or 70 biomarkers and endophenotype of human disease in this biobank. And again, explored relationships between IL-6 receptor inhibition and the effect on these outcomes.
Dr. Greg Hundley:
Very nice. Well, Marios, let's turn to you. Could you describe the results? What did you find?
Dr. Marios Georgakis:
Yes. Hello from my side as well. So, as Martin mentioned, we explored associations between genetically down-regulated IL-6 signaling and 1,400 clinical outcomes, as well as with 360 biomarkers in another, I would say hypothesis reapproach. So, following corrections from output testing, we found significant associations with genetically down-regulated IL-6 signaling activity with 16 clinical outcomes and 17 biomarkers. As we had shown in the past, genetically down-regulated IL-6 signaling activity was associated with several cardiovascular phenotypes, specifically atherosclerotic phenotypes, primarily including coronary artery disease manifestations, but also for example, abdominal aortic. Interestingly though, we also found a significant association with a lower risk of type two diabetes, as well as with a lower glycated hemoglobin, another finding that was consistent not only in the UK biobank, but also in two cohorts that we use for validation. So in the past, there have only been data from small observational studies and small case series in patients with rheumatoid arthritis supporting these findings, but to date, no data from large clinical trials.
Dr. Marios Georgakis:
Furthermore, we find significant associations between genetically down-regulated IL-6 signaling and higher total cholesterol, but also higher HDL cholesterol levels, but no association with LDL cholesterol. This further supports associations of IL-6 signaling downregulation with, let's say more favorable argument among the profile. Now, why is this important? This is a very interesting finding because previous clinical trials had suggested that IL_6 receptor inhibitors might lead to increases in total cholesterol levels, which would, of course, be an undesired side effect for people who'd ever envisioned using IL-6 receptor inhibitors in the context of lowering cardiovascular risk.
Dr. Marios Georgakis:
Here, however, we show, and our results support, that this increases primarily the results of the effects of IL-6 signaling bar down-regulation on HDL and not LDL levels. On the negative side, and finally, we found significant associations between genetically down-regulated IL-6 signaling and the number of potential side effects, particularly strong associations with bacterial infections, such as cellulitis and urinary tract infections, which is probably also related to the identifed association with the lower risk of neutropenia. So while these are well-described side effects of IL-6 signaling and condition in the context previous clinical trials, this, we believe, disagreement with our findings adds additional confidence to, let's say, the validity phenome-wide association state.
Dr. Greg Hundley:
Very nice Marios. Really appreciate this exciting work. And now we want to turn to our associate editor, Doctor Svati Shah. And Svati, you have many papers come across your desk, what attracted you to this paper? And then how do you put the results that these men have presented into context with other papers in this area of investigation?
Dr. Svati Shah:
Yeah. Great question, Greg, and thanks for having me. I thought this paper was really important, but I want to start at a broader level, and that's why it's attracted my attention is, I think genetics can not sort of inherently appeal to the broad Circulation reader. It can feel somewhat esoteric. We do these genome-wide association studies, these whole-exome association studies, and we find new genes and we're really excited about them as people who live in the genetic epidemiology realm. But when we think about the broader circulation readership and the broader cardiology readership, how does this really relate to how I take care of patients, and what might be important for me in my cardiovascular realm? And I think this paper really highlights the power of human genetics and how we really understand things that have clinical utility.
Dr. Svati Shah:
And let me just expand on that really briefly. And that is, in the human genetics realm, we can look at what we call human knockouts. We're not actually doing gene editing in humans, but looking at people who have loss of function variants. They're emulating a drug for example. And we also have PheWAS, which is a phenome-wide association study, where we say, "We're just going to look at lots of different clinical things and biomarkers and try to understand things that are associated." And then finally we have Mendelian randomization, which allows us at a very statistical level to really assess causality. We know there are things that are correlated with each other, but we don't necessarily know that they're causal, and this is a statistical way for us to potentially assess causality. I say that very carefully because it's a statistical way to do that.
Dr. Svati Shah:
And what's really cool about this paper is they combine PheWAS and Mendelian randomization, but with a very clinically important aspect. What are the potential good side effects, the on-target things that we want to try to address with these potential drugs, like tocilizumab, and what are potential side effects of these potential drugs. And in this case, because they combined PheWAS, they're able to look across all kinds of things. So the things that we already know about, they're not looking at a drug per se, but they're emulating a drug by looking at these genetic variants to say, "Okay. Well, we're going to look across all these different clinical factors." So it's not only things that have been evaluated in these clinical trials, but even just beyond that. And then the Mendelian randomization piece allows them to be able to say, again, statistically, are these causal. So if you antagonize these receptors, does it 'cause' these downstream effects. So, that's what was really cool to me about this paper. Is it really highlights the potential for human genetics in a very short term translational clinical potential.
Dr. Greg Hundley:
What a wonderful explanation for our listeners here. Well, let me ask each of you, Martin, Marios, and then Svati, what do you see as the next research endeavor in this space? Martin, you first.
Dr. Martin Dichgans:
And I completely agree with Svati that we have to utilize genetics in order to improve our means of treating patients, and I think that's obviously our aim here. And what this study shows, and let me just briefly also confirm what you said, we were intrigued by how the genetic data reflect what we see, for instance, in clinical trials. Just to expand a little bit on that aspect, the seven genetic instruments, which consisted of seven snips, single nucleotide polymorphism, when we looked at the effects of genetic lowering in this context on upstream and downstream, known upstream and downstream biomarkers of IL-6 signaling, this really very much matched what we know from clinical trials with tocilizumab so with pharmacologically lowering IL-6 signaling. Again, giving us confidence that it's informative and we will see with genetics what we are going to expect in the future in clinical trials.
Dr. Martin Dichgans:
So now getting to your point here and providing an answer, what we see as the next step, we should, for instance, combine the genetic data we have here with genetic data on other approaches to see whether, and maybe Marios can be more specific about this, whether by combining two different approaches, for instance, LDL lowering and targeting residual inflammatory risk, whether we could in future clinical trial provide additional benefits to high-risk patients with a cardiovascular disease. And I think that will be a very important area. Also, I think we should extend this approach to other inflammatory cytokines that have come up in Mendelian randomization analysis to explore their potential in future clinical trials.
Dr. Greg Hundley:
Marios?
Dr. Marios Georgakis:
Yeah. So just to add a little bit on Martin's summary, I would say here that now that we have established the efficacy of anti-inflammatory approaches in lowering cardiovascular risk, both with clinical trials, but also with showing genetic and clinical evidence, I think that the next step is first to identify the proper clinical scenario where anti-inflammatory approaches targeting IL-6 signaling would be used for reducing cardiovascular risk in order to design the proper clinical trials. And secondly, as Martin mentioned, to explore whether targeting IL-6 signaling would, one, pass additive benefits on Kruppel available approaches such as lipid-lowering approaches, and second, to see whether the risk-benefit balance of anti-inflammatory targeting IL-6 signaling would be acceptable in the clinical setting.
Dr. Greg Hundley:
And Svati.
Dr. Svati Shah:
Yeah. It's hard to follow up on those comments. I'll say, since I am very interested in diabetes and insulin resistance, the cholesterol story is fantastic, but I think the fact that they see effects on, again, statistical lowering of hemoglobin A1C and type two diabetes is fascinating to me. I would take it even a little step further. I think we need clinical trials. These data are very suggestive. It sort of flips the story almost. We've seen, even in some of the clinical trials of these drugs, that there are beneficial metabolic effects with regards to glucose, although some of the data are contradictory. So flipping it and saying, we know that inflammation is complex and we know that IL-6 has pro and anti-inflammatory roles in inflammation, and we know that diabetes with regards to inflammation is very complex, but maybe these drugs potentially are useful in type one and type two diabetes. So I think we need carefully designed clinical trials, potentially, to understand the role of blocking inflammation, and in particular IL-6 signaling, in patients who have diabetes.
Dr. Greg Hundley:
Excellent. Well, listeners, we want to thank Dr. Martin Dichgans, and Dr. Marios Jojakas, and our own associate editor, Dr. Svati Shah for bringing us this study incorporating phenome-wide association and Mendelian randomization to identify a relationship between down-regulated IL-6 signaling with subsequent clinical cardiovascular outcomes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021.
This week features two Feature Discussions. In our first feature discussion, Nikkil Sudharsanan and Associate Editor Ntobeko Ntusi as they discuss the article "Variation in the Proportion of Adults in Need of BP-Lowering Medications by Hypertension Care Guideline in Low- and Middle-Income Countries: A Cross-Sectional Study of 1,037,215 Individuals from 50 Nationally Representative Surveys." Then in our second feature discussion, join author Aloke Finn and Associate Editor Jeffrey Saffitz as they discuss the article "Microthrombi As A Major Cause of Cardiac Injury in COVID-19: A Pathologic Study."
One addendum to the Feature Discussion with Drs. Sudharsanan and Ntusi:
· Dr. Sudharsanan wanted to clarify that treatment needs were determined for each country based on multiple blood pressure measurements taken on the day of the survey; however, all the estimates were based on BP measured on just one day, rather than over several weeks as is done in clinical practice. This is related the final question posed in the first Feature Discussion.
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Greg Hundley Associate Editor for the Pauley Heart Center in Richmond, Virginia at VCU Health.
Dr. Carolyn Lam:
Guess what, Greg, it's another issue with a double feature. We are going to be discussing microthrombi as a major cause of cardiac injury in COVID-19.
Dr. Greg Hundley:
Yes, Carolyn and our second discussion will be centered on blood pressure lowering in low and middle-income countries. But how about you and I both grab a cup of coffee and jump into the other articles in this issue.
Dr. Carolyn Lam:
Sure thing. I got my coffee and let's start with gestational diabetes. Now, we know that leads to an earlier onset and heightened risk of type 2 diabetes, which is a strong risk factor for cardiovascular disease. But Greg, do you think that attaining normal glycemia following gestational diabetes can ameliorate the access risk?
Dr. Greg Hundley:
Carolyn, that's a really great question. I would think so but how about you tell me what these authors found.
Dr. Carolyn Lam:
Yep. This next paper it's from Dr. Gunderson from Kaiser Permanente, North California and colleagues. They exactly sought to answer the question and realize that it was unclear whether attaining normal glycemia can ameliorate the excess cardiovascular disease risk that's associated with gestational diabetes. So they evaluated gestational diabetes history and glucose tolerance after pregnancy and found out whether or not it was associated with coronary artery calcification in women. The obtained data from the CARDIA study which is a US multicenter community-based perspective cord of young black and white adults age 18 to 30 years at baseline.
Dr. Carolyn Lam:
This is what they found. Women without previous gestational diabetes showed a greater increase in the risk of coronary artery calcification associated with worsening glucose tolerance. However, women with a history of gestational diabetes had a twofold higher risk of coronary artery calcification across all subsequent levels of glucose tolerance. Midlife atherosclerotic cardiovascular disease risk among women with previous gestational diabetes is therefore not diminished by attaining normal glycemia. And this is discussed in an accompanying editorial by Dr. Jennifer Green from DCRI entitled Cardiovascular Consequences of Gestational Diabetes.
Dr. Greg Hundley:
Carolyn, well, sounds like I was wrong but our next paper, it's going to review for us a little bit about IgE. Remember that immunoglobulin associated with itching. So Carolyn immunoglobulin E or IgE belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor in pathological cardiac remodeling and heart failure or a non. So in this study, the investigative team measured serum IgE levels and cardiac IgE receptor expression in diseased hearts from humans and mice.
Dr. Carolyn Lam:
Oh, Greg, I'm itching to find out what this study showed.
Dr. Greg Hundley:
Yes, Carolyn, going from the quizmaster now to is it comedy now? Serum IgE levels were significantly elevated in patients with heart failure as well as in two mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin two infusion. Now, interestingly Carolyn, IgE receptor expression levels were also significantly up-regulated and failing hearts from human and the mouse model.
Dr. Greg Hundley:
Carolyn, the authors found that IgE induction plays a causative role in pathological cardiac remodeling at least partially via the activation of IgE receptor signaling in cardiac myocytes and cardiac fibroblasts. So future studies are needed to determine if therapeutic strategies targeting the IgE receptor axis and as to whether they may be effective for managing IgE mediated cardiac remodeling.
Dr. Carolyn Lam:
Fascinating. I never thought of IgE involved in cardiac remodeling. Now, this next paper really interesting. Regulators are always evaluating the use of non-interventional real-world evidence studies to assess the effectiveness of medical products. The RCT DUPLICATE Initiative was formed to use a structured process to design real-world evidence studies to emulate randomized control trials and compare results. Now, this paper represents the first 10 trials emulations in RCT DUPLICATE, and it's from Dr. Jessica Franklin from Brigham and Women's Hospital and Harvard Medical School in Boston and her colleagues. And they did this to evaluate cardiovascular outcomes of antidiabetic and antiplatelet medications.
Dr. Greg Hundley:
Wow, Carolyn. So how does they do this?
Dr. Carolyn Lam:
So they use patient level claims data from US Commercial and Medicare-PEERS and implemented inclusion exclusion criteria of the trial selected primary endpoints and compare the populations to emulate those of each of the corresponding randomized controlled trials within the trial mimicking populations, they then conducted propensity score matching to control for more than 120 pre-exposure con founders.
Dr. Greg Hundley:
So Carolyn, were they able to emulate their randomized clinical trial results?
Dr. Carolyn Lam:
Now, despite the attempts to emulate the trial design as close as possible, there were still differences between the randomized control trial and the corresponding real-world evidence study population. The regulatory conclusions were equivalent in six of 10 studies. The real-world evidence emulations achieved a hazards ratio estimate that was within the 95% confidence interval from the corresponding trial in 8 of 10 studies. Agreement between the trial and real-world evidence findings varied depending on which agreement metric was used.
Dr. Carolyn Lam:
Interim findings indicated that selection of active comparative therapies with similar indications and use patterns enhance the validity of the real-world evidence. And so, even in the context of active comparators concordance between trial and real-world evidence findings was not guaranteed partially because trials were not emulated exactly. More trial emulations are needed to understand how often and in what context real-world evidence findings will match the trials. And yet these initial findings of RCT DUPLICATE really indicate circumstances when real-world evidence may offer causal insights where trial data is either not available or cannot be quickly or feasibly generated
Dr. Greg Hundley:
Well, Carolyn, that is really interesting findings there because we're all trying to decide what to do with these large data sets and combining the results of millions and millions of data points and very interesting findings in this study. How about we see what else is in the issue?
Dr. Carolyn Lam:
Absolutely. Well, let me start. There's an exchange of letters among doctors Villarreal, Cárdenas Suri, [and] Navarro-Castellanos regarding the Multi-system inflammatory syndrome in children. The ECMO needs and Kawasaki disease likeness. There's also an ECG challenge by Dr. Pillai entitled "A Tale of Two Blocks".
Dr. Greg Hundley:
Well, Carolyn, I've got a very nice In-Depth review from Dr. Van Belle regarding transcatheter aortic valve replacement in bicuspid aortic valve stenosis. And there's a Research Letter from Dr. Lew entitled “Short-Chain Enoyl-CoA Hydratase Mediates Histone Crotonylation and Contributes to Cardiac Homeostasis.” And then finally, Dr. Nordin Hanson from Amsterdam has a very nice piece on the Clinical Implications of Basic Science Research entitled “DAMPening Mortality in COVID19: Therapeutic Insights from Basic Cardiometabolic Studies on S100A8/A9.” Well, Carolyn, how about we check out the double feature.
Dr. Carolyn Lam:
Definitely let's go, Greg.
Dr. Greg Hundley:
Well listeners, we are here for our first feature discussion on this March 9th issue and we have with us Nikkil Sudharsanan from Heidelberg and also our own Associate Editor Ntobeko Ntusi from Cape Town. Welcome gentlemen. Nikkil, could you please describe for us the hypothesis that you wanted to test your study population and your study design?
Dr. Nikkil Sudharsanan:
Yeah, so for our hypothesis, we really wanted to know, depending on which hypertension treatment guideline you chose, what implications does it have at the population level for the number of people in low and middle-income countries that would require treatment or that you would want to place on treatment. And we were really looking at not just one country, but a whole range of 50 low and middle-income countries. And so our study population is actually from this pretty remarkable data source that combines the World Health Organization surveillance data for many countries with other sources of data, to try to create a comparable almost low and middle-income country super dataset that's specifically designed to answer questions around cardiovascular disease. So our study population was really based on population representative samples for each of the 50 countries we considered. And in most of the countries we focused on the adult population. So those ages 30 and above.
Dr. Greg Hundley:
And your total sample was over a million participants, correct?
Dr. Nikkil Sudharsanan:
Yeah, it's a really huge sample. And I think it's a testing to some of these data sources, especially the ones in India and Brazil, but collected just really large sample sizes that contributed to this huge global population.
Dr. Greg Hundley:
Very nice Nikkil. And what did you find?
Dr. Nikkil Sudharsanan:
So the big finding is we actually went into it not knowing how the choice or how strong the choice of a blood pressure treatment guideline would be on the number of people that required treatment and were really surprised to see that we took more treatment guidelines, the 2018 American College of Cardiology, American Heart Association guidelines, the kind of typical 140 by 90 blood systolic diastolic blood pressure threshold that you see as part of a lot of guidelines. The UKs NICE guideline and then the WHO Hearts guideline, which is based on their pen and package of essential non-communicable disease interventions.
Dr. Nikkil Sudharsanan:
And we started a really, really pronounced difference in the proportion and size of the adult population that you would recommend or place under hypertension treatment, depending on which of these guidelines used to decide who gets treatment across these countries. So at the top, we found the American College of Cardiology, American Heart Association guidelines, and for the countries we were considering it put about 27% of women and a really high 35% of men as recommended for blood pressure treatment.
Dr. Nikkil Sudharsanan:
And then very closely followed to that was the 140, 90 threshold. So it was still high, but not as high, I would think it was around 26% of women and 31%. And then between these two guidelines and the UK NICE and WHO Hearts, there was a really big drop-off in how many people would actually be recommended for blood pressure treatment.
Dr. Nikkil Sudharsanan:
The NICE guideline, for example, only have 12% of women and about 16% of men and the WHO Hearts is by far the lowest, which only about 10% of women and 11% of men. So I think our first really striking finding was that this choice is not trivial. And depending on which guideline you actually choose to decide who gets treatment in that country, it has really big implications for how many people in that country are going to need treatment.
Dr. Greg Hundley:
Very good. And Ntobeko, how do you put the results of this study in the context with other research perform to study hypertension?
Dr. Ntobeko Ntusi:
Thank you, Greg. So we know that although more than 80% of the global battle of Cardiovascular Disease, okay. As in low and middle-income countries, the data around respecters for cardiovascular disease has largely come from high-income countries. And the INTERHEART study was really the first publication about 15 years ago to try and address this question. And it was very apparent both in the INTERHEART study as well as the INTERHEART Africa study of hypertension was one of the key respecters not only for my myocardial infraction, but for cardiovascular disease in general.
Dr. Ntobeko Ntusi:
In the INTERHEART study hypertension having a hazard ratio of two and the population attributable risk of 17%. And then the INTERHEART Africa study having a hazard ratio of over six. And this paper is really an important application in my view, showing that in a comparison of over a million individuals from 50 countries, there is great variation in the proportion of individuals that need to be treated for hypertension, based on the choice of guideline and definition of hypertension. And if you look at figure one, this is variable from anywhere from 9% to 35%.
Dr. Ntobeko Ntusi:
The other important contribution of this paper is that the proportion of the population that needs to be treated for hypertension increases with age, which is something that we know but strikingly more than 60% in those over the age of 60 years. And for me, they are really great core key messages that I think are important contributions from this publication. The first one being that the choice of hypertension treatment guideline significantly influences the denominator of what you consider to be hypertensives in your population. The second one is that many people in low and middle-income countries are still unaware of their status of elevated blood pressure and the need for treatment. And I think this is a key point to emphasize.
Dr. Ntobeko Ntusi:
The third important message is that these first two points I've made have got huge implications for the scale-up costs and healthcare system capacity and that countries need to choose definitions for diseases. And this needs to be aligned with national health policy as well as available resources. And then finally, a key part of the discussion, which I asked the author to address was really around our understanding of the barriers to optimal management of blood pressure in low and middle-income countries and how these gaps can be oppressed. And they speak to the economic and human resources, the health policy, the importance of population screening and importantly education at every level.
Dr. Greg Hundley:
Very good. Nikkil I'd like to come back to you and then maybe 20 seconds or so, what do you think is the next study that needs to be performed really in this area of research?
Dr. Nikkil Sudharsanan:
I think there may be two, one is to really build on this in terms of what we showed this is the proportion of people that would require treatment and that's how it varies across these guidelines. I think it's important to also tie that to the resource implications directly, like Dr.Ntusi said, to actually show this guideline would require this many resources versus this many for that guideline. I think that will really help countries in deciding what's actually feasible guideline to implement.
Dr. Nikkil Sudharsanan:
And the second one, which is I think a much more challenging study to do is just a study of all these guidelines are based on mostly data from high-income countries. And even among these high income countries, there's these discussions on what the appropriate level for treatment is and what point you should initiate treatment. And it seems like this really has not been done with low and middle-income country populations. So we're arguing about four different guidelines that were built for high-income country populations. And I think it would be really important to see some sort of trial or long-term observational study actually in terms of averting cardiovascular disease events which guidelines actually makes the most sense for these countries.
Dr. Greg Hundley:
Very good. Ntobeko, anything to add to that?
Dr. Ntobeko Ntusi:
I think I agree completely with Nkkil and I think this paper has a number of really important strengths, and I think those strengths and key contributions have to be taken in the context of one significant limitation and how we interpret these results. And that's the fact that when we normally see a patient in the clinic to diagnose hypertension, we would take two or three blood pressure measurements. In this study, they only took a single blood pressure measurement and that's the basis for the conclusions and for me a key limitation, but nonetheless, I think a very important contribution.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Nikkil Sudharsanan from Heidelberg and Ntobeko Ntusi from Cape town for bringing us this important study, indicating that worldwide there's substantial variation really in the proportion of adults in need a blood pressure lowering medication, depending on which hypertension guideline is used. Well, let's move on now to our second feature discussion.
Dr. Greg Hundley:
Listeners, we are now to our second feature discussion and we have with us Dr. Aloke Finn from the Cardiovascular Path Institute in Gaithersburg, Maryland and our content editor expert for pathology, Dr. Jeff Saffitz from Beth Israel Deaconess. Welcome gentlemen. Aloke, could you describe for us, what was the question you wanted to address with this researching? What was your study design and your study population?
Dr. Aloke Finn:
Great. Greg, thanks for your interest in our article and for highlighting it. We were really interested in understanding what the pathologic causes for cardiac injury were in people hospitalized with COVID-19, as you know, it's been reported in the literature that people with COVID-19 with cardiac injury do worse than those without cardiac injury, but the mechanism is not still well understood. So the study design was really based upon a collaboration with a group from Italy in the Lombardy region, where they had had a terrible outbreak in 2020, as you remember in February. And they had a number of hospitalized. People die from COVID-19 infection, and they too were interested in understanding the pathologic causes of chronic injury. We got IRB approval and those hearts were sent to us during the middle of this pandemic in the February, March time. And we were able to examine 40 of those hearts and report our pathologic findings. And these were unselected cases of hospitalized patients dying of COVID-19.
Dr. Greg Hundley:
That was great. And tell us a little bit what were your study results?
Dr. Aloke Finn:
So we, first of all, did an analysis based upon the presence of myocardial necrosis. So that was the sort of the selection factor, which hearts had myocardial necrosis which parts didn't have myocardial necrosis. We found that 35% of the hearts in this 40 cases had myocardial necrosis. Now, we divided those into the type or pattern of myocardial necrosis. Was it acute myocardial infarction? Was there a large area of infarction greater than one centimeter squared or was there focal myocardial necrosis less than one centimeter squared. It's small areas of focal myocardial necrosis. We've found that most cases of patients dying of COVID-19 with myocardial necrosis had focal myocyte necrosis. Not large areas but small areas of myocyte necrosis. And we looked for the cause of those necrosis, majority of those cases with focal myocyte necrosis had microthrombi as the cause of that necrosis. So that suggests the major mechanism of myocardial injury in COVID-19 patients is microthrombi.
Dr. Greg Hundley:
Very nice. Well, Jeff, let's turn to you. How do we put the results of this study in the context with perhaps other pathologic studies that have been obtained from hearts of individuals that succumb to COVID-19?
Dr. Jeffrey Saffitz:
It's a very important question. And I want to say that at the outset, there have been many papers published focused on the pathologic findings of COVID-19 patients who have come to autopsy. And I have to say that the quality of these papers has been quite variable. In many cases, the pathology being shown is actually post-mortem artifact. In other cases, the interpretation of the pathology is incorrect. And so I think we have to be very careful in a study like this to make sure that what is being reported is actually valid and meaningful in the context of the important clinical questions being posed. And in this case, I can say the pathology was really extremely impressive and very convincing.
Dr. Jeffrey Saffitz:
Another important aspect of this study has to do with the comparison of the composition of the microthrombi that were identified in patients dying from COVID-19 versus patients who have other types of coronary thrombosis, but in a different setting. And here, there were some interesting observations that provide insights, not only into mechanism of thrombosis, but also potential information about how one might want to target antithrombotic therapy in these patients. So I would really like to hear more from Dr. Finn on this interesting aspect of this study.
Dr. Aloke Finn:
Jeff, thanks for your comment and your question. I think I agree with you, this was another interesting aspect of the study. What was done was that were able to examine the constituents of thrombi, different types of thrombi both in the setting of patients who had COVID-19 and non COVID-19 STEMIs as well as microvascular thrombi described in the COVID-19 patients, as well as embolized thrombi that embolized a small microvascular within the heart. And what we essentially found was that these thrombi, that are COVID microthrombi are distinct in their constituents. Distinct in that they had more fibrin and more compliment activation than the other types of thrombi that we're studied. So I do think this begins to unravel the question about how are these thrombi forming and are they different from the type of thrombi we normally treat? And the answer is, yes.
Dr. Greg Hundley:
Very nice, Aloke. What study do you think needs to be performed next in this space? And after you, I'll ask Jeff the same question.
Dr. Aloke Finn:
Greg, I would like to know whether or not therapies like anticoagulant, anti-compliment, antiplatelet therapies can decrease the risk or the effect of the COVID-19 on myocardial injury. Is will we see a benefit to anticoagulant or antithrombotic strategies in the study? I think that is the natural next question to ask.
Dr. Greg Hundley:
Very nice. And Jeff, anything to add?
Dr. Jeffrey Saffitz:
Yeah, well, I'm an experimental pathologist, so I'm always interested in disease mechanisms. And I would like to understand more about how these microthrombi form, the role of endothelial cell injury, the role of cytokine storm and other factors which we know are contributing. I think in the end having a more fundamental understanding of these mechanisms will provide important insights, not only in trying to manage heart disease, but in fact, other organ system disease, which is likely being mediated by a similar mechanism in the kidney and potentially in the brain and other organs as well. So I think this is a great example about how autopsy can provide really critically important information in a new human disease and set the stage for subsequent studies that will really provide important dew information.
Dr. Greg Hundley:
Excellent. Well listeners, we want to thank Dr. Aloke Finn from Gaithersburg, Maryland, Dr. Jeff Savitz from Boston, Massachusetts for this excellent discussion and revealing the pathologic results of 40 hospitalized patients from Italy that expired after COVID-19 highlighting the cause of myocardial necrosis and how it was related to the presence of microthrombi.
Dr. Greg Hundley:
On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
This week, join author authors John J.V. McMurrary and Milton Packer, and Associate Editor as they discuss their Perspective article "How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction? A Redefinition of Evidence-Based Medicine."
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, this feature discussion is going to knock you off your seat, because it did me. It's about treatment sequencing in HFrEF and discussing it with some luminaries on the field, Dr. John McMurray and Dr. Milton Packer. You are going to love it. I loved it. But I'm going to make you wait. How about you grab some coffee and let's start with some of the other papers in today's issue first.
Dr. Greg Hundley:
All right, Carolyn. How about if I go first? I'm going to start with a paper from Dr. Liam Brunham from the University of British Columbia. Well, Carolyn, the high density lipoprotein or HDL hypothesis of atherosclerosis has been challenged by clinical trials of cholesterol ester transfer protein, or CETP inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of HDL cholesterol, or HDL-C, declined drastically during sepsis. And this phenomenon is explained in part by the activity of CETP, a major determinant of plasma HDL-C levels. So Carolyn, these authors tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts in animal models of sepsis.
Dr. Carolyn Lam:
Huh. Interesting. And what did they find?
Dr. Greg Hundley:
Well, Carolyn, results from both the human UK Biobank and the mouse model experiments suggested that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.
Dr. Carolyn Lam:
Wow. So is this ready for clinical applications somehow?
Dr. Greg Hundley:
Well, Carolyn, two conclusions from this work. First, high density, lipoprotein cholesterol, a commonly used biomarker for cardiovascular risk assessment, may also predict risk of death from sepsis. And then second, cholesterol ester transfer protein inhibitors that have been tested in clinical trials of cardiovascular disease could be repurposed and studied in clinical trials of sepsis.
Dr. Carolyn Lam:
Ooh, exciting. Well, Greg, for my paper, I'm going to ask you a question. Have you ever thought about what the temporal changes in medical prevention and adverse outcomes are in patients with symptomatic peripheral artery disease after revascularization? Well, wait no longer. Our next paper addresses that. It's from Dr. Sogaard from Aalborg University Hospital in Denmark and colleagues who identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark from 2000 to 2016. And this is what they found.
Dr. Carolyn Lam:
First, the profile of patients with PAD who underwent lower extremity revascularization changed towards older age and a higher prevalence of comorbidity. Despite increases in age and co-morbidity, medical prevention of adverse events improved substantially over time, particularly in the first part of the study period and among patients who used medications chronically.
Dr. Carolyn Lam:
Now in contrast, initiating treatment after revascularization increased modestly among treatment-naive patients. Now concurrently, prognosis improved for almost all adverse outcomes in patients of both sexes, all age groups, and in all high-risk co-morbidities. In particular, the risks of myocardial infarction and cardiovascular death declined by more than 40%.
Dr. Greg Hundley:
Well, Carolyn, are there any other findings with clinical implications here?
Dr. Carolyn Lam:
Yes. So that was the good news earlier. But despite overall improvements, significant disparities remain. Less than 40% of treatment-naive patients initiated cardioprotective therapy after revascularization, underscoring the need for raising levels of awareness and education in the vascular community, general practitioners and patients of this. Major amputations also remained unchanged and thus more work is needed to understand relationships between the preventive measures, revascularization and amputation.
Dr. Greg Hundley:
Great summary, Carolyn. My next paper comes from Dr. Rachael Cordina from the Royal Prince Alfred Hospital, University of Sydney. Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well-defined. So the investigators here aim to study neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry and postnatal clinical factors.
Dr. Carolyn Lam:
Okay, you got our attention. What did they find, Greg?
Dr. Greg Hundley:
Thanks, Carolyn. So participants with a Fontan circulation, without a pre-existing major neurological disability, were prospectively recruited from the Australia and New Zealand Fontan registry. And the investigators found that neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller grey and white matter brain volume. Understanding, therefore Carolyn, modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.
Dr. Carolyn Lam:
Indeed. Well, this next paper I want to talk about is the first detailed endothelial cell cysteine-S self-hydrome.
Dr. Greg Hundley:
Self? S self-hydrome? What is that, Carolyn?
Dr. Carolyn Lam:
Good. I needed to catch your attention. Let me tell you about it. So in vascular endothelial cells, cysteine metabolism by cystathionine gamma-lyase, or CSE, generates hydrogen sulfide- related sulfane sulfur compounds. And these exert their biological actions via cysteine-S self-hydration of target proteins. So the paper we're talking about today by Dr. Fleming from Goethe University in Germany and colleagues, they aimed to map the S self-hydrome, which is the spectrum of proteins targeted by this hydrogen sulfide-related sulfane sulfur compounds, or H2Sn, in human endothelial cells. And they did this using liquid chromatography and tandem mass spectrometry.
Dr. Carolyn Lam:
So here's what they found: vascular disease was associated with mark changes in the S self-hydration of endothelial cell proteins involved in mediating responses to flow. Integrins were most effected by S self-hydration and the modification of beta-3 integrin resulted in reshuffling of the intramolecular disulfite bonds to preserve its extended and open confirmation. Loss of beta-3 integrin self-hydration, on the other hand, inhibited endothelial cell adhesion, impaired mechanosensing and attenuated flow induced phase with dilation. Thus, short term H2Sn supplementation could improve vascular reactivity in humans, highlighting the potential of interfering with this possibly to treat vascular disease.
Dr. Greg Hundley:
Very nice, Carolyn. You know, just more from the world of hydrogen sulfide and endothelial function. Thanks so much. Well, the next paper I have comes to us from Dr. John McEvoy from Johns Hopkins University School of Medicine. So Carolyn, recent clinical guidelines support intensive blood pressure treatment targets. However, observational data suggests that excessive diastolic blood pressure lowering might increase the risk of myocardial infarction. Therefore reflecting, does a J or U-shaped relationship exist when we're following the treatment of diastolic blood pressure? So Carolyn, these authors analyzed 47,407 participants from five cohorts with a median age of 60 years. First to corroborate prior observational analysis, the authors used traditional statistical methods to test the shape of association between diastolic blood pressure and cardiovascular disease.
Dr. Carolyn Lam:
Okay. So was it J or U?
Dr. Greg Hundley:
Okay, Carolyn. So interesting, traditional observational analysis of the cohorts suggested a J-shaped association between diastolic blood pressure and myocardial infarction. However by contrast, linear MRI analyses demonstrated an adverse effect of increasing diastolic blood pressure increments on cardiovascular disease outcomes, including myocardial infarction. Furthermore non-linear MRI analyses found no evidence for a J-shaped relationship. Instead confirming that myocardial infarction risk decreases consistently per unit decrease in diastolic blood pressure, even among individuals with low values of baseline diastolic blood pressure. So Carolyn, in answer to you, no, the J or U-shaped curve does not exist.
Dr. Carolyn Lam:
I suppose depending which way you look at it. Very interesting. Well, let's finish up with what else is in today's issue. There's an AJ update by Dr. Elkin on COVID-19 at one year, the American Heart Association president reflect on the pandemic. A white paper by Dr. Zannad on challenges of cardio kidney composite outcomes in large scale clinical trials. A research letter by Dr. Kass on the reduced right ventricular sarcomere contractility in HFpEF with severe obesity. Another research letter by Dr. Messas on the feasibility and performance of non-invasive ultrasound therapy in patients with severe symptomatic aortic valve stenosis. A first in human study.
Dr. Greg Hundley:
Right, Carolyn. So I've got an exchange of letters from Dr. Vazgiourakis addressing a prior publication entitled Right Heart Dysfunction in COVID-19 Patients: Does Mechanical Ventilation Play an Additional Role? And then finally, an exchange of letters from Drs. Carrizales-Sepúlveda and Topalisky regarding the prior paper, The Spectrum of Cardiac Manifestations in COVID-19. Well, Carolyn, I'm really excited to get to that feature that you explained to us right at the beginning. Very exciting.
Dr. Carolyn Lam:
So am I. So am I. Thanks, Greg.
Dr. Carolyn Lam:
Wow. Today's feature discussion could not be more star-studded in my point of view. We are talking about the very, very hot topic of how do we sequence treatments in heart failure with reduced ejection fraction now? A really hot topic because just last year in 2020, we suddenly got a bonanza of positive trials and everybody's grappling with how to put it all together.
Dr. Carolyn Lam:
Now who better than the two authors I'm going to talk to today, Professor John McMurray from University of Glasgow and Professor Milton Packer from Baylor University Medical Center in Texas. So welcome both. John, Milton, I'm almost tripping over myself to talk about this because this is an amazing perspective piece. Everybody must get your hands on it and even look at the figure while you're listening to this. We're going to divide today's discussion into just three simple questions. Why do we need a new sequencing approach? How in the world do you come up with a new sequencing approach? Based on what? And finally, what is that new approach that you're both proposing? So maybe I'll start off with you, John. What's wrong with what we've been doing?
Dr. John McMurray:
So Carolyn, I think we've maybe neglected the fact that while we think of, for example, cancer as something that's incredibly urgent to diagnose and to treat as fast as possible, to give the patient all those life-saving therapies, we haven't had the same urgency in our treatment with heart failure. And our existing approaches, as you know, being largely one of start with the first treatment that was ever tested in the trial, up titrate to the pill dose, take your time, then on the second, third and so on. And of course, what that means is that it takes months for patients to be treated with all of the fantastic life-saving options that we have available for them. And we know that that's failing.
Dr. John McMurray:
We've seen from numerous registries, CHAMP registry in particular springs to mind, where that's simply not happening. It's probably taking too long. It's too complicated for both the doctor and the patient, and we need to change it. And I suppose Milton will tell you his view, but I think my view and I think his as well, was that the SGLT2 inhibitor story really brought this question, I think, to the fore because here is our fourth life-saving drug that if we do things the same way might not get started for six months. And we really felt that we need to rethink what we're doing. Milton, I'm sure, will say whether he agrees with that. But I think that was sort of where the starting point was.
Dr. Carolyn Lam:
Great. But if I could interject a bit, so now we're talking about that left side of the panel, where in your beautiful article where you're showing, we start with ACE inhibitors and ARBs, and then go on to beta blockers and mineralocorticoid receptor antagonists, and so on. I would love to know, and Milton I'm sure you'll add, is it the sequence that's wrong? Or is it really just the timing? Or the fact that we're just all too lazy? What do you say to people who go, "But that's how the trials were done." Especially because you guys both led those amazing trials of ARNIs and SGLT2 inhibitors. It's just awesome.
Dr. Milton Packer:
So Carolyn, what's really amazing is that everyone assumes that that's how the trials were done. But two things, one, just because we did things in a certain way, developed things in a certain way, doesn't mean we have to prescribe them in a certain way. I mean, we developed digitalis before all of them and so does that mean we need to use digitalis in everyone? But a lot of the early trials, all the patients were, or most of the patients were, on cardiac glycosides.
Dr. Milton Packer:
There are four things that we've learned from the large-scale clinical trials. One is the order of drugs does not matter with respect to efficacy. The beta blockers work the same whether people are getting ACE inhibitors or not, MRAs are not effected by background therapy. Neither is neprilysin inhibitors. They work pretty much the same regardless of background therapy, so you don't have to sequence them in the order in which they were developed.
Dr. Milton Packer:
Two is low doses, low starting doses of these drugs seem to work amazingly well, perhaps surprisingly well. And the third thing is that they work very early. So in a lot of the clinical trials, nearly all the trials that were carried out, there was a meaningful separation of the curves and in effect size in the first 30 days of all of these trials. And in many of the trials, in the first 30 days, patients were still on the starting dose. Hadn't been uptitrated.
Dr. Milton Packer:
The last point is that these drugs can influence each other's safety profiles. So the result of all of this was for us to rethink what the sequence should be based not on how the drugs were developed, but how they might be most logically used with respect to relative efficacy, safety and ease of use.
Dr. John McMurray:
So, Carolyn, to go back to your question then is sort of what Milton is saying is that it's a bit of both of the things you asked about. It is about timing, but it's also about the order of the drug. And that last point Milton made is very important about the potential synergies in terms of making it easier to use treatments, but timing is critically important as well. I mean, we do tend in the conventional approach to therapy recommended in the guidelines to perhaps spend too much time trying to reach that target dose, and then doing that before moving on to the second drug. So again as Milton pointed out, if you're getting early benefit from all of these treatments, fundamentally what you want is as many of these treatments started as quickly as possible as you can do safely. And that may be facilitated by some of the synergies between treatments as we, I think, rather provocatively suggested in the new algorithm, might even be possible to start two treatments at once.
Dr. Carolyn Lam:
Okay. Now I know everybody's really, really wondering what that new algorithm is, but I'm going to lengthen the pain a little bit more because this is critically important. You've already started discussing the how did you come up with an algorithm. It seems a lot of, yeah, very reasonable approaches, but could you give us specific examples of actual scientific interrogation of the data from the trials that you've led, frankly, to show us these points, that maybe support that we can come up with a reasonable new approach? Those points that Milton very rightly put, the treatment benefit of each class is independent. Give us some examples of that. The dose issue, the side effects, how one could help in that too. Could you give us some examples?
Dr. Milton Packer:
Oh, my God. So let me say that there's so many pieces of evidence and please read the article. We try to summarize as much of them as possible. But in all of the major clinical trials, there was a separation that occurs within 30 days. That's true across every single major trial. Anyone who thinks that the treatment effects of these drugs are delayed, that it takes months to evolve, we're getting statistical significance within two to four weeks across all of the drugs.
Dr. Milton Packer:
Second is, in many of the trials, for example, COPERNICUS trial with carvedilol, the trials with MRAs, even the trials with ACE inhibitors, during that first 30 days when the curves were separating, patients hadn't been uptitrated. They started on low doses and remained on relatively low doses and the curves were separating. So we knew that the drugs had early effects at low doses, low starting doses. And we also have randomized trials that really tell us that if you go to high doses for some of these drugs, you get a little bit more benefit, but you don't get as much benefit as starting another drug with a different mechanism at a low dose.
Dr. Milton Packer:
And lastly, we know that some of these drugs actually prevent the side effects of others. There's evidence that neprilysin inhibitors and SGLT2 inhibitors mitigate the hyperkalemia produced by spironolactone and aplerno. So these are just a few examples.
Dr. John McMurray:
Sorry, Carolyn. To add a couple more, we obviously know that the treatments work independently. We primarily knew that from subgroup analyses, but also from trials like RALES for example, where spironolactone was tested in addition to an ACE inhibitor, but very, very few patients were on a beta blocker. Subsequently we tested different a MRA in patients who were taking both an ACE inhibitor and a beta blocker, and the benefit was essentially the same. And of course, our very first trial with an ACE inhibitor, the CONSENSUS trial, was actually done in a population where more than half of the patients were on a very large dose of an MRA. So you can sort of put all the trials together in a type of jigsaw and figure out that these drugs all clearly work independently.
Dr. John McMurray:
And then maybe the only other thing I would mention, because it's perhaps relevant to the new algorithm, is that we do have another key trial, which is, a trial I think often forgotten about, the CIBIS III, which was a study that tested whether or not you could start treatment with either a beta blocker or with and ACE inhibitor in patients with HFrEF, showing that you could start with a beta blocker in patients who had not yet received an ACE inhibitor and do that safely and efficaciously. So there's a lot of material out there that you can sort of put together to answer all of these questions.
Dr. Carolyn Lam:
Great. And now drum roll. Okay. What is the new algorithm? John, you want to introduce it? Or Milton? Up to you.
Dr. Milton Packer:
John can start. That's fine.
Dr. Carolyn Lam:
Well, which one, Carolyn? I suppose the one in the Circulation article is a three-step algorithm. It starts with the combination of a beta blocker, based as I mentioned, so there's three plus an SGLT2 inhibitor. So again, thinking about synergies, thinking about tolerability, thinking about size of effect and thinking about repetity of onset of benefit. So I think most of us would agree, beta blockers are incredibly effective treatments, life-saving treatments, reduce the risk of sudden death. We know that you can start a beta blocker safely as first-line therapy. We do know that there may be more intolerance in patients who are volume overloaded. So why not give a treatment that has a modest, initial diarrhetic effect when you're starting the beta blocker? In other words, the SGLT2 inhibitor. SGLT2 inhibitors work extremely quickly. There's no dose up titration needed. So they seem like the perfect combination to start with.
Dr. Carolyn Lam:
In step two, we suggested moving then to sacubitril valsartan, which in itself is two more drugs combination of an angiotensin receptor blocker and their prolines inhibitor. And then there's the third and final step. We suggested using a mineralocorticoid receptor antagonist. But Milton and I have had a lot of discussion about this. I think we're not saying that all those are necessarily the three steps for all patients. There may be different approaches in different people depending on patient's characteristics. But really the point here was, the provocative statement was we should be able to do this quickly in all patients. And this in fact was an approach to get all four of those drugs started potentially within four weeks.
Dr. Milton Packer:
So Carolyn, the mantra here, our motto going forwards, is four drugs in four weeks.
Dr. Carolyn Lam:
Okay.
Dr. Milton Packer:
An angiotensin receptor blocker, a beta blocker, an MRA, an SGLT2 inhibitor. Four drugs in four weeks. And if you're going to start all four drugs in four weeks, in all honesty, the order probably doesn't matter that much. John and I happen to think that if you have to define a first step, a combination of a beta blocker and an SGLT2 inhibitor simultaneously as step one makes a lot of sense. And then you can follow up with sacubitril valsartan and an MRA.
Dr. Milton Packer:
But here's the thing that's really important: do not take months to follow up. What we're proposing in this algorithm is you start a beta blocker and an SGLT2 inhibitor on day one, and you then follow through with sacubitril valsartan and an MRA within the next couple of weeks. But here's what's really important and we really need to emphasize this: this is a algorithm that assumes that someone's not on any of these drugs already. And of course, most of these patients are taking some of these drugs already. But the other thing that's really important is that we're also assuming that physicians are being very meticulous about background use of diuretics, so that patients really have to be maintained in a clinically euvolemic state in order to make this algorithm work.
Dr. Carolyn Lam:
Okay, well, I'm picking myself off the floor because it certainly was provocative. I love it. I love it for that. It's the first time I've ever seen any algorithm start with a beta blocker and SGLT2 inhibitor. You first go, "Where's the ACE and how come the new kid on the block is right on top?" So I really like that because it must challenge our current thinking. In other words, if we just look at the data for what it is, let's see how we could think it over. So salute you for that. But let me just press on a little bit. So four drugs in four weeks. That's really great. Are there any particular patients you may say the ARNIs come on top or the MRAs? Specific situations or...?
Dr. Milton Packer:
Well, Carolyn, as John has already said, the physicians need to understand the principles, but the application of those principles have to be individualized. So if a patient has a borderline blood pressure, you would probably be well advised to put the MRA before sacubitril valsartan. Depending on renal function, you may decide to advocate one drug a little bit earlier or preferentially compared to another. There are hundreds of individualized nuances, but to get tied up in these is to miss the point of our paper. The point of our paper is that we need to do things quickly... Four drugs, four weeks... And we need to not rely on our historical testing in order to determine the optimal sequence. If you embrace those conclusions, then patients and physicians can individualize their care to the greatest optimal degree. But our current approach, which is a historically-driven algorithm that takes six months to execute, it doesn't work.
Dr. John McMurray:
Carolyn, we obviously did give a lot of thought to the initial treatments, and we did realize that it would potentially be a surprise to people. But just to reiterate, I don't think there's much debate about the incredible benefits of beta blockers, the size of that benefit. We know that the benefit is apparent within 30 days. So Milton and we had Henry Krum's very nice paper about that in JAMA from the COPERNICUS trial, but we're seen it in the other trials. You know that SGLT2 inhibitors have had early benefit. You think about these two drugs being used in a newly presenting patient with HFrEF, probably don't even need to do any electrolyte monitoring, provided your patients not volume overloaded or recently decompensated. That patient's very unlikely to have any significant intolerance to these two treatments.
Dr. John McMurray:
They don't, in those sorts of patients, substantially reduced blood pressure in either drug, beta blockers certainly don't affect kidney function. SGLT2 inhibitors have minimal effect on kidney function. If your GFR is relatively normal, you probably don't even need to check it. And of course, there's no effect on potassium. So in terms of getting two treatments onboard quickly that will have a rapid benefit, are likely to be well-tolerated in the type of patient that we just described, and where they might have monitoring necessary is minimal, then this seemed to be the best option. And as Milton said thereafter, it's maybe less important what order you do it in as opposed to the speed with which you do it. And you're right, you would definitely probably tailor this approach according to the patient characteristics, but this was a general starting point to stimulate debate, which it seems to have done.
Dr. Milton Packer:
So Carolyn, there's something important. If you believe in what we've proposed, then at the end of four weeks, every patient with heart failure and reduced ejection fraction would be on low starting doses or four foundational drugs. Our estimate is if doing that would provide them with a substantial benefit, maybe 70, 75% of the benefit of bringing all of those doses to target doses. And if you can do that, you can do all four drugs at starting doses at four weeks and provide that magnitude of benefit really quickly? That has a big impact on patients. And that has a big impact on public health.
Dr. Carolyn Lam:
Wow. Just thank you so much for igniting this debate. I wish we could go on forever. I just had to share that when we editors looked at this paper, it did spur a very robust debate. But as you can see, we're publishing it as you've proposed it because we do see where you're coming from. It is very interesting. And I just want to reiterate what you both just said, to listeners out there, remember this is referring to a patient who is compensated. Diuretics are still part of it. Remember that the key message is to get everyone on the four foundational therapies within four weeks. And I just love the way you pushed the boundaries with this. Really, really appreciate it. Milton, you look like you want to say something else. If you'd like closing words, I'd love to...
Dr. Milton Packer:
We really thank Circulation for having the courage to do this. And please understand, John and I strongly feel that this is the start of a debate. This is the start of a discussion. This algorithm is a proposal to get people to start thinking differently. This is not the final word on the subject by far. We think this is the beginning of a very important discourse that will evolve over the next year or more. And we just wanted to remind people what the clinical trial evidence actually shows about these drugs, because we think it has been frequently misunderstood much to the detriment of patients with heart failure.
Dr. Carolyn Lam:
Yes. And John, any last words?
Dr. John McMurray:
I would go back to where I started, Carolyn. In a way, what's important here is to inject a sense of urgency back into the way in which we treat patients with heart failure and reduced ejection fraction. It deserves that sense of urgency, as I mentioned that, for example, cancer does. And also thank you for summarizing, I think, what we tried to get across absolutely accurately.
Dr. Carolyn Lam:
Okay. So John, Milton, so far I take it. I take your points well, but as a practitioner, what I would do, frankly, is if I have a patient that I'm starting a beta blocker and an SGLT2 inhibitor, I would surely just start an ACE inhibitor perhaps, or ARNI, at the same time. I don't see why I need to delay it. How about that? Even faster?
Dr. John McMurray:
Okay, well, I'll let Milton answer the faster, but I would say one thing, Carolyn, the new algorithm doesn't mention ACE inhibitors or angiotensin receptor blockers as a monotherapy. Because I think those days are gone. I really do think that we shouldn't go through that cycle of starting a RAS blocker, uptitrating it, then switching to an ARNI because that's a waste of time. You're delaying the introduction of life-saving therapy. And this is the whole point to, again, get that sense of urgency across in implementing all of these treatments as quickly as possible.
Dr. Milton Packer:
And Carolyn, if you want to go faster, that would be fine. Maybe we shouldn't have proposed four drugs in four weeks. We should have proposed four drugs in four days. But Carolyn, I think that changing the way people think is a gradual process. Perhaps four drugs in four weeks is a good starting point. If everyone feels comfortable with that and understands why we are proposing that, then in another six months or so, Circulation can invite John and I to come back and propose four drugs in four days. But let's see what happens.
Dr. Carolyn Lam:
Kudos. Thank you so much. Well, thank you once again, John and Milton. That was an incredible discussion. A beautiful paper.
Dr. Carolyn Lam:
Thank you so much, listeners. I'm sure you enjoyed that as much as I have or probably more. But thank you and please don't forget to tune in again next week. From Greg and I, here's Circulation on the Run.
Dr. Greg Hundley
This program is copyright of the American Heart Association, 2021.
This week, join author Chintan Dave and Associate Editor Naveed Sattar as they discuss the risk of cardiovascular outcomes in Type 2 Diabetes patients following the addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-IRA therapy.
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I love today's featured paper. It's a question everybody's asking. It's about cardiovascular outcomes, potential benefits, following the addition of SGLT2T2 inhibitors versus sulfonylureas to baseline GLP-1 receptor agonist therapy. Now, okay, I'm going to keep you waiting because that was just a hook. We got to get to us summaries first. And I'm going to start. The first original paper I want to describe is an analysis of myocardial infarction from the ischemia trial. And it looks at the impact of different definitions on the incidents, prognosis and treatment comparisons.
Dr. Carolyn Lam:
Because I know you're going to ask, I'm going to tell us a little bit about ischemia. So in an ischemia and initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic, heart disease, and moderate to severe myocardial ischemia. The most frequent component of the composite cardiovascular end points was myocardial infarction. So in the current report from Dr. Chaitman and colleagues from St. Louis University school of medicine, the aim was to compare treatment effects on the primary and major secondary competent end points in the ischemia trial using the pre-specified primary and secondary MI definitions.
Dr. Greg Hundley:
So Carolyn, what were those two EBI definitions, the primary and secondary?
Dr. Carolyn Lam:
Right. Now, I'm going to try to simplify this. So, for procedural MI, the primary MI definition use CK-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin.
Dr. Greg Hundley:
Great, Carolyn. So what did they find?
Dr. Carolyn Lam:
So procedural MI definition had an important impact on event frequency and subsequent prognosis. When the pre-specified secondary MI definition was applied, the conservative strategy had a significantly lower composite event rate for the primary and major secondary trial end points, due to an increased number of procedural MIs in the invasive strategy. Furthermore, spontaneous Type One MI events associated with increased risk of cardiovascular death were reduced with an invasive strategy, which is either PCI or CABG.
Dr. Greg Hundley:
Nice, Carolyn. Well, my first paper actually is a favorite topic of yours, HFpEF. And it really involves the central command and the regulation of exercise rate response. It comes to us from Dr. Ben Levine and colleagues at the University of Texas Southwestern Medical Center in Dallas.
Dr. Carolyn Lam:
Yay.
Dr. Greg Hundley:
All right, Carolyn. So chronotropic incompetence is common in HFpEF. And it's linked to impaired aerobic capacity. Whether upstream, autonomic signaling pathways are responsible for raising exercise heart rate are impaired in patients with HFpEF, That's really unknown.
Dr. Carolyn Lam:
Yep. It is something that we wonder. And so what did Dr. Levine find?
Dr. Greg Hundley:
Thanks Carolyn. So the central command, so vaguely mediated and the metabo-barrow receptor function, which is sympathetically mediated in patients with HFpEF, We're not different from healthy senior controls, despite significantly lower peak whole body exercise, heart rates. So these results, Carolyn, demonstrate key reflex autonomic pathways, regulating exercise, heart rate responsiveness are actually intact in patients with HFpEF. Great new work from Dr. Ben Levine.
Dr. Carolyn Lam:
And I love the way you summarized that. Thank you, Greg. Well, my next paper is the first report implicating the cross priming function of dendritic cells in immunopathology after Type Two MI. And that includes inflammation, fibrosis and functional decline.
Dr. Greg Hundley:
So tell us a little bit more Carolyn about these dendritic cells?
Dr. Carolyn Lam:
Ah-ha so I was ready for that question. So after ischemic injury to the myocardium, dendritic cells respond to cardiomyocyte necrosis present the cardiac antigen to T-cells and potentially initiate a persistent auto-immune response against the heart. So cross priming dendritic cells may have the ability to activate both CD4-positive helper and CD8-positive cytotoxic T-cells in response to necrotic cells. And may thus be crucial players in exacerbating auto-immunity targeting the heart.
Dr. Carolyn Lam:
So, in this study, authors led by Dr. Sattler from Imperial College, London, performed some elegant mouse experiments and showed that cross-priming dendritic cells were present in the heart and activate it after ischemic injury. Depletion of these dendritic cell cross priming function, inhibited accumulation, and activation of cytotoxic T-cells and stopped myocardial immunopathology and functional decline. So with cross-priming, these authors provided a targetable pathway to prevent activation of T-cells cyto-toxicity and persistent post Mia immunopathology exacerbating heart failure risk.
Dr. Greg Hundley:
Oh, beautiful. Carolyn, what a great description there. So my next paper comes to us from Dr. David Park from the New York University school of medicine. So Carolyn elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling of the left atrium that begets atrial myopathy and arrhythmias. At present the underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. So the purpose of this study for these investigators was to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans, as well as mouse models. And explore the role of ETV1 in atrial electrical and structural remodeling.
Dr. Carolyn Lam:
Ah, another study involving both animal and human models. Very important subject too. So what were the results?
Dr. Greg Hundley:
Well, Carolyn, evidence from both the Cleveland Clinic, Biobank Human Subjects Repository and the animal science experiments revealed that ETV1 is downregulated in the left atrium during cardiac pressure overload. Thereby contributing to both the electrical and the structural remodeling that we observe in the left atrium during cardiac pressure overload.
Dr. Carolyn Lam:
Nice. Well, let's quickly finish up with what's in the mailbag. We've got a research letter by Dr. Randi on the lack of evidence of AEs to expression and replicative infection by SARS-CoV-2 in human endothelial cells. There's another by Dr. Stokes on the association of cigarette and electronic cigarette use patterns with levels of inflammatory and oxidative stress biomarkers among US adults. And another research letter by Dr. Hemelsoet on screening for Fabry disease in male patients with arrhythmia requiring pacemaker or ICD.
Dr. Greg Hundley:
Thanks Carolyn. So I've got a paper it's a cardiovascular case series from Dr. Workman that involves a case of presyncope after transcatheter aortic valve replacement. Dr. Özeke has an ECG challenge reminding us that common things occur commonly. Dr. Zaha has a Perspective entitled, "Mending Broken Hearts, a New Treatment Paradigm for Immune Checkpoint Inhibitor Induced Myocarditis." And then finally, Dr. David Goff, the director of the NHLBI has a wonderful perspective piece (Special Report). And it really addresses some results from the Bethesda conference at the National Heart Lung and Blood Institute and the American Heart Association. And it was co-sponsored the bending curve of cardiovascular disease mortality, the Bethesda plus 40 years Symposium.
Dr. Greg Hundley:
The report, Carolyn, summarizes the relevant research, policy, and practice opportunities discussed at the symposium, including participant led discussion that explored the challenges and barriers in promoting cardiovascular health, across lifespan. And established a potential framework for observational research interventions that would begin in early childhood. Well, Carolyn, how about now we jump forward to that feature discussion.
Dr. Carolyn Lam:
All right, now we can go.
Dr. Greg Hundley:
Well, listeners, we are to the feature discussion today. And we have with us Dr. Chintan Dave from Rutgers University in New Jersey, and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. Welcome gentlemen. Chintan, could you explain to us some of the background information that went into the construct of your study and then what hypothesis did you want to test?
Dr. Chintan Dave:
So just for background, so we know that artheriscraotic cardiovascular events in heart failure typically occur in higher prevalence in patients with type two diabetes. What's been really exciting in recent years is that certain second-line therapies, namely SGLT2 inhibitors and GLP-1 receptor agonist in these large cardiovascular outcome trials have shown to reduce the incidents of cardiovascular events. So from these trials, we can infer that SGLT2 inhibitors typically reduce heart failure hospitalizations, and also have an impact on 3P-MACE, which is just the composite of cardiovascular death, non-fatal MI and non-fatal stroke hospitalizations. While GLP-1 receptor agonist tend to reduce, also have an impact on 3P-MACE, but they also have some modest benefits in heart failure hospitalizations as well.
Dr. Chintan Dave:
So now that we know that these agents reduce cardiovascular risk, what's not known is, whether or not, if we can use these agents together to further maximize a reduction in cardiovascular events. So in the cardiovascular outcome trials the dual use of SGLT2 two inhibitors and GLP-1 receptor agonists was rare and ranged from between 0% to 5.3%. So as a starting point, we said, "Okay, let's look at observational data to see what happens when you add SGLT2 inhibitors to patients who are already using GLP-1 receptor agonist." And we hypothesized that, given the orthogonal pharmacodynamic effects on cardiovascular risk, adding SGLT2 inhibitors to existing GLP-1 receptor therapy should further reduce cardiovascular events.
Dr. Greg Hundley:
Very good. And can you describe for us your study population and study design?
Dr. Chintan Dave:
Sure. So we used three databases in the US. Two of these databases were commercial claims data, which is typically your employer based insurance plans, which have patients between the ages of 18 and 64. And we supplemented that data with Medicare fee for service claims, which have patients over the age of 65. So within these three databases, we identified patients who have a diagnosis of type two diabetes and are already a GLP-1 receptor therapy or GLP-1RAs and initiating either SGLT2 inhibitors or sulfonylureas.
Dr. Chintan Dave:
And after we identified this patient population, we controlled for several pertinent variables that could be considered confounders, including socio-demographic variables, diabetes complications, and cardiovascular conditions. And we had two primary endpoints. The first primary end point of interest was a composite cardiovascular endpoint, which is defined as the composite of non-fatal MI or nonfatal stroke hospitalizations in all cause mortality. The reason we used all cause mortality instead of cost specific mortality is basically because we didn't have information on cause of death. So we have to resort to a more generic definition of mortality in the composite cardiovascular endpoint. The second primary endpoint that we used was heart failure hospitalizations. So we then in this population, estimated hazard ratios using basically a time to event framework.
Dr. Greg Hundley:
Okay. And what were your results?
Dr. Chintan Dave:
So after applying the eligibility criteria in all three databases and after doing a one-to-one propensity score matching, we had 12,500 patients who initiated SGLT2 inhibitors and 12,500 patients in the sulfonylurea groups. For the true primary end points the addition of SGLT2 inhibitors to baseline GLP-1RA therapy was associated with a 22% decrease in the incidents of composite cardiovascular end point or an adjusted hazard ratio of 0.78. And the caught 95% confidence intervals were statistically significant. For the endpoint of heart failure hospitalizations, we noted a 36% decrease in the risk of heart failure hospitalizations with the adjusted hazard ratio being 0.64. And again, that was statistically significant as well.
Dr. Chintan Dave:
The CCE or the Composite Cardiovascular Endpoints was driven primarily by non-statistical decreases in the risk of MI by about 25%, in all cause mortality by about 32%. But we also found no effect on stroke, which is also in line with what others have reported. The other thing we looked at was also to look at any evidence for heterogeneity in treatment effects by presence of cardiovascular diseases. And we found no statistical significant difference in that aspect. The last thing we looked at also was to look at any evidence of heterogeneity by baseline cardiovascular disease in the patient groups. And we found no evidence to that effect.
Dr. Greg Hundley:
Very nice. Well, Naveed help us put this study in perspective with some of the other research that I know you're familiar with related to the use of SGLT2 inhibitors and GLP-1 receptor agonists.
Dr. Naveed Sattar:
Yeah. Thanks Greg. So as we all know, the biggest gains in diabetes in the last few years is these two costs of the trucks SGLT2 inhibitors and GLP-1. We believe and the evidence suggests that SGLT2s, are more cardiorenal in its benefits, and GLP-1 more atherothrombotic. So the hope is that if you combine these drugs, you get additional benefits, but there are no trials that have actually tested this. So this particular paper being kind of first observational, look at adding an SGLT2 versus another drug on top of a GLP-1, tries to get at that particular question. And it provides an early hint that yes, if you add an SGLT2 on top of the GLP-1, you get additional benefits. Giving us some insight that yes, you combine these two classes of drugs, you might get additional benefit in one drug on its own.
Dr. Naveed Sattar:
Of course, this is not trial. Some of our readers are going to be nihilist and will not believe the data because it's not a trial, but that's fine. But it's done as well as it possibly can. This observational propensity analysis is well matched. The data have some kind of external validity in the sense that the greatest benefits or risks reductions, but for heart failure post-acquisition, which is what we would believe ratio to inhibitors. So there is some sense of validity here, but clearly colleagues, they want to know, and I actually had a patient in the clinic on Tuesday who was on a GLP-1 and actually was an SGLT2. And I wanted to add the GLP-1. And this kind of evidence provides me some evidence of confidence that yes, by adding both drugs, I might get additional benefits in that one drug on its own.
Dr. Naveed Sattar:
So what you're going to ask next, Craig, and I'll give my answer first. What we really need to do now is actually do the trials. And I think the trials will predominantly work, adding GLP-1 on people who are on SGLT2, because I think more people will be initially an SGLT2 because it's a oral therapy. Then we'll add GLP-1. Although we do have a new oral GLP-1 in play as well. So, that's the kind of paradigm we're in. Some hints, the combination gives you more than the single drug and I think that's really quite promising for people.
Dr. Greg Hundley:
Very nice. So Naveed suggesting a clinical trial to confirm some of these results. Chintan, do you have anything to add? What study do you think or what area of investigation in this field do you feel is next in line?
Dr. Chintan Dave:
Yeah, I mean, I would just start by saying that I agree with everything that Naveed said in the sense that this is a starting point. And that I think the key take home from this study that sort of is going to be published is basically that not only do SGLT2 inhibitors reduce the cardiovascular events in patients using GLP-1 therapy, but the fact that the magnitude of this reduction is very similar. What was noted in cardiovascular outcome trials of SGLT2 inhibitors for GLP use was very minimal. In other words, you can super impose the cardiovascular benefit profile of the SGLT2 inhibitors, which were seen in trials two patients using GLP-1 therapy.
Dr. Chintan Dave:
Now the converse is what needs to be done next, basically, where we need to look at what happens when you add GLP-1 receptor agonist, to SGLT2 inhibitors, as Naveed just said. And he raised a really good point in that more patients are going to be on SGLT2 inhibitors, because they want to avoid GLP-1 receptor agonist because they don't want to use injectable therapies. Of course we have oral semaglatites maybe that may mitigate these issues. But the fact that that aspect is still unknown, could potentially be really good idea for future studies. So that potentially would be a nice, good step.
Dr. Greg Hundley:
Excellent.
Dr. Naveed Sattar:
Can I see one last thing, Greg? There is a trial coming this year called AMPLITUDE‐O, which is a GLP-1 trial, which does have a fair number of people on base than SGLT2s. We might be able to get a curly hint at that ongoing trial in the next six months to a year.
Dr. Greg Hundley:
Excellent. Well, we want to thank both Chintan Dave from Rutgers and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. And really presenting information from US Claims databases highlighting the addition of SGLT2 inhibitors to GLP-1 receptor agonists and finding there was an association with a further reduction of cardiovascular risk relative to the use of GLP-1 agonists alone. On behalf of both Carolyn and myself, we want to wish you a great week. And catch you next week On the Run. This program is copyright of the American Heart Association, 2021.
This week, Circulation on the Run highlights the articles that are part of the Go Red for Women issue. Please join Senior Associate Editors Sana Al-Khatib and Biykem Bozkurt as they provide summaries for the articles found in this special 5th Edition of Go Red for Women.
TRANSCRIPT BELOW
Dr. Sana Al-Khatib:
Greetings. And welcome to this podcast that will showcase the contents of the Fifth Annual Go Red For Women Issue of Circulation. I am Sana Al-Khatib. I am a Professor of Medicine at Duke University and an electrophysiologist. And I am a Senior Associate Editor for Circulation. And I'm delighted to introduce my co-editor for this issue, Dr. Bozkurt.
Dr. Biykem Bozkurt:
Thank you, Sana. I'm Biykem Bozkurt, Professor of Medicine from Baylor College of Medicine in Houston. And I'm also a Senior Associate Editor at Circulation. And we're delighted to do this podcast. We'll be covering very exciting articles. We're very proud of our Go Red For Women Issue.
Dr. Sana Al-Khatib:
And you're exactly right, Biykem. We are indeed excited about the content that we will be sharing with you. And I will actually start with a couple of articles, tackling arrhythmias and covering some important topics in this field. So the first paper is actually an original research article that summarizes the results of sex and the outcomes of catheter ablation in the CABANA trial. And as you know Biykem, CABANA was a randomized clinical trial of patients who were either older than 65, or if they were younger than 65. They had to have risk factor, at least one risk factor for stroke. And those patients who had AFib were randomized to catheter ablation strategy versus pharmacologic strategy. In this particular secondary analysis of the CABANA trial, the authors looked at association between sex and outcomes of catheter ablation. And this is a really important question in the field of electrophysiology because several prior studies had suggested that women may be at an increased risk of adverse events and complications from invasive procedures.
Dr. Sana Al-Khatib:
So it was really good to see the results of this analysis and some of their findings were as follows. They enrolled 819 women in CABANA Biykem, which is a really good number because it accounted for 37% of patients enrolled in that trial. And this is something that we all strive to do in terms of enriching clinical trials with good women representation. And 1,385 of the patients were men. And compared with men, women had some baseline characteristics that were different. They were older. They were more likely to be symptomatic to present with paroxysmal atrial fibrillation. And when they looked at the outcomes of women, they found that the risk of complications was actually pretty infrequent in both sexes. And there was no indication that women had a higher risk of complications, so that was really reassuring to see. And you may recall that in the main trial and when they analyze data based on the intention to treat principle, they found no significant difference in the primary endpoint between ablation and pharmacologic therapy.
Dr. Sana Al-Khatib:
And just as a reminder, the primary endpoint was a composite outcome of deaths, disabling stroke, serious bleeding, or cardiac arrest. And in this secondary analysis focused on sex differences, they again found no difference in that primary outcome between ablation and pharmacologic therapy, regardless of sex. But when they looked at the risk of recurrent AFib, that was definitely significantly reduced in patients undergoing ablation. And that was true for men as well as for women although it seemed that difference was even larger for men.
Dr. Sana Al-Khatib:
I would have loved to see some data on quality of life Biykem, but these results are definitely reassuring and certainly indicate that in our female patients that we see in practice who are symptomatic with atrial fibrillation, passive ablation should certainly be considered as one of the treatment options. So with that in mind, I'm going to switch gears and share with you some of the results from his second paper in the Go Red For Women Issue that presented the results of an analysis of the engage a SME 48 trial. And that analysis aimed to examine the efficacy and safety of edoxaban in women versus men.
Dr. Sana Al-Khatib:
And this was a really large trial. They included 21,105 patients. Again, representation of women was pretty good at 38%. And they enrolled patients with AF who had a chart score of at least two. And they randomized them either to a higher dose of edoxaban, lower dose of edoxaban or warfarin. And the primary endpoint of the trial, where the composite of stroke or systemic embolism looking at efficacy and ISTH defined major bleeding, looking at safety. And not surprisingly, there were some differences in the baseline characteristics between men and women, with women being older, having lower body weights, more likely to have hypertension, renal dysfunction, but less likely to have diabetes, coronary artery disease. What was interesting Biykem, is that when they looked at the pretreatment endogenous factor Xa activity, this was significantly higher in women at baseline compared with men. But when they looked at the treatment effect of edoxaban, it appeared to be greater in women, such that when you look at the resulting endogenous factor Xa activity, after a treating these patients, the end result was actually similar between the two sexes, two to four hours after the dose.
Dr. Sana Al-Khatib:
But then also when you look at the treatment effect, they found a similar reduction in the risk of stroke, systemic embolism, and major bleeding with edoxaban in women versus men. However, actually women assigned to the higher dose of edoxaban, experienced a greater reductions in hemorrhagic stroke, intracranial bleeding and life-threatening or fatal bleeding compared with men. So these are really important findings, very interesting findings because, intracranial bleeding, life-threatening bleeding, really dreaded outcomes of anticoagulant therapy in patients with atrial fibrillation. So very exciting results. With this, I will turn over to you Biykem.
Dr. Biykem Bozkurt:
Thank you, Sana. We also have great papers on ischemic heart disease. There's a fascinating research paper on coronary optical coherence tomography, and cardiac MRI to determine the underlying causes of MINOCA, myocardial infarction with non-obstructive coronary arteries in women. This I find it almost like having a magical mirror showing exactly what's happening inside the heart, in the setting of MINOCA, which is seen in approximately six to 15% in my cases and disproportionately affecting women. The investigators performed coronary optical coherence tomography, which captures very small micrometers structures with very high resolution providing information on tissue composition.
Dr. Biykem Bozkurt:
They also did cardiac MRI in approximately 116 women diagnosed with MINOCA by cat. The optical coherence tomography identifies a culprit lesion in approximately health, surprise, which was most commonly plaque rupture. TMR was abnormal in approximately three quarters with an ischemic pattern in health, non-ischemic pattern in approximately 20% like myocarditis, takotsubo or non-ischemic cardiomyopathy with the combined non-ischemic cardiomyopathy with the combined OCT and MRI, they were able to identify hypothesized cause for MINOCA in approximately 85%, and they couldn't identify any abnormality in about 15. Overall with both modalities, ischemic etiology was determined to be the cause in approximately three quarters, non ischemic etiology, in about 20% and no mechanism could be identified as 15%.
Dr. Biykem Bozkurt:
We also had a resource letter, which I find to be quite complimentary to the topic, this time, examining coronary vascular response to vasoactive breathing maneuvers in ischemia with no obstructive coronary arteries or INOCA. This time assessed by another fancy modality oxygenation sensitive cardiac MR in female patients with recurrent chest pain, with no obstructive coronary artery by coronary angiography. By comparison of 20 women with INOCA, chest pain without any obstructive disease to 20 age matched healthy volunteers, they found no differences in LV volumes function, LV mass, or global oxygenation. But women with INOCA had significantly higher regional variations in response to these breathing and breath holding maneuvers, suggesting heterogeneous coronary vasomotor activity.
Dr. Biykem Bozkurt:
This regional heterogeneity suggested alterations in microvascular dysfunction, which is rather unique and supports the concept of the microvascular dysfunction, which may explain the presence of ischemic symptoms in the absence of epicardial coronary disease, but also in the absence of global coronary perfusion abnormalities, which have been reported and have been discorded in some of the former literature. So this study also implies a potential role for this perhaps new diagnostic modality, the oxygen sensitive cardiac MR, to have a potential investigator role for future clinical studies in patients with the INOCA. The third patients on the realm of ischemic heart disease reports analysis, highly awaited analysis on the trends in returns events, following myocardial infarction among US women and men by using administrative records from approximately 1.4 million hospitalized patients with MI between the dates of 2008 and 2017.
Dr. Biykem Bozkurt:
And following them for returned to MI CHT events, heart failure hospitalization, and all-cause mortality within a year post Mi. The investigator has reported the following, the baseline and recurrent event rates for MI and coronary heart disease event rates were higher for men than women. Heart failure hospitalization rates were higher in women than men. The good news is though the rates of recurrent MI, recurrent coronary heart disease events, heart failure hospitalization, all-cause mortality within a year after MI, declined considerably both in men and women and with proportionately greater reductions for women than men. However, this should not create any complacency because the rates remained still quite high and coronary heart disease is still the number one killer for both men and women. I know we have fascinating papers on sex differences in sudden cardiac arrest. So I will turn the mic to you, Sana for you to comment on those.
Dr. Sana Al-Khatib:
Thank you very much, Biykem. A really interesting papers that you presented there. So when it comes to sudden cardiac death, which is an area that is near and dear to my heart, we actually have two very interesting papers. The first paper is an original research article that examined sex differences in outcomes among resuscitated patients with out of hospital cardiac arrest. And those were patients who were successfully resuscitated from arrest and were enrolled in the continuous chest compression trial. And they applied a rigorous statistical analysis to their data, looking at this association while adjusting for important factors. They also looked at DNR status, withdrawal of life sustaining therapy, order status to see if there are any inner actions there. And they included 4,875 successfully resuscitated patients, of whom 1825 were women. Again, good representation of women here, 37%. And a bit more than 3000 of their patients were men, against some differences in baseline characteristics between women and men, with women being older, they were less likely to receive Bystander CPR and had a lower proportion of cardiac arrests that were witnessed or had shockable rhythm.
Dr. Sana Al-Khatib:
So when they looked at survival to hospital discharge, that was significantly lower among women compared with men. So you're looking at a survival that was 36.3% in men versus 22.5% in women. So that's actually a really big difference. And it's going to be important to understand better and look at more granular data that would account for that difference. They also looked at the association between sex and survival at discharge, and they found that this was modified by DNR and withdrawal of life saving therapy status, such that women had significantly reduced survival at discharge, among patients who were not made DNR, didn't have a withdrawal of life support order. And so they highlight these differences and really push for the need to try to understand reasons for these so that we can work on improving prognosis and outcomes for women.
Dr. Sana Al-Khatib:
The second paper is really interesting. This was a research letter that looked at sudden cardiac arrest in young women. And although several prior studies have looked at sudden cardiac arrest in men versus women. This particular one was focused on young women, defined as women younger than 40 years of age. And this actually delved into that pair sudden death expertise center registry, which is a prospective population-based registry that collects data on cardiac arrest in Paris and its suburbs. And they looked at those cardiac arrests occurring between 2011 and 2018. Their definition of sudden cardiac arrest was closure. And they had 14,210 sudden cardiac arrests that were recorded with 1062 young, meaning under 40 years of age victims of whom three 36 were women. And they found that the mean age at the sudden cardiac arrest was 31.3 years.
Dr. Sana Al-Khatib:
And the interesting findings were as follows, sudden cardiac arrest was the first manifestation of any underlying disease in 89 cases. So 63%. So that was actually a high number. Of course, looking at risk factors, those were not surprising in terms of the presence of hypertension, hyperlipidemia, diabetes, overweight, smoking, 22 patients had a previous history of cardiovascular disease. Only 16.5%, were mainly non-ischemic heart disease. Minority had family history of sudden cardiac arrest at a young age and under the age of 50. And the vast majority of those events occurred at home and only five really occurred in the setting of vigorous exercise or sports. Initial shockable rhythm was found in 73, meaning 29% paces and so on and so forth. They really provide more information about the circumstances of the cardiac arrest that would be really interesting to look at.
Dr. Sana Al-Khatib:
And finally, when they looked at cardiac etiologies, those were observed in about 50% of the cases, including non-ischemic cardiomyopathy, ACS, non-structural heart disease, coronary syndrome, MINOCA was uncommon, actually only one case and so on and so forth. So definitely I invite you to delve more into the content of this paper, to learn more about this condition. Biykem, I will turn over to you.
Dr. Biykem Bozkurt:
Fascinating results and quite striking. We have a very interesting study that I think is going to be of interest to our listeners on which actually portrays what happens to the heart in the setting of metabolic syndrome during pregnancy. The investigators want to find out if obesity or metabolic syndrome could disrupt the physiological adaptive cardiac remodeling that happens normally during pregnancy. This is an important question because as you know, Sana, there has been a significant increase in the prevalence of obesity and metabolic syndrome in women of childbearing age with more than 30% of females in their reproductive years being obese. So in this study, investigators compared pregnant female mice who develop metabolic syndrome after 50% fat diets to non-pregnant female mice or pregnant female mice that are non-metabolic and being fed by controlled diet. And the pregnant mice with metabolic syndrome had increased cardiac mass, pathological hypertrophy and fibrosis, and up regulation of fetal genes associated with pathological hypertrophy.
Dr. Biykem Bozkurt:
And they also showed that the mice had cardiac dysfunction when challenged by angiotensin two infusion after delivery. So these suggests that metabolic syndrome or obesity could disrupt the physiological adaptation that is expected during pregnancy and may result in pathological cardiac remodeling that could predisposed not only to future cardiovascular complications, but also added risk to adverse outcomes during pregnancy.
Dr. Biykem Bozkurt:
Another paper that is, which I find to be very important is drug discontinuation clinical trials. As you know, women are underrepresented across cardiovascular clinical trials and in several observational studies, women have been reported to be less likely than men to adhere to prescribed medication, including cardiovascular medications, which may contribute to worse prognosis. The reasons for this has been unclear. And the investigators in this study examined the association between sex and premature study drug discontinuation and withdrawal of consent in 11 large-scale TIMI trials with approximately 200,000 subjects. After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation and withdrawal of consent. Importantly, this was not explained by differences in comorbidities neither by reporting of adverse events.
Dr. Biykem Bozkurt:
This is important because we always attributed the differences in drug discontinuation to the differences in pharmacodynamics and pharmacokinetic profile and the woman experiencing higher incidence of adverse drug reaction with cardiovascular drugs. This was not the case in this study. And moreover the difference was not restricted to certain medications. It was seen in a wide range of study drugs, such as antiplatelets, anticoagulants, lipid-lowering drugs, antidiabetic medications. And also there was a large sex difference in regional representation. The drug adherence in North America demonstrated a significantly higher discontinuation in women than in men. The difference was relatively modest in Europe, Middle East Africa and Asia. And there was no difference between the two sexes between men and women in South and Central America. These results may suggest that there are potentially attributable reasons due to differences in access to health care, social, economic, cultural factors, non study related costs, transportation, family obligations, as well as concerns about drug safety and confidence in the healthcare system that may have played a role. Back to you, Sana.
Dr. Sana Al-Khatib:
Very interesting results, Biykem. So the next paper is actually a research letter that I really enjoyed reading, looking at sex differences in blood pressure associations with cardiovascular outcomes. And what the authors did is they studied more than 27,000 participants. 54% of whom were women. And these people had no baseline cardiovascular disease, but they had standardized systolic blood pressure measurements performed in one of four community-based cohort studies, for example, Framingham, Eric, so on and so forth. And when they looked at the sex pooled analysis, the threshold for incident MI and heart failure, was 120 to 129 millimeters mercury and for stroke was 130 to 139. In sex specific analysis, interestingly though, they observed increasing cardiovascular disease risk beginning at lower threshold of systolic blood pressure for women than for men. The incidents of cardiovascular disease proportionately increased beginning at a lower range of systolic blood pressure in women compared to men.
Dr. Sana Al-Khatib:
And in multi-variable adjusted analysis, the presence of a systolic blood pressure of 100 to 109 relative to a systolic blood pressure of less than 100 was associated with incident cardiovascular disease in women, but not men. So really interesting findings. And the authors actually states that maybe these findings could be related to differences in vascular anatomy, physiology between men and women, but they say that taken together their findings along with prior results, suggest that maybe the possible need for a lower sex specific definition of optimal systolic blood pressure for women. So really interesting. So they push for people to really do some research to validate these findings and explore these ideas further.
Dr. Sana Al-Khatib:
And then the last paper that I will present as to do with sex stratified, a gene regulatory networks. And basically looking at these to examine female key driver genes of atherosclerosis. And what the author said is that for years, we have known about sex differences in CAD with women developing more stable atherosclerosis than men. However, the underlying vessel biology had been unknown, and so they were trying to shed some light on this. And they integrated female gene regulatory networks with some single-cell RNA sequencing of the data from human atherosclerotic plaque and single-cell RNA sequencing of advanced atherosclerotic lesions in knockout mice.
Dr. Sana Al-Khatib:
And basically what they found is that by comparing sex specific GRNs, they observed clear sex differences in network activity. Within the atherosclerotic tissues, genes, more active in females were associated with missing chemo cells, endothelial cells, whereas genes, more active in males were associated with the immune system. And they determined key drivers of these GRNs being active in female with CAD being predominantly found in smooth muscle cells. So it was really interesting because they say, well, if we, based on these novel insights into molecular mechanisms that underlie sex differences, within atherosclerosis, perhaps, people can develop sex specific therapeutic targets. So I thought that was really interesting, Biykem. Back to you.
Dr. Biykem Bozkurt:
Very interesting, indeed. The final paper I want to comment on a very interesting research letter on temporal trends in proportion of women, physician speakers at major cardiovascular conferences. The investigators collected data on approximately 80,000 speakers from large annual cardiovascular conferences. They selected the ones that had more than 2,500 attendees, such as ACC, AHA, ESC, TCT, HRS, and they show that between 2015 and 2019, the proportion of women speakers increased modestly over time. But unfortunately the invasive fields such as EP interventional cardiology had the lowest proportions of women speakers in single digits. Speaker roles also varied by gender with more men serving in all the roles than women. Furthermore, all high-profile interventional on EP talks were given by men. Non-invasive specialties were more balanced. Women comprise approximately 46 to 50% of high profile speakers in non-invasive conferences. But across the board, women were poorly presented among late-breaking clinical trial presentations, almost in all conferences.
Dr. Biykem Bozkurt:
So overall the investigations concluded that though they were below, but gradually increasing in woman physician speakers at major cardiovascular conferences all the time. It appears that more women were often being tasked with giving more presentations, not more high profile ones. And they underlined the policy of women in high profile roles and almost near absence from the podium at late-breaking clinical trial presentations, reflecting exclusion of women in major roles at national meetings, underlining the need for structural and cultural change. So overall, fascinating papers, which we believe will add significantly to the field. On behalf of my co-editor, Dr. Dr. Sana Al-Khatib, I would like to thank our contributors, the authors, co-authors, investigators for their submissions, the Circulation Staff, a special call out to Sara O'Brien for creation of a very impactful Go Red for Women Issue, [and] our editors for making this endeavor successful and our listeners for joining.
Dr. Sana Al-Khatib:
I also want to thank everyone and thank you Biykem. It was indeed a pleasure to work with you on this issue. Thank you. And thanks to all.
Dr. Biykem Bozkurt:
Thank you.
Dr. Greg Hundley:
On behalf of Carolyn and myself, We want to wish you a great week and we will catch you next week On the Run. The program is copyright of the American Heart Association, 2021.
This week features Two Feature Discussions. In our first discussion, author Thomas Metkus and Guest Editor Allan Jaffe discuss the article "Myocardial Injury in Severe COVID-19 Compared to Non-COVID Acute Respiratory Distress Syndrome." Then in our second discussion, author Naveed Sattar and Guest Editor Ileana Piña discuss the article "Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)."
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, Associate Editor, Director of the Pauly Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Guess what? Double feature again, this episode with the first talking about empagliflozin and its effect on left ventricular volumes in patients with type two diabetes, pre-diabetes, and HFrEF, and this is the sugar DM heart failure study.
Dr. Greg Hundley:
Carolyn, the second of our double feature Tuesday is a paper that involves myocardial injury in severe COVID-19 compared to non-COVID acute ARDS. Well, let's grab a cup of coffee and Carolyn this week, I'm going to jump into my first paper, which comes to us from Dr. Are Kalstad from the University of Oslo at the Oslo University Hospital. Carolyn, this study tested the hypothesis that the daily addition of 1.8 grams of N-3 PUFA to standard of care, secondary prophylaxis in elderly patients who have survived a acute MI would reduce the risk of subsequent cardiovascular events during two years of follow-up.
Dr. Carolyn Lam:
Interesting, Greg and a clinically important question. So what did they find?
Dr. Greg Hundley:
Yes, Carolyn. They enrolled 1,027 subjects who were randomized in this investigator initiated, multi-center randomized clinical trial of adding that 1.8 grams of n-3 PUFA, 930 milligrams of EPA, and 660 milligrams of DHA versus placebo, which was a corn oil supplement, daily to the standard of care in 70 to 82 year old patients with recent, so within two to eight weeks, acute myocardial infarction. The authors found that they could not detect reduction in clinical events in these elderly patients with the recent acute EMI treated with the 1.8 grams of n-3 PUFAs daily for two years. So, a negative study, Carolyn.
Dr. Carolyn Lam:
Surely, we'll add to that debate that's just so interesting surrounding the PUFAs. But let's go onto another paper I want to tell you about, it provides novel insights into the complex crosstalk between the cardiac endothelial cells and cardiomyocytes during cardiac repair after myocardial infarction. This paper is from Dr. Taleb and colleagues from Park Inserm in France. Their study suggested a deleterious role for endothelial indoleamine 2,30-dioxygenase-1, which I'm now going to abbreviate as IDO, which is an enzyme involved in tryptophan catabolism. They found that the specific deletion of IDO in endothelial cells enhanced cardiomyocytes survival and contractility leading to cardiac function improvement. The IDO dependent effects were mediated by endothelial cell production of kynurenine. The study in essence found that therapeutic strategies targeting cardiac IDO could, in fact, constitute an innovative approach to curb cardiac dysfunction following MI. This was followed by an editorial by Drs. Ma and Wang from Thomas Jefferson University.
Dr. Greg Hundley:
Very nice, Carolyn. Great studies again from the world of basic science. Well, my next paper comes to us from Professor Gerasimos Filippatos from the University of Athens Hospital. Carolyn, this was a sub-study of the FIDELO-DKD trial that evaluated the effect of the nonsteroidal selective mineralocorticoid receptor antagonists finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type two diabetes with optimized renin angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. Here the authors report the effect of the finerenone on individual cardiovascular outcomes and in patients with and without a history of atherosclerotic cardiovascular disease.
Dr. Carolyn Lam:
This is a much anticipated paper. Very excited for you to describe the findings, Greg.
Dr. Greg Hundley:
Thanks, Carolyn. Among patients with chronic kidney disease and type two diabetes, finerenone reduced the incidents of the composite cardiovascular outcome, that included time to cardiovascular death, myocardial infarction stroke, or hospitalization for heart failure. Additionally, there was no evidence of differences in treatment effect based on pre-existing cardiovascular disease status.
Dr. Carolyn Lam:
Emerging therapies. Isn't that awesome? Well, some other papers in this issue, there's a White Paper (Frontiers) about the therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing PCI, a North American perspective, 2021 update by Dr. Angiolillo. There's a Research Letter on the gradient of risk and associations with cardiovascular efficacy of ertugliflozin by measures of kidney function, and these are observations from VERTIS-CV trial by Dr. Cherney. There's also a sub-study analysis from Explorer HCM, and that is entitled “Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy.” This is by Dr. Saberi. There's another Research Letter on COVID-19 myocardial pathology evaluation in athletes with by CMR and that's by Dr. Clark.
Dr. Greg Hundley:
Very nice, Carolyn. I have an exchange of letters from Dr. Alkhalil and Kuzemczak, as well as Dr. Navarese regarding the article, “Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: A Network Meta-Analysis of 52,816 Patients From 12 Randomized Trials.” Next, there's another exchange of letters from Dr. Kastrati and Ferracane regarding the article, “Comparative Efficacy and Safety of the Same Oral P2Y12 Inhibitors in Acute Coronary Syndromes.” Dr. Karabinos has a nice ECG challenge. It's a bizarre down sloping ST segment elevation challenge. Finally, Carolyn, there's a Perspective piece from Dr. Okorodudu entitled, “Exposure to Cardiology as a Strategy to Increase Black Men Involvement in Medicine.” Well, Carolyn, how about we get on to those two feature discussions?
Dr. Carolyn Lam:
Oh, yes. Exciting. Let's go.
Dr. Greg Hundley:
Well, listeners, we are here for our first feature discussion today on this February 9th. We have with us Dr. Tom Metkus from Johns Hopkins and Dr. Allan Jaffe from Rochester. Tom, can you tell us what was the background that really framed this study and what hypothesis did you want to address?
Dr. Thomas Metkus:
This study really arose out of a time and a place in the COVID pandemic. If you can all turn your clocks back to late last spring, we were all enmeshed in the clinical care of many patients with COVID here in the United States, depending on your geography, and also reading an increasing number of reports from other centers that had been enmeshed in the pandemic for some time about myocardial injury, elevated troponin, different aspects of cardiac disease in patients with COVID-19. My background is as a cardiac intensivist, dual boarded in cardiology and critical care, and so this was of particular interest to me, specifically so in that my clinical practice at the time was in a COVID ICU. I spent much of the day every day taking care of these patients, so conceptualizing what myocardial injury meant, what's the pathogenesis, and what does it mean, was an open-ended question at the time. There are certainly many reasons to think that COVID-19 is particularly cardiotoxic. There's obviously the pro-thrombogenic nature of the illness. There's the inflammatory nature of the illness.
Dr. Thomas Metkus:
Yet, we also found that clinically, there was certainly many patients with COVID-19 who acted like they had myocardial injury from ARDS and pneumonia and we had investigated this in some prior studies prior to the pandemic. Really, the aim of the study was to clarify to the extent that we could and contribute to the growing body of knowledge about what is the prevalence and prognostic significance of myocardial injury in COVID-19. We felt that we had a unique lens on this because we also had a cohort of patients with generic ARDS who had cardiac biomarkers assessed, gave us a nice opportunity to do that.
Dr. Thomas Metkus:
Our hypothesis, that was really based on our clinical gestalt at the time from being in the ICU every day with COVID-19 patients, was that there are assuredly COVID-19 patients who have unique features of myocardial injury, myocarditis or malignant arrhythmias, or requiring mechanical support. But perhaps more, or at least a majority have myocardial injury that looks and acts an awful lot like it would in a sepsis patient, in an ARDS patient. We hypothesized that myocardial injury in COVID-19 would be more similar than different to the generic ARDS population. As such, we drew a population of patients with COVID-19 from our health system here across several hospitals, and did a bit of a comparison with our historical cohort of ARDS patients.
Dr. Greg Hundley:
Great description, Tom. Tell us a little more about that study population. You said there was going to be a comparison. What were some of the outcomes that you wanted to evaluate?
Dr. Thomas Metkus:
Right. This question alludes to an important point as we try to delve and do inference around the COVID literature in general, which is to say the pandemic is heterogeneous across geography and across time. In looking at this study, or indeed any study, and understanding of the study population where these ambulatory patients or intubated patients or patients on the ward, for example, as well as any comparison group are these sepsis patients, pneumonia patients, influenza patients, it's just imperative to do inference and to place the study in context. This study, we sought to look at only intubated patients, and that was partially driven by clinical interest, partially driven by the ability then to provide a comparison to our ARDS cohort. So, intubated patients with COVID-19.
Dr. Thomas Metkus:
The comparison group is from a study of acute respiratory distress syndrome patients. Primary lung injury patients that were drawn in turn from NHLBI sponsored areas, network clinical trials. That was a study that was a secondary analysis that we did where we checked troponin levels in everybody. A true cross sectional assessment. That's important in that there's a selection bias, isn't there, when you just look at patients who had troponin drawn in the context of clinical care? So, I think for this study in particular, it's important to note that the comparison group of ARDS patients was truly cross-sectional and that it was a population defined who had biomarkers assessed in the entirety; whereas our COVID-19 population was intubated patients who had troponin checked at the point of clinical care.
Dr. Thomas Metkus:
Now, to address some of the potential biases that are inherent in that assessment of exposure, we purposefully looked at only patients who had troponin assessed within 24 hours of intubation, really to sync up time zero in a sense. It's also important to note the time course of the pandemic. These patients were all in the late spring and very early summer. This was really before steroids, before the recovery trial, before steroids became standard of care. And really, health systems wonder a fair bit of duress at that time and indeed, as many of the listeners will know, the outcomes for hospitalized patients have improved since then for many reasons. But it's only to point out that this study was a place in geography and a place in time, and there are certainly implications about that that I'm sure we'll focus on subsequently.
Dr. Greg Hundley:
How many subjects did you enroll and what were your study results?
Dr. Thomas Metkus:
Our COVID-19 patient population here in the Johns Hopkins Hospital included 243 patients. All of them were intubated with COVID-19, so severe disease. Of those, we reported that just over half had clinical troponin levels greater than the upper limit of normal. We assessed the main clinical factors associated with elevated troponin in that patient population, which are largely similar to other reports and they include chronic kidney disease, lactate levels of the marker of malperfusion, ferritin fibrinogen levels as markers of systemic inflammation. We showed as have others that there's a graded increase in mortality with increasing amounts of myocardial injury. Then, probably what I would found the most interesting component of the study is that when we did covariate adjustment for features of critical illness, renal failure, lactate, how severe your hypoxemia was, vasopressor use, age, and sex. Age, sex, and multi-organ dysfunction in a sense.
Dr. Thomas Metkus:
The association of troponin with mortality attenuated quite significantly. That's similar to what we found in a general ARDS population and consistent with a paradigm of myocardial injury in the non-cardiac critically ill. I think the final finding that we would emphasize is that after you adjust for those mediating factors, the incidence of myocardial injury in COVID-19 was at least comparable to that in the general area's population. It gives an idea to place myocardial injury in context, in my view, as a function of critical illness in most COVID-19 patients. Surely, not all. There are patients with unique syndromes, but in many or most.
Dr. Greg Hundley:
Well, Alan, let's turn to you. Help us put these results that Tom has described for us really in the context of what we're learning about the heart and in patients with COVID-19.
Dr. Allan Jaffe:
Well, let me start by saying that as a cardiologist, too, at the Mayo Clinic in Rochester, Minnesota, we've studied previously patients with acute respiratory failure. In point of fact, although most of you are not quite as old and may not remember, when we first started seeing ARDS patients, many of the same issues that are here today for COVID, came up. For example, and people may not remember this, we actually did a randomized trial of anti-platelet therapy in patients with ARDS because we were convinced that thrombosis was ubiquitous and was a frequent contributor to the illness that we saw. So that if one thinks about it in another sense and says, "If you'll correct for modern day technology that gives us some additional insights, how different really is COVID ARDS from standard ARDS." I think what this paper has substantiated is that there are lots and lots of similarities that exist. I think that's important because it keeps us from chasing around and looking for some additional issues for us to try and take care of or treat additionally.
Dr. Allan Jaffe:
That said, I think the way to conceptualize it is some of the troponin elevations are because patients who have chronic heart disease get COVID and they may have those elevations right at admission. There's an acute component having to do with critical illness that is nicely described in this manuscript. Then, there are those unique clinical features, whether you think it's myocarditis, I'm not sure how common myocarditis, type 2 MI, ischemia, a variety of things, and maybe a new type of myocarditis that we're finding with some very peculiar cells that we see in interstitium with or without increases in troponin. But I think it puts it into the bucket of saying, treat these patients conventionally and look for the other complications. I think that's a terribly important message that I was attracted to when I read this paper. So, thank you, Tom.
Dr. Greg Hundley:
Very good. Well, Tom, what do you see as the next study really to be performed in this space? I'll ask you first and then come back and gather some of Allan's thoughts.
Dr. Thomas Metkus:
Absolutely. I love that framing about kind of COVID in the heart, which is to say that there are some things that are direct pathogenic related to COVID and there are some things that are secondary, and then there are some things related to patients with underlying heart disease coming to care. I think the next set of studies that can help us disentangle this are related to that paradigm in that more multimodal phenotyping, biomarker phenotyping, but also echo phenotyping and MRI phenotyping, we're starting to see those come down the pike to say, here's the biomarker evidence of myocardial injury, but what does that mean, functionally? What does that mean from an imaging perspective? The second important facet for the next series of studies will be the long-term follow-up. We know from the general critical care literature, that there is indeed a powerful and important entity of the post critical illness syndrome, and in COVID that's come to be called long COVID or the long hauling. We've known that even patients with general critical illness get that and to the extent that the heart plays a role in that, it implies one needs to follow these patients prospectively.
Dr. Thomas Metkus:
I think the other implication of this work for the next set of studies is that there are many biases that can be brought to bear when reviewing the pandemic literature and assuredly an editorial team sees the entire spectrum of them, but they would include, as I alluded to, careful selection of patients assuring meaningful classifications of exposure at a uniform time assuring adequate comparison groups. That's really going to be the key to doing good inference. Then, the final thing I'll add is that the next set of studies should and will integrate clinical research and clinical epidemiology with causal inference principles with using what we're learning from the basic science community, to have conceptual models about how has COVID affecting the heart at the cellular level, et cetera, et cetera, et cetera. In a sense, that community of researchers that you see coming together in this pandemic is why doing this work is very rewarding and I think meaningful. I think those are all features of the next set of studies that should include indeed epidemiologic analysis, randomized trials, and basic science analysis.
Dr. Greg Hundley:
Allan, do you have anything to add?
Dr. Allan Jaffe:
Well, I want to endorse the idea that one of the problems in this field is that patients present at different times with different clinical syndromes, because some of them have been at home, some of them have been hospitalized, some of them are recognized de novo late. One of the things that's necessary as a consistent repetitive approach so that we get consistent data, not only on each COVID patient sequentially, but also on the control group that is important. The other point I'll emphasize that Tom mentioned is that individuals who have elevated troponins who are critically ill with ARDS and most likely with COVID as well, have some sort of underlying cardiovascular disease. Often once those patients leave the hospital there, the troponin is out of sight and out of mind. COVID is reminding us by showing us the panoply of additional clinical syndromes that exist post-hospitalization. That as with ARDS, I would argue, that's a mistake. These patients need to have follow-up with cardiology to investigate what that underlying cardiovascular component is.
Dr. Greg Hundley:
Great. Well listeners, we want to thank Dr. Tom Metkus from Johns Hopkins om Johns Hopkins and Dr. Allan Jaffe from the Mayo Clinic in Rochester, Minnesota for bringing us this study regarding intubated patients with COVID-19, indicating that the myocardial injury shares many similarities to that experienced by patients with ARDS. Now listeners, we will turn to our second feature discussion on this February 9th.
Dr. Greg Hundley:
Well, listeners, welcome to our second feature discussion today. We have with us, Dr. Naveed Sattar from Glasgow, Scotland, and our guest editor, Dr. Ileana Pina from Detroit Medical Center. Welcome to you both. Naveed, we'll start with you. Could you describe some of the background that helped you formulate this study and what hypothesis did you want to address?
Dr. Naveed Sattar:
Yeah, thanks Greg. When I was watching the empirical outcomes study, I almost fell off my seat when I saw the results in heart failure, hospitalization. I actually, I sent a text to John McMurray who wasn't actually at the meeting and I sit next door to John McMurray who's obviously preeminent heart failure. I worked also with many of the fantastic heart failure colleagues, Mark Pietri, Cardic Joon and colleagues. At that time I felt, well, actually it wouldn't it be lovely, I was aware of MRI studies they've done on other drugs in heart failure and I thought, well, if this drug effects improves heart failure, well potentially, although we didn't have it amply reduced at the time or have heart failure, they've come subsequently. Perhaps it changes, lead to cardiac remodeling.
Dr. Naveed Sattar:
So we've designed the randomized placebo control trial of empirical fluorescent versus placebo and 105 patients who had heart failure with ejection fraction below 40%. We wanted big 4th ventricles as Professor McBuddy would tell me, we have lots of debates about these things to really give us adequate power follow-up for at least 36 weeks to see if we can see improvements in left ventricular installment volume or global longitudinal strain, which were our primary outcomes.
Dr. Greg Hundley:
Very nice. Great overview of the study design. Who did you enroll? I know patients with an ejection fraction less than 40%, but equal numbers of men and women, was this ischemic heart disease?
Dr. Naveed Sattar:
I think the majority of patients were male about two-thirds average age, 68, pretty much like the empirical reduced to that by half population. About 80% here had type two diabetes, about 20% had pre-diabetes. The other characteristics, the majority had class 2, NYHA Class IV heart failure, minority Class III. About a third were already on arnes. Also, the background theoretically was fantastically well.
Dr. Naveed Sattar:
The other critical thing we really did, we excluded people with atrial fibrillation because that really affects the quality of the MRI. Our group and it's a brilliant journey to be, I'm not a heart failure expert, but working with all these colleagues, they have brilliant experience in this. They know the mistakes to avoid, and one of them is, do not include people with atrial fibrillation because your MRIs will just not be readily interpretable. Also, it needs to be big enough. It needs to have big enough volumes to begin with to be able to see a change. It needs to be long enough to potentially see the remodeling. All that experience of John, Mark and Pandeep were put together in a really tight protocol. When the results came, I almost, again, fell off my seat because well, it worked. I guess, you're going to ask me about the results and what we find.
Dr. Greg Hundley:
Absolutely. Tell us about those results. We're waiting to hear.
Dr. Naveed Sattar:
Two primary outcomes were really what we saw was a reduction in the left ventricular and systolic volume index and by six mils per meter squared, and the diastolic volume index by 8.2 mils per meter squared. We didn't see a change in global longitudinal strain. We did not see changes in KCCQ or six minute walk test, but actually the reality is we now know the size of this chart is underpowered to see changes in six minute walk tests or KCCQ, in lieu of another trial that has some changes in that, but we didn't see them and I think our study was done ... I can tell you, Greg, the amount of work that went in this study, the quality control that people should look at the supplement when it comes out, the degree of attention to imaging protocols and quality control was, I think in my experience, unparalleled.
Dr. Naveed Sattar:
The team really pulled out all the stops to get this, but so the reductions in the volumes, that's probably the key thing. We think that this may reflect the reverse cardiac remodeling and that we think then fits in what you see with other drugs that benefit patients with heart failure. Because the bigger the volumes, the more people tend to die with heart failure or get readmitted. If you shrink the ventricles, that probably their contractility improves. What the actual mechanism is, I don't know, but I'm sure Ileana probably come in there in terms of discussing potential pathways. The final thing I should say is just for the internal validity or external validity, NT-proBNP did come down, suggesting less left ventricle wall stress. Schematic also went up. All the things that we've seen in the big trials was there so I think we've done a really strong, robust trial.
Dr. Greg Hundley:
Thank you, Naveed. Well, Ileana, as a guest editor, what attracted you to this paper? Then, how do you put the results from this study in the context with some of the other publications related to SGLT 2 inhibition in patients with heart failure?
Dr. Ileana Piña:
I think all of you know, that we, the heart failure community is pretty excited about these drugs and what they're doing. I also nearly fell off my chair when I saw the first EMPA-REG and I saw those curves splitting. Then, I further did that when the DAPA data came out and you see these curves split up almost immediately. What was attractive about this paper is that we really don't know how this happens. We think we do, but we really don't. We don't think necessarily that it's the glucose excretion, because that maybe happens in diabetics, but not necessarily in the non-diabetics. Yet the drugs seem to work in both. But remodeling is such a fascinating concept. I personally happen to love the concept of reverse remodeling. It's something that we in the heart failure community really believes that if we can reversely remodel the ventricle, then outcomes will get better.
Dr. Ileana Piña:
We really link them. Your proBNPs were elevated but not huge. This wasn't a very sick debilitated population. This was primarily Class II. Pretty well-medicated in background, you didn't necessarily give the doses clearly, but pretty well with percentages of RAS inhibition and everything else. Now you see that the volumes are coming down and you say, "Wow, is that what's it doing?" If it happens that quickly, because remember, we've got to explain why the curves of heart failure, hospitalizations split up almost immediately. You did show in your time of follow-up that these changes occurred during that follow-up. I am actually not at all surprised that you didn't see anything in the KCCQ because we know that first of all, the patients weren't that sick to start with so it's hard to see improvement when you don't have a lot of sickness and a six- minute walk. This group, for a six-minute walk, is going to have a very wide standard deviation. A six-minute walk doesn't really distinguish the people who are doing well. To me, it's more for the sicker.
Dr. Ileana Piña:
The fact that neither of these things change doesn't bother me at all. But I think that the next step before Greg asked me, is what's the outcome. In other words, can you tie that reverse remodeling directly to an outcome, be it mortality, which is getting argued out there, whether all the drugs are the same? Or just even the heart failure hospitalization, which I think is a very important outcome in this population. You did it well, you did it carefully, you can tell the data's very clean. You did do a little bit better with the women, so I can't scold you for that as I usually do, because you've had about 30 some percent women, which is very similar to what the big EMPEROR trial has had. I'm always fighting to get more women in the trial.
Dr. Ileana Piña:
At some point you may want to examine the reverse remodeling by gender, by sex, actually and see, even though you have a small number, you have 105 patients, you may not have enough data. But I think in the future, because we do believe that women remodel differently and reversely remodeled differently. That would be very interesting to see if there's any differences.
Dr. Greg Hundley:
Thank you, Ileana. Naveed, do you have anything to add? Ileana's really laid out on a nice course to follow forward. Do you have anything to add to her comments?
Dr. Naveed Sattar:
No, I completely agree with all of them. I think the key thing is nice that this came out straight after EMEPEROR-reduced and a year after that, for heart failure with the team that, John and colleagues were led out. I was involved in the EMPEROR-reduced so that the mechanism helps. I think clinicians buy into this concept. It does what they think drugs do to improve heart failure outcomes. I think that helps and it might help prescribing, get people the confidence that these drugs do work in a mechanism that works.
Dr. Naveed Sattar:
The only thing that I think we would love to have done is if doing the MRIs even sooner, how quickly do these actual volumes change? We think it's reverse remodeling, but maybe we need another trial doing MRIs at one month, three months just to see how quickly these volumes do actually change. Because I still think that's a bit of doubt. But having said all that, I've loved this journey working with my fantastic Hatfield colleagues, a brilliant team in Glasgow. We're now thinking about the next trial. Let's see where we get to in terms of algorithms and trials, but the diabetes, heart failure, kidney disease fraternity coming together is fantastic. I'd loved being part of that journey. So great.
Dr. Ileana Piña:
There's another interesting observation in your data was a hematocrit. It's really tiny, but the signal is there, which to me has also been fascinating. We see a lot of anemia in this population. A benefit in the hematocrit, I think, is really important. The fact that you did this with MRI, I don't think this is a good echo study, to do this with echo. I think you need the reliability and the precision of an MRI.
Dr. Naveed Sattar:
Yeah, I agree. We have other data coming up, Ileana, in terms of renal blood flow, because you've mentioned that as well at the same time, which we haven't yet analyzed. There's a lot more data which needs a good Biobank and pick some of these mechanisms. So, yeah, fantastic.
Dr. Greg Hundley:
Well listeners, this has been an excellent discussion and we want to thank Dr. Naveed Sattar from Glasgow and our guest editor, Dr. Ileana Pina from Detroit Medical Center, bringing us these results regarding the administration of empagliflozin and favorable changes in left ventricular volumes in patients with heart failure and a reduced ejection fraction.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021.
This week feature a Double Feature of Discussions. In our first discussion, author Larry Allen and Associate Editor Justin Grodin discuss the article "An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial." Then in our second discussion, author Benjamin Scirica and Associate Editor Sandeep Das discuss the Research Letter "Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control."
TRANSCRIPT BELOW
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Dr. Greg, I really love these double features that we have in 2021. Let me tell you about the first one. We are going to be talking about the EPIC heart failure trial. That's the electronically delivered patient activation tool for intensification on medications in HFrEF. Very important results.
Dr. Greg Hundley:
Yes, Carolyn. And the second feature is going to evaluate an algorithm based cardiovascular risk management program to improve lipid and hypertension control. But before we get to the double feature, how about we grab a cup of coffee and start with some of the other articles in the issue?
Dr. Carolyn Lam:
My coffee is right here and I want to talk about, guess what? SGLT2 inhibitors again for this first paper. Dapagliflozin, as we know, reduces the risk of end stage renal disease in patients with chronic kidney disease. We saw that in the DAPA-CKD trial. However, the primary and secondary preventive effects of SGLT2 inhibitors on cardiovascular outcomes have not been studied in patients with chronic kidney disease, with and without diabetes.
Dr. Greg Hundley:
Well Carolyn, remind us a little bit, what were the end points in the DAPA-CKD trial?
Dr. Carolyn Lam:
Okay, well yes. DAPA-CKD as a reminder, randomized more than 4,000 participants with chronic kidney disease to dapagliflozin, 10 milligrams daily or placebo. The primary endpoint was a composite of sustained decline in GFR of more or equal to 50% or end stage kidney disease or kidney or cardiovascular death. The secondary end points were a kidney composite outcome, the composite of hospitalization for heart failure or cardiovascular death and all cause death. Now the current paper is a pre-specified subgroup analysis where authors led by Dr. John McMurray from University of Glasgow, divided patients into primary and secondary prevention subgroups according to the history of cardiovascular disease. And results showed that dapagliflozin reduced the risk of the primary composite outcome to a similar extent in the primary and secondary prevention groups. This was also true for the composite of heart failure hospitalization or cardiovascular death and all cause mortality. The combined cardio renal benefits of SGLT2 inhibitors in patients with chronic kidney disease with and without diabetes therefore are substantial, whether there is history of cardiovascular disease or not.
Dr. Greg Hundley:
Not very nice, Carolyn. Well, my paper comes from Dr. Pradeep Natarajan and his colleagues at the Massachusetts General Hospital. And Carolyn, this study evaluated whether premature menopause is associated with CHIP. For our listeners, CHIP stands for clonal hematopoiesis of indeterminate potential and it is the age related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy. And previously it's been shown associated with accelerated atherosclerosis.
Dr. Carolyn Lam:
Yikes. Greg, is pretty much our menopause associated with CHIP?
Dr. Greg Hundley:
Well Carolyn, the investigators, among 19,606 women, they identified 418 or 2.1% with natural premature menopause and 887 or four and a half percent with surgical premature menopause. Premature menopause, especially the natural premature menopause was independently associated with CHIP among post-menopausal women. Natural premature menopause, therefore may serve as a risk signal for predilection to develop CHIP and CHIP associated cardiovascular disease.
Dr. Carolyn Lam:
Interesting. Okay. Well, my next paper really provides the first evidence for endogenous induction of type-1 protein kinase A disulfide formation in the heart and this occurring after ischemia and re-profusion in both humans and mice.
Dr. Greg Hundley:
Ah Carolyn, so tell us more about this interesting paper.
Dr. Carolyn Lam:
Well, this is from Dr. Simon from University of Oxford and colleagues who used high spatial and temporal resolution imaging modalities in conjunction with an interesting redox dead type-1 protein kinase A knock-in mouse model and demonstrated that disulfide modification targets this type-1 protein kinase A to the lysosome where it acts as a gatekeeper for two poor channel mediated calcium release and prevents inappropriate triggering of calcium release from the sarcoplasmic reticulum. In the post ischemic heart, they found that inhibition of lysosomal calcium release by these oxidized molecules was crucial for limiting infarct size and preserving cardiac function during re-profusion. All this thus offering a novel target for the design of cardio-protective therapeutics. This is discussed in an editorial by Doctors Westenbrink, Nijholt, and deBoer from University Medical Center Groningen.
Dr. Greg Hundley:
Thanks, Carolyn. Very nice. Well, my last paper comes from Dr. Nicholas Marston and colleagues from the TIMI study group at Brigham and Women's Hospital of the Harvard Medical School. Carolyn, genome wide association studies have identified single nucleotide polymorphisms or SNIPs that are associated with an increased risk of stroke. The authors sought to determine whether a genetic risk score could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors across five trials involving the spectrum of cardiometabolic disease.
Dr. Carolyn Lam:
Interesting. And these genetic risk scores are very hot. What did they find?
Dr. Greg Hundley:
Thanks, Carolyn. Among 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up of two and a half years. Across a broad spectrum of subjects with cardiometabolic disease, a 32 SNIP genetic risk score was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation, but lower CHA2DS2-VASc two scores, the genetic risk score identified patients with risk comparable to those with higher CHA2DS2-VASc two scores.
Dr. Carolyn Lam:
Wow, that really is impressive. Well, guess what? We've got some other articles in today's issue. There's a beautiful White Paper about the definitions and clinical trial design principles for coronary artery chronic total occlusion therapies and this from the CTOARC consensus recommendations by Dr. Rinfret and colleagues from McGill University. There's a Research Letter entitled, The Randomized Control Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients with Type II Diabetes. And this is from Dr. Hong and colleagues from Yonsei University College of Medicine in Korea.
Dr. Greg Hundley:
Thanks, Carolyn. Well I have an exchange of letters from Doctors Albiero and Xie regarding the previously published paper, Patent Foramen Ovale Could be a Source of Paradoxical Embolism and Lead to Adverse Outcomes in Hospitalized Patients with COVID-19 Pneumonia and DVTs.” There's also a Perspective piece to the 2020 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease from Dr. Bavry. And finally Carolyn, Dr. Tung has an ECG Challenge entitled, “Narrowing the Differential Diagnosis for a Wide Complex Tachycardia.” Well, how about we get on to both of our double features.
Dr. Carolyn Lam:
Let's go, Greg.
Dr. Greg Hundley:
Well listeners, we are here for our first feature discussion and we have with us today, Dr. Larry Allen from University of Colorado and our own associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical School in Dallas, Texas. Welcome gentlemen. Larry, could you walk us through the background that really formulated your hypothesis? And then what was the hypothesis that you wanted to test with your study?
Dr. Larry Allen:
Well, thanks again for having me. I'm a heart failure doctor. The research group that I work with has spent a lot of time on patient empowerment and think about medication prescribing for HFrEF as shared decision making. Thinking about this as a discussion between the patient and me, rather than me deciding what to do. As you know, patients are now coming into the office because they've seen direct to consumer advertising around medications, but typically those are very biased. They're advertisements that are for only patented drugs. And what I'm really trying to think about is what is my patient's overall regimen in terms of heart failure?
Dr. Larry Allen:
And so we developed a tool which was a three minute video to tell patients that they should come into their visit and be excited to have discussions about their medicines and then a one page checklist that basically said, "Here's what an optimal regimen of medicines looks like for a patient with heart failure and reduced ejection fraction and nobody's really on a perfect regimen, but these are all the possibilities that you could have." Our hypothesis was that if we delivered that to patients before the clinic visit, that it would lead to better prescribing of these drugs. Essentially we imparted on a randomized trial within our healthcare system to do that and that's what we're discussing today, the results of the EPIC heart failure trial.
Dr. Greg Hundley:
Very nice, Larry. Tell us a little bit, what patients did you enroll in your trial? And then what outcomes did you work to assess?
Dr. Larry Allen:
We're part of the UC Health System, which has 12 hospitals, but a number of cardiology clinics across the front range of Colorado. Our entire system is on a single instance of the EPIC electronic health record so we're now able to essentially automatically identify all the patients in our system who have HFrEF. We generated lists of patients who had HFrEF who were going to see a cardiology provider in clinic and then we identified them ahead of time, enrolled them in the study prospectively. And the enrollment was for them to agree to be randomized in the study and then for us to be able to collect data on them.
Dr. Larry Allen:
The patients were kind of a wide range of HFrEF. They were an average of 65 years old, about 70% of the patients were male and reflected the race and ethnicity of Colorado with 11% Blacks and about 7% Hispanics. And everybody in the study had an ejection fraction of 40% or less on their last echocardiogram or other recent cardiac study. And then they were randomized to either get this three minute video sent to them as an email or as a text link that kicked them over to the one page checklist. And then we had them come in. A 145 patients came to clinic having got the information and a 145 patients just came to clinic like usual.
Dr. Greg Hundley:
Very nice. What did you find, Larry? What were your results?
Dr. Larry Allen:
Yeah, so we found not surprisingly that the majority of patients who were in usual care had no change to their medical regimen. What we found in the patients who received the EPIC heart failure three minute video and checklist, we saw about a 19% absolute increase in intensification of guideline directed medical therapy. And then we found that most of that was actually an increase in beta blocker dose prescribing. To some extent, the cheapest therapy that could be increased on a drug that people are already on.
Dr. Greg Hundley:
Very good. Well Justin, we'll turn to you. Help us put the results from Larry's work in the context of A, management of patients with heart failure and reduced ejection fraction and then also B, tell us a little bit about what attracted you to this article and maybe even where you see some of this going next.
Dr. Justin Grodin:
Thanks, Greg. And Larry, obviously I want to echo Greg's comments by thanking you for your submission. This was a paper that we thought obviously very highly of. Greg, for your first point, we've got novel therapies, but really one of the major issues now is not can we find a newer, better drug? I think we've all come to this realization, it's scalability and implementing these therapies into our regular practice, like beta blockers, RAS inhibitors and mineralocorticoid receptor antagonists. And as Larry said, the problem now is not the quality of our therapies, it's really scaling it and getting it to everyone. It's also increasing these therapies to optimum dosages in patients that can tolerate it over time.
Dr. Justin Grodin:
And then, to answer your second question, I think some of the things that struck us by this was that this is a wonderfully simple intervention that truly does empower patients. The majority of our interventions to optimize medical therapy has been targeting the physicians, the APP, the nurses, et cetera. This is beautiful in that it empowers the patient and we are putting the ball in their court. And I think to kind of dovetail with your third question, this is a health system clinical trial and I think that tells us a few things. I think one, it provides the framework on how one could perhaps implement that in their health systems. And we'll have to see if this is something that could translate to other health systems across the country or multiple centers. But I think really the intrigue with this work is that it all comes back to empowering the patients.
Dr. Greg Hundley:
Very nice.
Dr. Larry Allen:
Greg, I wanted to just add one thing that in the heart failure community, there's this argument going back and forth about whether the lack of optimization of guideline directed medical therapies is due to intolerance or whether it's due to therapeutic inertia. And one of the things I like about this study is on face value, we're empowering patients, but the fact that by asking patients to get involved in prescribing decisions, I think one of the take home messages is that this is partially about therapeutic inertia and that as clinicians, we have a lot of things we're dealing with. And if patients come in to the clinic visit and they're motivated to make these changes actually, we can intensify the therapy.
Dr. Greg Hundley:
Very good. Larry and Justin, both one at a time here quickly, in the last minute that we have, what do you see as the next study, Larry, that needs to be performed in this space?
Dr. Larry Allen:
I see two things quickly. One is, as Justin mentioned, validating that this kind of intervention, while simple can be pragmatically deployed in other health systems and in other contexts. The second thing is how do we integrate this kind of small intervention with the larger overall care of patients? One of the concepts that I've talked a lot about over the years with others, including Len Stevenson, is this concept of an annual heart failure review, where rather than seeing people on multiple short visits where we tackle small issues, we actually create a little bit of time to stand back and take a global view of heart failure therapy and how that heart failure therapy fits into the goals of care for the patient, the other medical problems they have and where they're headed.
Dr. Greg Hundley:
Very good. Justin, anything?
Dr. Justin Grodin:
Greg, I have to agree with Larry. I think he hit the nail on the head with his first comment. At least for me from an editorial standpoint is really we like to see how generalizable this is and really this implemented in other health systems. I think that's the logical next step. I can tell you, at least from our discussions at our medical center about this manuscript since it's been published at Circulation is, is there something like this we could implement in our own health system? Or in the health systems that we're affiliated with?
Dr. Larry Allen:
And I would just add that this research and the intervention was funded by the American Heart Association under the strategically focused research network for heart failure and so we've made the interventions public they're online at the research website we have, patientdecisionaid.org.
Dr. Greg Hundley:
Well fantastic. Well listeners, we want to thank Dr. Larry Allen from University of Colorado and our associate editor, Dr. Justin Grodin from UT Southwestern, for bringing us this article, demonstrating a process that facilitates patient physician interactions to improve the administration of guideline based therapy to patients with heart failure and reduced ejection fraction. And so we're going to wind up this feature discussion and we will head to our next feature.
Dr. Greg Hundley:
And we have with us Dr. Benjamin Scirica from Brigham and Women's Hospital and our own associate editor, Dr. Sandeep Das from UT Southwestern. Benjamin, could you tell us a little bit about the background information that you used to formulate your hypothesis that you wanted to test for this study?
Dr. Benjamin Scirica:
Thanks so much first for the invitation. It's a great honor to obviously be in Circulation and to be part of this podcast. We started with the recognition that in our practice, which is similar, I think to a lot of the United States, we are not doing as good a job as we could in terms of care for a lot of the chronic cardiovascular conditions we see. And hypertension and high cholesterol are one of those clear areas where we know there are very good guidelines with clear indication for therapy in specific situations and that these drugs that are available are predominantly generic. But when we looked at our registries, we found that we were not doing as well as we thought. We felt that there are a lot of reasons for that.
Dr. Benjamin Scirica:
A lot of it was based on the fact that for something good to happen, the right thing to happen, you have to have a patient and a doctor in the same room, the doctor has to recognize that there's a problem. They have to know that there is something they can do about it. They have to be able to convince the patient or educate the patient that they should start this new therapy. They have to know how to start the therapy and then have the ability to follow up and make sure that there is longitudinal care for these chronic diseases.
Dr. Benjamin Scirica:
And that's a lot to ask for any of us when we have 15 minutes to see the patient, we may only see the patient a couple times a year at most. And so we felt that our hypothesis is, could we design a program, would be delivered remotely, that would not require a doctor in the middle of all of these decisions and that we could scale by using lower cost resources, non-licensed healthcare coordinators or navigators and pharmacists who could follow very clear treatment algorithms to be able to identify patients and prescribe the right medicines to patients at the right time, based on their cardiovascular risk.
Dr. Greg Hundley:
What was your study design? And what was your study population?
Dr. Benjamin Scirica:
This is an active, ongoing quality improvement program where our hypothesis is that by doing this, we could improve patients' lipids and cholesterol prescriptions compared to prior. And we did some analysis and we saw that a lot of these patients had not been on optimal therapy for many years, even though they've been in our system. With the limitations of not having randomization, we identified these patients and through different clinics in the different hospitals, and would either have patients referred to us by providers or more commonly go and find them within the registries and identify the patients and contact them and have them enter our program where they would usually take somewhere between eight to 12 weeks to be actively managed, to get to their goals and then they'd enter a maintenance program. The report that we do now is that the story of the first 5,000 patients who we enrolled in our program of whom about 35% were still in management at the time we presented these ongoing results.
Dr. Greg Hundley:
Roughly how old were these participants? And what was the breakdown in terms of gender or sex distribution?
Dr. Benjamin Scirica:
We found that about 12% were over 75 years old, a little over half were female. We had 71% who are non-Hispanic Caucasian and 8% who were non-English speaking. In terms of their cardiovascular risks, about a third of the patients had established cardiovascular disease, about a quarter of the patients had diabetes and about a third had an LDL of more than 190 milligrams per deciliter, but no history of ASCVD or diabetes. And then for hypertension, we really would take anybody whom the physician felt required further blood pressure management, because their blood pressure was over 130 over 85.
Dr. Greg Hundley:
And what did you find?
Dr. Benjamin Scirica:
We found that of the 5,000 patients that we enrolled, about 4,000 were in the lipid program, a little over 1,400 we're in the hypertension program, so some patients were in both programs and in the lipid patients, in those patients who achieved maintenance, we increased lipid therapy, any lipid lowering therapy, from about 78% up to 97%. And that was predominantly through statins but we doubled the use of ezetimibe from 9% to 17%. We saw a small increase in PCSK9 inhibitor use from 1% to 3%. And if we looked at LDL reductions, it was a 52 milligram per deciliter reduction in LDL from an average LDL of a 125 down to 73 in those folks who achieved maintenance. For blood pressure, again, in those patients whom we successfully treated who are about 600 patients, we saw a 14 millimeter systolic blood pressure reduction and a seven millimeter mercury diastolic blood pressure reduction.
Dr. Greg Hundley:
Wow. Well Sandeep, what drew your attention to this? And then also, how do you put the context of these results with others that really are working in this wing of data science in cardiovascular medicine?
Dr. Sandeep Das:
Great question. We have a large body of literature that suggests that the use of these fantastic evidence based therapies like statins, like blood pressure medications is poor and we really struggle to improve those numbers. I wanted to applaud Ben and his group for really taking on, in a robust way, an important topic and subject. The other thing that really attracted me to this study, there was a hypertension expert here named Ron Victor back when I first started as a fellow. Fantastic researcher and he did a project called Colloquia called the Barbershop Project about leveraging pharmacists and barbers to improve the blood pressure control of African American men in the community.
Dr. Sandeep Das:
The idea is that you get out there, you got to go to where the patients are rather than expecting them to come to you. And you got to figure out ways to engage them, activate them, get them to participate in their own care. A fantastic study, but the one thing that always, we discuss that study, the thing that always jumps out is, well how do you scale it? How do you use it in a real practice? To me was also a very exciting aspect to this. The goal is to take steps to generalize from clinical trials to real world practice, because we got to get this to patients.
Dr. Greg Hundley:
Very nice. Well Ben, coming back to you, what do you see as next steps for your research here? And then even in the field?
Dr. Benjamin Scirica:
The first is, are there other disease areas we can do this in? I think the second part is how to test different techniques to try to improve the ability to scale it to broader populations and keep the cost down. And I think it is a combination of trying to find the right tools, whether they're digital or not and the right techniques to be able to activate patients, educate them, such that they are asking the question, "How come I'm not on these medicines? How come I'm not on this?" And I think we could do a lot in terms of AB testing in there. The part that I think is challenging in these healthcare studies and quality improvement studies, is that randomization would be great. How can we do it streamline? Do we need to get consent? Can it just be that approved drug A can be tested against approved drug B because there is clear equipoise. And I think by doing that, we could lower the bar for really pragmatic randomization in practice and be able to have much more rapid cycles of improvement and optimization on therapy.
Dr. Greg Hundley:
Very good. Sandeep, do you have anything to add?
Dr. Sandeep Das:
I'll echo Dr. Scirica's called arms here that we need to have a way to do this, do trials in this space pragmatically. I agree with that strongly. I did have a few thoughts on next directions. I work in a population of the urban poor of Dallas County with a lot of my clinical time and these patients have poor health literacy so I think that one question, not question but suggestion or comment to Ben and his group would be to think hard about how you would expand this to lower resource setting or to people that would be a little harder to reach. And even as sort of an aspirational goal, how do you expand it into the community? The other question that I would have is how much of this can we get by with adherence interventions? It's one thing to prescribe, but it's another thing to figure out how to get people to adhere to meds.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Ben Scirica for Brigham and Women's and Dr. Sandeep Das from UT Southwestern, bringing us this really interesting research that has been providing early results of a remotely delivered pharmacist led lipid and hypertension management strategy that dramatically increased medication compliance and improved hypertension control and lipid management.
Dr. Greg Hundley:
On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature discussion, actually our whole issue, is going to involve the flozins, empa, dapa, et cetera, but that feature discussion will get some results from the EMPEROR-Reduced trial. Well Carolyn, how about we grab a cup of coffee and this is your area, so we're going to let you run with it today.
Dr. Carolyn Lam:
Man, and I can't wait to talk about this. Yes, the sodium-glucose cotransporter 2 inhibitors or SGLT2 inhibitors, are indeed now the foundational therapies for patients with heart failure with reduced ejection fraction. Initially developed to improve glucose control in patients with type II diabetes, SGLT2 inhibitors have beneficial cardiovascular and renal effects in patients with diabetes, HFrEF, chronic kidney disease. Well, today's issue contains two pre-specified subgroup analyses from DAPA-HF and EMPEROR-Reduced, both trials evaluating SGLT2 inhibitor effects on renal outcomes, as well as cardiovascular outcomes, by baseline renal function in patients with HFrEF. The first paper comes from Dr. Jhund and colleagues from the University of Glasgow and it is revolving around the DAPA-HF trial.
Dr. Greg Hundley:
Ah Carolyn, tell us a little bit about DAPA-HF.
Dr. Carolyn Lam:
Gladly. In DAPA-HF, the SGLT2 inhibitor, dapagliflozin, reduced the incidence of the primary composite outcome of cardiovascular death or worsening heart failure in patients with HFrEF, with and without diabetes and an estimated GFR of greater or equal to 30. Of more than 4,700 patients with a baseline GFR, 41% had a GFR less than 60. The effect of dapagliflozin on the primary and secondary outcomes did not differ by GFR category or examining GFR as a continuous variable. The pre-specified composite renal outcomes, which in DAPA-HF was a more than 50% sustained decline in GFR, end stage renal disease or renal death. Now this composite renal outcome was not reduced by dapagliflozin, but the rate of decline of GFR between days 14 and 720 was less with dapagliflozin.
Dr. Greg Hundley:
Carolyn, what's the take home message here?
Dr. Carolyn Lam:
Dapagliflozin slowed the rate of decline in GFR in patients with HFrEF, both in patients with and without diabetes. There was no difference in the efficacy of dapagliflozin by baseline renal function in preventing the risk of cardiovascular death or worsening heart failure.
Dr. Greg Hundley:
Okay, well now how about the EMPEROR-Reduced trial?
Dr. Carolyn Lam:
All right. Well, let me remind you first that in EMPEROR-Reduced the SGLT2 inhibitor empagliflozin also reduced cardiovascular death or heart failure hospitalization and total heart failure hospitalization and slowed the progressive decline in kidney function in patients with heart failure with reduced ejection fraction with and without diabetes. Now, more than 3,700 patients were randomized, of whom 53% had chronic kidney disease, defined as a GFR less than 60 or a urinary albumin to creatinine ratio above 300 milligrams per gram. Empagliflozin reduced the primary outcome and total heart failure hospitalizations in patients with and without chronic kidney disease. Empagliflozin also slowed the slope of GFR decline and the risk of the pre-specified composite kidney outcome, now defined as a sustained, profound decline in GFR, chronic dialysis or transplant, was reduced similarly in patients with and without chronic kidney disease.
Dr. Carolyn Lam:
The effect of empagliflozin on the primary composite outcome of cardiovascular death and heart failure hospitalization, as well as the key secondary outcomes of total heart failure hospitalization and GFR slope, were consistent across the broad range of baseline kidney function measured by clinically relevant GFR subgroups or by albuminuria and including patients with a GFR as low as 20. Above all, empagliflozin was well tolerated in these patients with chronic kidney disease. All of this is discussed in a beautiful editorial by doctors Carnicelli and Robert Mintz.
Dr. Carolyn Lam:
Now, can I tell you about yet another paper with the SGLT2 inhibitors? This time a pre-specified comparison of the effect of empagliflozin in patients with and without diabetes.
Dr. Greg Hundley:
Ah, great Carolyn. What did this study find?
Dr. Carolyn Lam:
Well, this is from Dr. Stefan Anker from Berlin and colleagues, including myself and of the more than 3,700 patients enrolled in EMPEROR-Reduced, 50% had diabetes, 34% had pre-diabetes and 16% had normal glycemia. Empagliflozin reduced the risk of the primary outcome similarly in patients with and without diabetes. Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total heart failure hospitalizations, on the decline in EGFR over time or on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with pre-diabetes or normal glycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome. Empagliflozin also did not lower HbA1c in patients with pre-diabetes or normal glycemia and was not associated therefore with an increased risk of hypoglycemia.
Dr. Greg Hundley:
Carolyn what's the take home message here?
Dr. Carolyn Lam:
Well, empagliflozin significantly improved cardiovascular and renal outcomes in patients with HFrEF, independent of baseline diabetes status and across the continuum of HbA1c.
Dr. Greg Hundley:
Very nice Carolyn. Well, my paper comes from professor Wai Ho Tang and it's a basic science paper. Carolyn, aberrant expression of circular RNA or CircRNA, contributes to human diseases. CircRNAs regulate gene expression by sequestering specific microRNAs. In this study, the authors investigated whether CircMAP3K5 could act as a competing endogenous microRNA-22-3p sponge and regulate neointimal hyperplasia.
Dr. Carolyn Lam:
Wow, that's interesting. And what were the results?
Dr. Greg Hundley:
Carolyn, the authors identified that CircMAP3K5 is a master regulator of TET2-mediated, vascular smooth muscle differentiation. Targeting CircMAP3K5, microRNA-22-3p and the TET2 axis, may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis as well as atherosclerosis.
Dr. Carolyn Lam:
Oh, nicely summarized. Thanks Greg. Well, we've got other papers in today's issue. There's an ECG challenge by Dr. Frész on acute coronary syndrome with tall R waves and inverted T waves in the precordial leads, an ignored entity. We have an exchange of letters between Drs. Vandecasteele and Zhao regarding the article, Cardiac Over Expression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.
Dr. Greg Hundley:
Thanks Carolyn. I have some Research Letters. The first Research Letter is entitled, “Cardiovascular Toxicities Associated with Loperamide: An Analysis of the World Health Organization Pharmacovigilance Database,” and the corresponding author is Dr. Pierre Ollitrault. The second Research Letter is entitled, “Incessant Pericarditis as a Risk Factor for Complicated Pericarditis and Hospital Admission,” and it comes from Professor Massimo Imazio. And then finally, there's a White Paper (Frontiers) for atrial fibrillation screening research priorities from the NHLBI workshop with the corresponding author being Dr. Emelia Benjamin from Boston University School of Medicine. Well Carolyn, how about we jump in to more SGLT2 and another feature discussion?
Dr. Carolyn Lam:
Yes, can't wait. Thanks Greg.
Dr. Greg Hundley:
Well listeners, we're now to our feature discussion and we have with us today, Dr. Milton Packer from Baylor University Heart Vascular Center in Dallas and also our own associate editor, Dr. Justin Ezekowitz from Edmonton. Milton, welcome and wanted to ask you first off, tell us a little bit about the background that got you to want to perform this study. And what hypothesis did you want to address?
Dr. Milton Packer:
Greg, first of all, I'm delighted to be here with you and Justin. And as everyone knows, SGLT2 inhibitors have had a remarkable track record in trials of type II diabetes, trials of chronic kidney disease and now trials of patients with heart failure and a reduced ejection fraction. And in these trials, SGLT2 inhibitors have had two important benefits. The first benefit has been a reduction in serious heart failure events, primarily a reduction in heart failure hospitalizations. And the second has been a reduction in serious adverse renal outcomes. And that has been now shown consistently in trial after trial in diverse populations.
Dr. Milton Packer:
Now we carried out a trial called EMPEROR-Reduced with was the trial in patients with heart failure and a reduced ejection fraction. It was a sister study, so to speak, with a very parallel trial called DAPA-HF, which was carried out with dapagliflozin. And both DAPA-HF and EMPEROR-Reduced were studies, were trials of SGLT2 inhibitors, dapagliflozin and empagliflozin in people with heart failure and a reduced ejection fraction. And they produced remarkably consistent results. And specifically a reduction in serious heart failure events and serious adverse renal events.
Dr. Milton Packer:
But the trial studied complimentary patient populations. We studied patients that were a bit sicker than patients in DAPA-HF. And Greg, what's really fun is that each trial designed its own case report forms so that we collected information that the investigators were really interested in and they were not necessarily the same types of information across the two trials. One of the things that was really interesting about EMPEROR-Reduced was we were really interested in these heart failure events. We wanted to understand them. We wanted to understand whether they occurred as outpatients, inpatients. If they occurred as inpatients, what kind of hospitalizations were these? Were these serious hospitalizations? Were these short term, very mild hospitalizations? This paper, the hypothesis in this paper was to take a look at what empagliflozin did in patients with heart failure and reduced ejection fraction, specifically with respect to outpatient and inpatient worsening heart failure events.
Dr. Greg Hundley:
Very nice. How many patients did you include? What were the characteristics of the study population? And what was the design?
Dr. Milton Packer:
We enrolled, randomized 3,730 patients. All patients had heart failure with a reduced ejection fraction. All were receiving all appropriate treatments for heart failure. Interestingly, 20% were receiving nephrolysin inhibitors, which is really a very high percentage, but they were also receiving inhibitors, renin-angiotensin system beta blockers, mineralocorticoid receptor antagonists and they were patients who had an average ejection fraction of about 27%, which is much lower than most heart failure trials recently. They also had meaningfully elevated levels of natriuretic peptides. These were sicker patients and they had a much higher placebo event rate. They were randomized double-blind, one to one ratio to either placebo or empagliflozin. Dose was 10 milligrams once daily. And this was added to all previously existing therapy and patients were followed for double-blind therapy for an average duration of 16 months and we recorded prospectively information on outpatient and inpatient heart failure events.
Dr. Greg Hundley:
Very nice. What did you find, Milton?
Dr. Milton Packer:
We originally reported that in this trial, there was a reduction with empagliflozin on heart failure hospitalizations and that reduction was about 30%. We wanted to know, well, what else was going on with respect to these heart failure events? And so we asked the question, well, did empagliflozin reduce urgent and emergency room visits for heart failure? Did empagliflozin change the types of hospitalizations? We recorded the use of positive inotrophic drugs, vasopressor drugs, vasodilator drugs, cardiac devices, intervention, surgical interventions. And we found out that across the entire spectrum of heart failure outcomes, there was a reduction in serious outcomes with empagliflozin and they all were around a 30% reduction in risk. They varied a little bit from about 28 to 33, but approximately all were in the same ballpark. And what was really interesting was we had a fair number of hospitalizations where patients required IV inotropic drugs, vasopressors, mechanical intervention, they were reduced by 30% with empagliflozin. Hospitalizations associated with intensive care reduced by 30% with empagliflozin.
Dr. Milton Packer:
And then we looked at outpatient events. Outpatient intensification of diuretics reduced by 30, 33% with empagliflozin. We looked at New York heart class. And what was really interesting was that patients treated with empagliflozin had a 20 to 40% greater likelihood of showing improvement in New York heart class and a 20 to 40% lower likelihood of showing worsening in New York heart class. And those benefits, we're seeing within 28 days after randomization. This early effect is really interesting and it's generated a lot of discussion. And so we looked at our Kaplan Meier curves for the composite of cardiovascular death, heart failure hospitalizations, urgent care, emergent care visits, and we found that the two curves separated quite early and reached statistical significance only 12 days after randomization. This is a very early effect. I want to add that this early separation of curves has been reported previously with beta blockers, with mineralocorticoid receptor antagonists, with neprilysin inhibitors and now we can add this early separation with SGLT2 inhibitors.
Dr. Greg Hundley:
Very nice, Milton. Well, I'd like to turn now to our associate editor, Dr. Justin Ezekowitz. and Justin you've seen a lot manuscripts come pass through your hands. What attracted you to this manuscript? And then how do you put the findings that Milton has just described in the context with the other results that we have been witness to regarding SGLT2 inhibitors?
Dr. Justin Ezekowitz:
Thanks Greg. And also, thanks Milton for letting us look at this remarkable manuscript as I do think the clinical implications for a manuscript like this are quite profound. The first thing that really strikes me is we often get worried about looking at a number of different end points. Within a clinical trial, we often don't want to have too many looks at the data because of the risk of finding something that is spurious, is high, but in this case, the way the data was collected and the exploration is quite valuable. We can look at any one of the combinations of clinical end points that actually have direct clinical relevance for a clinician and the patient. And this paper really explored that in a lot of data, in a lot of depth and also helped us by putting the caveats around these findings that this is exploration, but it does anchor it in the SGLT2 world, but also the heart failure world.
Dr. Justin Ezekowitz:
And Milton, I think one of the striking findings that you showed and it's buried in many of the great figures and tables, is that one in two patients had something happen in the next year. In the next 12 months, that patient walking into an office for a routine followup, one in two had something and the reduction was pretty remarkable across the end point. Milton, I wanted to pick your brain on this one, just to understand when you look at the intensification of diuretics, that was anything from adding another 20 milligrams of furosemide, to doubling or tripling that. Do you think these findings are pretty ubiquitous across the patients enrolled? Or do you think they're a niche finding in only some patients at the highest risk?
Dr. Milton Packer:
Well, we actually looked at that. We actually looked at whether baseline variables influenced the effect on intensification of diuretics and it was across the board. Well, let me just say, across the board in the patients that we studied and obviously can't make reference to people we didn't study, but we didn't find any particular subgroup that responded particularly well with respect to either a hospitalizations or diuretic intensification or New York heart class changes. But Justin, there's one thing that you just said that is so important. And that is, our patient population was characterized by their physicians, 70% as having class II heart failure. And a lot of physicians think that class II heart failure represents a stable population, clinically stable population. And as you said, one in two patients in our study during followup had worsening heart failure, either represented as an inpatient or outpatient event. A class II patient with heart failure and reduced ejection fraction, even though they're getting optimal medical therapy, is not a clinically stable patient.
Dr. Greg Hundley:
Very, very interesting finding. Well, just to ask each of you, maybe Milton first and then Justin next, Milton, what do you think is the next study that we need to perform in this patient population using this class of drugs?
Dr. Milton Packer:
We're really excited about a new phase of heart failure research with SGLT2 inhibitors, which is to look at the impact of these drugs in patients with heart failure and a preserved ejection fraction. DAPA-HF and EMPEROR-Reduced were trials of inpatients with hard failure and a reduced ejection fraction. But we really, about half patients with heart failure, have an ejection fraction of greater than 40%. We really need to understand what SGLT2 inhibitors can do for these patients. And here's the good news. And there are two large scale trials that are both nearing completion. And the first of those trials will be reporting out in about nine months from now with the next trial following about six months later. We will in the next 12 to 18 months, have two major large scale trials of these drugs in a population which is highly different and yet complimentary to the patients who have been studied to date.
Dr. Greg Hundley:
Justin, how about you?
Dr. Justin Ezekowitz:
Well, to compliment what Milton is suggesting, I think that's one area. And I think the other area is in implementation science. Now that we have four big classes or groups of drugs, is to how to start these and how to optimize these efficiently in the first month to two months or even three months so the patients can get the benefit for all these medications. And I think what we need to really study is how do we do that? Because we have the drugs but the implementation is where we're not quite there yet. If we get the implementation and testing, randomized strategies and how to do it, I think we may be able to help more patients globally than with the addition of even any new drug that may come out onto the markets soon or in the future, as that remains one of our challenging topics.
Dr. Greg Hundley:
Well listeners, we want to thank Dr. Milton Packer for bringing this study to us at Circulation and also our own associate editor, Dr. Justin Ezekowitz and really highlighting how the initiation of this SGLT2 inhibitor, empagliflozin, at 10 milligrams per day, in a heart failure reduced ejection fraction population with an average left ventricular ejection fraction of 27%, resulted in a 12 day, at 12 days into therapy, a separation of the development of adverse heart failure related events that was then sustained over the next 16 months.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, I want to wish everyone a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
In this issue, author Monika Safford and Associate Editor discuss the article “Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the REGARDS Study (Reasons for Geographic and Racial Differences in Stroke).” Then authors Jennifer Ho and Timothy Churchill discuss their Research Letter “Evaluation of 2 Existing Diagnostic Scores for Heart Failure With Preserved Ejection Fraction Against a Comprehensively Phenotyped Cohort.”
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia.
Dr. Carolyn Lam:
Guess what, Greg? We're going to talk to a lovely friend and wonderful colleague Dr. Jennifer Ho soon regarding her research letter on the HFpEF diagnostic scoring criteria.
Dr. Greg Hundley:
Very nice, Carolyn. Well, I've also got another feature discussion in this issue involving the reasons for geographic and racial differences in stroke. It's from the REGARDS study. But first, how about we grab a cup of coffee and jump into the next articles in the issue.
Dr. Carolyn Lam:
I've got my coffee, Greg and I'm ready to tell you about acute infection and endotoxinemia. We know that infections are a well-established risk factor for cardiovascular inflammation, increasing the risk for a cardiovascular complication within the first weeks after that infection. However, what is the mechanism underlying such an association? Well here, Dr. Soehnlein from Germany and colleagues utilized a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation. Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice.
Dr. Greg Hundley:
So, Carolyn, what did they find?
Dr. Carolyn Lam:
Well they found that neutrophils and specifically neutrophil extracellular traps controlled accelerated atherosclerosis during endotoxinemia. These neutrophil extracellular traps or NET-resident histone H2a, heightened arterial monocyte recruitment in endotoxinemia in a mechanism involving electrostatic charge interaction. The clinical implications are that therapeutic neutralization of NET-resident cationic molecules, including histone H2a by use of antibodies or peptides may protect patients at cardiovascular risk during an acute infection from secondary events.
Dr. Greg Hundley:
Wow, Carolyn. Really interesting. Well, my paper comes from Dr. David Park from New York University School of Medicine. Carolyn, elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling in the left atrium that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The authors sought in this study to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.
Dr. Carolyn Lam:
Nice. And so what did they find, Greg?
Dr. Greg Hundley:
Well Carolyn, using the Cleveland Clinic Biobank of human left atrial specimens and their mouse models, these authors found that ETV1 is down regulated in the left atrium during cardiac pressure overload, thereby contributing to both electrical and structural remodeling of the left atrium.
Dr. Carolyn Lam:
Nice. Well Greg, let's talk about what else is in today's issue. There's a Perspective piece from Dr. Delgado on “Changing the Paradigm in the Management of Valvular Heart Disease: In Addition to Left Ventricular Ejection Fraction, Focus on the Myocardium. There's a Research Letter from Dr. Lurz on closure of iatrogenic atrial septal defect following transcatheter mitral valve repair, the randomized MITHRAS trial. There's an exchange of letters between Dr. McAvoy and Dr. Kim regarding the article, Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults. And an ECG challenge by Dr. Avila on complete AV block cured by atrial pacing.
Dr. Greg Hundley:
Very nice, Carolyn. Dr. David Saadoun has an In Depth review on medium and large vessel vasculitis and Dr. Christy Avery has a Research Letter reporting on the trends in US cancer and heart disease mortality from the period of 1999 through 2018. Well, Carolyn, how about now we jump into those feature discussions?
Dr. Carolyn Lam:
Yep, double features. Here we go.
Dr. Greg Hundley:
Well listeners, this is the first of our double feature on this January 19th and we're so fortunate today to have Monika Safford from Weill Cornell in New York and our own associate editor, Mercedes Carnethon from Northwestern University in Chicago. Monika, we'll start with you. Could you tell us a little of the background information pertaining to this study and what hypothesis did you want to address?
Dr. Monika Safford:
Sure. Well, thank you first of all, for the opportunity. We've been studying social determinants of health. I think there's a lot of attention that has come on social determinants of health from health system perspectives in recent years but I think there's less of a recognition of individual practicing physicians of what they can do. What's happened is that there are population managers at most health systems and it seems like it's a fairly distant undertaking compared to day to day clinical care. We wondered whether there was a way to begin to integrate social determinants of health more in the day to day management of patients. And that was really the major motivation here was to take this fairly late recognition, I think, compared to the sociology world of the importance and the relative importance of social determinants to see if we could help clinicians actually use this information to inform their clinical management.
Dr. Greg Hundley:
Very nice. And so what was the study population that you worked with? And what was your study design?
Dr. Monika Safford:
Sure. The REGARDS study, REGARDS stands for reasons for geographic and racial differences in stroke, is a large national cohort, more than 30,000 people who live all over the 48 contiguous United States. About 44% of them are African-Americans and the rest are whites. Everybody was 45 and older at the time of their recruitment between 2003 and 2007. And we're now following them longitudinally for outcomes and among the outcomes are coronary heart disease and a causes of death. It's a terrific cohort to study racial disparities, if you're interested in differences between African-Americans and whites.
Dr. Greg Hundley:
And what did you find?
Dr. Monika Safford:
We did find, which was our initial hypothesis, that the greater the burden of social determinants that an individual is exposed to, the greater the independent risk. There's a definite graded risk. If you just simply count up social determinants, that should really be part of the social history that we're all taught to take in medical school. The greater the number, the higher the risk. And what was really quite concerning was that once you adjusted for all of the things that are available in a typical cohort study, physiologic measures, past medical history, health behaviors. There still was this massive, independent effect, 50% greater after accounting for all of those wonderful phenotypic markers that we have available in a cohort study.
Dr. Greg Hundley:
And what were some examples of these social determinants that we should all be thinking about?
Dr. Monika Safford:
Sure. Educational level. We all ask our patients, what was their educational attainment? Income has come a little bit under scrutiny. We don't typically ask our patients what's your annual household income? But there are lots of proxy markers so we are aware of what our patients can afford and can't afford when we prescribe medications. We have to know whether or not this is something that is within the realm of possible for individual patients. We should get a very good sense of what their financial situation is. Their social circumstances. Are they isolated? Do they live alone? Are we living in a state that is one of those states that doesn't really have a robust public health infrastructure? Are we living in a rural area? Are we in a health professional shortage area? Most physicians are aware of these types of variables.
Dr. Greg Hundley:
Very nice. Well, Mercy, let's turn to you. Can you help us put these findings that Monika is sharing with us today in the context with other studies that have performed really related to this topic?
Dr. Mercedes Carnethon:
Certainly. I'd love to summarize that as well as ask the question. We've known for some time that social determinants of health are associated with many different health outcomes, primarily cardiovascular diseases. We know that the access that individuals have to resources to promote their health and protect themselves really do influence what happens to them in the long run. I was extremely pleased to read this paper prepared by Monika and her group in the REGARDS study because it had many strengths that exceed those of prior studies, namely the large sample size, the significant representation of both Blacks and whites, as well as the ability to study both fatal and non-fatal outcomes. And I think that the summary provided by Monika was excellent and I would love to follow with a few questions if I might. Namely, were the social determinants similarly associated with outcomes in Blacks and whites? We know certainly in this country that the two are correlated. And I just wondered whether or not you saw similar patterns of association whereby those who had adverse social determinants of health also had higher rates of mortality in both Blacks and whites?
Dr. Monika Safford:
Yeah. Wow, what a great question. There's only so much that you can cover in one paper. In this paper, we were really focused on this concept of the burden and a simple count of social determinants of health. And we actually did not stratify by race. We didn't examine this separately by race, but that is exactly what we're doing in another similar study right now. That is a really, really important question because some of these determinants may not be similarly associated for Blacks and whites.
Dr. Mercedes Carnethon:
I'd like to follow as well, so what surprised you about the findings in this study?
Dr. Monika Safford:
Probably the biggest surprise was the difference in the association or the strength of the association between incident fatal CHD. This is primarily sudden death and this is what we all want to try to avoid because this is people who we don't yet recognize having coronary disease. And then when they die at their presentation, it's very frustrating. We sure would love to be able to intervene. We have gotten very good at intervening after people survive a myocardial infarction but the surprising thing was that the strength of this association was really much more pronounced for incident fatal CHD than it was for non-fatal MI. We don't understand the reason for that. That's a puzzling finding that we're definitely diving into as we speak.
Dr. Greg Hundley:
Monika, what do you see is the next study to be performed in this space?
Dr. Monika Safford:
What we're doing right now is we are demonstrating that this is a robust finding across a number of different endpoints. We have a very similar study on stroke, showing large magnitude of exactly the same finding. And we have one that's about to come out on diabetes, hypertension. We are really looking to demonstrate that this approach, this very simple approach of just counting up the number of social determinants, really is a cross cutting observation across a number of different cardio-metabolic outcomes, which would then lend credence to the possibility that physicians could really integrate this into their clinical care management. There's a whole host of studies that need to be done to better understand nuances such as those that Mercedes mentioned. We are really taking a deep dive into how to integrate social determinants of health on the ground into clinical care management, not just for larger health system population managers, but for individual clinicians.
Dr. Greg Hundley:
Mercedes, would you like to add anything?
Dr. Mercedes Carnethon:
I'm very pleased to see this work and I think that I really like the practical nature of it and with the counting of the social determinants of health. I think you're right that we often can go very deep in cohort studies and look at things in very nuanced way. However, I like that this presents an opportunity for clinicians interfacing with patients to have a quick and easy tool to recognize some of the background risks that they face. Thank you for this important work.
Dr. Greg Hundley:
Yes. Well listeners, we really appreciate the opportunity to speak today with Monika Safford from Weill Cornell in New York and our own associate editor, Mercedes Carnethon from Northwestern in Chicago and helping us to understand how social determinants can be used clinically to help identify those at increased risk of adverse cardiovascular events.
Dr. Greg Hundley:
Well, now we're going to turn to our second in our double feature and we'll get to that in just a moment.
Dr. Greg Hundley:
Well listeners, we're now on to our second feature discussion. It's a double feature on this January 19th. And we have with us Dr. Tim Churchill and Dr. Jennifer Ho, both from Massachusetts General Hospital in Boston, Massachusetts. Well Tim, we're going to start with you. Could you describe for us a little bit of the background related to your study? And what hypothesis did you want to address?
Dr. Timothy Churchill:
Absolutely. The background behind this study that we wanted to look at was the recent emergence of the H2PEF score and the HFA-PEFF diagnostic algorithm coming out of the European Society just about a year ago. And we wanted to look at how these two diagnostic tools perform in terms of diagnosis of HFpEF, which as we all know, is a really challenging and complicated, varied and challenging to diagnose condition. And so our specific question, as more than a hypothesis per se, was really to investigate the diagnostic performance of both of these tools against what we consider really a gold standard hemodynamic definition of HFpEF using the patients who were undergoing comprehensive level three cardiopulmonary exercise testing with invasive hemodynamics.
Dr. Greg Hundley:
Very nice. Tell us a little bit, how did you configure your study population? And what was your study design?
Dr. Timothy Churchill:
At our institution, we have a large cardiopulmonary exercise testing program and we took patients coming in from there and who had a preserved ejection fraction, which we defined in line with guidelines as 50% or above and then available transthoracic echocardiography that we could review. And we performed a detailed research over read on the clinical transthoracic echo that had been performed. And we coupled that with the lab data that was drawn on the day of the exercise test, coupled that with the medical history that was previously collated and we tried to look at a population that had all of the necessary score components to assess each of these two scores.
Dr. Timothy Churchill:
And then what we did was we calculated each of the two scores and compared their outputs against, again, as I said, what we consider our gold standard definition of HFpEF, which is a invasively defined definition that accounts for both filling pressures, as well as the relationship of the pulmonary capillary wedge pressure to cardiac output with exercise. Trying to account for the changes in the wedge with increases in flow, increases in cardiac output with exercise.
Dr. Greg Hundley:
Very nice. And just quickly, how many patients did you include in this study? And did you have an equal representation of men and women?
Dr. Timothy Churchill:
We ended up including a 156 patients and there was a female predominant in line with the overarching with both our overarching exercise testing cohort, but also in line with, I would say, the overarching prevalence of HFpEF in many other studies. We ended up with 67% women with an average age of 59 years old.
Dr. Greg Hundley:
Very nice. What did you find?
Dr. Timothy Churchill:
I would say our biggest message, our biggest takeaway was that we found that both of these scores performED quite well overall and performed in a broadly similar fashion. We did note however, that there was a significant under ascertainment of HFpEF at some of the lower scores, which we highlighted as a potential weakness in terms of using these scores for the diagnosis of community HFpEF in that there was a certain number of patients with low scores who would be classified as either not having HFpEF or a low probability HFpEF, who we found to fit our hemodynamic definition. And so we highlighted that as a potential weakness or potential consideration of these. That's one area where these scores might potentially miss people.
Dr. Greg Hundley:
Very nice. Well, let's turn to Jennifer. Jennifer you are spending much of your career helping the world understand more or bringing to light more information really in this field of heart failure and specifically focusing on patients with preserved ejection fractions. How do you put your findings here in the context with some of the other world's literature relative to patients with heart failure preserved ejection fraction?
Dr. Jennifer Ho:
Thank you, Greg. First off, I just want to say that we greatly appreciate the opportunity to participate in this podcast and on behalf of all of our coauthors, we're just thrilled to be here. I guess there are a couple of points that I would take away to try to place our study within the clinical context of HFpEF in general. Number one, we know that HFpEF diagnosis is challenging, which I think is something so fundamental to our field and needs a lot further work. But a lot of other groups have really struggled with trying to define HFpEF and really figuring out who these patients are. There's a lot of work going on there.
Dr. Jennifer Ho:
I would say that our findings really show that these non-invasive tools developed by other groups do help enrich for individuals with HFpEF and that they perform quite well with some potential of misclassification in these lower risk individuals. I'll also say that what's new in our study is that we were able to show a direct relationship of these scores and functional implications that really affect how our patients feel. And so we were able to show that these noninvasive scores really enrich for patients with lower exercise capacity as measured by peak VO2, two worse chronotropic response to exercise, and also worse hemodynamic responses to exercise. And so I think that that's really powerful in taking these noninvasive scores that have been developed by other groups and really showing that there are direct functional consequences for our patients depending on where you're scoring.
Dr. Greg Hundley:
Very nice. Jennifer, where do you think we take these scoring systems next? What do you think is the next research that needs to be performed in this particular space?
Dr. Jennifer Ho:
That's a great question, Greg. I think we do recognize that our sample may be subject to referral bias. These are all patients who were referred for clinical indications for a cardiopulmonary exercise test with invasive hemodynamic monitoring. And so I do think that validation of these scores is necessary across wider samples so we can really affirm generalizability overall. I think on a more fundamental level, so much more work is needed in the HFpEF space in general to better understand disease pathogenesis. We recognize that there's heterogeneity with respect to clinical presentation, with respect to cardiac and extra cardiac organ involvement, with respect to how we even define the disease in the first place. I think a lot of work needs to really focus on potential deep phenotyping approaches and other approaches to tease apart potential subgroups of individuals that have HFpEF that might be more uniform so we can understand all the contributors that really lead to this disease.
Dr. Greg Hundley:
Very nice. Tim, would you like to add anything?
Dr. Timothy Churchill:
I would really echo. I think the biggest immediate question in my mind would be replicating this model and or similar approaches to really using invasive validation in other contexts that may or may not have the same referral population. One of the biggest things that drove this original study originally was that many of the other validation efforts that have formed so far have been based on consensus. And so we think there's a lot of value added by the invasive hemodynamics. And so I think extending that approach, I think can offer a lot of additional value as well in different contexts.
Dr. Greg Hundley:
Very nice. Well listeners, we really want to thank both Dr. Jennifer Ho and Dr. Tim Churchill for bringing us this very informative study and helping us evaluate these new noninvasive scoring methods and comparing them with really well done invasive measures to best characterize patients with HFpEF. And then as Dr. Ho said, perhaps identify groups that further phenotyping may be indicated in other research studies to identify those that are best suited for specific therapies to improve their overall condition.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
This week's episode features authors David Kasss and Kavita Sharma as they join Greg to discuss their article "Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run. Your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
I am so excited about today's feature paper. It talks about my favorite topic, heart failure with preserved ejection fraction, or HFpEF, this time giving us really novel myocardial gene expression signatures in human HFpEF. Can't wait to go to that, but I also can't wait to share about some of the really cool papers in today's issue.
Dr. Carolyn Lam:
Now, we know that mitral valve-in-valve and valve-in-ring are alternatives to surgical reoperation in patients with recurrent mitral valve failure after a previous surgical valve repair or replacement. But, what are the outcomes after transcatheter mitral valve-in-valve or valve-in-ring procedures? And what is the clinical significance of post-procedure residual mitral stenosis or regurgitation? Well, we're going to find out in today's paper. Dr. Dvir from Hebrew University in Israel and authors examine the midterm outcomes in the Valve-in-Valve International Data registry, which is a multicenter collaboration and rolling cases performed between March, 2006 and 2020, in 90 centers worldwide.
Dr. Greg Hundley:
Wow, Carolyn. So what did they find?
Dr. Carolyn Lam:
Well, a total of 1079 patients were included with a median follow-up of 492 days. 4-year Kaplan-Meier survival rate was 62.5% in the valve-in-valve, versus 49.5% in valve-in-ring procedures. Significant residual mitral stenosis occurred in 8.2% of the valve-in-valve, and 12% of the valve-in-ring patients. Significant residual mitral regurgitation was more common in valve-in-ring patients. The correlates for residue mitral stenosis were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual mitral regurgitation was a valve-in-ring procedure. Significant residual mitral stenosis and residual mitral regurgitation were both independently associated with repeat mitral valve replacement.
Dr. Carolyn Lam:
So, significant residual mitral stenosis and/or mitral regurgitation were not infrequent after mitral valve-in-valve and valve-in-ring procedures, and we're both associated a need for repeat valve replacement, so strategies to improve post-procedural hemodynamics in mitral valve-in-valve and valve-in-ring should certainly be further explored.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my first paper, it really involves results from the American Heart Association COVID-19 Cardiovascular Disease registry, and it comes from our own associate editor, Dr. Justin Grodin from UT Southwestern Medical Center. So Carolyn, obesity may contribute to adverse outcomes in coronavirus disease, or COVID-19. However, studies of large, broadly-generalizable patient populations are still lacking in the effect of body mass index, or BMI, on COVID-19 outcomes, particularly in younger, adults remains uncertain.
Dr. Carolyn Lam:
Yeah. It is an important question. And so, what did they find?
Dr. Greg Hundley:
Well, Carolyn, obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if they're young. So individuals less than age 50 years. Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals, regardless of age.
Dr. Carolyn Lam:
Wow. An important public health message. Well, my next paper is a basic science one from doctors, Rayner and Karunakaran from University of Ottawa Heart Institute in Canada. For the first time, they investigated the role of RIP kinase 1, a coordinator of NF-kappa B inflammation and cell death, in atherosclerosis.
Dr. Carolyn Lam:
They found that RIP kinase 1 expression was highly expressed in early atherosclerotic lesions in humans and mice. In vitro, both basal and TNF alpha stimulated NF-kappa B activity, and resultant inflammatory gene expression was reduced in macrophages and endothelial cells when RIP kinase 1 was silenced. In vivo therapeutic administration of RIP kinase 1 antisense oligonucleotide markedly reduced atherosclerotic lesion size and macrophage content.
Dr. Carolyn Lam:
Together, these findings suggest that RIP kinase 1 drives inflammation in early atherosclerosis, and targeting RIP kinase 1 therefore provides a novel preventive strategy to treat atherosclerosis.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next paper comes from Dr. Kristin Stanford from The Ohio State University. So, Carolyn, brown adipose tissue is an important tissue for thermogenesis, making it a potential target to decrease the risk of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified brown adipose tissue as an endocrine organ.
Dr. Greg Hundley:
While brown adipose tissue has been implicated to be protective in cardiovascular disease to this point, there are no studies that identify a direct role for brown adipose tissue to mediate cardiac function. This study was performed to address this issue.
Dr. Carolyn Lam:
So what did they find?
Dr. Greg Hundley:
Okay, Carolyn. The authors found that transplantation of brown adipose tissue improves cardiac function via the release of the lipokine 12,13di-HOME. Sustained overexpression of 12,13di-HOME using tissue nanotransfection negated the delirious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13di-HOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13di-HOME increase mitochondrial respiration. So, Carolyn, these results identify an endocrine effect of brown fat to enhance cardiac function.
Dr. Carolyn Lam:
So interesting. Well, there are other very interesting types of papers in today's issue. There's an exchange of letters between Drs. Gui and Nahrendorf regarding the article Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes.
Dr. Carolyn Lam:
In cardiology news, Tracy Hampton highlights articles from Nature Biomedical Engineering on AI-based eye movements for cardiovascular risk prediction, from Science on the metabolic profiling of the failing and non-failing heart, and from Science Translational Medicine on the heart healing effects of extracellular vesicles.
Dr. Carolyn Lam:
There's an On My Mind paper by Dr. Pelliccia on gaps in evidence for risk stratification for sudden cardiac death in hypertrophic cardiomyopathy, as well as a Research Letter by Dr. Brown on the association of inducible myocardial ischemia with long-term mortality and benefit from coronary artery bypass graft surgery in ischemic cardiomyopathy, which is a 10-year follow-up of the STICH trial.
Dr. Greg Hundley:
Nice, Carolyn. Well, my articles: Professor Himbert has an In-Depth article on the current indications for transcatheter mitral valve replacement using transcatheter aortic valves, valve-in-valve, valve-in-ring, and valve in mitral annulus calcification. There's a Research Letter from Dr. Martin (Than) regarding the single troponin rule-out of myocardial infarction. And finally, Professor Isser has an ECG challenge involving chest pain with ST-segment elevation in a young woman with a broken heart.
Dr. Greg Hundley:
Well, now how about we proceed to that feature discussion?
Dr. Carolyn Lam:
Yay. Let's go, Greg.
Dr. Greg Hundley:
Well, listeners, we want to bring you to our feature discussion today, and we have with us Dr. David Kass and Dr. Kavita Sharma both from Johns Hopkins University in Baltimore, Maryland. David, could you tell us a little bit about the background related to this study and what hypothesis did you want to test?
Dr. David Kass:
Sure, Greg. My pleasure to be here. We have long had an interest in the syndrome we know as heart failure with preserved ejection fraction, going back, really, decades, and the difficulty in assessing what's really wrong with the heart in this syndrome has been that we get so little information from the tissue itself, that most of the studies that have been done have been done at the macro level and physiology level and epidemiology level.
Dr. David Kass:
But at Johns Hopkins, Kavita Sharma, who now heads up our heart failure transplant group, had established a clinic, a HFpEF clinic, one of the very few in the United States, and the availability of both the patients through the clinic, and then as part of this, right heart catheterizations associated with endomyocardial biopsies being obtained, was really a very extraordinary opportunity to examine tissue at a molecular level, essentially for the first time. There's been no other data set quite like this one.
Dr. David Kass:
So, we had already established both a patient population, very, very well-phenotyped, very much symptomatic, and we had a tissue bank. And as part of a consortium, a network consortium grant that was sponsored by the American Heart Association, called the Go Red for Women Network, we had a project that basically was focused on trying to better understand HFpEF.
Dr. David Kass:
The impetus was really, no one knew anything about what's going on in the heart at the molecular level. Really. There had not been transcriptomic analysis ever done before, and there were plenty of questions that we thought this might be able to answer. Among them, how really different are these hearts from patients who have, what we'll call, garden-variety heart failure, heart failure with a low ejection fraction? That's seemingly not so controversial now, but actually there's still controversy as to exactly what's wrong with these hearts, and so we thought we would be able to tease that out.
Dr. David Kass:
Then it's also been, I think, widely discussed that this is a very heterogeneous disease or syndrome, really, that has a lot of different factors, comorbidities, that are associated with it. So question two was really, how cohesive is the molecular signature that you might see in the myocardium? Is it going to be hopelessly heterogeneous as well, in which case, what does that say about our possibility to develop drug therapies when the underlying biology may be very, very heterogeneous? And if not so heterogeneous, question followup would be, what signatures might be there in subgroups that we could identify, and with subgroup analysis then, help us target in a more personal medicine fashion, ultimately, a therapeutic for the syndrome?
Dr. Greg Hundley:
Very nice. So, David, how did you assemble a study population, and what was your study design?
Dr. David Kass:
In this sense, this was very much an ongoing effort by Dr. Sharma and what was the HFpEF clinic team. Back, probably about 4 years ago, maybe even more, she had started to become interested in this and had amassed a clinic population while she was a resident, and then as a senior resident became more and more interested in this and this became her fellowship project when she was a cardiology fellow at Hopkins.
Dr. David Kass:
And by the time I became more involved with this, basically she had it in operation with study nurses and seeing patients. It was very clinically-oriented. There was some sort of more, I would say, population-level data being collected and studies being done, but nothing like quite what we did here. But that was there.
Dr. David Kass:
So, in terms of a study design, this was almost more a biobank. At this point, there was a cadre of patients she had been following. She had been following this group for some time. Basically, in a freezer we had endomyocardial biopsies under an IRB-approved protocol that had been obtained, and in part we were sort of waiting to get enough tissue together so we had a large enough data population and enough sample, and then really thinking through what might we be able to look at in these pieces, knowing full well that very little had been done. So almost anything we came up with, and we've been doing quite a few other things now as well, was going to be new, so I suppose the simplest study design of all.
Dr. Greg Hundley:
So, what did you find?
Dr. David Kass:
Well, going through those initial questions. Question number one, is there a unique molecular signature? We're looking at using what's called RNA-Seq, which is the newest generation of RNA gene expression analysis, in these myocardial biopsies. The answer was, yes, actually. There was a very unique signature. And this was all done using what we call agnostic bioinformatics approaches, where you just give the data, you give all the genes that are different between HFpEF and a control group, we had a control group, donor hearts. You look at basically the HFrEF group, the people with low ejection fraction, versus control. What are those differentially expressed genes? And of course you have your control.
Dr. David Kass:
So there are three groups and you get a series of little dots in what's called principal component analysis, and it was very clear, right from the beginning, that these groups separated, and this was just purely a statistical approach to say, are they different?
Dr. David Kass:
And then we asked further, are they still different even if we adjust for what are the common comorbidities and the things that differentiated, often, HFpEF from other forms of heart failure, specifically age, sex, having a large body mass index, having diabetes, these were all things that were more prevalent and more severe in the HFpEF group. So we adjusted for these things, again, sort of statistically, and redid this, and it's still absolutely separated. So question one, are they different at the transcript level? Yep. They're different.
Dr. David Kass:
And then, question two is basically, despite the heterogeneity, if you start digging into the genes, what kinds of genes are being differentially regulated? Is there a signature that becomes cohesive and consistent among the patients within the HFpEF group? The answer to that was, yes. And this too was very interesting because we also did an adjustment for the comorbidities, and what we found were the genes that were upregulated in HFpEF, that actually turned out mostly to be down-regulated in the other form of heart failure. Genes specifically associated with the manufacturing of ATP by mitochondria, the ATP synthase genes, those genes were significantly upregulated in HFpEF, but once you adjusted for body mass index, a lot of those pathways disappeared. So, the class of genes that were up regulated was in fact related to comorbidities.
Dr. David Kass:
Then we did the opposite. We looked at those genes that are down-regulated, and found that a large group of genes that were quite different, that are not on the tip of most people's tongues for what goes on in heart failure, mostly associated with protein processing, trafficking, autophagy, the process of protein recycling, endoplasmic reticular stress, which was something that the journal senior editor, Joe Hill, had talked about and published about earlier in the year in a mouse paper where he first came up with this idea that ER stress might be important. Well, looks like it's important in these humans. So, we found some unique signatures.
Dr. David Kass:
And then the last thing I suggested we would look at is whether we could get subsets from the molecular signatures, and the answer to that was, yes. Here we kind of threw the genes at a program and said, "You come up with clusters, purely based on the genes." That's it. No clinical information whatsoever. What it came out with were three groups, and very interestingly, there was a mortality difference between these groups just based on their transcript. One of the groups looked at pretty close, or closer, to HFpEF to reduced EF heart failure, and indeed, the genes that it came up with were typical of hypertrophy and remodeling and matrix remodeling, and that was the one with a group with the highest mortality. And then there was sort of a very different group with small hearts, relatively low levels of natriuretic peptide, an inflammatory pathway signature. Not the kind of thing we're to looking at and say, "Oh yeah, this is obviously heart failure," and yet they were equally symptomatic, tended to be a few more on the female side than male side.
Dr. David Kass:
So, I think, in the end, that study was very successful for all the things we were trying to do, really. That it's distinctive, that there are subgroups that we can identify at the transcriptome level, despite the heterogeneity, and we've got a list of genes now, pathways, really, that look to to be uniquely relevant.
Dr. Greg Hundley:
Very nice summary. Well, let's turn to your colleague, Dr. Kavita Sharma, who is also with us today and helped assemble this wonderful cohort. Kavita, how would you put these findings in the context with some of the other literature that's been published in heart failure preserved ejection fraction?
Dr. Kavita Sharma:
Hi, good morning. Thanks for the opportunity. That's a great question. The idea of trying to phenotype HFpEF has really been around, for now, a couple years, and that's driven by the fact that we have no therapeutic agents to date that have really affected outcomes in this population, in spite of the fact that half of all heart failure is classified as HFpEF and we have many therapies for HFrEF, or low ejection fraction patients.
Dr. Kavita Sharma:
And the thought is that, perhaps, it's a heterogeneous population and we're lumping to many different types of patients together. And so there have been a number of efforts to date to try to phenotype this population, but most of these have been centered around clinical comorbidities, and distinct groups have been identified, but without a clear sense of what is driving mechanistic differences between the groups, and then how to take it to the next step to target therapeutic agents to specific populations within HFpEF.
Dr. Kavita Sharma:
I think this is a big step closer to trying to really understand how we can target therapies. So, we've seen efforts at phenotyping and there are some overlap between the three groups that we identified from our RNA sequencing work, but this is now giving us a clue as to how to target mechanisms of disease.
Dr. Greg Hundley:
Very nice. Well, Kavita what do you see is the next study to perform, really, in this space, to follow your work?
Dr. Kavita Sharma:
Our goal is to really perform a comprehensive, as we call it, omics approach to phenotyping and HFpEF. We are actively looking at metabolomics, both from the blood and the tissue in collaboration with investigators at U Penn, we hope to also look at proteomics, and eventually single cell sequencing, as well as really trying to understand some of the actual myocyte-level contractility issues. And this is work that actually has just come out as well from our group, looking at sarcomere function in HFpEF from the right ventricle. Our hope is that each of these areas is going to further our understanding of myocardial deficits, so to speak, and areas that we could target for therapies.
Dr. Greg Hundley:
Very nice. David, do you have anything to add to that?
Dr. David Kass:
No. I think Kavita said it very, very well, and clearly the goal is to ultimately develop a more mechanistically-driven, personalized approach to the subsets of HFpEF so that hopefully we get a therapy that actually is going to work. These are not tiny subsets of this group. Remember this is half of all heart failure and that's a big number, and even a subgroup that might represent one-quarter of half of all heart failure is still a big number, and so none of this is ever going to be like an orphan disease suddenly where we're dealing with a very small group of people.
Dr. David Kass:
But even if it was, it would still be a major step forward, but it's not going to be that. I think what you're going to hopefully come up with, with a signature that can be targeted and with the therapy that's effective on the basis of that, is going to, I think, help a large population.
Dr. Greg Hundley:
Well, listeners, we want to thank Dr. David Kass and Dr. Kavita Sharma, both from Johns Hopkins University in Baltimore, Maryland for bringing us this new information related to RNA sequencing to really help better phenotype patients with heart failure and preserved ejection fraction, so that in the future, we may have therapies that can help this patient population.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.
This week's episode is special: To start 2021, Circulation's Digital Strategies Editor, Amit Khera, hosts a look back at Circulation's response to the Covid-19 pandemic. Circulation's Executive Editor James de Lemos and Senior Associate Editor Biykem Bozkurt discuss the initial days of Covid manuscript submissions to Circulation. Then Amit interviews author Fatima Rodriguez and her findings of racial and ethnic differences of patients suffering from Covid-19. Finally, Amit interviews authors Nicholas (Nick) Hendren and Justin Grodin as they discuss their article, which was one of the first science outputs from this AHA COVID registry.
TRANSCRIPT BELOW:
Dr. Amit Khera:
Well, welcome to Circulation on the Run. This is Amit Khera. I am digital strategies editor for Circulation, and I have the privilege of standing in for Carolyn Lam and Greg Hundley on this very special edition this week. We have no Circulation issue, so we get to use this and we thought we would use it for a really special look at COVID the Circulation response. It's a time to take a pause and reflect on what we've seen so far this year and what science and initiatives have come out of Circulation. And it's a real privilege today to be joined by first senior associate editor of Circulation, Biykem Bozkurt, who's professor of medicine at Baylor College of Medicine, and also James de Lemos. He's executive editor of Circulation and professor of medicine at UT Southwestern Medical Center. Welcome to you both.
Dr. James de Lemos:
Thank you.
Dr. Biykem Bozkurt:
Thank you, Amit.
Dr. Amit Khera:
Well, Biykem, I'm going to start with you. I remember when COVID came out, it was, we were all overwhelmed. The data were coming fast and furious. Most importantly as cardiovascular specialists we wanted to know how to manage these patients and what manifestations we're seeing. Things were coming from all over the world, and you were tasked with the challenge of, well, how do we organize and curate all this? And what can Circulation do to be most helpful in this response? And you came up with some really creative ideas that I really lodge you for. Maybe you can tell us a little bit about what was going through your mind when this was starting and what are some of the initiatives you started around that?
Dr. Biykem Bozkurt:
Thank you, Amit. And I really appreciate your pushing it to reflect. In early March it was clear that COVID was surging and we had to create a platform rapidly to disseminate the insights and the best practices from around the world in a timely fashion, and also inform future research for the fight against COVID. We discussed amongst the senior editors, and it was apparent early on that we would not have large-scale multicenter trials. And most of the information was going to come from site experiences and our cohorts, which were so valuable, and everybody was yearning for that information. With that framework in mind, we thought the best platform would be to do a call for submission of rapid research letters. And also we thought of interviews with experts from the hotspots, and we rapidly assembled a Circulation COVID editorial team, which comprised of me along with my colleagues, Salim Virani, Erin Michos, and then both of whom are the guest editors at Circulation, along with Mark Drazner, Darren McGuire and yourself.
Dr. Biykem Bozkurt:
And we created a call for rapid research letters for COVID and also started doing short video interviews from pandemic hotspots around the globe. We wanted these interviews to be dynamic, informative, conversational, both recognizing the crisis and the human factor as well as the best practices. We were so hungry for information. So we thought of a dyad approach where the interviews would be conducted by early career fellows in training, along with regional experts from the hotspots who were leading the fight formulating solutions. And we are so indebted to these experts and heroes for sharing their stories and experience on the cardiovascular presentations and the practices and how they were managing their patients. And these were called COVID updates from the front lines.
Dr. Biykem Bozkurt:
We had approximately 19 interviews with leaders from Seattle. That was one of the early hotspots. Then we moved on to Singapore because they were having such valuable and successful interventions. Then we went over to Madrid, Spain, where there was a huge hotspot, of course New York City. Then we interviewed with Milan, Italy, Brescia, Italy, Wuhan, China, New Orleans, South Korea, Salt Lake City, Paris, French, Houston, Texas, Atlanta, San Francisco, Delhi, India.
Dr. Biykem Bozkurt:
And we also try to address not only the local expert's approach to how to treat and manage and what they were seeing, but also strategically how the health disparities were being handled, how the emergency room or ICU clinicians were tackling COVID. We also try to provide a nursing perspective and even pandemic modeling. For our call for research letters we had approximately, or more than 1,000 papers submitted, 414 of those were original research letters and about 265 as research letters. So I think it was truly a gratifying experience that we were able to provide a voice for the frontline cardiovascular specialists, providing what they were seeing, what they were doing, and also a perhaps a platform that was quick enough, dynamic enough for us to disseminate information. And also a platform for publications as research letters, which are concise and addressing the issue at hand and creating a portfolio by which all the investigators could voice their observations.
Dr. Amit Khera:
Well, listen, first and foremost, that was a heroic effort and a huge volume of different components, both research components, regional research articles, research letters, and then the videos. And I'll say those videos included fellows. I know I watched many of them before I went on service and taking care of patients to learn what people were doing. And that's so different than what we do in a scientific journal where we peer review and all that. And I can't tell you how helpful that was. And then something else you said was the personal experience. I remember watching a few physicians talking about what it meant personally for them and their families and quarantining and how hard that was and the human toll. And boy, that was really amazing. And I know we'll look back on those years to come and as we think about what COVID was when it first started.
Dr. Amit Khera:
I'll pivot a little to some of the science. I think having seen this from a different vantage point, at first you weren't sure how many papers you'd get. We were all looking for sort of kernels. And then all of a sudden there's a deluge of papers, right? Can you talk to that experience about how you learned how to curate all this when it was sort of started slow and then it was overwhelming?
Dr. Biykem Bozkurt:
We knew we would get a lot of papers. We didn't realize the true magnitude. At the beginning we thought that the assigned group, which we call the COVID editor group would be able to handle this. And thus we were trying to triage and provide a structured approach to this. It was quickly clear with James and Joe's and Darren's help that we needed the remainder of the whole editorial board. I remember initially we started with that small group and immediately expanded it to the larger group for us to be able to tackle.
Dr. Biykem Bozkurt:
I think starting with March, there was a steady rise in the types of papers. The interesting concept was the observations eventually start coming with a certain repeated theme. And of course the ones who provided the initial observations usually had the innovative part of the initial, the first one to recognize it. And there was a lot of debate. For example, when we were first seeing the papers about, or the research letters about the clots we were saying, or asking the questions, "Whether these were higher than the other ICU patients and so forth?"
Dr. Biykem Bozkurt:
But as the numbers increased, it was the summation of the gestalt of I think what the papers were providing was also moving the field. So not only the volume, I think that was a very interesting experience. Of course how to deal with that on an operational level, at a journal level. But also cataloguing and creating these, okay, these appear to be myocarditis, these appear to be potentially the clots. And then recognizing the how the story's evolving about COVID. And of course, intermittently we had the commission request and ask individuals to provide reviews that are with the insights, creating the synthesis from this culmination of this large volume of papers. And I think we try to do that in a timely manner periodically.
Dr. Amit Khera:
Yeah.
Dr. James de Lemos:
Actually just how hard it was to evaluate science in the midst of a pandemic. You know, what these investigators were doing in the midst of their surges was frankly heroic in the beginning. They were terrified, didn't know what was happening in their sites and they were submitting research. But the challenge is that it's not the kind of research we're used to evaluating in Circulation in terms of very well controlled clinical studies with good control groups and clear experiments. We were forced to evaluate research in a war zone basically and decide when something was actionable enough that we thought the clinical community could get ahold of it.
Dr. James de Lemos:
And at the same time we also had to think about our mission to publish durable science that will last beyond a few weeks or few months of the pandemic. And it was a real challenge and credit to Biykem and Augie here, who's running this podcast for the nights and weekends that we're done evaluating these and the many discussions about really what's the bar for research to get published in the midst of a pandemic. None of us and any of the journalists had ever been through this before.
Dr. Amit Khera:
I think those are great points. And I may even add to that just as much as there was the wanting to get things out that would help clinicians on the front lines, also responsibility of not publishing something erroneous where people would do the wrong thing. And we've certainly seen that along the way. So that was an added challenge. James, I'll pivot to you a bit more on this, in reflection, if you think about the papers now that you'd be able to look back, what are some of the ones that you remember the most, or you think were most impactful published in Circulation so far?
Dr. James de Lemos:
Well, some of the ones at the very beginning that were really written with almost a 24 or 36 hour cycle to get information out, there was a research, a review paper rather by Nick Hendren and Les Cooper that really came out almost the first weekend after this group launched. Biykem was involved in that. It was a remarkable effort to summarize really weeks old data on the potential cardiovascular complications. And it was an instant classic. Another one I think that has been tremendously important and durable was the report from Bonnet's group in France on the MIS-C syndrome in children that has been really paradigm changing. I think it was, it won the Willerson award as our top clinical paper of the year because the editors and editorial board felt that this was the most impactful paper we published of all papers in the year. And I think it certainly was amazing work to pull together that kind of series in such a short period of time and define a syndrome really that had never been reported before.
Dr. Amit Khera:
Yeah. You know, I'm looking here out of the maybe near a 1,000 papers or so of different varieties that came through, those are certainly two very memorable ones and several others. Biykem, I'm thinking about some other articles and even some really interesting frame of reference pieces that people, just sort of personal reflections. What are some of the ones that you remember?
Dr. Biykem Bozkurt:
The sequence of how it evolved is truly, left a sort of enduring impact on me. The first one that I remember was Kevin Clarkson's paper that provided the initial review, and we all were reading that, of course. Nick Hendren and of course Mark Drazner's paper also added a larger framework of the whole spectrum of cardiovascular disease or cardiovascular abnormalities with COVID. We, I think, try to provide a right balance in terms of the research papers and have received a large scale of papers on DVT and PE. And we then clustered quite a few of those. One of which was from Wuhan, China and the others were from U.S. And that became a very nice complimentary portfolio of three DVT PE papers, which I thought was very helpful at that juncture, because that came a little bit later in the timeframe. I can't recall, I think it was around June timeframe where we were able to formulate, really, this is truly a pattern.
Dr. Biykem Bozkurt:
The other very interesting paper that I remember is a series of echocardiographic imaging of all hospitalized patients from Israel. This was published in July. This was one of the first structured screening by echocardiography of all comers to the hospital. And it was about a 100 patients and it was by Topilsky. If I remember correctly, it was published in July. And that was the first one stating that a large number of patients had abnormality in the cardiac structure and predominantly RV, which until that time it was anecdotal case reports. We were all hearing about the RV and PE.
Dr. Biykem Bozkurt:
Then I think in July we had Peter Lewis' very nice review. And of course, Damien Bonnet's the multi-system inflammatory syndrome in the pediatrics, especially how to manage it. We also had a HRS partnership on guidance for how to do EP studies during the time of COVID, and a variety of frame of references. Some of which were about certain different approaches. We had one paper about senior woman leaders as to how they were supporting their colleagues. We also had early career faculty members who had provided their frame of references about social consciousness and ethical dilemmas, all of which were a true complimentary portfolio, providing not only the scientific expertise about human factor in managing this.
Dr. Amit Khera:
Well, you certainly have a great perspective on all the articles that came through, Biykem, and listed several of the highlights and James, I'm going to pivot you and ask you, what comes next? As one of the senior editors along with Biykem for Circulation, what do we need to see next in cardiovascular space or literature as it relates to COVID? I appreciate there's also what's happening with COVID in general, but what do we need to know and what's the level and bar of science now?
Dr. James de Lemos:
The bar is back to requiring excellent science, even for COVID cardiovascular disease, really. Because we know enough about the disease that we need the best information that's clinically actionable and meet sort of usual circulation standards. And what I'd say we need next is we need long-term outcome data. So we have a lot of information about short-term cardiovascular complications of the illness, but the next wave, and we're going to get through this, right? The end, the light is on for the end of this thing. But then the next phase is what's the long-term implications of cardiac injury that occurs in the hospital? What are the cardiovascular manifestations of these long haulers? And I think that will be the kind of research that's durable really over the next few years.
Dr. James de Lemos:
I'm very, very hopeful that we won't be talking about hospitalized COVID in 2022, that that will run its course and not be a dominant theme in Circulation. But I do think we're going to need long-term follow-up of cardiovascular issues for these patients. Particularly given the subtle cardiac abnormalities that Biykem was talking about that we've been reporting in the hospital.
Dr. James de Lemos:
The other piece I would just say is that we know almost nothing about cardiovascular manifestations of non-hospitalized COVID. Almost everything that we've published and other journalists have published has been about the minority of patients that get hospitalized. But we do need to know more about the many larger proportion that never get hospitalized.
Dr. Amit Khera:
That's a nice segue when we talk about sort of high quality science and maybe slowing things down just a bit to make sure we're getting the best answers. And that's a pivot to the AHA COVID-19 Cardiovascular Disease Registry, something which you have co-chaired and spearheaded. And we recently had a milestone at DHA scientific sessions. We had the first output just in a few months to already have some high-quality research coming out, we're going to hear in just a bit from two of our featured articles that were leg breaking science out of that registry in shortly. Tell us a little bit about the inception of that registry, what led to it and sort of how did it form?
Dr. James de Lemos:
Well, the impetus was really the same as what Biykem was talking about with her nights and weekends trying to generate information for practitioners. It was that feeling of powerlessness that we all had early on, knowing that this surge was coming, developing in other parts of the country and realizing that we knew nothing and all of us felt the need to fight back. And as you know, Amit, this really grew out of work of our young people that we developed, or I should say we, meaning our fellows developed a program to teach us about COVID and to study COVID in the patients at our two teaching hospitals. And that really led us to realize that the field needed generalizable knowledge that was beyond single center experiences and their work really directly led to the idea to approach the American Heart Association about a multicenter registry and then Sandeep Das, one of our associate editors and a faculty member at UT Southwestern and I pitched this to the AHA and then we put together a great steering committee and launched this.
Dr. James de Lemos:
And I think the unique thing about this that we tried to do was in the same, we recognized that the window for discovery was short and the usual way of registry research wouldn't work. And so what we did is we democratized the process. So we allowed multiple teams of investigators to be doing science simultaneously on a secure platform at the AHA, the precision medicine platform. And that's allowed dozens of projects to forward in parallel so that within this six month timeframe we have these two papers published, but we've got a lot of other, what we hope will be important work that can still make a difference in the pandemic.
Dr. Amit Khera:
Well, thank you for that. And I won't steal this under the upcoming articles to talk more, but congratulations to you on seeing this come to fruition, all the fruits of your labor in a very short amount of time. So we look forward to seeing many, many more papers coming out of it. I want to wrap up by just saying, I know we are certainly not done with the COVID pandemic, but it is a new year by the time this podcast comes out. And so we want to make sure we have time to reflect on what lessons were learned. What we learned about scientific publishing in these really trying times. And I want to congratulate you both on coming up with some very creative strategies to be as contributory as possible to what the field needed at the time. And I think you achieved that and we look forward to continuing to learn from Circulation and from the work coming in about this pandemic and many more things to come. So thank you both for your time today.
Dr. James de Lemos:
Thank you.
Dr. Biykem Bozkurt:
Thank you.
Dr. Amit Khera:
So now we're moving on to the featured article. This is the first of two, and I'm fortunate to be joined by my colleague here, Dr. Fatima Rodriguez, who's an assistant professor at Stanford in the division of cardiology. Welcome, Fatima.
Dr. Fatima Rodriguez:
Thank you so much, Amit for the invitation.
Dr. Amit Khera:
Well, you had this really important article on racial and ethnic differences in presentations and outcomes in those hospitalized with COVID and certainly there's been a lot about racial and ethnic differences. Tell me a little bit about the genesis of this particular article. What made you decide to use the registry early on as one of the first studies to evaluate this registry?
Dr. Fatima Rodriguez:
So as you heard from Dr. James de Lemos and Sandeep Das, the American Heart Association very rapidly created this registry to democratize and accelerate the way we do research during the pandemic. And this topic of racial ethnic disparities was right off the bat selected as a priority area because of the inequities that we're seeing, and that have been magnified by the COVID-19 pandemic.
Dr. Amit Khera:
Well, there's so much that you found and when it came to who was affected and who ended up in hospital with COVID and then obviously exploring some outcomes, maybe tell us a little bit about what are some of the main findings of this work?
Dr. Fatima Rodriguez:
We had a lot of significant findings, but I would say that some of the most important findings is that black and Hispanic patients really accounted for over half of the hospitalizations and the deaths in the registry during this first data cut. A third of the patients that were hospitalized were Hispanic and a quarter were black. Asian patients that we also studied had more severe presentations when they were admitted to the hospital. We were also surprised that race and ethnicity itself was not independently associated with worse in-hospital outcomes or other adverse cardiovascular outcomes. But again, this suggests that we really need to move upstream from hospitalizations to deal with the factors that result in the higher rates of hospitalizations for these underserved communities.
Dr. Amit Khera:
You know, I think you just summarized it so well. And I think for many of us that saw this paper, we saw that there was no difference in in-hospital outcomes in general and after adjustment, which I think that was a little surprising. Maybe we shouldn't have been surprised. Or do you think that perhaps looking at all the sort of media and the press about adverse outcomes we should have thought differently, or do you think this is the actual finding that one can expect?
Dr. Fatima Rodriguez:
Yes, we were surprised as well. And our hypothesis was that race and ethnicity would be independently associated with worse in-hospital death, but also mace. But it actually turns out there have been many publications across many different sites in the United States that have documented similar findings. Again, the caveat being here is that these patients were hospitalized and as a clinician you and I know that once people get in the hospital, at least for a disease like COVID-19, the care is fairly protocolized. And more of the variation mortality has to do with where these individual patients are hospitalized. And again, not surprising with the new disease that there's a lot of in-hospital variation. So not to say that there aren't disparities, but at least the hospital itself does not seem to be a cause of disparities and outcomes by race and ethnicity.
Dr. Amit Khera:
I mean, that's an incredible important finding to your point about once you get to the hospital people seem to do comparably well. So I think you said this in your conclusion as well. We really need to work upstream and is also profound that 58% were Hispanic or non-Hispanic black that were hospitalized with COVID. What are some of the upstream things we could be doing?
Dr. Fatima Rodriguez:
Yes, and this finding has been consistent across many studies. And I think that this reflects the over representation of these communities and the essential workforce, right? People that are not able to isolate. People that need to show up to work every day. People that live in multi-generational households and therefore exposed to the virus and higher rates of transmissions. So first I would say we need to try to do things to prevent the transmission in the first place in the communities. For essential workers they need to be provided the protective gear to again prevent them from the transmission. And now things are different then when we did this study. Now we have a vaccine that's about to be rolled out that we were discussing before, and we really should prioritize these communities in the vaccine rollout as well.
Dr. Amit Khera:
All great points. And as we drill down a little deeper into some of your findings, I think one that really stuck out to me was how much younger the Hispanics and non-Hispanic blacks were. I think average age of 57 and 60 versus 69 in non-Hispanic whites. Tell me a little bit about your thoughts on what is driving that younger age as well?
Dr. Fatima Rodriguez:
Yes, I agree that that was a fairly striking finding, especially Hispanic patients were on average 57-years-old compared to non-Hispanic whites who were 69-years-old when they were hospitalized. So more than 10 year difference. Again, I think a lot of this reflects the nature of the workforce and help individuals are higher rates of getting exposed, but also likely reflect some of the underlying co-morbidities. Remember, these are patients that are sick enough to require hospitalization. And again, we know that individuals that have higher rates of diabetes, obesity, and other risk factors have a higher tendency to be hospitalized.
Dr. Amit Khera:
You know, you also looked a bit at Asians, I should mention that. I think some of the findings were increased respiratory complications and perhaps some issues related to delayed some of the observations around Asian patients.
Dr. Fatima Rodriguez:
So the Asian patients did comprise a smaller portion of our registry, but again, still a notable finding that they tended to be sicker at time of presentation. We developed a cardio-respiratory disease severity scale specific to COVID, modified from the WHO scale. And again, found that patients even after adjusting for all other factors did tend to have a higher disease severity when they came in. One of the hypothesis of why this was the case is that they tended to have longer delays from symptom onset to both hospital arrival and to the diagnosis of COVID-19. And our study didn't look up why, but there have been some other studies that have suggested perhaps that there's been some hesitation in the Asian community to seek medical care for a variety of factors.
Dr. Amit Khera:
You know, and I think as we try to think about what are some implications of this work and what are next steps that could be one is to how do we enhance understanding of the need for prompt care in the Asian community, that could be one take home. One other tantalizing finding was this observation of less Remdesivir use amongst non-Hispanic blacks in this study, you made a point of that. What do you make from that, and what are some of the reasons you think are for that?
Dr. Fatima Rodriguez:
Absolutely. And we were interested in looking at how COVID-19 specific therapies varied by race ethnicity. And of course, things have changed dramatically in this area. As an example, Hydroxychloroquine was the most frequently used drug, and we know we don't use that right now in practice because it's not recommended. However, and Remdesivir is one of those drugs that does have fairly good evidence to use. And we saw that less than 10% of patients in our registry were on Remdesivir during the study period, with black patients being the least likely to be on this drug. Part of this may be explained by the lower rates of clinical trial participation among these patients, and then the other may be just higher rates of comorbidities. But again, might preclude the use of this drug. And we actually have a paper coming out from our registry, exactly looking at the differences in clinical trial participation by race and ethnicity.
Dr. Amit Khera:
Well, certainly look forward to seeing that. I think that would be an important followup to this. So I guess, leaving you the last word. This was I think a really important finding, helping us understand where the problem is, if you will. Actually there's numerous problems, but your point about upstream focus. So what's next? What do we do next in this field in terms of helping eliminate these disparities that we're seeing in COVID-19?
Dr. Fatima Rodriguez:
Yes, our hope when we started this registry is that we would have nothing to say at this point, this far along in the pandemic. I will also say one point that we didn't discuss is that mortality was high, and it was high among all groups. So we still have work to do in the inpatient setting to lower mortality, especially as the pandemic continues. But again, our work really suggests that we need to move upstream and focus specifically on vulnerable and marginalized communities, such as racial ethnic minorities to try to prevent the high rates of COVID-19 infection, and in particular high rates of severe COVID-19 infection.
Dr. Amit Khera:
Well, that was a fantastic review. And congratulations again on this leg-breaking science at the AHA sessions and one of the first early manuscripts coming out of the AHA COVID-19 registry. So thank you again, Dr. Rodriguez. It was a true pleasure to have you on today.
Dr. Fatima Rodriguez:
Thank you so much, Amit.
Dr. Amit Khera:
And now for our second featured article, we have Dr. Nicholas Hendren, who's chief cardiology fellow at UT Southwestern Medical Center and Dr. Justin Grodin, who is an assistant professor in the heart failure transplant section at UT Southwestern Medical Center. Their articles entitled Association of Body Mass Index and Age With Morbidity and Mortality in Patients Hospitalized With COVID-19, also from the AHA registry and also a late breaker at the AHA scientific sessions. Welcome gentlemen, and congratulations to you both.
Dr. Justin Grodin:
Thank you.
Dr. Nicholas Hendren:
Thank you.
Dr. Amit Khera:
Well, I'm going to jump right in, this obviously was a really exciting article. One, because of course it's timely with COVID. Secondly because it's one of the first science outputs from this AHA COVID registry, so we're all very excited about it. And importantly, really impactful findings I felt. So maybe I'll start with you, Justin. Tell us out of all the different questions and people were working on this registry, how did this sort of move to the top? What was the impetus behind this question?
Dr. Justin Grodin:
Well, I mean, I think the answer really lies from clinical experience. I think as you know, Amit, and as Nick knows, we quickly understood as the pandemic evolved that in addition to what we would call more traditional risk factors like cardiovascular disease, diabetes, hypertension, et cetera, and old age, we noticed that the young individuals that were hospitalized with this disease were actually more likely to be overweight or obese in comparison with their older counterparts. So really based on those empiric clinical observations we hypothesized that that would certainly influence outcomes for those that are in the hospital or ill enough to be in the hospital with this disease. As most COVID research has gone, we're basing kind of a hypothesis based on pure clinical assertion. So that was really, the origin was very organic and really based at observations made at the bedside.
Dr. Amit Khera:
I think that makes a lot of sense, and as you pointed out, with COVID drinking from the fire hose initially and hearing a lot of reports about interplay of obesity. But I think the value here of the registry was which was systematic curation and acquisition of patient data. So definitely makes a lot of sense why you pursued this. And I think what you found first and foremost was that the prevalence of obesity was higher in your patients hospitalized with COVID than those from exchange of the U.S. population. And then I'll turn to you, Nick. Tell us a little about what you all discovered, what happened with these folks with obesity? What was the course? What were some of the findings?
Dr. Nicholas Hendren:
You know, as Dr. Grodin mentioned, we were really interested at the intersection between the obesity epidemic and the COVID-19 pandemic. And they're major questions focused on two parts initially, which is, are people who are obese at increased risk of dying in the hospital? And the second part being, if you're hospitalized and obese, are you more likely to be intubated? And the answer to both of those after adjusting for the traditional risk factors like age, renal function, et cetera, were yes. And so what we observed was that people who are younger than 50 and severely obese, that means a BMI greater than 40, were at increased risk of dying. And that includes young people who otherwise might not think that they were high risk of dying. And then we observed that your body mass index, if you're obese, again a BMI greater than 30, puts you at increased risk of ending up on the ventilator unfortunately.
Dr. Amit Khera:
So really I'm going to dig deeper here as you all did in this paper. At first, obviously the prevalence of obesity was higher. Secondly, as you pointed out certain complications like being on the ventilator and I think VTE and other complications, and then some really interesting finding was this interaction with age. Maybe, Nick, tell us a little bit more about that age interaction.
Dr. Nicholas Hendren:
I think a lot of people are familiar with that age is one of the strongest, if not the strongest risk factor for dying from COVID-19. And what we were interested in was, if you adjust for age and try and take away the association between age, what is the risk of obesity in and of itself? And so we looked at patients that were less than or equal to 50 years old, kind of 51 to 70 and older than 70 years old. And really wanted to look at for those individuals that are obese in those age groups, what are their outcomes? What is their risk? And what we observed was that if you're older than 70 and obese, your risk of dying is probably not all that different by BMI. But if you're younger than 50 and obese, your risk is significantly higher if you're obese than if you were normal weight for that age group.
Dr. Amit Khera:
It's pretty fascinating this age interaction, that obesity seem to be more of a bad actor, if you will, in young people than it was an older people. And Justin, why do you think you find that? What was the rationale or biology there?
Dr. Justin Grodin:
You know, Amit, I think that's a great question. And that's a question that we were asking ourselves. As with other diseases, individuals that are more obese tend to be younger in general. So it's very unusual to see somebody that's older that is otherwise obese. So we do see a little bit of an imbalance in the age distribution, favoring higher obese groups in those that are younger. And that certainly could have influenced some of the observations that we saw. And then I think what's perhaps more interesting is, really what makes these young people that we would otherwise think would be low risk, high risk? What is it about obesity that portends a higher risk with COVID-19?
Dr. Justin Grodin:
And Nick and I, we speculated in the manuscript and really the reasons are threefold. At least we think, obviously it could be more than that. But number one is that we all know that obesity can be associated with metabolic diseases, diabetes, and whether or not there's some subclinical or undiagnosed form of that that is also contributing to risk in these people mediated by obesity could be one possibility.
Dr. Justin Grodin:
The second is actually directly related to the SARS-CoV-2 virus itself in that the ACE2 receptor is actually abundantly expressed in adipocytes. And so we know that obese individuals have more adiposity perhaps putting them at higher risk. And then the third reason is that individuals that are more obese actually have just more mass on their thorax and that might influence some of their pulmonary dynamics and might put them at increased risk for adverse events.
Dr. Amit Khera:
All certainly great hypotheses, and obviously further things to test. I'm looking at your conclusions and essentially you reminded us that preventive strategies in obese people regardless of age is something we need to focus on. So I think that's a really important take home point. Last question. Do you, Nick, I want to first congratulate you. I know way back when we were just thinking about the problem of COVID and begin to collect our own data and that germ of an idea really snowballed into this idea of the AHA COVID registry, and you had a critical role in that. I remember talking to you and you were putting in data on nights and weekends. How does it feel now to see the output of your work really so quickly and so such impactful work after doing all this labor and working so hard to get this up and running?
Dr. Nicholas Hendren:
Well, I think anytime you're able to have at least a small amount of success or something that's felt to be valuable to the contributions, it's always a nice thing. And it was such a team effort all the way through and from the American Heart Association to our attendings, Dr. de Lemos who spoke earlier and Dr. Grodin and all of our team members. And so it's really impressive how the entire field of medicine and cardiology has come together and try and battle COVID across all lines. And so to contribute to that in even a small way is hopefully helpful. And hopefully people will read our information and make choices that will help keep them safe and keep people out of the hospital and doing well off the ventilators.
Dr. Amit Khera:
Well, thank you. And congratulations to you both on a really fantastic work and impactful paper. And that's it for me, I'm Amit Khera, digital strategies editor for Circulation covering for Carolyn Lam and Greg Hundley, who you'll hear from next week. Thank you all for enjoying our podcast today.
Dr. Amit Khera:
This program is copyright of the American Heart Association 2021.
New in 2021, we will feature 2 Feature Discussions every other week. For this week, we start with author Michael Gold and editorialist Sana Al-Khatib as they discuss the article "Primary Results from the Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low Ejection Fraction (UNTOUCHED) Trial." Then, we switch to an important discussion about children and COVID-19 as author Israel Valverde and Associate Editor Gerald Greil discuss "Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Greg Hundley:
And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we have two features in this issue.
Dr. Carolyn Lam:
I know.
Greg Hundley:
Yeah. And I've got the first one. It's going to be evaluating the acute cardiovascular manifestations in 286 children with multi-system inflammatory syndrome.
Dr. Carolyn Lam:
Wow. That is so important in the current pandemic. Well, the other is also so important. It's really, really critical results from the subcutaneous ICD trial called UNTOUCHED. I think that one might change clinical practice. So, do you want to tell us about other papers first?
Greg Hundley:
Yes. Carolyn, I'm going to grab my cup of coffee and we'll get started and my first paper comes from China. Professor Junbo Ge. So Carolyn PCSK9, mainly secreted by the liver and released into the blood elevates plasma load density lipoprotein cholesterol by degrading LDL receptors. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, as well as the underlying mechanisms still remain unclear.
Greg Hundley:
So this group detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin a2b beta-3 activation, alpha granule release, spreading and clot retraction. They also investigated the underlying mechanisms. Using myocardial infarct models, they explored the effects of PCSK9 on microvascular obstruction and infarct expansion, post myocardial infarction.
Dr. Carolyn Lam:
Oh, nice. And what did they find?
Greg Hundley:
Well, Carolyn, PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, as well as myocardial infarct expansion post MI by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors, or aspirin, abolished the enhancing effects of PCSK9 supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.
Dr. Carolyn Lam:
Wow. Very interesting. Indeed, the pleiotropic effects. Well guess what? My paper talks about the first non-LDL lowering treatment that has been shown to reduce CABG in a blinded randomized trial. Greg, can you guess what that treatment was? Well, here's a hint, here's a hint. It's the REDUCE-IT trial.
Greg Hundley:
Well, Carolyn, thanks for the hint. It must be icosapent ethyl.
Dr. Carolyn Lam:
Indeed, indeed. As a reminder, REDUCE-IT was a multicenter double-blind placebo controlled trial, which randomized statin treated patients with elevated triglycerides, controlled LDL and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl at four grams daily or placebo. The primary and secondary composite end points were significantly reduced. The current paper examined all coronary revascularizations, recurrent revascularizations and revascularization subtypes. First revascularizations were reduced by icosapent ethyl versus placebo with a hazard ratio of 0.66, which is a number needed to treat of only 24. Similar reductions were observed in total revascularizations and across elective, urgent and emergent revascularizations. Icosapent ethyl significantly reduced PCI and CABG with a hazard ratio of 0.61. So, icosapent ethyl reduce first and total coronary revascularization, including PCI and CABG in patients with elevated triglycerides and high cardiovascular risk despite well controlled LDL. Isn't that cool?
Greg Hundley:
Very nice Carolyn. Well, my next paper comes from Professor Kari Alitalo, from the University of Helsinki. So Carolyn recent discoveries have indicated that in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. The author set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B or VEGF-B in the heart and the effect of VEGF-B on recovery from myocardial infarction.
Dr. Carolyn Lam:
So what were their results?
Greg Hundley:
Well Carolyn, the myocardial VEGF-B trans-gene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in sub-endocardial myocardium in adult mice and structural and functional rescue of cardiac tissue after myocardial infarction. So VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue. Well, Carolyn that's all of the main articles. How about we turn to some of the other articles and letters in the issue?
Dr. Carolyn Lam:
Yeah. Why not? And Greg, let me start by talking about an exchange of letters between Dr. Wei and Dr. Fox on interpreting the net clinical benefit from rivaroxaban plus aspirin versus aspirin for chronic vascular disease. There's also an ECG challenge by Dr. Patel elusively entitled, A Rainy Day. Here's a hint, it's about hypothermia. In cardiology news by Bridget Kuhn. She talks about how the pandemic throws cardiovascular trials off course, there is an On My Mind paper by Dr. Most entitled, The Striking Similarities of Multi-system Inflammatory Syndrome in Children and a Myocarditis-like Syndrome in Adults: The overlapping manifestations of COVID-19. As a couple of Research Letters, one by Dr. Malhotra on Defining the Normal Spectrum of Electrocardiographic and Left Ventricular Adaptations in Mixed Race, Male, Adolescent Soccer Players, as well as by Dr. Qi on adherence to a healthy sleep pattern and incident heart failure, a prospective study of more than 400,000 UK Biobank participants.
Dr. Greg Hundley:
Very nice Carolyn. Well, I've got a primmer review of Cardiac Involvement in Multi-system Inflammatory Syndrome in Children with the corresponding author being Dr. Kevin Freedman. Well, how about we get off quickly to those next two feature discussions?
Dr. Carolyn Lam:
Yay! Let's go, Greg.
Dr. Greg Hundley:
Well, listeners, we are to the first of our double feature for the new year 2021. And with me is Israel Valverde from King's College in London and our own associate editor, Dr. Gerald Greil from UT Southwestern in Dallas. Welcome gentlemen. And as we get started Israel, could you tell us a little bit about the background that framed this study and the hypothesis that you wanted to address?
Dr. Israel Valverde:
Thank you. I mean, the main problem we had in Europe around April 2020, was that both the Center for Disease Control and Prevention in the U.S. simulated a clinical ALIT about a newly described immune disease and inflammatory syndrome in children associated with a COVID infection. And there were similarities with all the well-known syndromes, such as viral myocarditis, Kawasaki disease, Kawasaki shock syndrome, and toxic shock syndrome, that we were a bit of confused, because of the overlap in clinical presentation, because it was a true diagnostics challenge. So the hypothesis in this study is we wanted to describe the cardiovascular implications in this newly described sinus syndrome.
Dr. Greg Hundley:
Very nice. So tell us a little bit about your study design and what study population did you assemble to address this question?
Dr. Israel Valverde:
I think that was the most difficult thing in the study, because thanks to the Association For European Pediatric Cardiology, the APC, we coordinated a multicenter study involving all they would appear on centers that we were 55 centers from 17 countries all over Europe. And we were able to recruit 286 children with this new newly described syndrome and cardiovascular manifestations.
Dr. Greg Hundley:
And tell us, what did you find?
Dr. Israel Valverde:
I think we can summarize that in three main findings. First is that cardiac involvement is very common in children with multi-system inflammatory syndrome associated with coronavirus disease, 2019 infection. Second, that inflammatory markers were significantly raised in most children, particularly their C-reactive protein, ferritin, pro-calcitonin, N-terminal pro BNP natriuretic peptide, interleukin 6, and D-dimer level. And finally, that 65% of patient with MIS-C had evidence of previous infection with severe acute respiratory syndrome coronavirus too, either by PCR, immunoglobulin M or immunoglobulin G.
Dr. Greg Hundley:
Were there any particular aspects of your results that may have segregated to the boys versus the girls?
Dr. Israel Valverde:
Not really. We couldn't find any differences between boys and girls, because our study population was quite similar, but we couldn't find any differences between them. What we found is that there is a huge difference between children and adults.
Dr. Greg Hundley:
And what was the age range of these children?
Dr. Israel Valverde:
From a couple of weeks, until 18 years old.
Dr. Greg Hundley:
And no differences in the scope of the syndrome that they experienced in the younger children versus the-
Dr. Israel Valverde:
Initially we found two peaks. Similarly to the peaks of viral myocarditises, which is affecting more of the children below two years, and also adolescence.
Dr. Greg Hundley:
Well Gerald, multi-system inflammatory syndrome in children. How to results from this study compare with perhaps other inflammatory disease processes that have been observed in children, such as Kawasaki disease, et cetera.
Dr. Gerald Greil:
So we and Circulation were very lucky to get a bunch of submissions regarding a MIS-C and also have a radio article regarding this and I would like to point our readers towards that. I think the key issue is it's a new disease entity. The community is pretty clear about it, that other diseases like Kawasaki disease have similarities, but it's not the same thing. And we wanted to be very clear about this. Obviously, more things need to be investigated, but the key findings where Dr. Valverde pointed out in other study groups within the U.S. and within Europe, all point to the same direction, that is a new entity, we need to further investigate.
Dr. Greg Hundley:
How about the cardiovascular aspects, what differences in cardiovascular disease with this syndrome, again, relative to other perhaps inflammatory diseases that might affect the heart in children?
Dr. Gerald Greil:
As far as we know. And once again, when we're talking about a very preliminary data, is that the outcome in children having MIS-C usually good. Dr. Valverde pointed out in his study series of more of 286 children, there was only one death and recovery was pretty high rate. We have similar findings from U.S. groups, other findings from a group in Paris and Europe. So, I would like to point our readers to other summaries where it's pretty clear that it's a new disease entity. Overall, it's actually rare in children. So we want to make a pretty clear point that it's a rare disease, which at this point in time seems to have a good outcome.
Dr. Greg Hundley:
Well Israel, I'm going to come back to you. What do you see is the next study that should be performed perhaps in this general area of cardiovascular disease for children?
Dr. Israel Valverde:
So I think what we have learned is that the way to move forward is the collaboration between centers. So now that we have a large study multicenter group, our idea is continue describing the long-term outcomes of the study population, because most of them recovered, but a few of them keep, for example, coronary artery dilatation. So do they recovering when you have time until you have time, do they do the ejection fraction, the function of the heart go back to normality soon? Or do we have to wait? So I think that's the next step forward to probably the long-term outcome of the study population.
Dr. Greg Hundley:
Longitudinal follow-up. And Gerald, do you have anything to add to that?
Dr. Gerald Greil:
I would just like to reiterate what Israel said, that we need to focus on multicenter studies. I hope Circulation can be a platform to reunite different groups around the world. Because as I mentioned before, I think we have a new disease entity in front of us. We don't know the long-term outcomes. And in the interest of our children confronted with new disease, we need to be very, very careful to learn how we need to follow up these children and how we potentially need to treat them in the long-term.
Dr. Greg Hundley:
Well, listeners, this has been a fantastic discussion with Dr. Israel Valverde from King's College in London and our own Dr. Gerald Greil from UT Southwestern, revealing some aspects of this multi-system inflammatory syndrome that's associated with COVID-19 in children. And so, on behalf of Carolyn and myself, well, we've got to get to the next feature. So, I'm not going to let you go just yet. Well, listeners, we are in the double feature year 2021. In our second feature discussion today, we have Dr. Michael Gold from Medical University of South Carolina and our own associate editor, Dr. Sana Al-Khatib, who has written an editorial on this paper. And she is from Duke University. Welcome to you both. Michael, we'll start with you. Could you describe for us a little bit about the background related to this paper and what hypothesis did you want to address?
Dr. Michael Gold:
Well, thank you. And thank you for this opportunity. The implantable defibrillator is a fundamental aspect of the treatment and prevention of sudden cardiac death. It's been around for almost 40 years now and is commonly used in the system has evolved from being a surgical procedure, requiring a thoracotomy to a transvenous procedure in which leads could be placed into the heart. While it's very effective, the major limitation of this in many people's minds were, major limitations were both of complications associated with the transvenous lead. Those include infections and lead failures, as well as unnecessary or inappropriate shock to patients. And based on that, the subcutaneous ICD was developed as the latest iteration of this technology in which a lead is placed under the skin and tunneled up along the sternum, so that one could sense and shock the heart when necessary without being subjected to an intravascular lead.
Dr. Michael Gold:
And the device has been around for 10 years or so. It's proven to be effective, but primarily used in niche populations of younger patients, patients with poor vascular access and those considered at relatively low risk with few comorbidities, such as patients with Brugada syndrome or long QT syndrome or possibly hypertrophic cardiomyopathy. We felt it was important both to establish the role of the subcutaneous ICD in a more typical group of defibrillator patients, as well as with the multiple evolutions now of programming, as well as technology within the device of seeing if the more modern contemporary devices were as effective in these sicker populations, and also could reduce some of the issues seen earlier in terms of higher rates of inappropriate shock therapy.
Dr. Greg Hundley:
So Michael we're working with subcutaneous ICDs. What was your study population and how did you design this study to really test the efficacy of the subcutaneous ICDs relative to the more conventional transvenous lead systems in these high-risk patients?
Dr. Michael Gold:
So what we did was to first identify a population and the most common population price of the implantation in the United States have for sure, in many of the countries is primary prevention patients and low ejection fraction. So we restricted the study to patients with an ejection fraction less than 35% and primary prevention, meaning have never had an episode of sustained ventricular tachycardia or cardiac arrest. So starting with that population, this was a prospective large registry. The bandwidth was out there to do a very large randomized trial, which was just done, although not as in a sicker patient population that study called PRAETORIAN was going on simultaneously. And what we decided was to be aggressive if you will. And we defined our endpoints for the study by looking at identified studies previously with transvenous ICDs that have the most contemporary programming and the lowest risk of inappropriate shock.
Dr. Michael Gold:
So we used the MADEIT-RIT study, which most people probably would consider it to be the ultimate, if not one of the two contemporary studies for that. And we wanted to essentially compare head-to-head results with that, obviously without those specific patients, but using that as in some ways a historical control or benchmark. So, we set what we wanted to use as our performance goal based on the MADEIT-RNT study for inappropriate shocks, as well as looked at complication rates, using performance goals that have been well-established by the FDA. And we use an 18-month time window, because that's a time when most inappropriate shocks as well as most complications will show up with this device.
Dr. Greg Hundley:
So what did you find?
Dr. Michael Gold:
So, what we found was first that we accomplished the goal of having patients who were had much more comorbidities or sicker, if you will. A majority of patients of the over 1,000 patients in the study had ischemic heart disease. I mean, ejection fraction, it was down 26%. In perspective, the early studies of the S-ICD, I mean, ejection fractions are 40% higher, almost 90% of patients have heart failure rather than a third of patients in previous studies and the incidents of diabetes, kidney disease, hypertension and other things with two to three times higher than what would have been done or shown in any early registries of the S-ICD. So we're very pleased about that. Again, there were over 1,100 patients in this study. And what we showed was that at 18 months, the inappropriate shock rate for the whole population was only 4%, hopefully 2.7% annually, which is quite low compared to any other S-ICD study and was very favorably compared with the MADEIT-RIT study easily met the performance goal for that.
Dr. Michael Gold:
And if we looked at that subgroup of patients who had generation three of the most modern of the S-ICD devices that have a newer discrimination algorithm, that number even became lower than that. So again, very, very reassuring to see what we found there and for the generation three device, it was only 2.9% of patients in 18 months had any inappropriate shock for that. And if we then looked at the other aspects of it, the all shock rate for appropriate and inappropriate shock was only 10% of 18 months, which meant the performance goal for that as well. And what's important about the all shock rate is that it's nice to show that the device can defibrillate a patient in the lab when you're testing them. And this was successful in 98, 99% of the time, which is typical for transvenous or subcutaneous devices. But when we looked at spontaneous arrhythmic events, it was highly effective, 100% of VT storms, and all but one case of a VTVF episode was converted with defibrillator, that one case actually spontaneously converted, but was officially listed as a failure, because it didn't convert right away.
Dr. Michael Gold:
But no patients had a cardiac due to ventricular fibrillation that could not be successfully treated or ended up requiring external defibrillation. And finally, despite a much sicker population, again, if you will, we showed that at 18 months, the overall complication rate from the device was only about 7% in total, which again is very low compared to what we'd expect to see with other devices. And no patient developed a bloodborne infection or a true lead failure, which is one of the major complications that, and dreaded complications of transvenous devices.
Dr. Greg Hundley:
Well, Sana as our editorialist, what stood out to you as being really important findings in this study?
Dr. Sana Al-Khatib:
First of all, I want to start by congratulating Michael and his team on the completion of this important study. And I agree that this has been a really important addition to the armamentarium of studies related to subQ-ICDs. We have had registries in the past. In fact, Michael alluded to the publication of the PRAETORIAN trial, which was really the first trial to compare the S-ICD with the transvenous ICD in a randomized control trial design. However, despite the important contributions of the PRAETORIAN trial, there were several things that remain unaddressed or unanswered in terms of the rate of the end points, especially in appropriate shocks with the newer S-ICD models. So where we had an abundance of those in the UNTOUCHED study, and then really the important question of do the results of that trial, which was largely not done in the United States, apply to the average patient, seen in the United States.
Dr. Sana Al-Khatib:
And then could those results be extrapolated to sicker patients, because as Michael very nicely highlighted that those patients were not as sick as patients that we see in routine clinical practice. So from my perspective, those are the findings of the UNTOUCHED study are really important, because we now have confirmation that the S-ICD is actually effective and safe in a patient population representative of the average patient seen in clinical practice in the U.S. with a primary prevention indication for the ICD, no really sicker patients, good representation of women, black patients. So overall, I think this trial really gives me a reassurance that the subcutaneous ICD is safe and effective, that the rate of inappropriate shocks with the newer generation of ICDs is really low. That said, I just wanted to highlight a couple of points that I'm hoping to see more data on as we go forward.
Dr. Sana Al-Khatib:
The study was only 18 months long. It would be good really to have a longer studies. Again, the average age of patients enrolled in the trial was on the younger side in the 50s, and I would love really to see more data on the S-ICD in older patients. And also as Michael said that these results were obtained in patients who had a primary prevention indication for the ICD on the basis of systolic heart failure. Well, we have other patient populations. And especially with, for example, patients with hypertrophic cardiomyopathy, where the rate of inappropriate shocks might be higher, and it would be great to see even more data as we go forward on that patient population and other subgroups of patients that were not included or not well-represented in the trial, but overall a really important trial.
Dr. Greg Hundley:
Very nice Sana. And Michael, just swinging back to you, what do you think are some of the next studies that might be performed in this space?
Dr. Michael Gold:
No, I think that Sana made some nice points. I should point out that, in its, I think appropriate vision, the FDA require as long-term evaluation of devices and studies. So the S-ICD post-approval study, which I'm fortunate enough to be involved with as well, is a five-year followup study. We've already published a little bit on two and three-year data, but we will have five-year data on this device in a patient that is closer to the S-ICD than the early registries. It was not restricted to just low EF patients, but it was a U.S.-only study of over 1,500 patients. So, a larger study that has the typical distribution of patients that we see in a U.S. practice who would be eligible for the S-ICD, those without pacing indications and both primary and secondary prevention patients. So I think that will be very important.
Dr. Michael Gold:
Where the technology is going is largely, there will still be iterations of longer battery life, smaller devices and those things, but there's been a real push to be able to also provide pacing therapy without the need for intravenous leads. So there are several models and systems approaches being used, including adding a lead-less pacemaker that will communicate with a subcutaneous ICD or placing a lead under the sternum, still extra vascular with the capabilities of pacing. So I think the next sort of group of trials will likely be seeing on this device other than simply looking at other populations in a little more depth will be further expansion of the technology to allow for a greater use of a device for those patients who may require a pacing.
Dr. Greg Hundley:
Well listeners, we want to thank Dr. Michael Gold from Medical University of South Carolina and Dr. Sana Al-Khatib from Duke University, our editorialists for describing this study. And in regards to those, or in regards to subcutaneous ICDs, providing confirmation that these devices are both effective and safe, particularly in a U.S. population for primary prevention of sudden death and really a high-risk patient population with low ejection fraction. On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the Run. This program is copyright of the American Heart Association, 2021.
This week's episode features author Peter Schwartz and Associate Editor Sami Viskin as they discuss the article "Exercise Training-Induced Repolarization Abnormalities Masquerading as Congenital Long QT Syndrome."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to learn a little bit more about long QT syndrome and whether or not those that are athletes should continue exercise training. Maybe some can and before, we thought that they couldn't. But before we get to that, how about we take a look at some of the other papers in this issue.
Dr. Carolyn Lam:
Wow, that was a good hook, Greg. But yes, I want to tell you about this first paper, which is all about weight loss and changes in body composition. So, we know that intentional weight loss is associated with a lower risk of heart failure and atherosclerotic cardiovascular disease, especially among patients with type 2 diabetes. However, what is the contribution of baseline measures and longitudinal changes in fat mass versus lean mass and waist circumference to that risk of heart failure and myocardial infarction in patients with diabetes?
Dr. Carolyn Lam:
Well, investigators led by Dr. Pandey from UT Southwestern and colleagues evaluated more than 5,000 adults from the Look AHEAD Trial without prevalent heart failure. Fat mass and lean mass were predicted using validated equations and compared with DEXA measurements in a subgroup. Adjusted Cox models were then used to evaluate associations of baseline and longitudinal changes in fat mass, lean mass, and waist conference over one and four years follow up with the risk of overall heart failure, HFpEF, and HFrEF and myocardial infarction.
Dr. Greg Hundley:
Interesting, Carolyn. So, what did they find?
Dr. Carolyn Lam:
So, among patients with type 2 diabetes and who were overweight or obese, fat mass and lean mass could be estimated using anthropometric equations with good overall agreement compared with DEXA, so that's the first finding. Next, a decline in fat mass and waist conference, but not lean mass, were each significantly associated with a lower risk of heart failure, but not myocardial infarction.
Dr. Carolyn Lam:
Furthermore, a decline in waist circumference was significantly associated with a lower risk of HFpEF, but not HFrEF. Fatness and waist circumference may represent key modifiable targets for lifestyle interventions to reduce the risk of heart failure with preserved ejection fraction in type 2 diabetes. Cool, huh?
Dr. Greg Hundley:
Yeah. Very nice, Carolyn. Well, my first paper comes from Professor Davide Capodanno, and it's examining self-expanding bioprostheses for TAVR. So, Carolyn, there are few randomized trials comparing these bioprostheses for transcatheter aortic valve replacement or TAVR, and no trials have compared TAVR bioprostheses with the supra-annular design. So, this SCOPE 2 trial was designed to compare the clinical outcomes of the ACCURATE neo and the CoreValve Evolut valves.
Dr. Greg Hundley:
Now, it's a randomized trial performed at 23 centers in six countries between April 2017 and April 2019. And patients greater than 75 years with an indication for transfemoral TAVR as agreed by the heart team were randomly assigned to receive treatment with either the ACCURATE neo, so there are 398 of those patients, or the CoreValve Evolut bioprostheses, also 398 patients. The primary endpoint powered for non-inferiority of the ACCURATE neo valve was all-cause death or stroke at one year. The key secondary endpoint powered for superiority of the ACCURATE neo valve was new permanent pacemaker implantation at 30 days.
Dr. Carolyn Lam:
Okay. So, what were their results?
Dr. Greg Hundley:
Well, Carolyn, the transfemoral TAVR with the self-expanding ACCURATE neo did not meet non-inferiority compared to the self-expanding CoreValve Evolut in terms of all-cause death or stroke at one year. And was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACCURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and one year. Cardiac death at 30 days was 2.8% versus only 0.8% with the CoreValve Evolut. And moderate or severe aortic regurgitation at 30 days was 10% versus only 3% and they were significantly increased again in that ACCURATE neo group.
Dr. Carolyn Lam:
Wow. Okay. Thanks for that, Greg. Well, my next paper is from the basic science world. Dr. Colucci from Boston University Medical Center and colleagues tested the hypothesis that sarco/endoplasmic reticulum, calcium ATPase or SERCA, which is a major regulator of calcium homeostasis in the heart, whether or not it plays a critical role in mediating mitochondrial calcium and mitochondria-dependent apoptosis in response to reactive oxygen species.
Dr. Carolyn Lam:
So, in adult rat ventricular myocytes expressing an oxidation-resistant mutant of SERCA in which the cysteine-674 was replaced by serine. Mitochondrial calcium and the rise in mitochondrial calcium to exposure to an oxidant were decreased as was apoptotic myocyte death by mitochondrial pathways. Mice with the same SERCA mutation were protected from adverse cardiac remodeling, apoptosis, and progression to heart failure following chronic aortic constriction.
Dr. Greg Hundley:
Mm-hmm (affirmative) Carolyn, so this is another one where I get to ask you, what were the take home messages and what were the clinical implications?
Dr. Carolyn Lam:
I thought you'd ask that, Greg. So, these findings indicate that by contributing to sarcoplasmic reticulum calcium load, the chronic oxidative activation of SERCA may play a critical role in promoting the adverse effects of hemodynamic overload leading to pathologic remodeling. These findings illustrate the importance of post-translational modifications of SERCA and raise the possibility that the expression of a redox-insensitive form of SERCA may be of value in the treatment of heart failure.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next paper also comes from the world of basic science and looks into the mediators of atrial fibrillation. So, as some background, Carolyn, ibrutinib is a Bruton's tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. But it also increases the risk of atrial fibrillation, which remains poorly understood.
Dr. Greg Hundley:
So, the investigators performed electrophysiologic studies on mice treated with ibrutinib to assess the inducibility of atrial fibrillation. In human subjects, again, one of the strengths of some of these basic science papers in Circulation, the pharmacovigilance database or VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of atrial fibrillation.
Dr. Carolyn Lam:
Oh, that's really interesting, Greg. So, it seems like these authors were working toward understanding the mechanism of atrial fibrillation in those receiving ibrutinib. So, what did they find?
Dr. Greg Hundley:
Right, Carolyn. So, the authors found that using chemoproteomic profiling they were able to identify a short list of candidate kinases that was narrowed by additional experimentation, leaving C-terminal Src kinase or CSK, as the strongest candidate for ibrutinib-induced atrial fibrillation. Cardiac-specific CSK knockouts in mice led to increased AFib, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AFib associated with kinase inhibitors blocking CSK versus non-CSK inhibitors with reporting odds ratio of eight. So, Carolyn, perhaps CSK inhibition is the mechanism by which ibrutinib leads to atrial fibrillation.
Dr. Carolyn Lam:
Wow. That is convincing. Well, there are other really nice papers in today's issue. First, there's a research letter by Dr. Iglesias on the effects of fentanyl versus morphine on ticagrelor-induced platelet inhibition in patients with STEMI, the PERSEUS randomized trial. There's also a research letter by Dr. Young entitled the characteristics and outcome of COAPT eligible patients in the MITRA-FR trial. Another research letter by Dr. Zhang on specific modified mRNA translation system.
Dr. Greg Hundley:
Very nice, Carolyn. Well, I've got an exchange of letters by Dr. Spal, Whitlock, and Kebabs regarding the article, Impact of Left Atrial Appendage Exclusion on Short-Term Outcomes in Isolated Coronary Artery Bypass Graft Surgery. And then our own Mark Link discusses changes for practicing physicians regarding the new AFib guidelines.
Dr. Greg Hundley:
And finally, Dr. Vera Bittner has a perspective piece on the new 2019 ACC/AHA Guidelines on the primary prevention of cardiovascular disease. So, this new primary prevention guideline two fills a critical gap by pulling together and updating, as appropriate, guidance on nine topic areas of risk assessment, diet, exercise and physical activity, obesity, type 2 diabetes mellitus, blood cholesterol, hypertension, smoking cessation, and aspirin use.
Dr. Carolyn Lam:
Nice. Well, Greg, guess what? That brings us to the last issue in 2020. Can you believe it, Greg? It's been just so great working with you. It's been such a privilege working with Circulation. And, drum roll, new for 2021, Circulation on the Run is returning with a new format. Watch out for it. Let me give you a hint, it's going to come with a double feature per issue. Isn't that great, Greg?
Dr. Greg Hundley:
Absolutely. Some of the things that you hear folks really enjoy those opportunities we have with authors to review their papers. Well now, with many of the issues next year, we'll have two feature discussions.
Dr. Carolyn Lam:
Exactly. So, you've been listening to Circulation on the Run, but we've been listening to you, too. So, join us again in 2021 for our new features and new format. Thanks.
Dr. Greg Hundley:
And yes, Carolyn, but first, we've got to go and listen to this issue's feature discussion and talk about that long QT syndrome, exercise training-induced repolarization abnormalities. They can masquerade, perhaps, as long QT syndrome.
Dr. Carolyn Lam:
Cool.
Dr. Greg Hundley:
Welcome, listeners, to our feature discussion today. And we're very fortunate, we have Prof. Peter Schwartz from Istituto Auxologico Italiano in Milan and our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center. And we're going to be reviewing exercise training induced repolarization abnormalities, masquerading as congenital long QT syndrome. Well, first Peter, we'd like to start with you. And could you tell us, or provide us with some of the background information of why you wanted to perform this study and what hypothesis did you want to address?
Prof. Peter Schwartz:
The background is a very simple and I've been involved in the long QT syndrome since exactly 50 years. And as a partial result of that, I developed the idea that usually I... despite my making many errors in many areas, usually I don't miss the diagnosis of long QT syndrome. As a matter of fact, the study that you're publishing now is the result of a complete serendipity. It was not planned. We had to no hypothesis. It simply started because at one point I entered the impression that we might've made a diagnostic error and this bothered me very much.
Prof. Peter Schwartz:
It all started about eight, 10 years ago. When in some cases of our patients in whom we had made a clear diagnosis of long QT syndrome. At their yearly controls, we found that the LQT had been completely normalized. So I was pretty upset about it because I couldn't understand it. And my first reaction a natural reaction was to blame my associates, "We have made a mistake. You've did an error. There was an error in measurement." But as a matter of fact, there were no errors.
Prof. Peter Schwartz:
So I start thinking, "What the hell is going on here?" Now we are in a fortunate position because due to my long standing activity in the long QT syndrome, we are a referral center for all cases or most cases in Italy where people are suspected have the long QT syndrome. In Italy by law, anyone who wants to practice any type of sport at an amateur level or pro-competitive level, needs to have an eligibility certificate. So they have to go to sport doctors and it eases when the problems arise because not infrequently these doctors with somewhat limited experience in diagnosing prolongation and abnormalities in the QT intervals, are worried to make a mistake because a mistake can be a fatal one if the subject allow them to practice pause or die suddenly on to field. So they tend to refer them to us.
Prof. Peter Schwartz:
And so the advantage in my position was that we had a large number of these kids or young people coming to us. When I started to realize that it was not one accident, but another accident, another situation where these young people who clearly had to stop training in an intensive way, because they will no longer allowed by the sport doctors to practice sport. And the normalization of the T-wave abnormalities of the QT interval. I said, "Well, I mean, there must be something here."
Prof. Peter Schwartz:
So we start collecting the data, increasing the numbers, and I think it should be evident there was no design. I mean, it was a clinical observation that was evolving with time, but with adequate numbers. And then of course at one point we start following it more carefully, everything. And these led to the actual numbers that, in my opinion, were sufficiently strong to junior agents in need to publish it and to give a message because essentially this situation in one in which is very possible that even good and experienced doctors make a mistake. And the mistake could be a very bad thing, because if you miss the long QT syndrome and there is, of course, the patient is at risk of dying. But if you leave it, someone is affected and he is not affected, you are affecting his or her quality of life because they cannot practice sport, you generate anxiety. So a proper diagnosis is important. This was the basis of our study.
Dr. Greg Hundley:
Very good. So, it sounds like you're going to be performing a cohort study. Can you describe for us a little more specifically, how many subjects did you include? And who did you include in this cohort? And what measurements did you address?
Prof. Peter Schwartz:
So essentially we looked at the consecutive cases, sent to us by sport doctors with a suspicion of long QT syndrome. They were, if I remember, correctly 310 such individuals about 100 were found not to have the long QT syndrome. And these doctors were concerned they made the wrong measurement and measurement error. All the things that happened that are very well-known. About the remaining 200 in, I think about 120, we had a genetic confirmation of the long QT syndrome. We found disease causing mutation. So, that was pretty clear.
Prof. Peter Schwartz:
Then we had a group of individuals who are genotype-negative. We know very well. I mean, I proposed this thing in 1979, 1980, confirmed it in 1999, that there are some individuals affected by the long QT syndrome. But whoever I did a normal QT interval and that's a possibility, who are genotype-negative.
Prof. Peter Schwartz:
So, it's not surprising that in some cases we have genotype-negative individuals, but with a pattern so clear in terms of long QT syndrome that will make it to diagnosis. Within this group of genotype negative, there was another, let's call it a subgroup. I think it was about 15, 18% of the entire group who were genotype-negative, no family, sorry, neither had an event, a typical, absolutely typical electrocardiographic pattern with a fairly long QT interval QTc in the range of 490. So clearly prolonged significant repolarization abnormalities.
Prof. Peter Schwartz:
But when they were stopped in terms of exercise within three, four or five months, their pattern normalized completely, the QTc went back to normal, repolarization abnormalities disappeared. So this is the group on which we did focus and focusing for the next studies. And in some of them, when we told them, "You don't have the long QT syndrome, is a reaction that we interpret is due to the mechanical stretch of your heart because of very intense exercise training."
Prof. Peter Schwartz:
Some of them did return to practice sport in a very intensive way and all these patterns reappeared again, proving, I think this was the most important point. I mean, shows that you can go back and forth if you stretch the heart in this way, the abnormalities reappear.
Prof. Peter Schwartz:
So this is the essence of the study that carries in my opinion, a number of practical implications, because I think that now, when we are dealing with these youngsters, where we would be making a complete diagnosis. In some cases, I actually started even beta blockers, which is... I mean, afterwards it turns out to be an error and it bothers me, because I don't like to make an error with these patients. But they were so clear. I mean, I could have bet anything that they are affected by the long QT syndrome. But within four or five, six months, they were completely back to normal.
Prof. Peter Schwartz:
So the essence of the studies that we think the youngsters who practice intensely sport, some of them react to these physiological similar situation in an abnormal way. In analogies like with the food allergy. I mean, if you take something that bothers you and the point is, then you just avoid it. With exercise, of course is more difficult for other reasons, but probably it's the quantity of exercise.
Prof. Peter Schwartz:
Now, one change I've observed in recent years is that for youngsters practicing sports, a lot of things have changed. I've done a lot in sports myself soccer, tennis before moving toward golf. But in our days we were just playing, yes, we were playing a lot. But what has changed now is that all these kids have a trainer. They are sent for regular exercise two hours a day, five days a week. And that is probably too much for some of them.
Prof. Peter Schwartz:
So we need to recognize that there are certain individuals who, for whatever reason, I suppose that there is a genetic predisposition tend to react to these excessive amount of exercise training with abnormalities in their electrocardiogram. And for them, probably the logical thing is to reduce the amount of exercise. I would not stop it completely, they should reduce the dose and then have probably a normal life.
Prof. Peter Schwartz:
This is also raises the analogy with drug-induced long QT syndrome. When you have a parent in normal individuals who take any drug that contains an IKr blocker and they could develop to a certain point and the long QT syndrome. Now the situation with exercise is probably not so severe. I don't think the risk is so high, but clearly it is people have a tendency to react to possibly a variety of stimuli with QT prolongation. so they should be more careful about it.
Dr. Greg Hundley:
You know, I'll tell you, I think the world thanks you for your just observational skills and working through that whole situation that you observed in a very precise, organized fashion to bring us this interesting result. Well, Sami, can you help... Obviously this caught your eye as an associate editor at Circulation. What else attracted you to this study? And how would you like to comment on what Dr. Schwartz has just provided to us?
Dr. Sami Viskin:
Well, in Circulation, we were immediately attracted to this study, especially coming from Peter. Peter has been a pioneer in the entire area for long QT for many, many years. We call him Mr. QT because of his contributions to the field. So we're immediately interested in the paper, which is fascinating. It came a few months after we had reviewed a different paper that deals with patients who have the positive-phenotype, for long QT syndrome and have negative-genotype.
Dr. Sami Viskin:
That was a paper published in the July issue of Circulation with senior author Connie Bezzina. They performed a genome-wide association study to 1,800 patients with long QT, and they compared them with 10,000 healthy individuals. And what they found in these patients who represented 11% of the entire long QT syndrome population was that even though they do not have mutations, they tend to have several genetic variance together. None of them is severe enough to cause the disease but present by itself when they were in their group together in a single individual, then they create the phenotype of long QT syndrome, which is as severe as the phenotype of those who have bona fide mutations.
Dr. Sami Viskin:
So, that article was like the background for this one. And in fact, one of the arguments one could do is that the athlete's described by Peter could just have phenotype-positive, genotype-negative long QT, but what Peter would make sure to stress is that they do have electrocardiogram, but not only they do not have symptoms, they have a low pre-test probability of having the disease because they were discovered by screening and also they have a negative family history. So it's a different group of individuals what Peter is describing here. And time will tell. I mean, I'm sure we will be seeing more publications on this, and I will tell you, it's probably that we just looking at a new form of acquired long QT syndrome. Time will tell.
Dr. Greg Hundley:
Very nice. Just briefly, both gentlemen, maybe in 20 seconds or so, what do you think is the next study that needs to be performed in this new group that's been discovered?
Prof. Peter Schwartz:
Greg, we have already started the next study. We are going to compare 700 relatively younger athletes who have intensive exercise and who have a completely normal QTc and completely normal T wave to all our subjects that have defined these phases in our study that performing a similar level of exercise show these changes. And then we are collecting their DNA, and we're going to have an whole exome study for the possibility of identifying some genetic markets that might predispose to something like this.
Prof. Peter Schwartz:
One possibility that I'm interested in is the possibility that the underlying mechanism, maybe something related to the so-called sex activated trainers, which might lead to an increase in intracellular calcium and produces alterations. There are other possibilities, but this is one. And in doing this study, we are also going to begin to look at echocardiography and imaging to see if there are different patterns in terms of mechanics that might contribute to explain.
Prof. Peter Schwartz:
So the point is that on the one hand we wanted and we did confirm the clinical data. So, we know that we are dealing with a factor and we think that's a fact as practical implications for management. Now, the next questions, which I wish to attack as well is why is it, what is the underlying mechanisms?
Dr. Greg Hundley:
Very good, Sami.
Dr. Sami Viskin:
That exactly the direction we were expecting to see if they have a similar polygenic risk score factor as in the study by Bezzina.
Dr. Greg Hundley:
Very nice, well listeners, this has been a wonderful discussion. And we also want to thank Dr. Peter Schwartz for all of his efforts for many years in this area of long QT syndrome and bringing this new finding to light that there is now an observation that not necessarily are all long QTs. Number one of the 300 subjects, 100 actually didn't have it. And then there are some that are phenotype-positive, but not genotype-positive. And we have more to learn about the variance that swings with the presence of the long QT after strenuous exercise. Well, on behalf of Carolyn and myself, we want to thank Peter, thank Sami Viskin and wish all of you a great week. And we will catch you next week on the Run.
This program is copyright the American Heart Association, 2020.
This week's episode features author Adnan Kastrati and Associate Editor Dharam Kumbhani as they discuss ticagrelor or prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature Ticagrelor Prasmul in patients with ST segment elevation myocardial infarction undergoing primary PCI. More on that story later, though. How about we grab a cup of coffee and look at some of the other papers in the issue. Would you like to go first?
Dr. Carolyn Lam:
I would. And actually, I'm going to talk about two papers and they're all about BET, BET or promo domain, an extra terminal epigenetic reta proteins. And in particular, this one called BRD4. Now these proteins have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecular BET protein inhibitors, such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet genetic studies elucidating the biology of BET proteins in the heart have not been conducted. Well, at least until this week's issue where we have not one, but two papers, both elegantly using mouse genetic studies.
Dr. Carolyn Lam:
In the first from Dr. Srivastava from Gladstone Institute of Cardiovascular Disease in San Francisco and Dr. Jain from Perlman School of Medicine in Philadelphia and their colleagues, they found that BRD4, that particular BET epigenetic reader protein, forms a transcriptional regulatory module with GATA4, a lineage determining transcription factor in cardiomyocytes. This BRD4 GATA4 module was a critical orchestrator of mitochondrial bioenergetics in the adult heart.
Dr. Greg Hundley:
Well Carolyn, that is a wonderful summary. What are the clinical implications?
Dr. Carolyn Lam:
Identification of this new BRD4 interaction partner, such as GATA4 could provide new insights into developing epigenetic based therapies for heart failure. And the second paper is from Dr. Joseph Hill and Thomas Gillette from University of Texas Southwestern Medical Center and their colleagues. And what they found was that BRD4 was essential to the maintenance of mitochondrial electron transport chain function via transcriptional regulation of a nuclear mitochondrial gene network. BRD4 heterozygous deletion resulted in delayed heart failure, whereas pharmacological BRD4 inhibition using JQ1 induced modest changes in mitochondrial genes suggesting potential cardiac toxicity in targeting BRD4 at baseline.
Dr. Greg Hundley:
So what does this mean for us clinically, Carolyn?
Dr. Carolyn Lam:
As more potent and specific inhibitors are developed targeting BRD4 for clinical settings in oncology and other diseases, we must carefully monitor bezel cardiac performance for functional and mitochondrial deterioration. Important clinical message there.
Dr. Greg Hundley:
Great job, Carolyn. Well, my first paper is entitled "An Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaques" And it comes to us from Dr. Tomas Neilan and his colleagues at the Mass General Hospital. The study was situated in a single academic medical center. And Carolyn in this paper, there are actually three studies described. First, there's a primary analysis that evaluated whether exposure to an immune checkpoint inhibitor during treatment for cancer was associated with atherosclerotic cardiovascular events among 2,842 patients versus 2,842 controls that were matched by age, a history of cardiovascular events and cancer type.
Dr. Greg Hundley:
In the second study, a case crossover analysis was performed with an at risk period defined as the two year period after, and the control period as the two year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events including myocardial infarction, coronary revascularization, and ischemic stroke. And secondary outcomes included the individual components of that primary outcome.
Dr. Greg Hundley:
Finally, in the third study in this paper, there's an imaging stub study of 40 individuals, and it looked at the rate of atherosclerotic plaque progression compared from before and after starting the immune checkpoint inhibitor. All study measures and outcomes were blindly adjudicated in this third study.
Dr. Carolyn Lam:
Wow, a three in one. That really sounds novel. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. In the matched cohort study, there was a three-fold higher risk for cardiovascular events after starting an immune checkpoint inhibitor. There was a similar increase in each of the individual components of the primary outcome. In the case crossover study, there was also an increase in cardiovascular events from 1.37 to 6.55 per hundred person years at the two year time point.
Dr. Greg Hundley:
And then lastly, Carolyn, in the imaging study, the rate of progression of total aortic plaque volume was three fold higher after immune checkpoint inhibitors from 2.1% per year to 6.7% per year after receiving these agents. The association between immune checkpoint inhibitor use and increased atherosclerotic plaque progression was attenuated with the concomitant use of statins or corticosteroids.
Dr. Carolyn Lam:
Wow, Greg. So I suppose what all this shows is that we need to be aware of the cardiovascular risk prior to, during and after treatment with immune checkpoint inhibitors and perhaps, you know, optimize these cardiovascular risk factors. Thank you, Greg.
Dr. Greg Hundley:
You bet. Well, Carolyn, my next paper is from Dr. George Vlachojannis from University Medical Center at Utrecht. These authors conducted a randomized control multi-center trial in the Netherlands enrolling STEMI patients planned to undergo primary PCI. Now patients were randomly allocated to receive in the ambulance before transfer a 60 milligram loading dose of Prasugrel, either being crushed or as integral tablets. The independent primary end points were thrombolysis in myocardial infarction, TIMI three flow in the infarct related artery at initial coronary angiography, and complete greater than they go to 70% ST segment resolution one hour post primary PCI. The safety end points were TIMI major and bleeding academic research consortium, or BARC, greater than three bleedings and secondary end points included platelet reactivity and ischemic outcomes.
Dr. Carolyn Lam:
Nice trial design. So what did they find?
Dr. Greg Hundley:
Well, Carolyn, a total of 727 patients were assigned to either crushed or integral tablets of Prasugrel. The median time from study treatment to wire crossing during primary PCI was 57 minutes, and the primary end point of TIMI three flow in the infarct related pre primary PCI artery occurred in 31% in the crushed group versus 32.7% in the integral group. No difference, P .064. Complete ST segment resolution one hour post primary PCI was present in 59.9% in the crush group and 57.3% in the integral group. Again, no difference, P equals .055. Platelet reactivity at the beginning of primary PCI measured as the P2Y12 reactivity unit, differed significantly between the groups. Crushed was 192 versus integral was 227 and the P value was less than 0.01. TIMI major and BARC greater than three bleeding occurred in 0% in the crushed group and 0.8% in the integral group and in 0.3% in the crushed group versus 1.1% in the integral group respectively. So there were no differences observed between groups regarding ischemic events at 30 days.
Dr. Greg Hundley:
So Carolyn, in conclusion, prehospital administration of crushed Prasugrel tablets does not improve TIMI three flow in the infarct related artery, pre primary PCI or complete SD segment resolution one hour post primary PCI in patients presenting with STEMI planned for primary PCI.
Dr. Carolyn Lam:
Interesting and interesting stuff with platelet reactivity and bleeding. Thank you, Greg. Well, there are other papers in today's issue. There's an in-depth paper by Dr. Katsanos on stroke prevention in atrial fibrillation, looking forward. There's a research letter by Dr. Berger on myocardial injury in adults hospitalized with COVID-19 and another by Dr. Hacker on again, immune checkpoint inhibitor therapy and how that induces inflammatory activity in large arteries.
Dr. Greg Hundley:
Well, Carolyn, I've got a couple other papers to talk about in this issue. There's a On My Mind piece from Dr. deFilippi entitled "Navigating Testing for COVID-19." There's a Perspective from Dr. Ridker entitled "Equipoise Trust and the Need for Cardiologists to Randomize Patients into Anticoagulation Trials in the Time of COVID." There's an ECG challenge from Dr. Arias entitled, "A Paced Tachycardia." And then finally, there's an exchange of letters from Drs. Liu regarding a prior publication entitled "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets." Well, Carolyn, how about we get to the world of anti-platelet therapy, ticagrelor prasugrel in patients with ST segment elevation myocardial infarction, shall we?
Dr. Carolyn Lam:
Yes, let's go Greg.
Dr. Greg Hundley:
Well welcome, listeners, to our featured discussion today on this December 15, and we are going to learn and discuss a little more, a paper pertaining to ticagrelor versus prasugrel in patients with ST segment elevation myocardial infarction. And our lead author today is Adnan Kastrati from Deutsches Heart center in Munich. And we also have our own Associate Editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas. Welcome, gentlemen. Adnan, maybe I'll start with you. Could you tell us a little bit about the background related to this article and what was the hypothesis that you wanted to address?
Dr. Adnan Kastrati:
First of all, thank you very much for having me here to share with you some thoughts. Thank you, Dharam, for handling our paper in Circulation. We are very honored to have it published there. About these are the ISAR REACT-5 series of studies dedicated to optimizing the antiplatelet therapy in patients and anticoagulant therapy in patients with acute and chronic coronary syndromes, mostly who are undergoing a PCI procedure. We started to think about that study immediately after the publication of the platelet trial. We showed the superiority of prasugrel in patients with acute coronary syndromes. These were the two new ADP receptor antagonists at the time. And so as a physician, we are interested to know which of them was better because there was no direct comparison. And so that's why we decided to have an open-label trial randomized. Most of the centers were situated in Germany. Two centers were situated in Italy. The private end point was adopted to the private end point of the trials in this skill. Only one difference was there, instead of cardiovascular death, we put all cause death in the primary end point. Why? Because all cause death may also reflect the gradient end bleeding between the two drugs. We wanted to have a more integrative endpoint in this sense. So it was a combination of all cause death, myocardial infarction, and stroke.
Dr. Adnan Kastrati:
It was a one year followup study. The study had two groups of steady patients, which was about 40% of the patients, included in the multicentral trial. And what we found in this trial, it was the same results as it was found in the whole trial. The advantages seen for prasugrel was present here also. Although we lost the significance in the evaluation of the primary endpoint. It was a 31% increase or 24% decrease with prasugrel in that sense. But otherwise everything was in the same direction as in the whole trial. And if you look also in the components of the primary end point…, you have the chance to see that numerically, it was the same trend for all components. Although the trial was not powered for going to evaluate the component of the prime end point. This was the main result.
Dr. Greg Hundley:
It sounds like you had 1,653 patients with STEMI randomized to receive ticagrelor or prasugrel and 10% experienced the primary end point in the ticagrelor group, but only 7.9% in the prasugrel group. But the P value was only .10. We saw trends toward favoring prasugrel rather than sort of a definitive difference. Is that a correct summary?
Dr. Adnan Kastrati:
Yes, it is a correct summary. I would say this group of patients is the most interesting subgroup of patients in ISAR 5 trial. Why? Because the pretreatment strategy is the same. Because there have been a lot of discussions about non-S-segment segment elevation acute myocardial infarction due to the difference in pretreatment. Although it was intentional, some people felt it's different and they said you have two different strategies there. In the STEMI subgroup, the pretreatment strategy was the same, so it was a head to head comparison of two drugs, even according to the same strategy. This is one.
Dr. Adnan Kastrati:
Second, you have to look back at the trials in the same field…Both these trials, if you look closely to the results of for STEMI patients, both of these trials haven't shown a significant result for the STEMI subgroup. For plateau it was a P value of 007 and for tritan it was a P value of 0014 only. Why? Because in the tritan it was very specific. They included also patients after fever analyzes and the significance came only from the comparison of tritan in this group, not in the primary PCI group. In the plateau and ISAR-5 we excluded these patients.
Dr. Greg Hundley:
Dharam, we're going to turn to you now. Adnan's really framed this study nicely, but can you help us from your perspective, put this study in perspective with others that have been published in this space?
Dr. Dharam Kumbhani:
Yeah, thanks, Greg. And I want to congratulate Adnan and his group for providing the field with another really well conducted study in a very important field. The center has done some very, very landmark trials, and I think this is another one of those. It sort of helps us understand potentially the best treatment mechanism or protocol for patients undergoing primary PCI for STEMI in this case. As you nicely outlined sort of the background for this, the only other trial that I'm aware of in this space is directly comparing pasugrel and ticagrelor head to head was the Prague 18 trial, which was smaller. I think it was about under 1100 patients. So even the STEMI cohort here was larger than that trial. But that trial ended up being terribly underpowered and unfortunately, also discontinued prematurely. So there wasn't really any significant difference that was noted in that trial and there was also a high crossover to clopidogrel in that other trials.
Dr. Dharam Kumbhani:
So I think that trial, in fact, we had published a trial in circulation as well. And I think this study sort of helps to advance the field a little bit by providing a head to head comparison between the two drugs. If I may extend some of the discussion points that were brought up earlier, I think, again, there is a couple of things that jumped out to me. One is, as you mentioned, the semi cohort is very interesting and very important. The p-value for interaction between the STEMI and the non-STEMI population was not significant for the primary end point. So that is certainly important when considering these results.
Dr. Dharam Kumbhani:
And the second thing is the differences that were noted in the rates of reinfarction, both spontaneous as well as PCI related. And although that is very interesting, we certainly have to keep that first point in mind when considering that. I think it becomes more hypothesis generating that MI rates ended up being higher with ticagrelor compared with prasugrel, and then sort of trying to tease that out in terms of, was that just a play of chance? Do we end up seeing that, is there a real biological reason for that? All of the trials was extremely well done. There were about 29 patients that did not have one-year follow-up and there were about 67 or so MI events. I think it's very interesting, and I think for at least for me, when I review this trial, I think it brings up some very interesting hypotheses that I think we would need to test further. Those anyway, my sort of high-level thoughts on this excellent trial.
Dr. Greg Hundley:
Very good. Well, I'd like to ask you just in 20 seconds, each of you, what's the next study that needs to be performed in this field? Adnan, start with you.
Dr. Adnan Kastrati:
I don't expect trials doing the same thing that we have done in ISAR-X5. We are planning now that ISAR-X6 trial. They are finalizing the protocol, and it will be a large trial of 9,000 patients with acute coronary syndromes in which will test the need for aspirin after discharge. That means all the spaces will be with the potent P2I12 inhibitors. And one group, it will be a placebo controlled trial. One group will have aspirin after discharge, the other placebo. And this is now, for us, the most important thing in this area.
Dr. Adnan Kastrati:
If I have the chance to respond to Dharam about the mechanistic insights of this effect, I would say that we have shown aggressive cardiology, our data about platelet function. It is the biggest platelet function studies in this area, 600 patients. We have tested in patients after PCI. We tested ADP in used aggregation after ticagrelor and prasugrel. And prasugrel was associated with a 30% reduction in platelet aggregation in these patients. And I think that this offers the mechanistic basis also for our results. And the results will be published shortly.
Dr. Greg Hundley:
Very nice, and Dharam.
Dr. Dharam:
Thank you for that response, Adnan. And Greg, to your question, I agree. I think it would be hard, although the field would really benefit from having a head to head comparison between these two drugs again in a larger study. I do think a lot of the interest and excitement in the ACS field is on de-escalation strategies as the outline. And so I suppose that that's sort of where we'll see a lot more in terms of clinical trials.
Dr. Greg Hundley:
Very good. Well listeners, this has been a wonderful discussion and we appreciate the input from the primary author, Dr. Adnan Kastrati, from the Deutsches Heart Center in Munich and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern. Really reviewing prasugrel versus ticagrelor for primary PCI in patients with STEMI only, and showing really no difference in their primary endpoint of death, myocardial infarction, and stroke, with however an increased risk of reinfection in the patients receiving ticagrelor only.
Dr. Greg Hundley:
So on behalf of Carolyn and myself, we wish you a great week and look forward to catching you next week On the Run. This program is copyright the American Heart Association, 2020.
Dr. Carolyn Lam :
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley :
And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Carolyn Lam :
Greg, today's feature paper is a research letter, but, oh my gosh, it is so interesting. It's about surgical explantation of transcatheter aortic bioprosthesis. TAVRs we know is on the rise and so is the rise of surgical explantation cases and we really need to understand it better. Hang on, we're coming to that, but maybe, let's start with some other papers in the issue first, shall we? Let me go first, you go grab your coffee and listen because we're going to talk about the efficacy of ertugliflozin on heart failure related events in patients with type II diabetes and established atherosclerotic cardiovascular disease in the results of the VERTIS CV trial.
Dr. Greg Hundley :
Carolyn, tell us a little bit about the VERTIS CV trial.
Dr. Carolyn Lam :
Sure. The primary results of the VERTIS CV trial have already been published. This cardiovascular safety trial was actually performed to satisfy the 2008 guidance from regulatory agencies for new antihyperglycemic agents. It found that patients with type II diabetes and atherosclerotic cardiovascular disease randomized to ertugliflozin achieved the primary objective of non-inferiority to placebo in time to first major adverse cardiovascular event or MACE, a composite endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke. The first secondary outcome in the hierarchal testing sequence was superiority for the time to composite of cardiovascular death or heart failure hospitalization, which was not met and therefore formal hypothesis testing ended with this endpoint. Now in today's paper, the authors led by Dr. Cosentino from Karolinska Institute and Karolinska University Hospital in Stockholm, Sweden, present the results from pre-specified analyses of the effect of ertugliflozin versus placebo on a series of heart failure related outcomes from this VERTIS CV trial.
Dr. Greg Hundley :
Ah, Carolyn. Tell us what were the results of this new study.
Dr. Carolyn Lam :
Of more than 8,200 randomized patients, almost 24% had a history of heart failure and almost 61% had a pre-trial ejection fraction available, including 959 patients with an injection fraction less than or equal to 45%. While ertugliflozin did not significantly reduce first heart failure hospitalization or cardiovascular death, it did reduce first and total hospitalization for heart failure events with a relative risk for first heart failure events being similarly beneficial number one, in those with versus without a history of heart failure and number two, in those with a history of heart failure with reduced ejection fraction or preserved ejection fraction. However, the risk reduction tended to be greater for those with an ejection fraction less than or equal to 45%. Although, the test for interaction by injection fraction was not significant. The effect of ertugliflozin on risk for first heart failure hospitalization was consistent across most baseline subgroups with a greater effect in three populations, including those with impaired kidney function and those taking diuretics. Now, this is discussed an editorial by Doctors Faiez Zannad and Martin Cowie. You must pick it up and read it.
Dr. Greg Hundley :
That's great, Carolyn. What a fantastic another piece of information on the SGLT2 inhibitors.
Dr. Greg Hundley :
Well, my first paper comes to us from Dr. Peter Liu from the University of Ottawa Heart Institute and his colleagues. Carolyn, this article focuses on cardiac hypertrophy, which as you know, is a key biological response to injurious stresses such as pressure overload. Also as you know, when cardiac hypertrophy is excessive, it can lead to heart failure. Innate immune activation by danger signals through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain-containing protein 1, or NOD1 and its adaptor receptor interacting protein, RIP2, may play a major role in cardiac remodeling and progression to heart failure. These authors hypothesized that NOD1 and RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone.
Dr. Carolyn Lam :
I like that, NOD1 and RIP2. What did they find?
Dr. Greg Hundley :
These authors found that innate immune NOD1/RIP2 signaling was a major contributor to cardiac remodeling following stress. This process was critically joined by and regulated through the mitochondrial danger signal protein adapter MAVS. The authors found that this novel complex coordinates remodeling, inflammatory response and mitochondrial energy metabolism in stressed cardiomyocytes, thus NOD1/RIP2 MAVS signaling complex may represent an attractive new therapeutic approach toward modulating LV hypertrophy mediated heart failure.
Dr. Carolyn Lam :
Very nice, Greg. Now in the next paper, do you remember the VOYAGER PAD trial? Well, it was the trial that demonstrated superiority of rivaroxaban plus aspirin versus aspirin alone to reduce major cardiac and ischemic limb events following lower extremity revascularization. Now clopidogrel is commonly used as a short term adjunct to aspirin after endovascular revascularization. However, does clopidogrel modify the efficacy and safety of rivaroxaban in this setting? Well, that's the question that today's paper is addressing and it is led by corresponding author, Dr. Hiatt from University of Colorado School of Medicine.
Dr. Greg Hundley :
What did they find, Carolyn?
Dr. Carolyn Lam :
Well in the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia, regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use as well, but with a trend for more ISTH major bleeding with clopidogrel use more than 30 days than a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization, regardless of concomitant clopidogrel with a short course of less than 30 days associated with less bleeding.
Dr. Greg Hundley :
Very nice, Carolyn. Well, my next paper comes to us from Dr. Hinson from the Jackson Laboratory for Genomic Medicine. Carolyn this paper focuses on a particularly challenging heart failure associated sarcomere gene, cardiac troponin T, that is encoded by TNNT2. Remember Carolyn, this is a thin filament protein that functions in the tripartite troponin complex, where calcium binds and triggers twitch force. Relative to other sarcomere genes, pathogenic TNNT2 variants are associated with poor prognosis as they carry an increased risk of sudden cardiac death that is disproportional to myocardial remodeling. The investigators used human pluripotent stem cell derived cardiomyocytes in cardiac microtissue and single cell assays and functionally interrogated 51 TNNT2 variants, including 30 pathogenic likely pathogenic variants and 21 variants of unknown significance called VUSs. They utilized RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants.
Dr. Carolyn Lam :
Wow. And so what were those consequences, Greg?
Dr. Greg Hundley :
They found that hypertrophic cardiomyopathy associated TNNT2 variants increased cardiac microtissue contraction while dilated cardiomyopathy associated variants caused decreased contraction. Both of which parallel changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and could be utilized to predict TNNT2 variant pathogenicity. In summary Carolyn, this research found that number one, inheritance of pathogenic TNNT2 variance is a leading cause of cardiomyopathy and number two, the majority of TNNT2 variants identified in the human population are classified as those VUSs or variants of unknown significance, which limits their clinical utility in genetic testing. As such, reclassification of TNNT2 variants would improve cardiomyopathy risk determination and treatment responses for individuals harboring these variants.
Dr. Carolyn Lam :
Nice. Thank you, Greg. Well, in this next paper, I think the title summarizes it all: “Is There a Sex Gap in Surviving an Acute Coronary Syndrome or Subsequent Development of Heart Failure?” Well, Dr. Justin Ezekowitz from Vigor Center, University of Alberta in Canada and his colleagues used a large population based cohort of more than 45,000 patients with MI between April 2002 and March 2016, to examine the incidence and geographic findings, treatment and clinical outcomes of patients with a first time and MI. To elucidate the difference between sexes, a series of multi-variable models were created to explore all MI and non-ST elevation MI versus ST elevation MI over time.
Dr. Greg Hundley :
What did they find Carolyn?
Dr. Carolyn Lam :
Well, some attenuation of differences in clinical outcomes over time had occurred. Women maintained a higher risk than men of dying or developing heart failure in the subsequent five years post both STEMI or non-STEMI, even after accounting for differences in angiographic findings, revascularization and other confounders.
Dr. Greg Hundley :
Well, Carolyn, how about we get to some of the other articles in the issue. And I've got a really nice Research Letter from Professor Damien Bonnet entitled, “Addition of Corticosteroids to Immune Globulins is Associated with Recovery of Cardiac Function in Multi-inflammatory Syndrome in Children.” There's also a Research Letter from Professor Peter van der Meer entitled, “Human Pluripotent Stem Cell Derived Cardiomyocytes of Peripartum Cardiomyopathy Patients Reveal at Aberrant Regulation in Lipid Metabolism.” And Carolyn, finally I have an ECG Challenge entitled, “Wide QRS Complex Tachycardia in a Young Pregnant Woman, is it SVT or VT?” The age old question from Dr. Gunaseelan.
Dr. Carolyn Lam :
Nice. Well, there's also an exchange of letters between Drs. Ross and Loupy regarding the article, “Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy after Heart Transplantation: a Population Based Study,” and a beautiful Perspective piece by Dr. Verma entitled, “Two Tales, One Story and that is talking about the EMPEROR-reduced and DAPA-HF trials.” A beautiful summary there. Let's get on now though to that feature discussion. Shall we, Greg?
Dr. Greg Hundley :
You bet looking forward to it.
Dr. Carolyn Lam :
Transcatheter aortic valve replacement or TAVR has indeed become an established alternative to surgical aortic valve replacement for patients with severe aortic stenosis. Now, while the TAVR usage has increased, so has surgical TAVR valve explantation. However, that's not been really well described its clinical impact or outcomes well until today's research letter in Circulation, which represents the largest series of TAVR explants from a national database. And I'm so pleased to have with us the first and corresponding author, Dr. Shinichi Fukuhara from University of Michigan to describe the study as well as our associate editor, Dr. Tim Gardner from University of Pennsylvania. Welcome, gentlemen. Shinichi, if you don't mind for non-interventionists and non-surgeons like myself, why would you need to explant TAVR in the first place? Maybe you could start with that and then tell us about your study.
Dr. Shinichi Fukuhara:
First of all, thank you so much for the kind invitation. It's a great honor to be with you and Dr. Gardener. That's a very good question and a very timely question actually. When we started implanting TAVR valves probably about nine years ago or so, that was when the TAVR valve was FDA approved, we were not thinking about second TAVR procedure after the initial TAVR valve fails. And then as time goes on, we started to recognizing, some patients' TAVR valves started failing and these failure patterns can be paravalvular leak, can be structural valve degeneration, can be endocarditis. Not all patients with a failing TAVR valve can be treated with a second TAVR valve procedure and the most common driving factor at least in my program at the University of Michigan is unsuitable anatomy for a second TAVR valve and the most common anatomy pattern is a risk of a coronary artery obstruction by the second TAVR valve. These are the common scenarios where patients need TAVR valve explantation scenarios.
Dr. Carolyn Lam :
Thank you so much for that as a background. And as you nicely set up in your paper, as we do more TAVR, obviously there are going to be more situations like this. Please tell us what you found.
Dr. Shinichi Fukuhara:
First of all, what we found from this project, first, surgical TAVR valve explant procedure is not as simple as people thought it would be. I remember back in 2014, 2015 when I was still a trainee, people were talking about, which is better TAVR SAVR TAVR or SAVR TAVR SAVR? However, based on what we are just starting to see, TAVR SAVR sequence may not be a good option for younger people based on the present study data. The fact that more than 50% of patients who require the major simultaneous procedures such as aortic repair and the mitral procedures is a something TAVR implanters in our community should be more aware.
Tim Gardner:
I think it's very important for Shinichi to tell us to emphasize the mortality rate that you saw with the SAVRs following TAVR because that's really, I think the sobering information here. This is not comparable to doing a redo aortic valve or redo SAVR. Just tell us about that, Shinichi.
Dr. Shinichi Fukuhara:
First of all, these STS database. We have a STS predicted risk of a mortality, which is available for patients undergoing isolated SAVR procedure. And then based on the even isolated the SAVR procedure, the OE ratio of observed to expected mortality ratio was actually higher than 1.5 for isolated SAVR procedure in patients requiring TAVR explant. More importantly, patients who are requiring TAVR explanted SAVR, as well as a concomitant cardiac procedure are demonstrating almost close to 20% mortality rate, which is to me very striking after we analyze that data set. And this is something our community, the TAVR implanters in our community should keep in mind.
Dr. Timothy Gardner:
Yeah. Obviously not only is the surgery, the removal of the TAVR device and replacement with a surgical valve, not only is that complex anatomically and technically, but the associated mortality seen in this series of patients that they reported is higher than expected and actually quite high in terms of absolute operative or hospital mortality. I take this important research letter as a sort of a warning message to all of us, in particular, the cardiology community, to realize that once a TAVR valve is placed, it is more difficult and riskier to remove that and replace it with a surgical aortic valve replacement, if for some reasons such as endocarditis or valve failure or whatever comes to play.
Dr. Timothy Gardner:
And obviously as Shinichi has already said, when you're looking at a younger patient, patient under 60 for example, who needs an aortic valve procedure, you need to keep in mind whether as he said earlier, it's might be safer to do a SAVR first. And then if there's another procedure required, that could be because of valve failure, a TAVR could be done rather than just assuming that the TAVR is going to be there and that it can be easily replaced or taken care of. At any rate, I think that's the very important point of this paper. And I think this is really the first report and not only by the way, does it show that this is happening, but in the most recent year of your report, Shinichi, how many SAVRs after TAVR were reported, number of cases?
Dr. Shinichi Fukuhara:
The 2018, the last year of this study period was actually the highest obviously and it was a close to 300 cases reported. And then the number of case is a steeply increasing as I demonstrated in the figure one in the paper.
Dr. Timothy Gardner:
That really emphasizes obviously TAVR volume is increasing. TAVR is now being placed in younger patients who have perhaps a greater chance of requiring a second procedure. And if it has to be explantation of the TAVR because of the complexity and the inability to use another TAVR to fix the valve, the technical challenges and the operative risks are much higher.
Dr. Timothy Gardner:
Well, I just think that this is a warning call that we have to be realistic about the secondary requirements for patients that have TAVR and we don't yet even have a much more than a 10 year experience with TAVRs and we're seeing an increasing number of patients just in the STS database who are having to come back for TAVR explant and it's a difficult, challenging procedure. One point that Shinichi made in his article is that this technical challenge of TAVR explant may be something patients requiring this procedure may need to be referred to surgeons and hospitals with high aortic surgery volume. This is not necessarily a procedure that a surgeon can get experienced with and comfortable with doing two or three a year. That's another bit of the message here.
Dr. Carolyn Lam :
Thanks, Tim. And Shinichi, what would be your take home message to the clinical community listening in?
Dr. Shinichi Fukuhara:
Thank you so much. Yeah, this is a little bit redundant statement, but I think that another important message from this paper is that these low risk younger patients choosing to have a TAVR procedure as the initial valve therapy should be informed of the future procedure risks of a TAVR explant which frequently requires more of device explanating and the possible unplanned concurrent procedures and for these reasons careful assessment of aortic root anatomy and the feasibility of a repeat TAVR procedure should be part of with the initial TAVR workup. If we decide to proceed with TAVR for younger patients and then therefore heart team approach remains extremely important in the TAVR practice, that's my take home message.
Dr. Timothy Gardner:
And I'd like to reinforce that. This is, as we know, the heart team concept has been so important in providing optimal care for patients with aortic valve disease and this is a reminder of part of the discussion that should be happening at the heart team level.
Dr. Carolyn Lam :
Thank you so much. Clear take home messages that you've got right here on Circulation on the Run.
Dr. Greg Hundley :
This program is copyright the American Heart Association, 2020.
This week's episode features author Torbjørn Omland and Senior Guest Editor Vera Bittner as they discuss the artile "Growth Differentiation Factor-15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized with COVID-19."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn our feature this week gets into inflammatory biomarkers in patients that have been hospitalized with COVID-19, but before we get to that, how about we grab a cup of coffee and work through some of the papers in the issue. Would you like to go first?
Dr. Carolyn Lam:
Absolutely. With both the coffee and the papers. So great, for this first paper, have you thought about concentric versus eccentric cardiac hypertrophy? We traditionally associate them with pressure versus volume overload respectively in cardiovascular disease, both though conferring an increased risk of heart failure. These contrasting forms of hypertrophy are characterized by asymmetric growth of the cardiac myocytes in mainly width or length respectively. However, the molecular mechanisms determining myocyte preferential growth in width versus length remain poorly understood.
Dr. Carolyn Lam:
That is until today's paper, and it is from Dr. Kapiloff from Stanford University, and Dr. Rosenfeld from UCSD, School of Medicine and their colleagues, and what they did was used primary adult rat ventricular myocytes, as well as Adeno associated virus mediated gene delivery in mice, to define a regulatory pathway controlling pathological myocyte hypertrophy, and they found that asymmetric cardiac myocyte hypertrophy is modulated by serum response factor phosphorylation, constituting an epigenomic switch balancing the growth in width versus length of adult ventricular myocytes In vitro, and In vivo.
Dr. Carolyn Lam:
Serum response factor phosphorylation was bi-directionally regulated at signalosomes organized by the scaffold protein muscle, A kinase anchoring protein beta. This newly identified molecular switch controlled a transcriptional program responsible for modulating changes in cardiomyocyte morphology that occurs secondary to pathological stressors.
Dr. Greg Hundley:
Very nice, Carolyn. So switches controlling this transcriptional program. Tell us a little bit, and bring us back to the clinical relevance of this and starting with that concentric versus eccentric hypertrophy?
Dr. Carolyn Lam:
I thought you may ask. The identification of a molecular mechanism regulating that asymmetric cardiomyocyte growth, really provides a new target for the inhibition of pathological cardiac hypertrophy. Studies in mice using these Adeno associated virus based gene therapies to modulate that signalosome, really provided proof of concept for translational potential in the treatment of pathological cardiac remodeling and prevention of heart failure.
Dr. Greg Hundley:
Oh, wow. Very nice, Carolyn. Well, my first paper comes to us from Professor Dirk Westermann from Hamburg, and focuses on cardiogenic shock patients, and veno-arterial ECMO, the results from the international multicenter cohort study. So Carolyn this study evaluated data from 686 consecutive patients with cardiogenic shock treated with VA ECMO with or without left ventricular unloading using an Impella, and they conducted this at 16 tertiary care centers across four countries. They examined the association between left ventricular unloading and 30 day mortality.
Dr. Carolyn Lam:
Huh, so what did they find?
Dr. Greg Hundley:
Okay. Carolyn. Well, left ventricular unloading was used in 337 of the 686 patients enrolled, and after propensity matching 255 patients with left ventricular unloading were compared with the 255 patients without left ventricular unloading. In the match cohort, left ventricular unloading was associated with lower 30 day mortality without differences in the various subgroups. However, complications occurred more frequently in patients with left ventricular unloading, like severe bleeding, which happened in 38.4% versus only 17.9% in those without unloading. There was also access-related ischemia and renal replacement therapy.
Dr. Greg Hundley:
So Carolyn, the take-home message from this International multi-center cohort study, is that left ventricular unloading is associated with lower mortality, and cardiogenic shock patients treated with VA ECMO, despite higher complication rates. In the absence of randomized trial data these findings support the use of left ventricular unloading and cardiogenic shock patients treated with VA ECMO, and call for further validation, ideally in a randomized controlled trial.
Dr. Carolyn Lam:
Very nice. Well for my next paper, Greg, it's all about desmin. Now we know that mutations in the human desmin gene caused myopathies and cardiomyopathies. Well, today's authors, Dr. Hermann and Schroeder from University Hospital Erlangen in Germany and Dr. Lilienbaum from University of Paris and France and their colleagues, report an adolescent patient who underwent cardiac transplantation, due to restrictive cardiomyopathy caused by a heterozygous R406W desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin, and to intercalated disc proteins. Effects of this mutation on the molecular properties of desmin were then addressed by cell transfection and In vitro assembly experiments. They further generated these desmin mutation knock-in mice haboring the orthologous form of the human, R406W-desmin.
Dr. Greg Hundley:
So Carolyn, what did they find?
Dr. Carolyn Lam:
Well, they demonstrated a novel pathomechanism in which cardiotoxic R406W-desmin, could adapt dual functional status with the abilities to integrate into the indogenous intermediate filament network, and to cause formation a protein aggregates. This R406W-desmin modified the extra sarcomeric cytoskeleton, such that desmin filaments were not anchored to desmosomes anymore. Thereby destroying the structural, and functional integrity of intercalated discs.
Dr. Greg Hundley:
What are the clinical implications?
Dr. Carolyn Lam:
Well, since these cardiotoxic desmin mutations could affect the integrity of intercalated discs, thereby inducing conduction defects and malignant arrhythmias, they suggest early implantation of pacemaker, or cardioverter defibrillator devices, may be considered to prevent certain cardiac death in patients with these mutations. Furthermore, state-of-the-art basic molecular risk stratification of desmin mutations may encompass a multidisciplinary experimental approach as exemplified by the approach taken here, which comprises assessment of the tissue pathology in conjunction with genome analysis and desmin assembly studies as well as patient mimicking cell and animal models for the In vivo validation of these mutations.
Dr. Greg Hundley:
Well, fantastic, Carolyn. Well, my next paper comes to us from Dr. Ravi Shah from the Massachusetts General Hospital. This study evaluated 2,330 white and black young adults, average age of 32 years, in the Coronary Artery Risk Development in Young Adults, or the cardiac study, to identify metabolite profiles associated with an adverse cardiovascular disease phenom that included, myocardial structure and function, fitness, vascular calcification, and then also mechanisms, and other cardiovascular outcomes that would occur over the next two decades. Statistical learning methods, including elastic nets and principal component analysis, and Cox regression generated parsimonious metabolite based risk scores, validated in over 1800 individuals in the Framingham Heart Study.
Dr. Carolyn Lam:
Wow. What did they show, Greg? Wow, that's a lot of work.
Dr. Greg Hundley:
Yeah. So Carolyn, the authors found two multiparametric metabolite-based scores linked independently to vascular, and myocardial health. With metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and finally collagen metabolism. Over nearly 25 year median follow-up, and cardia, this metabolite based vascular score, and the myocardial score, and the third and fourth decade of life were associated with clinical cardiovascular disease. Importantly, the authors replicated these findings in 1,898 individuals in the Framingham Heart Study followed over two decades, such that young adults with poor metabolite based health scores had higher hazard ratios of future cardiovascular disease related events.
Dr. Carolyn Lam:
Oh wow. Greg, what an elegant study with both development and validation cohort evaluating the metabolome.
Dr. Greg Hundley:
Yes. Carolyn. So metabolic signatures of myocardial, and vascular health in young adulthood specify known novel pathways of metabolic dysfunction, relevant to cardiovascular disease associated with outcomes in two independent cohorts. So these data suggests that efforts to include precision measures of metabolic health in risk stratification to interrupt cardiovascular disease at an early at stage, are warranted.
Dr. Carolyn Lam:
Wow. So interesting. Other very interesting articles in today's issue, there's an In Depth article by Dr. Angiolillo entitled, “The Antithrombotic Therapy for Atherosclerotic Cardiovascular Disease Risk Mitigation in Patients with Coronary Artery Disease and Diabetes.” There's also Research Letters, one by Dr. Sultan on, “The Longterm Outcomes of Primary Cardiac Lymphoma” and one by Dr. Wang on, “Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair Following Myocardial Infarction.”
Dr. Greg Hundley:
Great, Carolyn. Well, I've got a couple other articles in this issue as well. One is by Professor Ganesan Karthikeyan who has an On My Mind piece entitled an “Alternative Hypothesis to explain Disease Progression in Rheumatic Heart Disease.” Dr. Stuart Chen has an ECG challenge entitled, “Alternating QRS Duration and a Normal T-waves. What is the mechanism?” Then finally, Carolyn, a series of Letters to the Editor, one by Dr. Peterzan and the other by Dr. Mehmood regarding the prior published article, entitled “Cardiac Energetics in Patients with Aortic Stenosis and Preserved Ejection Fraction.” Well, Carolyn, how about we get onto that feature article and learn more about inflammatory biomarkers in hospitalized patients with COVID-19?
Dr. Carolyn Lam:
Yes. Let's go. Greg.
Biomarkers are really playing an increasingly important role in cardiovascular disease, and even in the current COVID 19 pandemic, there's been a lot of news about how biomarkers such as traponin may be prognostic, and in fact, we're all wondering about maybe even newer biomarkers. In fact, today's feature discussion does bring to light one of the newest, and in fact, this is the first publication on the role of Growth Differentiation Factor 15 or GDF-15 in COVID-19. We're so pleased to be discussing this with the corresponding author, Dr. Torbjørn Omland from University of Oslo, in Norway, as well as our senior guest editor, Dr. Vera Bittner from University of Alabama at Birmingham. So welcome both. Tobjorn, could you tell us a little bit about GDF-15 and what made you look at it, and what did you find?
Dr. Torbjørn Omland:
Yeah, so GDF-15, that's a very interesting biomarker. It's considered a biomarker of biological aging cellular stress, and perhaps also the inflammation, and tests being studied within the cardiovascular field for some years now, and it has been shown to be a strong prognostic indicator across the cardiovascular spectrum, actually. So it is a new biomarker in one sense, but there are some data already in the cardiovascular field.
Dr. Carolyn Lam:
Not in COVID. So this is the first study to really look at its prognostic value in COVID 19. So congratulations Torbjorn, and if I may also to the first author, Dr. Peter Meer, a good friend as well, but please, could you tell us about your study and what you found?
Dr. Torbjørn Omland:
Yes. So when the COVID pandemic hit Norway in the spring, we thought that we should plan a prospective biomarker study. So we had to really fast track approval by the IRB and so forth, and we're able to actually cover most of the patients that were hospitalized in our hospital, Akershus University hospital, which is right outside of Oslo, and it's a pretty large hospital by Norwegian standards. It covers about 11% of the Norwegian population.
Dr. Torbjørn Omland:
So in that period, when we were including, we had 136 patients hospitalized with confirmed COVID 19, and we have biobank bank samples from 123 of these, and then there have been reports from retrospective studies, first from China, that seemed to suggest that markers like cardiac troponin, Anti-Troponin T, and Ferritin were associated with outcome, but those studies were prone to selection bias in that the measurements were performed in the most sick patients. So in this study we included all patients and then we thought we should examine a broad panel of biomarkers, and that included Interleukin 6, CRP, Procalcitonin, Ferritin, and the D-dimer Cardiac troponin, and N-terminal pro B, and GDF-15.
Dr. Carolyn Lam:
Wow. Thank you, Torbjorn. Even before you carry on with the results, can I just say having visited your hospital in pre-COVID days, I can only imagine what a work of love this was to do it prospectively. Any particular experiences to talk about, to get a fast-track even in the midst of to perform a well done prospective study, that must have taken a lot.
Dr. Torbjørn Omland:
Yes. But it's also interesting in that the whole sort of ablation on Norway was very much into this from the highest political level. Also, the decision that the older research on COVID should be prepared to retire, then the IRB had an eight hour and deadline for them to approve or not approve the study. So that's went surprisingly smoothly, I must say.
Dr. Carolyn Lam:
Wow, that's great. So what did you find?
Dr. Torbjørn Omland:
Yeah, so we found that among these biomarkers, several seem to predict outcome, and the primary end point of this study was to combined end-point of the hospitalization in the ICU, or death. We found that also markers like cardio traponin, BNP, ferritin, and the D-dimer and so forth, in univariable analysis, were very associated with outcome, but when we perform a more comprehensive, mostly variable modeling, then the prognostic value of some of these markers disappeared. In contrast, for GDF-15, it seemed to perform very strongly, both on the baseline sample, and interestingly also it increased in those reaching the primary end-point during the hospitalization. So it provided a very strong and independent information also when we adjusted for clinical risk scores, like the NEWS score. So that was a very pleasant surprise to see that there was one marker that's actually performed so well. The other marker that's also performed well was Ferritin.
Dr. Carolyn Lam:
Very interesting, and so the new score being the National Early Warning Score. Thank you. Verra, I really love to bring in your thoughts. I mean, could you take us behind the scenes with the editors? What did you think when you saw this paper?
Dr. Vera Bittner:
As you know, I mean, a lot of journals have been inundated by COVID papers, and so this one stuck out to us, because it's the first time that we had seen that anybody linked GDF-15 to a COVID population, even though it has been out in the literature for ACS, and in my prognostication, and in a healthy populations, and in chronic coronary disease populations, heart failure, and so on. So this is the first time that we've seen it applied there.
Dr. Vera Bittner:
Then I would echo some of the things that Torbjorn said, that we were also impressed, that it was prospective, because when you look at some of the other biomarker studies, what was prognostic in one with then not shake out the other one, because either different variables were included in the models, because the population's differed. So to have something that was representative of the population that was actually admitted to this, Norwegian Academic Hospital, stood out to us. So we're excited to get this paper basically for circulation, and hope that it also will be impetus for future research.
Dr. Carolyn Lam:
Thank you so much for sharing that end for helping us publish such a beautiful paper. Did you have some questions for two of your own?
Dr. Vera Bittner:
Yeah. So what stuck out to me is that you had this a whole crew of biomarkers, and then when you looked ultimately at the final model, there were two that were standing out, that was ferritin, and it was the GDF-15, and then when I looked at your graph, it looks like not only did these biomarkers measure different contrasts, but their time-course also seemed to be different, and so I was just wondering whether you had thought about, maybe using these to joint the model outcome, and whether we might even be able to get more information that way.
Dr. Torbjørn Omland:
I think that's an excellent suggestion, and as you correctly pointed out, they do have different sort of profiles and ferritin being an acute phase reactant, having various sort of dramatic early rise whereas we see that GDF-15 increased progressively during the course of hospitalization in the most severe patients. I think when combining them, is actually a great IMT that we should look further into.
Dr. Carolyn Lam:
Very nice. Torbjorn, if I could, I've got a couple of questions too. So 123 patients, 35 of whom had the primary outcome, right? So that may be sort of seen as, is this too small? and they're all hospitalized patients. So could I ask, what do you predict maybe seen in a larger population or outside of Norway or in a non-hospitalized population?
Dr. Torbjørn Omland:
So as you say, we were early with this report, but since it was submitted, there has been a couple of smaller studies that seemed to confirm our results. So that is reassuring, but of course we would like to have studied this in logical patients. We are in touch with the other biobank samples that could possibly confirm the data. So that's one obvious step. Then it's very interesting, as you say, could we sort of expand this to also apply to non-hospitalized patients? I think that it would be a very interesting hypothesis to test, and I think there's still a pretty good rationale for this.
Dr. Torbjørn Omland:
It's interesting that the insoluble group actually showed a correlation that when the soluble ST2 concentrations and GDF-15. So there might be that those with more susceptibility to COVID infections, actually, I thought that, that is actually reflected by GDF-15 concentrations, but the challenge is how to sort of get a representative non-hospitalized population, but interestingly, I was approached by some of the hospital staff that actually are in contact with general practitioners, and wanted sort of implement this test also for this group.
Dr. Carolyn Lam:
So Verra, we're really grateful that Allan Jaffe was working with you in managing this beautiful paper, and if you don't mind me cheekily paraphrasing that you said you might channel him, if you could, what would the channeled Allan Jaffe perhaps say about what's needed in this whole biomarkers fear in COVID-19?
Dr. Vera Bittner:
Hopefully, many. A channeling element is obviously difficult, because he is such an incredible expert on biomarkers that I can't even pretend to be able to see, that you might be thinking, but it seems to me that one thing that we could all agree on is that it would be really exciting if something like the: get with the guidelines COVID registry, could decide to measure this marker perspectively in the participating hospitals, for example.
Dr. Vera Bittner:
Then be able to look at this in a much, much larger population. I mean, especially with different ethnic backgrounds as well. I mean, I noticed actually to my surprise that, this Norwegian study how to fairly high proportion of Asians in the sample, but that may not be the ethnic distribution that we might see in different regions of the US, or different regions of the world. So it would be really nice to incorporate the measurement of this biomarker in much larger datasets. So things can be explored a bit further.
Dr. Carolyn Lam:
That's excellent, and Torbjorn, if you could channel Allan. What would you say?
Dr. Torbjørn Omland:
That's a difficult path, but absolutely just to me what Verra said. Then I think the importance of prospective studies in the COVID biomarker field, I think is our at most importance.
Dr. Carolyn Lam:
I think on behalf of both Torbjorn and I, and in fact everyone in circulation. Thank you, Verra for the amazing work that you and your team do for circulation as well. Thank you so much for making the time to share your thoughts today and thank you for that beautiful, beautiful paper both of you. Thank you. (singing). Listeners you've been listening to Circulation on the Run. Thank you for joining us from Greg and I. Don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright, the American Heart Association 2020.
This week’s episode features author Emma Birks and Associate Editor Hesham Sadek as they discuss the article " Prospective Multicentre Study of Myocardial Recovery Using Left Ventricular Assist Devices (REmission from Stage D Heart Failure: RESTAGE-HF): Medium Term and Primary Endpoint Results."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center of VCU Health in Richmond, Virginia. Carolyn, our feature article this week, we're going to examine myocardial recovery using left ventricular assist devices, getting some early results from the RESTAGE-HF study. But before we jump to the feature discussion, how about we discuss some of the papers in the issue? Would you like to go first?
Dr. Carolyn Lam:
Yes I would. Have you thought about what's the benefit of emergent coronary angiography after resuscitation from out of hospital cardiac arrest for patients without ST elevation? It's an important question. Well, the portal study was reported by Dr. Kern from University of Arizona and colleagues, and this was designed to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated out of hospital cardiac arrest in patients without ST elevation. So adult comatose survivors without ST elevation after resuscitation, were prospectively randomized to early coronary angiography versus no early coronary angiography, where early was defined as less than 120 minutes from arrival at the PCI capable facility. The primary endpoint was a composite of efficacy and safety measures, including efficacy parameters of survival to discharge favorable neurological status at discharge echo measures of left ventricular ejection fraction, more than 50% and a normal regional wall motion score within 24 hours of admission.
Dr. Greg Hundley:
So, lots of data here. What did they find?
Dr. Carolyn Lam:
So, unfortunately the study was prematurely terminated before enrolling the target numbers of patients. A total of 99 patients were enrolled from 2015 to 2018 and 49 were randomized to early coronary angiography. The primary endpoint of efficacy and safety was not different between the two groups. Early coronary angiography was not associated with any significant increase in survival or adverse events. And early coronary angiography revealed a culprit vessel in 47% with a total of 14% of patients undergoing early coronary angiography, having an acutely occluded culprit coronary artery. So while this was an underpowered study, when considered together with previous clinical trials, it does not support early coronary angiography, comatose survivors of cardiac arrest without ST elevation, whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes does require additional study. And this is discussed in an editorial by Dr. Lemkes from Amsterdam university medical center.
Dr. Greg Hundley:
Very nice Carolyn. So at least the study that points us toward the next study that has to be performed and also does with other studies provide a little more clarity. Well, my next paper is from Professor Sanjiv Shah and--oh, wait a minute! And also from you as a co-author. Well, Carolyn, how about we have a little mini feature discussion where I can ask you some questions and then you can tell us all about your paper.
Dr. Carolyn Lam:
Happy to.
Dr. Greg Hundley:
Great. So Carolyn, what hypotheses were you testing and what was your study design and who was included in your study population?
Dr. Carolyn Lam:
Okay. So the question was we wanted to answer was thus a systemic pro-inflammatory state as indicated by proteomic profiling. Does that mediate the association between comorbidities and normal cardiac structure and function in HFpEF. To answer that we studied 228 patients with HFpEF from our multicenter promis HFpEF study. And these patients had 248 unique circulating proteins quantified using the old link multiplex immunoassay. Now I'm going to describe a complex analysis, but we basically had to first perform principal component analysis. And we did this to summarize 47 proteins known a priori to be involved in inflammation, and then used unbiased network analysis of all the 248 proteins to identify clusters of proteins that over-represented inflammatory pathways. We then used a mediation analysis to determine whether and to what extent inflammation mediates the association of comorbidity burdens with abnormal cardiac structure and function. And finally, we externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HFpEF.
Dr. Greg Hundley:
Wow Carolyn, such a great design and an app machine learning mediation analyses, and then validation in an independent cohort. So tell us, what did you find?
Dr. Carolyn Lam:
So first, comorbidity burden was associated with abnormal cardiac function and structure and with these principle components of clusters of inflammation proteins. Second, systemic inflammation was associated with echo indicators of worse hemodynamics, like higher EDE' ratio and worse, right ventricular function. And third, inflammation indeed mediated the association between comorbidity burden and many of these echo parameters with, and I'm going to name a couple of routines. So TNF-R1, uPAR, IGFBP-7 and GDF-15 being the top individual mediating proteins. In the validation cohort inflammation was up-regulated in HFpEF compared to controls and the most prominent inflammation protein cluster identified was also the same one as in PROMIS-HFpEF.
Dr. Greg Hundley:
Beautiful Carolyn. So with these new proteins identified, what's the take home message here?
Dr. Carolyn Lam:
Here it is. Proteins involved in inflammation form a conserved network in HFpEF. And this was found across two independent cohorts. This may mediate the association between comorbidity burden and echo indicators of worst hemodynamics and right ventricular dysfunction. In totality, these findings support the comorbidity inflammation paradigm in HFpEF.
Dr. Greg Hundley:
Great job Carolyn, I liked the mini feature. That was so nice having one of the authors of the study here to explain kind of a two for one here, because we're going to get a feature and a mini feature. Have you got another paper you want to tell us about?
Dr. Carolyn Lam:
Thanks Greg and that works both ways. This next paper provides insights into the identity origin and function of many cells that make up late stage atherosclerotic lesions. It also identifies the mechanisms by which these control plucks stability. So corresponding author, Dr. Owens from Virginia School of Medicine and colleagues conducted a comprehensive single cell RNA sequencing of advanced human carotid endarterectomy samples, and compared these with murine micro dissected advanced atherosclerotic lesions with smooth muscle cell and endothelial lineage tracing to survey all plaque cell types and to rigorously determine their origins.
Dr. Greg Hundley:
Carolyn you know, this is another great study where we have both human subjects research and small animals. What were their results?
Dr. Carolyn Lam:
They provided evidence that smooth muscle cell specific knockout of transcription factors, KLF4 versus Oct-4 showed virtually opposite genomic signatures and their putative target genes played an important role, regulating smooth muscle cells phenotypic changes. They also provided evidence that smooth muscle cell derived cells within advanced mouse and human atherosclerotic lesions exhibited far greater phenotypic plasticity than generally believed, with KLF4 regulating the transition to multiple phenotypes, including LGALS 3 plus osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis. So in summary, smooth cell phenotypic switching produces cells that can be beneficial or detrimental to lesion stability and may be an important mechanism controlling the risk of unstable atherosclerotic plaque and myocardial infarction or stroke.
Dr. Greg Hundley:
Oh, great job, Carolyn. Well, the next paper I have is from Professor Muredach Reilly from Columbia University. And Carolyn smooth muscle cells play significant roles in atherosclerosis via phenotypic switching, a pathological process and with smooth muscle cell D differentiation, migration and trans differentiation into other cell types yet how smooth muscle cells contribute completely to the pathophysiology of atherosclerosis remain somewhat illicit. So the authors sought to reveal the trajectories of smooth muscle cell trans differentiation during atherosclerosis, and to identify molecular targets for disease therapy by combining smooth muscle cell fate mapping and single cell RNA sequencing of both mouse and human atherosclerotic plaques.
Dr. Carolyn Lam:
Echoing what you said earlier, Greg, both animal and human data. Terrific. So what were the results?
Dr. Greg Hundley:
The authors found that smooth muscle cells transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. Smooth muscle cell derived intermediate cells termed stem cells were multiphoton and could differentiate into macrophage like and fibro chondrocyte like cells as well as returned towards the smooth muscle cell phenotype. Retinoic acid signaling was identified as a regulator of the transition of smooth muscle cells to stem cells and RA signaling was dysregulated in symptomatic human atherosclerosis. Finally Carolyn, human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene low PSI and correlated between coronary artery disease risk levels and repressed expression of these genes. Now, activation of RA signaling by all trans retinoic acid and the anticancer drug for acute promyelocytic leukemia blocked the smooth muscle cell transition to stem cells, and that also reduced atherosclerotic burden and then promoted fibrous cap stability. So a lot of clarification of the role of smooth muscle cells, trans differentiation and the development of atherosclerotic disease
Dr. Carolyn Lam:
Indeed and translational implications. Interesting. Now let's review some of the other papers in this issue. Shall we? First as an, on my mind paper by Dr. Kullo on familial hypercholesterolemia, a reportable disorder. There's an exchange of letters between doctors Lazzerini and Li regarding the article autoantibody signature in cardiac arrest.
Dr. Greg Hundley:
Thanks Carolyn. Well, I've got a couple other papers to tell you about really a series of research letters from the mailbag. So first Daniel Modin has a Research Letter entitled “Acute COVID-19 and the Incidents of Ischemic Stroke and Acute Myocardial Infarction.” Dr. Christian Mueller has a Research Letter entitled “Effect of a Proposed Modification of the Type 1 and Type 2 Myocardial Infarction Definitions on Incidents and Prognosis.” And finally Carolyn a Research letter from Dr. Jizheng Wang involving an East Asian-specific common variant in TNNI3 that appears to predispose to hypertrophic cardiomyopathy. Well, Carolyn, what a great issue and thank you for that many feature, but how about we proceed on next to our feature discussion?
Dr. Carolyn Lam:
Let's go, Greg.
Today's feature paper is one of those that I think is going to change clinical practice. So please listen up. It's about the RESTAGE-HF study. So pleased to have with us the first and corresponding author, Dr. Emma Birks from University of Kentucky Gill Heart and Vascular Institute, as well as our associate editor, Dr. Hesham Sadek from UT Southwestern to discuss this very important paper. Emma, could you please describe the RESTAGE heart failure study?
Dr. Emma Birks:
Let's say prospective study of patients getting left ventricular assist devices. So patients with very advanced heart failure are receiving left ventricular assist devices as either a bridge to transplant or as destination therapy. And they're seeing them for chronic heart failure because really all other medical therapy has failed and we use the pump to try and recover their own heart. So when the pump's implanted, we optimize the LVAD unloading, the maximum loading, and we give them a very aggressive medical therapy regime, unless they may not have tolerated these medications before because of poor blood pressure and renal dysfunction, we find they do tolerate them. So we give them in very aggressive doses and then we monitor their underlying function at regular intervals and try and promote recovery. So with that, we had done this in England in the past, in a single center study, but it had not yet been reproduced, which was obviously essential to have a bigger impact.
Dr. Emma Birks:
So we did a prospective study of six big US centers. We found that we've created a primary endpoint that was statistically powered in advance. And the primary endpoint was the number of patients that recovered within an 18 month period, that were explanted and remained off the pump and alive without transplant over for one year. So overall we found that of the 40 patients we recruited in the centers with chronic heart failure, we were able to explore 19. Of those that satisfied the primary endpoint, that was actually 40% of patients, with 52.3% being explanted overall. And importantly, patients were explanted in all six centers, so we found that the protocol was reproducible under the how much higher rate of recovery that you would otherwise see. Normally there is a database in the US that tracks outcomes from bad patients. And generally only 1-2% seemed to recover enough to be explanted generally. So this was a much bigger percentage.
Dr. Carolyn Lam:
Emma, first of all, congratulations, what an important trial and what stunning results. More than half of patients receiving that protocol were explanted. That's just remarkable. Now, could I just ask, what is it that you did that was different? I noticed you spent a lot of time saying this was an aggressive pharmacological protocol that was along with the LVAD unloading. Could you maybe elaborate on that a little bit more?
Dr. Emma Birks:
Yeah, I think that was a very important part of it. So generally I think when the LVAD goes in most centers, the patients are very sick, so most of those patients wouldn't then try and recover them or look at underlying functions. I think that was the first thing that was different was to try very hard. And then we had centers, the experience, I had done this before, it was also very helpful, all agreeing to do the same thing. We use a very aggressive regime of ACE inhibitors, Beta blockers, auto serotonin antagonists and ARBs. And that was also an unusual thing. We use the fact that they're supported with the pump to use both an ACE and an ARB together, but the idea that they have better blood flow in the cranial is way more tolerant and we give very high doses. So we use Lisinopril with the target dose of 40 milligrams, Coreg with a target dose of 50 BID, Aldactone 25 milligrams daily.
Dr. Emma Birks:
And then we add in losartan if they tolerate it and actually aim for 150 milligrams daily, so those doses are very high. And I think not normally given to people on LVADs. So you must've had the LVAD that don't tolerate the medical therapy and stop it. They might just have blood pressure control, etc. There is now also another INTERMACS trial, a sort of big study that's come out that actually shows benefit of neurohormonal antagonists in general. So that goes together with our study to show that they should already be given and then the regular testing. So we had quite thorough testing. So first of all, we do echos on the pump and then we do echos with the LVAD turned down to a speed at which is not contributing. So we do that and we do an echo at five minutes with it down 15 minutes, and then we walk the patient, distress them. Once we show that the hearts come down in size and improved function, then we do an exercise test, right heart cath on an off pump to look at the hemodynamics.
Dr. Carolyn Lam:
Wow. So tremendous effort and really the protocol is unique in and of itself, not just the pharmacological therapy, also the way this is monitored and decisions are made really, really amazing. Just one last question for me, because it's a humbling reminder of the importance of neurohormonal blockade in these patients. Do you continue that after they're explanted?
Dr. Emma Birks:
Yes, we do. And we continue aggressively and that's slightly different as well in that normally you wouldn't give a patient a nascent an up of course, but given that they've already tolerated it on the pump in that same patient. So we restart the same drug regime afterwards, and we actually like to get them to quite along that dosage before we discharge them from the XPLAN, we don't want to do that slowly. We get them back on it quite quickly. And then we follow them very carefully because we don't really know the long-term durability.
Dr. Carolyn Lam:
Wow, thank you. Hesham. I would love your thoughts on this paper. I mean, it really, really is remarkable results.
Dr. Hesham Sadek:
Yeah. I mean, I was very happy that we received this paper to review, frankly I've been following that work for a long time since the first new England paper that came out and I'd like to congratulate you for an amazing work. I think this will change the field. First, how was this trial different from the first trial, other than the fact that it's multicenter, what would you say are the major changes that you made to the protocol and what you've learned since the first trial?
Dr. Emma Birks:
Yes, you're absolutely right. We did make some changes. So first of all, it was six sites instead of one site. I think it was very important to reproduce it in the US but we changed the protocol itself as well. The first trial had optimization of the LVAD speed, really just by echo looking at the reduction in the ventricle size. It had the aggressive medical regime was very similar except this time we increased the Losartan dose from 100 to 150 after the Hill's trial came out. The testing was very frequent in the original English Sheffield study, probably a little bit too frequent to be able to be adopted on a wide scale. So we tried to reduce it down a little bit. So we decrease the frequency of the low-speed echos. I think we had them at six weeks, four months, six months, nine months in a year.
Dr. Emma Birks:
And after that, we saw if they were already improving and started and only did them at a year to 18 months, if they were improving. And then we also cut down the number of exercise tests. So we didn't do the exercise test until the echo was already showing significant improvement. For two reasons, one, we didn't find it very reliable and two, it was just too much testing for the patient. So it was more of a confirmatory test. In fact, it wasn't a requisite for a pump explantation. We didn't do a left heart catheter, which we did before. Previously we tried to measure LVEDP, this time we decided which was enough. So we just did a right heart cath on and off pump. And we did that once the echo was improved as well. So we rationalized that a little bit. And then the other important thing was before in hayfield study, once we saw the ventricular size come down and injection fraction start to improve, we actually added in Clenbuterol, which was a Beta-2 agonist.
Dr. Emma Birks:
And the idea with that was to cause a kind of physiological hypertrophy so that when you took the pump out, the heart didn't just dilate. We were worried about atrophy at the heart on the pump long-term. So we did that to try and improve the durability of recovery. So the reason we left off this time was really the previous protocol was very good, but was very complicated. So we wanted to see what rate of recovery we could get just with the aggressive reverse remodeling, neurohormonal drugs, plus the aggressive testing and the optimum loading with the idea that later on, we could add on either Clenbuterol or something later to improve the durability of recovery, if the ability of recovery is not good enough, but actually so far it's proven to be pretty good because the study itself takes quite a long time. It was sort of to recruit them. We had an 18 month period than the follow-ups. It was already a multi-year study. So we wanted to establish a regime that many centers could use to try and promote recovery.
Dr. Hesham Sadek:
I want to follow up on that last point, because as you know, I've looked at some of these Heights as well in our center, and we looked at the results with you and Stavros and others. So the myocytes size is expected to change, decrease with unloading, right with sufficient unloading. So how would you prepare the Myocardium to take on the normal afterload if you are not going to induce by a beta agonist, for example,
Dr. Emma Birks:
What I would like to do in the future is try using the pump itself actually. Sometimes there's heart recovers, the heart shrinks and actually start opening their own valve and working in the heart. Of course, when you have the HeartMate one, actually, sometimes wasn't synchronous with the heart. So sometimes the heart will beat against the pump anyway. Once you go to the continuous flow pumps, you've got continuous unloading. So I think it'd be very interesting to intermittently turn down the pump speed and load the heart to work it before you take the pump out. So I would really like to do that. I think that might be the next interesting phase of the study to improve your ability to.. So I guess once you've got maximum reverse remodeling and improvement in function, you could just turn the pump speed down to let the valve open.
Dr. Hesham Sadek:
Do you think perhaps if you do that, you will increase the percentage of patients that can be explanted? Do you think that could be a factor in the percentage of patient that can be explained?
Dr. Emma Birks:
I think it might be, it might more improve the, to your ability to make sure we have for a long, good echo function afterwards.
Dr. Hesham Sadek:
That's great. So another question this was limited to not ischemic cardiomyopathy patients. Can you elaborate a bit on why not include, for example, revascularized ischemic cardiomyopathy patients.
Dr. Emma Birks:
Yeah, so we did that really just because we didn't want to change too much from the original protocol. We also stuck with one device because we thought if you have multiple pumps, multiple diagnosis, it does get hard to analyze in a multicenter trial. So we did that on purpose and we were always trying to simulate the bridge to transplant population in the age group too. But actually interestingly, most of the patients recruited in the trial were destination therapy patients in the end.
Dr. Emma Birks:
I think this could be done with ischemic cardiomyopathy. I think we don't have enough data on ischemic cardiomyopathy to know whether it does or it doesn't recover. So I don't think our results say that it's only known as ischemics. I think it just means we haven't studied ischemics sufficiently. Logically they might have more scarred. It might be harder to get such a good percentage to recover. I think all of us in our individual centers have seen a few and we've sort of seen the on pump echo improved, and we've tested them and then taken some out. But most of these cases are anecdotal. So I think that is another important study that needs to be done, obviously a large group of patients.
Dr. Hesham Sadek:
I agree. So given that they're not ischemic cardiomyopathy, do you know how many of them had genetic testing or what is the percentage of monogenic cardiomyopathys or how do you think these patients would respond to this protocol?
Dr. Emma Birks:
But if you had a familiar history and actually found it didn't make any difference, whether they recovered or not. I think some of us have personally seen actually those were the familial cardiomyopathy tend to recover more actually again, anecdotally. We published a people before looking at the Titin gene saying that that did recover. I think actually only five of these patients, 12% of them had a family history, but some of them recovered
Dr. Hesham Sadek:
One final question, as you know, I'm a basic scientist. So ultimately the question I'm going to ask, what do you think the mechanism is? Is it that these hearts are just in a vicious cycle of remodeling and validation, increased pressure, and you were sort of giving it a chance for actual structural reverse remodeling where you changed the geometry of the myocardium and perhaps rest of myocardium, allow for improvement of calcium cycling dynamics, or do you think, is something more exciting? Like three-generation for example.
Dr. Emma Birks:
Yeah, that's very interesting because I think the LVAD doesn't unload, so it shrinks the ventricles. I think it does improve the geometry and the dynamics. And then you use the drugs where they may have felt before you almost put them from class four, heart failure into class three with the bad to give that chance to work again. And then I think various cellular and fibrotic factors have been looked at and it's hard because there was so many factors have been looked at that. You were going to find some that go up and some that go down and what's important. But the impression I get overall is that you do get improvement, the matrix limits, the recovery on the fibrosis and the matrix. Whereas you do get improvements of myocardial function and cellular function. The cells will tend to reverse the dysfunction and it's really whether that happens or not. It's probably limited a lot by the matrix
Dr. Carolyn Lam:
That is amazing here. Hesham, I'm going to put you on the spot. Do you have your own hypothesis about this
Dr. Hesham Sadek:
Based on the work that they did initially in the new England paper, we did actually a small pathology study looking at cell cycle of cardiomyocytes from the core samples and from the explanted hearts post-transplant and we saw evidence of increased cardiomyocytes cell cycle in these patients along with decreased DNA damage and some metabolic remodeling as well with mitochondria. So, you can't really tell much from tissue whether you regenerated it or not, but as you know myocytes don't divide and this is the basis for the lack of spontaneous regeneration of the myocardium. So if this in fact removes the block to cardiomyocyte cell cycle, then this might be a regenerative therapy mechanism.
Dr. Carolyn Lam:
Well, this is amazing. I wish we had all day to discuss this more. I mean, this is the only place you can get a discussion that goes from clinical to basic signs and back to clinical. Thank you so much, Emma and Hesham for sharing today. Thank you audience for joining us today. You've been listening to circulation on the run on behalf of Greg as well. Don't forget to tune in again next week.
Speaker 1:
Program is copyright the American heart association, 2020.
This week’s episode features author Jaime Layland and Associate Editor Dharam Kumbhani as they discuss the ariticle "Colchicine in Patients with Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial."
TRANSCRIPT BELOW:
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health, in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, for our feature discussion we're talking about a very hot topic these days, the role of colchicine, this time in patients with acute coronary syndrome, with Australian data. I cannot wait to get to that, but I'm going to make you wait because I want to tell you about a whole lot of other really cool papers in today's issue.
Dr. Carolyn Lam:
First, have you ever wondered what is the association between risk factor control and cardiovascular disease risk in type 2 diabetes? Well, today's paper answers that. It's from Dr. Wright from University of Manchester and her colleagues who looked at a retrospective cohort using data from the English practices from Clinical Practice Research Datalink, or CPRD, and the Scottish Care Information diabetes dataset. They also linked to hospital and mortality data and identified more than 101,000 patients with type 2 diabetes in CPRD matched with almost 379,000 controls without diabetes and almost 331,000 patients with type 2 diabetes in the Scottish Care Information diabetes database between 2006 and 2015. The main exposure was a number of optimized risk factors, and these are: (1) Nonsmoker; (2) total cholesterol less than 4 mmol/L; (3) triglycerides less than or equal to 1.7 mmol/L; (4) HB A1c less than 7%; and (4) systolic blood pressure less than 140 or less than 130 mmHg of high risk.
Dr. Greg Hundley:
Carolyn, I am very curious. Lots of data here. What did they find?
Dr. Carolyn Lam:
So the key findings were:
Dr. Carolyn Lam:
First, even with optimally managed risk factors, people with type 2 diabetes still had a 21% higher risk for all cardiovascular disease events and non-fatal coronary heart disease, and a 31% higher risk of heart failure hospitalization compared to patients without diabetes.
Dr. Carolyn Lam:
- Only 6% of people with type 2 diabetes had optimal risk factor controls, so a very low percent.
Dr. Carolyn Lam:
- The association between the number of elevated risk factors and cardiovascular disease events and mortality was much stronger in patients with type 2 diabetes but without cardiorenal disease compared to those with established cardiorenal disease. People without cardiorenal disease were also younger and more likely to have suboptimal risk factor control and fewer prescriptions for risk-factor-modifying medication.
Dr. Carolyn Lam:
So take-home message: Greater use of guideline-driven care, clinical decision support, drug intervention, and self-management support should be encouraged for risk factor control, and people with type 2 diabetes and without cardiorenal disease may especially benefit greatly from cardiovascular disease risk factor intervention.
Dr. Greg Hundley:
Very nice, Carolyn.
Dr. Greg Hundley:
Well, my first study comes from Dr. Gregory Lewis from Mass General Hospital in Boston, Massachusetts. Carolyn, another quiz: Have you wondered about differences in metabolism in those who exercise versus those that do not?
Dr. Carolyn Lam:
Greg, I wonder about that all the time when I'm running out there.
Dr. Greg Hundley:
In this study, cardiopulmonary exercise testing, or CPET, and metabolite profiling was performed on Framingham heart study participants aged about 54 years with 63% of them being women with blood drawn at rest in 471 subjects and then again at peak exercise in 411.
Dr. Carolyn Lam:
Nice, and kudos for the majority women. So what were the results?
Dr. Greg Hundley:
The authors observed changes including reductions in metabolites implicated in insulin resistance and increases in metabolites associated with lipolysis, nitric oxide bioavailability, and adipose browning. Exercise-induced metabolite changes were variably related to the amount of exercise performed, peak workload, sex, and body mass index. There was attenuation of favorable exercise excursions in some metabolites in individuals with higher BMI and greater excursions in select cardioprotective metabolites in women despite less exercise being performed. Four metabolite signatures of exercise response patterns were analyzed in a separate cohort. The Framingham offspring study of 2,045 were about age 55 years and 51% were women, two of which were associated with overall mortality over a median follow-up at 23 years.
Dr. Greg Hundley:
So Carolyn, in conclusion, the authors found acute exercise elicits widespread changes in the circulating metabolome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise that could be useful in future studies.
Dr. Carolyn Lam:
Beautiful. I'm going to keep exercising and I bet you will, too, Greg.
Dr. Carolyn Lam:
So this next paper is a mechanistic study that revealed a special population of tissue regulatory T-cells in the heart with a unique phenotype and pro-repair function. So this comes from corresponding author Dr. Cheng from Tongji Medical College of Huazhong University of Science and Wuhan Hubei, China. He and his colleagues studied the dynamic accumulation of regulatory T-cells in the injured myocardium in mouse models of myocardial infarction, myocardial ischemia re-perfusion injury, or cardiac cryo injury, and using state-of-the-art methods such as bulk RNA sequencing, photo conversion, parabiosis, single-cell TCR sequencing, adoptive transfer, and functional assays.
Dr. Greg Hundley:
Carolyn, interesting. What did they find?
Dr. Carolyn Lam:
They showed that regulatory T-cells that accumulate in the injured myocardium after myocardial infarction or myocardial ischemia re-perfusion injuries had a distinct transcriptome which differs from lymphoid organ regulatory T-cells and other non-lymphoid tissue, and this represents a novel population of tissue regulatory T-cells in the heart. These heart regulatory T-cells were mainly thymus driven and recruited from the circulation showed active local proliferation with the IL-33/ST2 axis promoting their expansion. With the phenotype of promoting tissue repair, heart regulatory T-cells over-expressing spark contributed to elevated collagen content and enhanced maturation in infarct scars to prevent cardiac rupture and improve survival after myocardial infarction.
Dr. Carolyn Lam:
So in summary, this paper identified and characterized a phenotypically and functionally unique population of heart regulatory T-cells, which may lay the foundation to harness these cells for cardiac protection in myocardial infarction or other cardiac diseases.
Dr. Greg Hundley:
Wow, Carolyn. Very interesting.
Dr. Greg Hundley:
Well, my next paper comes from Dr. Michael Rubart from Indiana University School of Medicine, and as some background it's going to discuss calmodulin. So calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a P.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying this N98S mutation knocked into CALM1 replicate the human arrhythmia phenotype and then to examine some of the arrhythmia mechanisms.
Dr. Carolyn Lam:
Okay. So what did they find?
Dr. Greg Hundley:
Carolyn, several techniques were used in this study. Mouse lines heterozygous for the CALM1 N98S allele generated using CRISPR and caspase 9 technology. Also, adult mutant mice and their wild-type litter mates underwent electrocardiographic monitoring. Ventricular D and re-polarization was assessed in isolated hearts using optical voltage mapping, and action potentials in wholesale currents as well as calcium influx were measured in single ventricular myocytes using patch-clamp techniques and fluorescence microscopy, respectively. Microelectrode techniques were employed for in situ membrane voltage monitoring of ventricular conduction fibers. Carolyn, it was really a comprehensive study.
Dr. Greg Hundley:
So what did the authors find? Heterozygosity for the CALM1 N9S mutation was causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTC interval prolongation, and bidirectional ventricular tachycardia. Second, beta adrenergically induced calcium influx L dysregulation contributed to the long QT phenotype. And finally third, they found that pause dependent early after depolarizations and tachycardia induced delayed after depolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constituted potential sources of arrhythmia in the CALM1 N98S positive hearts.
Dr. Carolyn Lam:
Wow. Sounds like a really comprehensive study. Thanks, Greg.
Dr. Carolyn Lam:
Let's talk about some other papers in this issue, shall we? There is a Perspective piece by Dr. Klassen on the COVID-19 pandemic, a massive threat for those living with cardiovascular disease among the poorest billion. There's an ECG challenge by Dr. Littman on a malignant electrocardiogram. Here's a hint: It's a pseudo-infarct pattern with important learnings. They're in an exchange of letters between Drs. Packard and Schwartz regarding the role of lipoprotein A and modification by alirocumab, a pre-specified analysis of ODYSSEY Outcomes randomized clinical trial.
Dr. Greg Hundley:
Oh thanks, Carolyn. I've got a couple other papers. Dr. Venkateswaran Subramanian has a Research Letter entitled Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice. Professor Jan Cornell has another research letter entitled Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease. The LoDoCo2 proteomic substudy. And then finally, Dr. Sanjay Kaul from Cedars-Sinai Medical Center has a white paper reviewing the benefit/risk trade-offs in assessment of new drugs and devices.
Dr. Greg Hundley:
Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and acute coronary syndromes.
Dr. Carolyn Lam:
Yeah. Let's go, Greg. Today's feature discussion is all about colchicine, that commonly used treatment for gout that has recently emerged as a novel therapeutic option in cardiovascular medicine. I am so pleased to have with us the corresponding author of today's paper, Dr. Jamie Layland from Monash University, as well as our associate editor, Dharam Kumbhani, from UT Southwestern to discuss this very important trial data from Australia. Jamie, could you start us off by telling us all about this Australian COPS trial?
Dr. Jamie Layland:
We performed the Australian COPS trial back in 2015, and it finished recruiting in 2018. Essentially the trial was a trial to look at the safety and efficacy of colchicine being used in acute coronary syndromes, and this was prior to the release of important trial COLCOT. So essentially we randomized patients who presented to the hospital with an acute coronary syndrome to receive colchicine twice daily for one month followed by colchicine once a day for 11 months, and we followed these patients up for a minimum of 12 months. This was performed across 17 sites across Australia, and we looked at a composite endpoint of total death, acute coronary syndromes, unplanned urgent revascularization, and stroke.
Dr. Carolyn Lam:
Nice. So Jamie, could I first clarify that this was an investigator-led trial, I'll bet, and man, first of all, applause for doing this. I can only imagine how much work this took and maybe then tell us about the results.
Dr. Jamie Layland:
Yeah. So this was an investigator-initiated trial through a network of academic investigators across Australia on limited research funding, so through philanthropic and institutional support. So it was a huge effort over a number of years, and I'm very thankful to the support of Circulation and Dharam in supporting the paper, which I think was a great success.
Dr. Jamie Layland:
So the results of this trial were a surprise to us all, but essentially this was a negative trial in the sense that colchicine did not improve the primary outcome, so there was no improvement in the rate of the COLCOT outcome. And interestingly, there was an increase in total mortality, in particular non-cardiovascular deaths were higher at five compared to the placebo at one. That was over a 12-month follow-up period.
Dr. Carolyn Lam:
Interesting. So Jamie, I'm going to ask the question that's on everyone's mind then: What's the difference between your trial and COLCOT?
Dr. Jamie Layland:
That's a great question. Obviously, COLCOT was a much larger trial. COLCOT was an international trial of over 4,000 patients. Similar patient demographics, similar patient subgroup of acute coronary syndromes. However, importantly, COPS was a trial of inpatient initiation of colchicine. So patients when they had their STEMI, or non-STEMI most commonly, they were given colchicine usually within 72 hours of their index hospitalization and sometimes sooner, and this was given prior to discharge. With COLCOT, the median time of administration of colchicine was around 14 days, so slightly different groupings there. However, in COLCOT you were allowed to administer colchicine as an inpatient. You can see obviously from the European side of cardiology the impressive data when colchicine was given earlier in COLCOT how this translated to improved outcomes. So clearly, there is a potential benefit there for early administration of colchicine when you look at these two trials.
Dr. Jamie Layland:
But we administered colchicine acutely when patients presented in their index hospitalization. We also importantly used a different dosing schedule to COLCOT. So COLCOT was 0.5 mg daily and we used 0.5 twice daily. This was for the first 30 days, and this was based on early data from the group from western Australia who showed that when colchicine was given to patients at a BD dosing in those patients who were already on aspirin and high-potency statins, there was a significant reduction in hsCRP, obviously a commonly used marker of inflammation at four weeks, and also based on data showing that there was a heightened inflammatory response in the early days following an acute coronary syndrome. So we felt that using this twice-daily dose would be advantageous and potentially helpful for our patients. So they're the two main differences between the studies.
Dr. Carolyn Lam:
Thanks for explaining that so clearly. Dharam, could I have your thoughts? This was, of course, discussed heavily, right, by the editors. Could you give us a sneak peek of what else was discussed?
Dr. Dharam Kumbhani:
The trial is very important, although it is smaller perhaps in sample size and kind of done with less resources than COLCOT. I do think this adds to the body of literature on colchicine for secondary prevention of CAD. And one of the interesting things is that we see we also have the LoDoCo2 trial, which was a slightly different population, Jamie, which was the chronic coronary artery disease patients, but also still looking at secondary prevention. What is really striking to me is that a very similar signal in non-CV death was noted in that trial as well. Again, it was not seen in COLCOT and LoDoCo1, but it was very interesting that a similar finding was there. So I do think this is something that the field will need to investigate more and really try to understand is this just noise and by chance alone, or is this something that that's a real signal for.
Dr. Carolyn Lam:
Jamie, what are your thoughts about that and in LoDoCo differences with your trial?
Dr. Jamie Layland:
Good question, and a very important topic that obviously is currently under discussion amongst the colchicine community. As I said, it was a surprising result. We weren't anticipating this non-CV death signal, but as Dharam said when LoDoCo2 came out, a fantastic trial again, but this signal of non-CV death. I don't know whether it's merely just a noise as you say or whether it's a significant finding, but clearly we need to do more research in this field to understand the mechanism and whether this is a real signal or not. It seems a little bit discordant with previously published work. So if you look at the literature in patients with gout from across the world, there's no real signal of increased non-CV death in those patients. However, with patients with acute coronary syndrome as we are administering the colchicine on a daily basis and then commonly this isn't used for gout, so that is a slight difference. But certainly, there was no signal in the non-CV literature to support the findings that we had and the signal in LoDoCo2.
Dr. Jamie Layland:
The other thing to note is in a cohort of five non-CV deaths, three out of those five patients were actually not taking colchicine at the time of their death. They stopped the drug prematurely. So I think we just need to take a step back and really await the results. Obviously, we've got two-year and five-year data coming out from the COPS trial which will be interesting to look at, but also the Clear Synergy trial from the McMaster team, that would be a very important trial providing more data on this potential signal. But reassuringly, and I feel more reassured knowing the COLCOT data, which is a slightly similar cohort to ours, showing that there was no trend towards increased non-CV deaths. So I think it's something that we have to be aware of and there will be lots of metro-analysis I'm sure being published in the coming months looking at this specifically. But yeah, I think we shouldn't cast any aspersions on colchicine yet. I think that's too early, but I do think we need more data.
Dr. Carolyn Lam:
Thanks, Jamie. Speaking of looking deeper in your data and looking at those who died and were they taking the medication and so on, you did some other post-hoc analysis, right? And maybe you could just describe briefly, for example, the 400-day followup.
Dr. Jamie Layland:
Yes. So the interesting thing with our data, and I had mentioned this before, is that we had limited resources, so we really wanted to do this trial, and obviously competitive funding is tricky at the best of times, but we were really committed to doing this trial and we had a group of investigators who were all committed to doing this trial. But for this to work, we had a single research nurse and a fellow performing the follow-up. So at times, there was a little lag between the timing of the follow-up. So we ended up getting follow-up which was slightly prolonged over the 12-month window. On average, it was around 400 days. When we looked at the 400-day data, we saw that there was an increasing separation of the biomarkers after 365 days.
Dr. Jamie Layland:
The results, this was obviously not the primary outcome, this was a sensitivity analysis, but there was a suggestion or a significance out to 400 days with an improvement with colchicine. However, this is the primary composite outcome, so revascularization, acute coronary syndrome, stroke, and total death notwithstanding this positive outcome, there was still this trend to high rate of mortality, so that has to be taken into consideration. But there was a suggestion that the longer the duration of colchicine was given for, it culminated into these lights affect. And we see from CT data that colchicine actually has some plaque-modulating effects and reduces high-risk or low-attenuation plaque. So you could hypothesize that as the majority of the benefits seen in colchicine in LoDoCo2, in COLCOT, and in COPS was the reductions in urgent revascularization, stroke, and acute coronary syndromes.
Dr. Jamie Layland:
So perhaps there is this effect that colchicine is having on plaque stabilization so we're seeing less longer-term events, but this is just hypothesis generated and we need more data to support that. But it is a very interesting finding nonetheless.
Dr. Carolyn Lam:
Thank you. Dharam, could I hand you the last word on where you think this field is going or where you think it should go?
Dr. Dharam Kumbhani:
I think Jamie put it really nicely. I think he outlined the study nicely with its strengths and its limitations, and I think this is obviously a debate between perhaps the colchicine believers and the ones that are still perhaps trying to understand a little bit more about its true role, because as was mentioned I think there's really a benefit in ischemia-driven revasc. I think we've seen that in almost all the colchicine trials. There is no reduction in mortality, and as we saw in the COPS data maybe it goes the other way. So I think from a pathophysiological standpoint it makes sense. I think there's good translational data to suggest that it would be beneficial in this patient population, but I think that's the beauty of having clinical trials and the ones that are done by different investigators and perhaps in different settings, because they help us answer the truth. And whether colchicine becomes a stable part of our armamentarium for secondary prevention of CAD going forward, I think the jury is still out and as was mentioned I think Clear Synergy would probably be very helpful in hopefully tying all this together.
Dr. Dharam Kumbhani:
So again, I want to congratulate Jamie and his team for really providing us with a very interesting trial done in a very pragmatic setting, and I think the field is very thankful to them for providing us with this information.
Dr. Carolyn Lam:
Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to join me and Greg again next week.
Dr. Greg Hundley:
This program is copyright the American Heart Association 2020.
This week’s episode features author Kazuomi Kario and Associate Editor Wanpen Vongpatanasin as they discuss the article "Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis: Practitioner-Based Nationwide JAMP (Japan Ambulatory Blood Pressure Monitoring Prospective) Study."
TRANSCRIPT BELOW:
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, when is the best time to check your blood pressure if you have a home monitoring device? Morning? Afternoon? Nighttime? And what do those nighttime fluctuations infer? Well, we'll hear a lot more in our feature discussion today, but first let's grab a cup of coffee and jump into some of the other papers in the issue. I'm going to start first this week, and my first paper comes from Dr Joe Wu at Stanford University. Carolyn, a quiz. Are all endothelial cells alike?
Dr Carolyn Lam: Jeez, Greg. Okay, I'm going to hedge. I bet a lot of them share similarities, but there may be some differences.
Dr Greg Hundley: Yes, Carolyn. Dr Wu and his associates perform a series of elegant experiments involving mice, and they found that certain tissue-specific endothelial cells cluster strongly by tissue, like those in the liver or the brain, whereas others from, for example, adipose tissue or the heart have considerable transcriptomic overlap with endothelial cells from other tissues. They identified novel markers of tissue-specific endothelial cells and signaling pathways that may be involved in maintaining their identity, and sex was a considerable source of heterogeneity in the endothelial transcriptome.
In addition, they found that markers of heart and lung endothelial cells in mice were conserved in human fetal heart and lung endothelial cells and identified potential angiocrine interactions between tissue-specific endothelial cells and other cell types by analyzing ligand and receptor expression patterns.
Dr Carolyn Lam: So interesting, Greg. You especially had me at sex differences. So, what's the take home message?
Dr Greg Hundley: Right, Carolyn. So this group discovered a series of transcriptional networks that maintain endothelial cell heterogeneity, and that angiocrine and functional relationships exist between tissue-specific endothelial cells. These findings open the door for future studies that can manipulate these pathways and perhaps modify processes, like atherosclerosis, that impact the endothelium.
Dr Carolyn Lam: Wow, that's cool, Greg. Well, from your paper, I'm going to a mechanistic paper too, and the next study really aimed to define cardiac fibroblasts' heterogeneity during ventricular remodeling, as well as the underlying mechanisms that regulate their function, so important questions here. And co-corresponding authors, Drs Prósper and Lara-Astiaso from Clinica Universidad de Navarra in Pamplona in Spain, as well as Dr Lindner from Maine Medical Center Research Institute in Scarborough, Maine in the U.S., and their co-authors, basically characterized cardiac fibroblasts after myocardial infarction using a whole host of very novel techniques like single-cell and bulk RNA sequencing, ATAC sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing.
Dr Greg Hundley: Very intriguing. What did they find?
Dr Carolyn Lam: They identified and characterized a unique cardiac fibroblast subpopulation that emerged after myocardial infarction in mice. These activated fibroblasts exhibited a clear profibrotic signature expressing high levels of collagen triple helix repeat containing 1 and localized into the scar. Moreover, the absence of this regulator resulted in pronounced lethality due to ventricular rupture. Finally, a population of cardiac fibroblasts with a similar transcriptome was identified in a swine model of myocardial infarction, as well as in heart tissues from patients with myocardial infarction and dilated cardiomyopathy.
Dr Greg Hundley: Ah, so important information on how fibroblasts start the scar formation after infarction. So, Carolyn what's the take home message here for this research?
Dr Carolyn Lam: Well, this paper really provides important information on cardiac fibroblast heterogeneity, their dynamics during the course of myocardial infarction, and the authors also redefine the cardiac fibroblasts that respond to cardiac injury and participate in myocardial remodeling. This study identifies collagen triple helix repeat containing 1 as a novel regulator of the healing scar process, and as a target for future translational studies.
Dr Greg Hundley: Great, Carolyn. You're doing such a great job. This is an issue for double quiz. Have you ever heard of treatments for hypertension incorporating Chinese herbal formula gastrodia-uncaria granules?
Dr Carolyn Lam: What? Are you trying to speak Chinese, Greg?
Dr Greg Hundley: Yeah (affirmative) Okay.
Dr Carolyn Lam: I'm sure you're going to tell us about it.
Dr Greg Hundley: Right. So this study is from Professor Yan Li from Ruijin Hospital in Shanghai, Jiao Tong University School of Medicine. Gastrodia-uncaria granules Carolyn, is a mixture of Chinese herbs that dates back many years, I think thousands, and in this study was used in patients with masked hypertension. So in the study, patients with an office blood pressure of less than 140/90 millimeters of mercury, but a daytime ambulatory blood pressure of 135 to 150 millimeters of mercury systolic or 85 to 95 millimeters of mercury diastolic, were randomized one-to-one to receive the treatment of, and I'm going to abbreviate it, GUG versus placebo, 5 to 10 grams twice daily for four weeks. The primary efficacy variable was the change in daytime ambulatory blood pressure.
Dr Carolyn Lam: Ah. (affirmative), so did it work?
Dr Greg Hundley: Well, in their intention-to-treat analysis, daytime systolic-diastolic blood pressure was reduced by 5 and 3 millimeters of mercury in the GUG group, and 3 and 1.6 millimeters of mercury in the placebo group, respectively. The between group difference in blood pressure reductions was significant, 2.5 and 1.7 millimeters of mercury, and 24-hour blood pressure by 2 and 1.5 millimeters of mercury, but not for the clinic and nighttime blood pressures. The per protocol analysis in 229 patients produced similar results. Only one adverse event, sleepiness during the day was reported and no serious adverse events occurred. So Carolyn, a potentially inexpensive regimen found useful in China for patients with masked hypertension. To learn more of the results of this interesting study, listeners are suggested to review the article in this particular issue.
Dr Carolyn Lam: Wow, interesting Greg. Okay. So from hypertension to CABG. Now we know that approximately 15% of saphenous vein grafts occlude during the first year after coronary artery bypass graft surgery, or CABG, despite aspirin use. So can ticagrelor added to standard aspirin improve saphenous venous graft patency at one year after CABG? Now this is the question that Dr ten Berg from St. Antonius Hospital from Nieuwegein in Netherlands, and colleagues sought to answer in the popular CABG trial, which was an investigator-initiated randomized double-blind placebo-controlled multicenter trial of 499 patients with one or more saphenous vein grafts, who were randomly assigned after CABG to ticagrelor or placebo added to standard aspirin.
The primary outcome was saphenous vein graft occlusion at one year assessed with coronary CT angiography occurred in 10.5% of the ticagrelor group, versus 9.1% in the placebo group, so that's an odds ratio of 1.29, and it was not significant. The secondary outcome of one year saphenous vein graft failure, which was a composite of vein graft occlusion, revascularization, myocardial infarction in the myocardial territory supplied by the vein graft, or sudden death, well, that occurred in 14.2% of patients in the ticagrelor group, versus 11.6% in patients in the placebo group. Again, not a significant difference.
Dr Greg Hundley: So Carolyn, a negative study? What's our take home here?
Dr Carolyn Lam: In this randomized double-blind placebo-controlled trial, the addition of ticagrelor to standard aspirin after CABG did not reduce the rate of saphenous vein graft occlusions at one year. Now, this conclusion differs from some other studies that investigated this research question, and this is discussed in this editorial that you got to pick up. It's by Dr Goldman from the University of Arizona.
Dr Greg Hundley: Wow, Carolyn. Great job. Well, we've got a couple more articles in this issue, and I'll start by describing a research letter by Dr Daviet regarding heparin-induced thrombocytopenia in COVID-19, and then Carolyn there's a second research letter from our own Torbjørn Omland regarding established cardiovascular biomarkers provide limited prognostic information in unselected patients hospitalized with COVID-19. And then finally, from Dr Chonyang Albert, a case series entitled, The Enemy Within: Sudden Onset of Reversible Cardiogenic Shock with Biopsy-Proven Cardiomyocyte Infection by SARS-CoV2.
Dr Carolyn Lam: We've also got an ECG challenge by Dr Sreenivasan entitled, A Red Flag ECG, also known as, and have you heard of this, South African flag pattern. Okay, here's a hint. It's an important, but subtle ischemic ECG change. You got to look it up. There's an On My Mind paper by Dr Alexander on at risk of depriving patients’ life-saving cardiac surgery, and those are the implications of the ischemia trial for CABG. A Research Letter shared by Dr Susen entitled, Endotheliopathy is Induced by Plasma from Critically-ill Patients and Associated with Organ Failure in Severe COVID-19. And finally, in Cardiology News, Tracy Hampton reviews the most recent literature in top journals like Nature, Metabolism, Cell, Stem Cell, and Circulation Research. Wow. Bonanza issue. So cool, but I really want to hear about the different blood pressure patterns now. Let's go to our feature discussion, shall we?
Dr Greg Hundley: Absolutely. Here we go. Well, listeners we are excited to get to this feature discussion to learn more about the use of ambulatory blood pressure measures, particularly those that are collected 24 hours and during the nighttime. We have with us, Dr Kazuomi Kario from the Jichi Medical University in Japan, and our own Associate Editor, Dr Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas. Welcome to you both. And Kazuomi, could you start us off please and just describe some of the background that led you to perform this study? And what hypothesis did you want to address?
Dr Kazuomi Kario: The old guidelines management of the hypertension and now recommend instead of the office blood pressure, now the ambulatory blood pressure management. So for example, the ABPN and also home blood pressure monitoring, but the 24-hour blood pressure reduction is very much important, all prefer the values, but also our hypothesis took on the 24-hour blood pressure quantity reduction, but also, we should normalize our circadian rhythm. Usually blood pressure reduced by 10 to 20% at night during the sleep compared to the daytime. But the other group, is exhibited and predicated known six bars and also is either higher at night during the nighttime period compared to the daytime. And also home blood pressure variability, that hurts blood pressure in the morning. So circadian rhythm normalization and also, I recreate blood pressure variability especially is more precise.
It's important for the quality control over for the hypertension management. So my hypothesis is that blood pressure reduction, the other most blood pressure, and the normalized circadian rhythm, under agitate, to keep agitate among as such. All the three components I did try to optimize 24-hour blood pressure control, so I want to confirm our hypothesis. To optimize 24-hour blood pressure control consists of these three components, 24-hour pressure reduction, and the normalize circadian rhythm and the keeping the other keep such, it shouldn't be; I have, have you left your prevention or not? That's my hypothesis and background.
Dr Greg Hundley: So with our 24-hour ambulatory monitoring evaluating in this study, do we have the normal dip during the evening? Do we have a rise associated with the circadian rhythm? What is the variability of the blood pressure over time? Tell us what study population, and how did you design this study to address your hypothesis?
Dr Kazuomi Kario: This population is the hypertension patients, 90% or more on the out-patients who keep the adequate, the active daily readings, and they are medicated, or usually conventional hypertension medication is the effective to reducing the office blood pressure and they can. But the other hypotension treatment may not be sustained to be reducing the nocturnal blood pressure and next morning people are taking pills. So it may be that the picture of the nighttime blood pressure and the morning blood pressure. So our hypothesis targets is already mitigated hypotension patient, but we should find out control for the current hypotension treatment. It should be the nighttime and next morning.
Dr Greg Hundley: So we're addressing whether the efficacy of or any hypertensive medications are maintaining low blood pressures at night and avoiding a surreptitious rise in blood pressure when we wake up. So how many patients did you enroll and what were your study results?
Dr Kazuomi Kario: The total study population number is 6,359 patients or enrolls. And we find out, compared to the daytime. Daytime also where the risk of the nighttime blood pressure other age, was more the precise this predictor of cardiovascular events. So, cardiovascular events consist of the atherosclerosis cardiac events consists of stroke and coronary artery disease. And also the nighttime blood pressure associated with the risk of the heart failure. And very interestingly, disrupted circadian rhythm, it rises at night higher during the nighttime compared to the daytime, it was independent of risks for the cardiovascular event, especially for the heart failure. So even after controlling for the daytime, even on the nighttime blood pressure, this pattern nighttime riser was an independent risk, so very interesting results.
Dr Greg Hundley: So elevations of systolic blood pressure during nighttime, during sleep were associated with future atherosclerotic cardiovascular disease, as well as heart failure. And one more quick point, was there a particular magnitude of rise of that systolic blood pressure at night was important. And did you find similar results for men and for women?
Dr Kazuomi Kario: Yes, similar results for men and the women. Theo other factor was age was increased. The almost the higher during the nighttime or other age of the rising pattern was 10 allowed during the nighttime compared to the daytime.
Dr Greg Hundley: So even a 10% increase in systolic blood pressure at night relative to daytime was important for forecasting these adverse cardiovascular events. So Juan pen, can you help us take these results from this elegant ambulatory monitoring study and put those in the context of other study results that have evaluated 24 ambulatory monitoring of blood pressure?
Dr Wanpen Vongpatanasin: I think the notion of nighttime blood pressure as the independent predictor of cardiovascular outcome has been shown in other cohort, but usually not this large magnitude, that is an international registry. I had call that in different countries around the world that demonstrate this. But again, like I said, it compiled from a smaller dataset, there's even fewer data sets in the United States. There's a cohort from Jackson Heart, but again, it's less than a thousand and most of other cohorts have looked at mostly a target organ level, not at the heart CV outcome.
So I think this add to an important observation, and I think that the results from the nighttime it's similar, but extended from previously that look at individual outcome using a adjudicated data committee that also a very distinctive feature of the study that is a committee that look at this and look at a specific outcome rather than just a retrospective using the death index from different countries. The other part is slightly different perhaps, and they learn from reading it is the extreme dipping, also dropped a lot. Initially people think that it might be associated with the worst outcome, but even to me I wasn't sure what this mean, but in this study the most extreme dip, maybe not, not as much that shouldn't be worried as much compared to the actual nighttime blood pressure itself or not dipping itself.
Dr Greg Hundley: Kazuomi what do you see as the next study that needs to be performed in this area of research?
Dr Kazuomi Kario: Oh, it's the observational study of the current medical situations maybe kind of situations. So next step, we should focus on that nighttime blood pressure; regardless of the office and the daytime, so even there are controls, if we should target the nighttime blood pressure and the toxicity controls, organ damage should be decreased and the subsequent cardiovascular events should be decreased. So observational study targeting the nighttime blood pressure is the next topic.
Dr Greg Hundley: And Wanpen do you have anything to add to that?
Dr Wanpen Vongpatanasin:I'd like to see more large observational study from the US with the diverse population, because the salt consumption in Asia, particularly in Japan, are probably among the highest. So perhaps the nighttime blood pressure, it's
confounded by high sodium and something, and we're not too far behind obviously, but it'd be nice to know what it means in the US. And obviously they're targeting nighttime blood pressure, it's the hot topic and that's by itself is probably another 30 minutes to an hour of discussion. But I think that that's very important area of research.
Dr Greg Hundley: Listeners, what a really wonderful discussion. And in this study from Japan of over 6,000 individuals treated for high blood pressure, those with 24-hour monitoring and exhibiting a rise in systolic blood pressure during the nighttime was associated with future cardiovascular events and an increase in the risk of heart failure. Moving forward from these experts, performing additional observational studies to confirm these findings and other populations, and perhaps a randomized trial, trying to target therapeutic interventions that would lower nighttime blood pressure may be warranted. Thank you Dr Kario and Dr Vongpatanasin. We wish you a great week and we look forward to catching you on the run next week. This program is copyright The American Heart Association, 2020.
This week’s episode features author Karolina Szummer and Associate Editor Emmanouil Brilakis as they discuss the article "Comparison Between Ticagrelor and Clopidogrel in Elderly Patients with an Acute Coronary Syndrome: Insights from the SWEDEHEART Registry."
TRANSCRIPT BELOW
Dr Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature article, we're going to investigate antiplatelet therapy use, but in older patients, as opposed to those that are middle-aged, and have sustained a prior acute myocardial infarction. But, before we get to that, how about we grab a cup of coffee and jump into the other papers in the issue?
Dr Carolyn Lam: Absolutely, Greg. I've got my coffee right here, and I really want to start with a paper that adds to our understanding of, guess what, the sodium=glucose cotransporter 2 inhibitors, SGLT2 inhibitors, and their diuretic and natriuretic effects in combination with loop diuretics. Of course, a clinically really important question since now we know that SGLT2 inhibitors improve outcomes in patients with heart failure in whom they are likely to be co-prescribed with a loop diuretic. So, Professor Chim Lang from University of Dundee and his colleagues performed the RECEDE-CHF trial, which was a randomized double-blind placebo-controlled crossover trial of 23 patients with type 2 diabetes and HF REF taking regular loop diuretics who were randomized to the SGLT2 inhibitor empagliflozin 25 milligrams once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urine volume from baseline at week 6.
Dr Greg Hundley: So, empa versus placebo. What did they find?
Dr Carolyn Lam: In patients with heart failure and type 2 diabetes taking a regular loop diuretic, empagliflozin caused a significant increase in urine volume at both day 3 and week 6, compared to placebo, as well as empa also caused a significant increase in electrolyte-free water clearance. Though there was a small non-significant increase in natural uresis with empagliflozin at day 3, this was absent by week 6. These results suggest that empagliflozin may have an advantageous diabetic profile in patients with type 2 diabetes and heart failure in addition to loop diuretics, with only a short transient natriuresis.
Dr Greg Hundley: Very nice, Carolyn. Great information. Diuretics, heart failure reduced ejection fraction, and empagliflozin. Well, my clinical paper comes from Dr Renato Lopes from Duke University Medical Center, and this is a sub study from the ISCHEMIA trial that evaluates whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in patients with a history of heart failure or left ventricular dysfunction when the EF is greater than 35%, but less than 45%.
Dr Carolyn Lam: Aw, that mid-range ejection fraction. Favorite topic. So, Greg, what did they find?
Dr Greg Hundley: Those with heart failure and left ventricular dysfunction randomized to the invasive versus the conservative strategy had a lower rate of the primary outcome, 17% versus 29%. Whereas those without heart failure and left ventricular dysfunction did not, 13% versus 14%. A similar differential effect was seen for the primary outcome, all-cause mortality and cardiovascular mortality, when invasive versus conservative strategy associated outcomes were analyzed with LVF as a continuous variable for those with and without prior heart failure.
Dr Carolyn Lam: Wow, that is clinically important, Greg. So, can you summarize our take home message?
Dr Greg Hundley: Well, Carolyn, ischemia trial participants with stable ischemic heart disease and at least moderate ischemia with a history of heart failure or LV dysfunction, were at increased risk for the primary outcome. And in this small high-risk subgroup with heart failure and an ETF between 35% and 45%, an initial invasive approach was associated with a better event free survival. This result should really be considered for hypothesis generation and future studies.
Dr Carolyn Lam: Greg, for the next paper, do you remember hydrogen sulfide? The stuff we learned about in school. It's the gas with that characteristic foul odor of rotten eggs. Well, guess what? This whole paper is about hydrogen sulfide, and in the body, it actually has antihypertensive and anti-inflammatory effects, and its endogenous generation key enzyme is cystathionine gamma lyase, or CSE, and that's expressed in CD4+ T cells. So today's paper provides insights into how all of these players work together in the development of hypertension.
To investigate the pathophysiological relevance of this CSE hydrogen sulfide system, co-corresponding authors, Doctors Geng and Cai from Fuwai hospital and Chinese Academy of Medical Sciences, Peking University Medical College, as well as Dr Xu from Peking University Health Science Center in Beijing. Well, they and their coauthors performed elegant experiments involving peripheral blood lymphocytes, isolated from hypertensive patients or spontaneously hypertensive rats. They also looked at mice with CSE-specific knockout in T cells, and CD4 null mice.
Dr Greg Hundley: Well, Carolyn, what did they find?
Dr Carolyn Lam: Well, they found that endogenous cystathionine gamma lyase, or CSE, and hydrogen sulfide, but not cystathionine beta-synthase, in lymphocytes, responded to blood pressure changes. Deleting CSE in CD4+ T cells exacerbated
angiotensin II-induced hypertension by reducing circulatory and renal T regulatory numbers. Hydrogen sulfide from CSE self-hydrates, liver kinase 1, thereby activating the AMP kinase energy pathway to promote TReg differentiation and proliferation, which then attenuates the vascular and renal immune inflammation, and thus, prevents hypertension.
Dr Greg Hundley: Carolyn, this sounds like a very thorough study. What are the clinical implications?
Dr Carolyn Lam: Endogenous CSE hydrogen sulfide in lymphocytes may be both a potential biomarker of hypertension, or its complications, or hydrogen sulfide donor may be a therapeutic approach to lower hypertension.
Dr Greg Hundley: Great, Carolyn. Well, my next paper comes from Professor Goo Taeg Oh from Ewha Women's University, and it really involves the world of inflammation. So Carolyn, as you know, macrophages produce many inflammation-associated molecules released by matrix metalloproteinases, such as adhesion molecules, as well as cytokines, which play a crucial role in atherosclerosis. In this paper, the authors investigated the relationship between Ninjurin-1, or nerve injury-induced protein 1, a novel MMP9 substrate expression, and atherosclerosis progression.
Dr Carolyn Lam: Ninjurin-1? Interesting. So, what were the results?
Dr Greg Hundley: Well, Carolyn, Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls, as well as athero-prone, apolipoprotein E-deficient, or APOE -/- wild type mice. Two important findings, Carolyn.
First, the authors in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted pro-inflammatory gene expression by activating mitogene-activated protein kinase, or MAP kinase, and inhibiting the phosphoinositide 3-kinase signaling pathway. Whole-body and BM-specific Ninj1 deficiencies significantly increase monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Now, in addition and secondly, macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessed both in vitro and in vivo.
Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of the disorder in mice, regardless of the presence of Ninj1.
So in summary, Carolyn, Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis.
Dr Carolyn Lam: Wow, Greg, that was incredibly summarized. Thank you. Let's go through what else there is in today's issue. In cardiology news, Bridget Kuhn talks about how the pandemic intensifies the push for home-based cardiac rehabilitation options. There's a white paper by Dr Ho and colleagues, including me, describing the diagnostic dilemma of HFpEF. There's a Research Letter by Dr Gill talking about the cardiometabolic trait sepsis and severe COVID-19, a Mendelian randomization investigation. There's also a Research Letter by Dr Wu on the atlas of exosomes microRNAs secreted from human iPSC-derived cardiac cell type.
Dr Greg Hundley: Carolyn, this issue is just packed with articles, because I've got five more to tell our listeners about. First, it's a research letter from Professor G. Hovingh, entitled, Inclisiran Durably Lowers LDLC and PCSK9 Expression in Homozygous Familial Hypercholesterolemia, The ORION-2 Pilot Study. Next, there's an ECG challenge from Dr Jason Gilge relating to AV conduction during atrial flutter. Next, Dr Keith Churchwell has a nice piece related to the importance of those involved in cardiovascular care and participating in their civic duties, including voting. Next, Professor Karthikeyan has nice On My Mind related to overestimation of stroke risk and rheumatic mitral stenosis and the implications for oral anticoagulation. And finally, Carolyn, another research letter, from Dr Pieter van Paassen, entitled, Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19.
Well, Carolyn, how about we get on to our feature discussion and review in older patients, which antiplatelet therapy may be safest?
Dr Carolyn Lam: Let's go!
Dr Greg Hundley: Well, listeners, now we're turning to our feature discussion, and today we'll talk about antiplatelet therapy. And then we have with us, Dr Karolina Szummer from Karolinska Institutet, and our own Associate Editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Welcome to you both, and Karolina, let's start with you. Could you describe for us your hypothesis and some of the background information that led you to perform this study?
Dr Karolina Szummer: Thank you so much for having me here and for sharing the ideas behind our study. Current recommendations recommend that we use high-potent antiplatelet agents for treating myocardial infarctions, and in particular, elderly patients are not included. So we decided to do an observational study to look at patients in our Swedish registries treated for myocardial infarctions who were 80 years and older.
Dr Greg Hundley: Very nice. Can you tell us a little bit more about your study design? And also the study population?
Dr Karolina Szummer: The startup populations are all patients who were admitted to an acute coronary care unit for treatment of myocardial infarctions, and they were all 80 years and older, and they were included from 2010 to 2017. So this encompasses the period during which treatment with ticagrelor was introduced. So we are comparing to ticagrelor versus clopidogrel for the outcomes during the year, following the myocardial infarction.
Dr Greg Hundley: And how many patients did you enroll in the study? And what were your study results?
Dr Karolina Szummer: We enrolled, in total, 14,000 patients, and these consisted of non-STEMI and of STEMI patients. The majority, about two thirds, were non-STEMI patients. We show, in this study, elderly patients have a lower risk of readmission for myocardial infarction or stroke, but they have a higher risk of having readmission for bleeding and death. So the risk-benefit ratio seems to be skewed towards having, probably, more harm with ticagrelor being more risky than clopidogrel in this study population of elderly.
Dr Greg Hundley: And was this true for both men and for women?
Dr Karolina Szummer: Yes. So this was true for both men and women. And we did a sensitivity analysis. We looked closer at those who are younger than 80 years old, and in this patient population, the results selected in the same way as for our cohort of elderly, they actually did have the same benefit with a low risk of MI, stroke, and death, and high risk of bleeding. But in the elderly, we noticed a signal towards harm with an increased risk of death.
Dr Greg Hundley: It sounds like with ticagrelor, did we have a lower risk of death and a slightly lower risk of myocardial infarction and stroke, but a higher risk of bleeding? Was that the findings?
Dr Karolina Szummer: So for the elderly, there was a high-risk of death and bleeding with ticagrelor compared to clopidogrel, but a lower risk of ischemic component of MI and stroke.
Dr Greg Hundley: And then with those under 80, those were the ones that had the lower risk of death, lower risk of MI and stroke, but the higher risk of bleeding?
Dr Karolina Szummer: Yes, that's correct. So really the end point that differs most is that there is sustainment towards higher mortality in the elderly, because in both younger and elderly, the risk of readmission for bleeding was elevated in both.
Dr Greg Hundley: Now, let's turn to our own Associate Editor, Manos Brilakis. Manos, can you help us put these results into perspective, relative to other studies that evaluate the efficacy of antiplatelet therapy, post myocardial infarction?
Dr Emmanouil (Manos) Brilakis: I would like to start by congratulating Dr Szummer. It's a wonderful paper, and, I think, provide some new insights on how to use the medications in the ACS patients. And going on the background, if we look at the guidelines, both the European guidelines, as well as the American guidelines, what they say is that both ticagrelor, as well as prasugrel, are preferred and recommended for patients with ACS, both non-ST elevation ACS, as well as ST segment elevation myocardial infarction. And actually, European guidelines say that clopidogrel should only be used when prasugrel or ticagrelor are not available or are contraindicated. And this is based on two trials.
One is the PLATO trial, and the other is the TRITON-TIMI 38, that both showed, actually, more benefit with the more intensive P2Y12 inhibitors. And this is what is extrapolated to all patient populations. But as you've heard before, there was only a minority of elderly patients that were included in those trials, about 13% to 15%, and that is why the present study is important, because it suggests that maybe we should look more carefully into the patient's age and potentially other characteristics like frailty or other comorbidities, that might actually alter the risk-benefit ratio. And maybe those medications should not be routinely given to all patients, but perhaps, elderly patients, or at least some of them, might not require, and actually be better off with clopidogrel.
Dr Greg Hundley: Let's turn back to Karolina. Karolina, the study was observational. What do you see as, perhaps, a next study to follow up the results that you've brought to us with this study?
Dr Karolina Szummer: So the next step would definitely be to do a randomized control trial in the elderly to explore this topic further, to really know for sure what the safety and efficacy is, and what's the best treatment would be for these patients.
Dr Greg Hundley: Very good. And Manos, do you have anything to add?
Dr Emmanouil (Manos) Brilakis: One more thing. So, there was actually a trial that compared ticagrelor as well as prasugrel with clopidogrel in elderly patients that was called the POPUlar AGE trial that was published last year. And actually this one, published earlier this year, and actually this trial randomized a thousand patients who were more than 70 years old, to either more-intensive or less-intensive. And the results were actually very similar to the findings from Dr Szummer's study from SWEDEHEART, showing that there was more bleeding without any ischemic benefit. And didn't show actually higher mortality but didn't show any significant benefit. So that actually adds to the data that maybe the elderly patients, the selection of antiplatelet agent should be taken into account.
And I think for me, this also extrapolates the high bleed risk, higher risk of bleeding, based on criteria, which we currently use mainly for duration. We say, for example, if you're precise DAPT score, which is a score for determining risk of bleeding, is high, you should consider shorter duration of DAPT, but it doesn't say anything about the type of DAPT. And for me, this makes sense that the high bleeding risk, and age is one of the main risk factors for high bleeding risk, should be taken into account also for determining the type of P2Y12 inhibitor.
Dr Greg Hundley: Well listeners, we've had a great discussion with Karolina Szummer from Karolinska Institutet, and our own Manos Brilakis from the Minneapolis Heart Institute, really reviewing the utility of ticagrelor versus clopidogrel in older individuals, above the age of 80, that have sustained myocardial infarction, and identifying that ticagrelor is associated with a higher risk of death and bleeding, as opposed to clopidogrel, opening the question up as to whether further studies in older individuals need to be performed to examine the efficacy of antiplatelet therapy.
So, on behalf of Carolyn and myself, we wish you a great week and look forward to catching you On the Run next week. This program is copyright the American Heart Association, 2020.
This week’s episode includes author John McMurray and Associate Editor Brendan Everett as they discuss the effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction.
TRANSCRIPT BELOW:
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, I hear you might have an interesting feature paper?
Dr Carolyn Lam: Oh, yes. I think everyone's going to look forward to this one, because we cannot get enough of the DAPA-HF study. This is another very important prespecified analysis, looking at the effect of dapagliflozin on outpatient worsening of patients with heart failure with reduced ejection fraction. Very important stuff coming right up, but first, I've got two papers looking at congenital heart disease that I'd like to share with you, Greg. Have you got your coffee?
Dr Greg Hundley: Yeah, I do. Let's get going.
Dr Carolyn Lam: Well, as you know, the mechanisms of congenital heart disease associated right ventricular dysfunction are not well-understood. And so, in this first paper, Dr Reddy from Stanford University and colleagues assessed lipid peroxidation, a potent form of oxidative stress, as well as mitochondrial function and structure, in right ventricular myocardium, collected from patients with and without right ventricular failure.
And what they found, was that right ventricular failure was characterized by increased oxidation of membrane phospholipids, known as lipid peroxidation and its products, such as 4-hydroxynonenal, or 4-HNE. Now, 4-HNE binds to metabolic and mitochondrial proteins, and was associated with decreased myocardial energy generation and mitochondrial structural disruption with increasing severity of right ventricular hypertrophy and right ventricular failure. Mechanistically, the authors showed that 4-HNE was sufficient to decrease energy generation by inhibiting electron transport chain complex activities and mitochondrial dynamics.
Dr Greg Hundley: Dr Carolyn, a lot of mechanism here. So clinically, what are the implications?
Dr Carolyn Lam: I thought you'd ask. Well, since standard heart failure therapies, such as ACE inhibitors and beta blockers, are ineffective in the treatment of right ventricular failure, developing therapies focusing on new targets, such as what we talked about, the lipid peroxidation, could improve right ventricular function in
congenital heart diseases by improving mitochondrial energy generation and cardiomyocyte survival.
Dr Greg Hundley: Ah, very interesting, Carolyn.
Dr Carolyn Lam: Thank you. The next paper, also very interesting, this time focusing on Tetralogy of Fallot, the most common cyanotic congenital heart disease. Now, this is from Dr Marijon from Hôpital Européen Georges-Pompidou in France and colleagues who highlighted, first, that sudden cardiac death represents an important mode of death in these patients with Tetralogy of Fallot, yet data evaluating the ICDs in these patient population, really, has remained scarce. And so, they use the nationwide French registry to include 165 patients with Tetralogy of Fallot with an ICD initiated in 2010 by the French Institute of Health and Medical Research. 63%, by the way, of these ICDs, were used for secondary prevention.
Dr Greg Hundley: Ah, Carolyn, I can't wait to see. What did they find?
Dr Carolyn Lam: So during a median follow-up of 6.8 years, 47% of patients received at least one appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% overall, 7.1% in the primary prevention, and 12.5% in the secondary prevention cohorts, respectively. 43% of patients presented with at least one ICD complication, and, importantly, QRS fragmentation was the only predictor of appropriate ICD therapies.
So, even before you asked me, Greg, the take home message is, patients with Tetralogy of Fallot and an ICD, experience high rates of appropriate therapies, including those implanted for primary prevention. The considerable long-term burden of ICD-related complication, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria, including QRS fragmentation, might improve our risk prediction.
Dr Greg Hundley: Oh, very nice summary, Carolyn. Learned a lot there. Well, I'm going to steer us to two other papers in the issue, and the first one is from the world of basic science, and it's from Dr John Cooke from the Houston Methodist Research Institute. So Carolyn, the angiogenic response to ischemia restores perfusion, so as to preserve tissue. Something we all know. A role for mesenchymal to endothelial transition in the angiogenic response is controversial, and this study utilized a murine model of hindlimb ischemia and an in vivo Matrigel plug assay, together with lineage tracing studies and single-cell RNA sequencing, to examine the transcriptional and functional changes in fibroblasts in response to ischemia, to determine if resident fibroblasts contribute to angiogenesis.
Dr Carolyn Lam: Ah, it's so interesting. Do fibroblasts contribute to angiogenesis? What did they find, can't wait?
Dr Greg Hundley: Yeah, Carolyn. So, in both mice and human-isolated fibroblasts, these author studies indicated the presence of subsets of tissue fibroblasts, which seemed poised to contribute to the angiogenic response. And the expansion of these subsets with ischemia was dependent upon activation of innate immune signaling, and this signaling contributed to recovery of perfusion and preservation of ischemic tissue. Really interesting findings. Didn't suspect the fibroblasts as being the contributors here.
Dr Carolyn Lam: Very nice, Greg. Thank you. You've got another one.
Dr Greg Hundley: Yes. So the next study is from Professor Phillips Tsao from Stanford University School of Medicine. Well, Carolyn, this is a genome-wide association study, and it's from the Million Veteran Program, testing 18 million DNA sequence variants in patients with abdominal aortic aneurysms. In the study, they identified 7,642 cases and 172,172 controls in veterans of European ancestry, with independent replication and another study in 4,009 72 cases and 99,858 controls.
Dr Carolyn Lam: Wow.
Dr Greg Hundley: So it's nice, they have a replication study. The authors then use Mendelian randomization to examine the causal effects of blood pressure on abdominal aortic aneurysms. And they examine the association of abdominal aortic aneurysm risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and lastly, derived a genome-wide polygenic risk score to identify a subset of the population at greater risk for disease.
Dr Carolyn Lam: Wow. So a GWA study with replication to identify those at risk for abdominal aortic aneurysms in huge cohorts. What did they find?
Dr Greg Hundley: Well, Carolyn, this study was managed by one of our experts in GWA studies, Dr Wendy Post, and through GWAs, the authors identified 14 novel loci, and there were already 10, so it brings the total number of significant abdominal aortic aneurysm loci to 24. So a new finding there. And in their Mendelian randomization analysis, they demonstrated that a genetic increase of 10 millimeters of mercury in diastolic blood pressure, as opposed to systolic blood pressure, likely had a causal relationship with the future development of abdominal aortic aneurysms. They observed that 19 of those 24 aortic aneurysm risk variants associate with aneurysms in at least one other vascular territory. And then lastly, a 29 variant polygenic risk score was strongly associated with abdominal aortic aneurysms, independent of family history and smoking risk factors.
So Carolyn, in conclusion, the authors in this study identify novel abdominal aortic aneurysm genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of abdominal aortic aneurysms, independent of their family history. And their data suggests that perhaps extending current screening guidelines to include testing for those with high polygenic abdominal aortic aneurysm risk, would significantly increase the yield of many of our current screening algorithms, as you know, that predominate based on smoking and age.
Dr Carolyn Lam: Wow. Very, very impressive and convincing data. Thanks, Greg. Let me tell you about other papers in today's issues. There's a research letter by Dr Tiburcy on inhibition of prolyl-hydroxylase domain enzymes, and how that protects from reoxygenation injury in the engineered human myocardium. There's another research letter from Dr Ohbe, entitled, The Risk of Cardiovascular Events after a Spouse's ICU Admission. And, one more from Dr Ganatra, on chimeric antigen receptor T cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma.
Dr Greg Hundley: You know, Carolyn, our research letters, they really pack a punch. Such very interesting research, in a nice concise format. I've got some other publications. So first, there's an On My Mind piece from our own Charlie Loewenstein, and also Dr Solomon from Boston, Massachusetts, involving, Severe COVID-19 as a Microvascular Disease, does endothelial exocytosis drive COVID-19? And next, there's a case series entitled, ECMO Therapy for Cardiac Lymphoma, and it's from Dr Oscar Cingolani. And then finally, Carolyn, a very nice ECG challenge from Dr Bansal, related to identifying the location of an AV block. Well, Carolyn, I'm really excited to get onto your feature discussion.
Dr Carolyn Lam: Let's go, Greg. Today's feature discussion looks at a prespecified analysis of DAPA-HF. My goodness, I don't think we can get enough of the data from DAPA-HF, and we have none other than be corresponding author, Dr John McMurray from University of Glasgow, to discuss this exciting paper, as well as our associate editor, Dr Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts. So John, today's feature paper, all about outpatient worsening of heart failure. Could you please start by defining what we meant by that, and why is it so important?
Dr John McMurray: Our interest in this actually started back when we did PARADIGM and we had collected, in a not very systematic way, information about episodes of outpatient worsening, so by that, I mean episodes of worsening symptoms and signs, not leading the patient to go to the emergency department or be admitted to hospital. The sort of worsening that a patient might tell you about in your outpatient clinic, say they're a bit more breathless or they've got a bit more ankle swelling, and you do something about it. And that's the critical part. You decide to increase their dose of diuretic, add another drug.
And in PARADIGM, we find that those episodes, first of all, were quite common, and secondly, and most importantly, we're actually prognostically very significant. They were associated with worse outcomes. So in that HF, we decided that we would collect these more systematically, we would try and define them a little bit more robustly, so we would require the investigator to report worsening signs and symptoms, and we also wanted evidence that additional treatment had been given and then that had been sustained for at least a month, because, as you know, diuretic dose can increase and decrease.
Then we prespecified, as you said, Carolyn, that we would then incorporate those manifestations of worsening, as an additional component to our primary composite endpoint, which was cardiovascular death, heart failure hospitalization, worsening of heart failure requiring intravenous therapy, so an urgent visit for that, that would often be in an emergency department, and then in addition to that, this further manifestation of worsening as the extra component to this broader composite outcome that we hoped would encompass the whole range of worsening of heart failure that a patient might experience.
Dr Carolyn Lam: Thanks so much, John, and you actually preempted my question of how it differed from the original primary outcome that included urgent heart failure visits, intravenous diuretic use, but not these nuance outpatient intensification of heart failure therapy that I really salute you for prospectively collecting information on. So could you summarize what you found, please?
Dr John McMurray: Well, first comment to make, Carolyn, is that we included those urgent visits requiring intravenous therapy, because, as you know, in the U.S., I think there is a move to try and avoid admission and to treat patients in the ambulatory care setting or non-ward setting. Although, I have to say, as it turned out, those episodes of worsening were very infrequent. There was, I think, 33 in total in DAPA-HF, compared to almost 600 of the other episodes of worsening. The ones that we almost feel at a brainstem reflex level when we see patients in our clinics.
So what did we find? Well, we find that when you add those episodes of worsening, then, of course, you considerably increase the proportion of patients who have, from what you might call, the most trivial manifestation, worsening the events we just talked about, all the way through to the very worst, in other words, death, from cardiovascular causes, in fact, so much so, that by about two years of follow-up, the Kaplan-Meier rate for that expanded composite endpoint was about 33%. And, as you know, Carolyn, we're talking about a trial that enrolled patients who were very well-treated by conventional standards and who, by and large, had mild symptoms, but 70% were NYHA class II. And yet, within two years, if you take into account all of these different manifestations of worsening, we had about one-in-three people in the placebo group that deteriorates, and we reduced the risk of deterioration with dapagliflozin, we reduced the instance of that expanded composite endpoint by 27%, and that was a highly statistically significant result.
And if you like numbers needed to treat, then for that expanded very broad composite endpoint, the number needed to treat over the median follow-up of 18.2 months, was only 16. And by the way, we did confirm that those outpatient worsening events were prognostically significant as well.
Dr Carolyn Lam: Very good. Brendan, could I bring you in on this? It's got such great implications, maybe you could share a little bit about what the editors thought when we saw this paper?
Dr Brendan Everett: One of the key things that the editors thought when they reviewed this, was the fact that, as you pointed out, you collected these outpatient worsening episodes prospectively across the trial and did so in a very rigorous and systematic way. And I think for those of us who take care of patients with heart failure, which of course is most cardiologists, these kinds of episodes where your patient calls you and their weight's gone up, or where they've gotten a little more short of breath, then you, over the phone, intensify their diuretic regimen, are incredibly common, and, of course, bothersome to the patient and challenging for the clinician who's caring for the patients too. So I think, in that sense, it's a really important paper. That was the other aspect, I think, that the editors were interested in. But the impact, the clinical impact on day-to-day care of patients with heart failure, was substantial.
The other part that I found intriguing, because of course, when you're caring for individual patients, you don't have a sense, necessarily, of what these episodes mean in a broader population for those patients' overall risk of bad outcomes. So you mentioned it right at the end when you were speaking a moment ago, about the association of these outpatient intensifications of oral diuretic therapy and their association with future bad outcomes within the trial. Could you tell us a little bit about what those were and why they ended up seeming so important, both to patients and to you as the trialist?
Dr John McMurray: We write about these being common, in fact, in the placebo group in DAPA-HF. I think it was 14% of patients had one of those episodes of outpatient worsening. And again, as you correctly identified, in the majority of cases, the therapeutic intervention by the physician, was simply to increase the dose of diuretic, although, actually about 40% of people also, at some point, had the addition of another drug.
So, in terms of the significance of those events, in PARADIGM, we find that they appeared to be associated with almost the same impact on mortality as being admitted to hospital with worsening heart failure. But in fact, in DAPA-HF, where we collected more of these events, so maybe we collected, perhaps, the more severe cases in DAPA where we collected them systematically, we find that the prognostic impact wasn't quite as large. So for example, if you were admitted to hospital with heart failure during DAPA-HF, then you were six-times more likely, subsequently, to die in that rather short follow-up period, than if you had no manifestation of worsening.
On the other hand, if you had an outpatient episode of worsening, then it was around a three-fold higher risk of death than if you had no manifestation of worsening. So, my take home from this was that these episodes really do matter to patients. Not only, of course, do they matter because it means the patient doesn't feel so good, but they matter because that patient suddenly is on a different prognostic trajectory, and you can change that by intervening.
So these events are common, they're prognostically bad news, and fortunately, we can reduce them. And maybe the last thing to say, which I also didn't mention, I apologize, was that, of course, if you look at that expanded endpoint, as you can imagine, because there's so many events now, you see the effect of treatment very, very quickly. So by day 27 after randomization, in other words, by day 27 after starting dapagliflozin, we had a statistically significant reduction in the occurrence of that comp standpoint, that then remained significant thereafter.
Dr Brendan Everett: Thanks, John. I had one other question that I hope doesn't take us too far into the weeds, but I think as a clinician, when you care for these patients, you try to intensify their outpatient therapy, and when that seems to fail, the patient then becomes admitted to the hospital. And I thought it was very interesting and thoughtful the way that you approach that problem, in other words, you have potentially, of this composite endpoint, you have the outpatient worsening that comes first, and then it's followed, in many cases, by a hospitalization for heart failure. How did you tease those two apart? And what analyses did you do to make sure that what you were really measuring was the effect of the outpatient intensification, rather than really just a prelude to a hospital?
Dr John McMurray: Very good question, Brendan. So, obviously, we were concerned about the possibility of double counting, so we did a primary analysis in which we built in a blanking window. So, for example, if you had an episode about outpatient and you or I increased the patient's oral therapy, but within 30 days, they were admitted to the hospital, then in our analysis, that patient only counted once, and the event that counted was the hospital admission, not the outpatient episode of worsening.
And then, as I said, we did a number of sensitivity analyses where we adjusted the length of that blanking period, because we recognized, obviously, that some people, that episode of outpatient worsening that you intervene for, your intervention may not work and they may still get hospitalized. So we try to, as you obviously identified when you read our manuscript, we tried to counter that by not double counting episodes of outpatient worsening that were closely adjacent to the hospital admission.
Dr Carolyn Lam: Could I end with just one quick question? You've published many times with us at Circulation, and I'd like to think that that's from a very good experience with us, with working with us, and I've noticed even in this discussion, it's just so interesting the exchange. And so, John, could you say a few words about publishing in Circulation, and why do it?
Dr John McMurray: Well, obviously it's our leading cardiovascular journal. As I was being trained as a fellow, it was every fellow's aspiration to publish a paper in Circulation. So reputationally, obviously, it's very, very important.
But why do I like Circulation other than that? Well, first of all, you handle papers quickly and efficiently. I think you're very fair. I really like the reviews. So I would say one of the greatest frustrations most authors, and certainly I know that from my own experience, is when you get poor reviews. I don't think I get those from
Circulation, so you obviously have a much higher quality review. I like the way the editors give you guidance about the manuscript and how to respond to the reviewers. That's really, really helpful, because sometimes you think, "Well, that reviewer’s comment doesn't make sense. Do I have to really do that?" But often, your replies to me, come with guidance about how to handle the different reviewers’ comments. So, all in all, it's fair. I would say that's always important. Everybody will not get every paper accepted, but I think you get a very fair response from Circulation. It's good. It's thoughtful. So, that's fine.
Dr Carolyn Lam: Thank you so much, John. I'm sure I'm speaking on behalf of Brendan as well, and kudos to him because obviously he managed this paper so well. Thank you, audience, for joining us today on Circulation on the Run. So don't forget to tune in again next week.
Dr Greg Hundley: This program is copyright the American Heart Association.
This week's episode includes author Daniel Lackland and Associate Editor Mercedes Carnethon as they discuss the article "Forty-year Shifting Distribution of Systolic Blood Pressure with Population Hypertension Treatment and Control."
TRANSCRIPT BELOW
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley associate editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature is good news. What do I mean by good news? It's going to be a tale of how hypertension has evolved in the Southeastern United States. And it's going to review how that's progressed its treatment efficacy in both those of white, and men and women of black race. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in this issue.
Dr Carolyn Lam: Man, you got my attention, Greg. You definitely got my attention.
Dr Greg Hundley: Very good. Well, Carolyn, my first paper is from the world of basic science, and it's from Dr Maya Kumar from Stanford University School of Medicine. This group maps the step wise remodeling of pulmonary arteries in a robust chronic inflammatory mouse model of pulmonary hypertension. A model that demonstrates pathologic features of human disease, including right ventricular pressures, medial thickening, neointimal lesion formation, elastin breakdown, increased anastomosis within the bronchial circulation and perivascular inflammation, all of those combined. And the author sought to define the cell behaviors underlying each stage of vascular remodeling, and identified a pathway required for neointima formation with the premise being that this understanding could be pivotal in modulating progression of disease in pulmonary hypertension.
Dr Carolyn Lam: Nice. So what did they find?
Dr Greg Hundley: Well, Carolyn, they found surprisingly. The neointima arises from smooth muscle cells and not the endothelium. Medial smooth muscle cells proliferate broadly too thick in the media, after which a small number of smooth muscle cells are selected to establish the neointima. These neointimal founder cells subsequently undergo massive clonal expansion to form occlusive neointimal lesions. The normal pulmonary artery smooth muscle cell population is heterogeneous, and the authors identify a Notch3-marked minority subset of smooth muscle cells as the major neointimal cell of origin. Notch signaling is specifically required for the selection of neointimal founder cells, and Notch inhibition significantly improves pulmonary artery pressure in animals with pulmonary hypertension, thus perhaps providing a new mechanism from which to test therapies to thwart the progression of disease in those with pulmonary hypertension. Very interesting basic science work.
Dr Carolyn Lam: Yeah. And very important too. Thanks Greg. Well, I've gotten another basic science paper too. First, let me ask you, do you think of DNA methylation much?
Dr Greg Hundley: We hear a lot about that, Carolyn. Methylation and changing DNA and how it might be transcribed. Tell us more.
Dr Carolyn Lam: DNA methylation is indeed a mechanism of gene transcription regulation. It's recently gained a lot of attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, the authors Dr Stenzig from University Medical Center, Hamburg-Eppendorf and colleagues knocked out the main de novo DNA methyltransferase in cardiomyocytes. Also, called DNMT3A in human induced pluripotent stem cells. They then assess the functional consequences of DNA methylation deficiency under control and stress conditions in human engineered heart tissue from these knockout derived cardiomyocytes.
Dr Greg Hundley: Wow, Carolyn. So what did they find here?
Dr Carolyn Lam: Three main consequences of DNMT3A knockout. Number one, there were gene expression changes of contractile proteins, such as higher atrial gene expression. Number two, there was ever an activation of the glucose lipid metabolic regulator PPAR gamma, which was associated with accumulation of lipid vacuoles in these knockout cardiomyocytes. And number three, HIF-1 alpha protein instability occurred, which was associated with impaired glucose metabolism and lower glycolytic enzyme expression rendering the knockout engineered heart tissues sensitive to metabolic stress such as serum withdrawal and restrictive feeding. So in conclusion, these results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.
Dr Greg Hundley: Wow, Carolyn. That was really fascinating, especially helping us understand how DNA methylation is operative, great summary there, and it's just organized so well. Learned a lot from that. I'm going to switch back and move into the world of clinical science on this next article. And it really fascinating, projecting outcomes using some biomarkers that I hadn't heard of previously. This paper is from Dr Alan Maisel from University of California, San Diego School of Medicine, and it evaluated the utility of advanced biomarkers for discriminating type one versus type two MI in patients presenting to the emergency room. In the study, two cardiologists adjudicated type one and type two MIs and six biomarkers were analyzed cardiac troponin I, copeptin, mid-regional pro-atrial natriuretic peptide, C-terminal proendothelin-1, mid-regional pro-adrenal Mendelian, and finally procalcitonin. And the prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular events or mace included the composite of acute MI, unstable engine of petrous, re-infection, heart failure, and stroke at 180 days of follow-up.
Dr Carolyn Lam: So what did they find with these very interesting biomarkers, Greg? Were they able to distinguish type one from type two MI?
Dr Greg Hundley: Great question, Carolyn. So among 2,071 patients type one MI and type two MI were adjudicated in 94 and 176 participants, respectively. Patients with type one MI had higher levels of cardiac troponin I while those with type two MI had higher baseline levels of all of the other biomarkers. Next, combining all the biomarkers resulted in a similar accuracy to a model using clinical variables and cardiac troponin I, and the addition of the biomarkers to the clinical model yielded the highest AUC, under the curve. Next, other biomarkers, but not cardiac proponent was associated with mortality and mace at 180 days among all the patients with no interaction between the diagnosis of type one or type two MI. Then conclusion, Carolyn, the assessment of these new biomarkers, reflecting pathophysiologic processes occurring with type two MI may help differentiate it from type one MI. Additionally, all the biomarkers measures except cardiac troponin I were significant predictors of prognosis regardless of the type of MI, both type one and type two.
Dr Carolyn Lam: That's really cool, Greg. Thanks. I'm going to end with a clinical paper too, and maybe ask you, Greg, you know so much about AI playing a role in cardiac MRI. Do you think it could do that in echo too?
Dr Greg Hundley: Leading question, Carolyn. Now, you have expertise in this area as well. I bet it could be helpful. Tell us what you've got in this paper.
Dr Carolyn Lam: Well, automated interpretation of echocardiography with deep neural networks and AI could support clinical recording and improve efficiency. Now while prior studies evaluated spatial relationships using still frame images and echo these authors who were led by Dr Tsai from National Cheng Kung University Hospital and college of medicine in Taiwan, these author's aim was to train and test a deep neural network for video analysis by combining spatial and temporal information to automate the recognition of left ventricular regional wall motion abnormalities on echo.
So they collected a series of transthoracic echocardiogram examinations performed between July 2017 and 2018 in two tertiary care hospitals. Regional wall abnormalities were defined by experienced physiologists and confirmed by train cardiologists. First, the authors developed a 3D convolutional neural network or CNN model for view selection to ensure stringent image quality control.
Second, a unit model segmented the images to annotate the location of each left ventricular wall, and third, a final 3D CNN model evaluated echo videos from four standard views before and after segmentation and calculated a wall motion, abnormality confidence level for each segment.
Dr Greg Hundley: Very nice, Carolyn. So a lot going on to identifying the wall and then performing analysis on those walls' segments. So what did they find?
Dr Carolyn Lam: So when a series of more than 10,600 echoes, their view selection model identified 6,454 or 61% of exams with sufficient image quality. The external validation was performed in 1,756 exams from an independent hospital. The final model recognizes regional wall motion abnormalities, and the cross validation and external validation datasets with an area under receiver operating characteristic curve of impressive now 0.91 and 0.89 respectively. In the external validation dataset, the sensitivity was almost 82% and specificity also almost 82%. And so in echo exams of sufficient image quality, it is feasible from this work for deep neural networks to automate the recognition of regional wall motion abnormalities using temporal and spatial information from moving images, further investigation is required to optimize the model performance and evaluate clinical application.
Dr Greg Hundley: Sounds very exciting. Helping facilitate the identification of regional wall motion abnormalities. Well, how about if we jump into some of the other articles in the issue, would you like to go first?
Dr Carolyn Lam: I'd love to Greg. There's Research Letter from Dr Wu on patient-specific induced pluripotent stem cells and how they implicate intrinsic impaired contractility in the hypoplastic left heart syndrome. There's an In-Depth paper by Dr McEvoy on lifelong aspirin for all in secondary prevention of chronic coronary syndrome. Is this still sacrosanct or is reappraisal warranted? In our Cardiovascular Case Series, Dr Grodin talks about an uncommon disease in a rare location, the mystery of the rapidly progressive cardiomyopathy. A very interesting one. You have to read it. We have a Research Letter from Dr Golbus on changes in type of temporary mechanical support device use under the new heart allocation policy. There's an ECG challenge by Dr Choxi entitled entitle, how me the P wave. Very interesting title. You got to pick it up. And there's an On My Mind paper by Dr Thibodeau on telehealth for uptight titration of guideline directed medical therapy and heart failure.
Dr Greg Hundley: Very nice, Carolyn. Well, I've got a couple of letters. First, there's an exchange of Letters to the Editor regarding the article ow Attenuation Noncalcified Plaque to Predict Myocardial Infarction: Are We There Yet? And it's from Dr Alfonso and then a response from Dr Williams, and finally, a Research Letter entitled The Effectiveness of Deep Sedation for Patients with Intractable Electrical Storm Refractory to Antiarrhythmic Drugs. And it comes from Dr Raphaël Martins. Well, Carolyn, how about we move on to that feature article and learn more about hypertension in the Southeastern United States?
Dr Carolyn Lam: You had me waiting right from the start, Greg. Let's go.
Dr Greg Hundley: Well, listeners, welcome to our feature discussion today. And we're going to be reviewing a paper regarding hypertension and with us, we have Dr Daniel Lackland from Medical University of South Carolina and our own associate
editor, Mercedes Carnethon from Northwestern University. Welcome to you both. Well, Dan let's get started with you. Can you tell us a little bit about the background information pertaining to your paper? And then what was the hypothesis that you wanted to test?
Dr Daniel Lackland: For decades, we've known that the Southeastern portion of the United States is a disadvantaged area, but a great geographic diversity where you had these great rates of disease. In 1960, there was NIH-supported the Charleston Heart Study and the Evans County Georgia Heart Study. And these were two databases that were trying to actually look for some type of a factor that was in this population that was leading to the great risk, we became the custodians of this database. And then the regard study focused in or structured around 2000 began to also look at areas of the Southeast. And so the question that we had was using these cohorts, looking at 40 years, have we seen a difference in blood pressure? We did see a difference in outcomes, but have we seen also the difference in blood pressure in this high-risk group?
Dr Greg Hundley: It sounds like your hypothesis was to determine whether blood pressure had diminished. And you've told us a little bit about your study design, but perhaps can you describe a little more of the study population.
Dr Daniel Lackland: In the Charleston Heart study, Charleston, South Carolina, it was basically the County and there was a random sample SLED it in that area and Evans County, Georgia Friday it was just everybody that was in the County. Curtis Hames was the individual at that time and put together these two nice cohorts. These were individuals, obviously in 1960 a time before we were treating blood pressure and recognizing pressure. So there was a blood pressure measurement, there was a cholesterol measurement and basically, a general overall assessment that was having in both of these cohorts in 1960. These individuals again were followed, and then when the regard study was started in the late 1990s, it did also again, blood pressure measurements, but with a focus in the Southeastern portion of the United States. And so you were able to see this population. So it was an opportunity to look at some cohorts that were readily available and using them for a unique way to consider it in this particular high-risk area.
Dr Greg Hundley: Very good. And so how many total subjects did you have?
Dr Daniel Lackland: In the Charleston Heart Study and Evans County, Heart Study you were looking at several thousand and you were comparing it to a slightly higher group from the regards where you're looking at 5,000 or so.
Dr Greg Hundley: So what did you find, Dan?
Dr Daniel Lackland: We found some wonderful things. Certainly, the blood pressures had come down just like national studies have shown. The top of the list was these excessive blood pressures, these severe blood pressures of where 10% of the African-American men and women in 1960 had systolic blood pressures greater than 2000. These were virtually eliminated. We didn't see this later on 40 years later, I think a wonderful accomplishment. The other piece is that while all the blood pressures came down, blood pressures came down significantly greater for African-American men and women and all facets. So those blood pressures that we would have considered high 140, whatever, those all came down there, and they came down greater than we saw among white men and women. We were seeing the gap that was so huge in 1960. The racial gap, starting to come together with a very positive type of sign.
The other piece excitingly, we saw the blood pressures in the lower percentiles coming down suggesting that maybe some of the lifestyle that we've been implementing around the country were also being implemented successfully in this high-risk Southeastern population.
Dr Greg Hundley: Very good. So Dan, in 1960, 10% of the men and women had systolic blood pressures greater than 200 millimeters of mercury. And you saw mark declines after the year 2000, and then also you saw declines for those that had mild elevations in blood pressure, systolic blood pressures in the 140-millimeter mercury range. And one quick question, was this true for both men and women?
Dr Daniel Lackland: Yes, indeed. Both men and women, everybody's blood pressure came down.
Dr Greg Hundley: So Mercedes, let's turn to you help us put this paper in the context with other manuscripts that we review at circulation, but also the world's literature.
Mercedes Carnethon: I'm really excited about the opportunity to feature these findings and circulation, because I think they provide a very unique contribution to the literature about the population trends and levels in blood pressure, in the United States and around the world. And one thing that's really important is we don't often talk about our population level successes. And as we know, hypertension is one of the leading drivers of cardiovascular disease. And particularly when we think about reasons for disparities in some of the diseases that Dan mentioned earlier, heart failure, renal disease, hypertension as a primary driver of this, as well as stroke.
I certainly can't leave that out. And so to hear that over time a population levels of blood pressure are shifting downward or are certainly shifted downward is really heartening news. It does back certain questions. We certainly still see disparities in blood pressure levels between blacks and whites in this country, but are most likely a primary driver of the disparities that we see in stroke, in renal failure, in certain cardiovascular diseases, and as well as heart failure.
And so it's wonderful to see this. And I asked Dan and his colleagues, this particular study data was from the baseline of the regard's cohort and extremely well-designed study that's captured individuals from across the United States. I have two questions, Dan. One is, were you able to tease out any
differences in blood pressure between those in rural versus more urban areas in the Southeast and the second, because this ended in 2005, what do you project would happen today? Do you think these trends are holding? Have we gotten better? Where do we stand?
Dr Daniel Lackland: That's wonderful questions. As far as the rural urban, in one sense or certainly Evans County, Georgia is all rural. And if you compared a little bit teasing out, as you've suggested, the Evans County rates were just exceptionally higher than the of the urban sides. If you will allow me for a moment to call Charleston, South Carolina is somewhat urban community. You did see some differences, but they were relatively subtle. Where we are today, if we look at the clinical data, it looks like the top of the list, those excessive, severe blood pressures that particularly we saw in black men and women in 1960 are gone. Now we're working on the moderate blood pressures that Greg had referred to. And I think that, that's fun on that. Those are also coming down. The exciting piece though, although also those lower blood pressures that you refer to, so that in that prevention side of it, those blood pressures are coming down. And that lifestyle, maybe our messages are gradually getting there to all of the population.
Dr Greg Hundley: Very good. Let me ask you here in closing, maybe 30 seconds for each of you, what do you think is the next study that needs to be performed in this particular area? Dan, we'll start with you.
Dr Daniel Lackland: I think we know that the interventions work for everybody. So I think we're one of the pieces. Again, is to look at the groups that we've been referring to now with the new guidelines and the new classifications of hypertension, looking at those people that we used to call prehypertension and now have become stage one hypertension, and also elevated blood pressure. Can we implement lifestyle interventions and get down a lower blood pressure? The other piece on the global side that we have mentioned, I think there are global populations around the world that actually unfortunately were similar to what 1960 South Eastern populations are. And I think this is a good model to make sure that we can take what we've done here and take it to other populations around the world.
Dr Greg Hundley: Very good, Mercedes?
Mercedes Carnethon: What I'm most curious about going forward is what proportion of this decline is due to pharma-cotherapies and what proportion is due to shifts in lifestyle behavior? As a data type of person, I would be very interested in teasing this out because there are multiple contributions to high blood pressure, some of which need to involve interventions at the individual level and others that can be implemented on a population scale. And those population scale interventions, for example, reducing sodium and certain foods have the potential to reach all populations, including vulnerable populations, and are less dependent on one's ability to adopt lifestyle changes individually. And so I would be most curious about trying to tease that out so that we can appropriately target resources that will reach the largest and most vulnerable populations.
Dr Greg Hundley: Well, listeners we're most appreciative to have this opportunity to speak with Dan Lackland from Medical University of South Carolina and Mercedes Carnethon from Northwestern University. And listen to them describe these very encouraging results from the regard study, showing that there have been detriments in both severe and mild to moderate hypertension over the last 40 years in the Southeastern United States. So on behalf of both Carolyn and myself, we wish you a great week, and we'll catch you next week on the run. This program is copyright the American Heart Association, 2020.
This week’s episode includes author Mark Chan, editorialist Thomas Wang, and Associate Editor Wendy Post as they discuss the prioritization of candidates of post-myocardial infarction heart failure using plasma proteomics and single-cell transcriptomics.
TRANSCRIPT BELOW:
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, really interesting, involving proteomics and single-cell transcriptomics, trying to identify how we could prioritize individuals after they've sustained myocardial infarction as to whether or not they'll develop heart failure. Lots to go over in that feature. But before we get to that, how about we grab a cup of coffee and start in with some of the other interesting papers in this issue?
Dr Carolyn Lam: Absolutely. I've got my coffee and I have to tell you though, I am so excited about this feature, it comes from Singapore, but my first paper too is about transcriptomic profiling. But Greg, I have to ask you first, have you heard of the cardiac cellulome?
Dr Greg Hundley: Oh my goodness, Carolyn. So you're starting the reverse-quiz strategy to help me. I have not heard of the cellulome. Help enlighten me.
Dr Carolyn Lam: I just love that word. We've heard of all kinds of other omes, but this cellulome is something I've learned through today's paper. So the authors today who are Alexander Pinto from Baker Heart and Diabetes Institute and colleagues, they developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome. And that refers to the network of cells that forms the heart.
The method was utilized to profile the cardiac cellular ecosystem in response to two weeks of angiotensin II as a pro-fibrotic stimulus. So what did they find? Well, they identified two previously undescribed cardiac fibroblasts populations that are the key drivers of fibrosis. Their names were Fibroblast-Cilp and Fibroblast-THBS4. Now, these do not correspond to smooth muscle actin-expressing myofibroblasts, which have been widely viewed as the primary drivers of fibrosis. So this is really novel. The cardiac cellular landscape was sexually dimorphic at the cell abundance and gene expression level, including cellular responses to angiotensin II induced tissue remodeling. So these data really provide insights into the cellular and molecular mechanisms that promote pathologic remodeling in the mammalian heart, and really highlight that early transcriptional changes precede chronic cardiac fibrosis.
Dr Greg Hundley: Very nice, Carolyn. Well, let me switch to the clinical realm. And my first paper comes from Professor Holger Thiele from the Heart Center Leipzig at the University of Leipzig, and it's involving general versus local anesthesia with conscious sedation for patients undergoing TAVI procedures. So the study comes from the SOLVE-TAVI study, and it's a multi-center open-label 2x2 factorial randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVR, comparing conscious sedation versus general anesthesia. And the primary efficacy endpoint was powered for equivalence, and consisted of the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatments, and acute kidney injury at 30 days.
Dr Carolyn Lam: Wow, Greg, as I understand it, about half of patients today receive TAVI or TAVR with conscious sedation. So it's really an important question. So what did they find?
Dr Greg Hundley: You're exactly right. So the composite end point occurred in 27% of the conscious sedation patients and 26% of the general anesthesia patients. Really equivalent. And this held true for each of those composite endpoints. In addition, there was a lower need for inotropes or vasopressors with conscious sedation, versus general anesthesia. Thus, these findings suggest that conscious sedation can safely be used for patients undergoing TAVR procedures.
Dr Carolyn Lam: Very important clinical one, Greg. Well, I've got a clinical paper for you too. And this one, trying to answer the question, what's the optimal duration of dual anti-platelet therapy, or DAPT, after PCI with drug-eluting stents. A very familiar, perhaps, an important question. So these authors, led by Dr Deepak Bhatt from Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, performed a systematic review and network meta-analysis of 24 randomized controlled trials comparing short-term DAPT, or less than six months, followed by aspirin or P2Y12 inhibitor monotherapy, versus mid-term DAPT, which was six months, versus 12 months DAPT, as well as an extended-term DAPT, which was more than a year after PCI with a drug-eluting stent.
Dr Greg Hundley: So Dr Carolyn, three groups, what did they find?
Dr Carolyn Lam: Compared to 12 months DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduced major bleeding after PCI with a drug-eluting stent, whereas extended-term DAPT reduce myocardial infarction at the expense of more bleeding events. Overall, the extended-term DAPT was associated with a higher risk of major bleeding compared with all other DAPT groups, except in patients with acute coronary syndrome.
Dr Greg Hundley: So extended, more bleeding complications. So take me home on this, Carolyn, what is the final message here?
Dr Carolyn Lam: Here's the message. Compared with 12-month DAPT, the net clinical benefit appears to favor short-term DAPT followed by P2Y12 inhibitor monotherapy instead of aspirin in select patients. Although, extended term DAPT has a role for patients who have a low bleeding risk, but a higher ischemic risk, such as those with acute coronary syndrome, thus a personalized approach appears to be warranted.
Dr Greg Hundley: Very good. Well, I'm going to turn back to the world of basic science and discuss a paper related to pulmonary hypertension. And it comes from Dr Sébastien Bonnet from the University Laval. So Carolyn, the subcellular mechanisms that govern the transition from a compensated to a de-compensated right ventricle in patients with pulmonary hypertension remain poorly understood, and as a consequence, there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. So this study investigated the long non-encoding RNAs, powerful regulators of cardiac development disease, in relation to adverse RV remodeling in pulmonary artery hypertension.
Dr Carolyn Lam: So these LNK RNAs, I think that's what they're called, right? Long non-coding RNAs, what did they find?
Dr Greg Hundley: This was another one of our really nice translational articles, because they combined results from both animals and human subjects. The authors demonstrated that the long non-coding RNA H19 is upregulated in decompensated right ventricles due to pulmonary hypertension, and the finding correlated with RV hypertrophy and fibrosis. Now, similar findings were observed in monocrotaline and pulmonary artery banded rats. The authors found that silencing H19 limits pathological RV hypertrophy, fibrosis, and capillary rarefaction, thus preserving RV function in those two models of pulmonary hypertension, both the monocrotaline and the pulmonary artery banded rats, without effecting pulmonary vascular remodeling.
And finally, Carolyn, the authors found that circulating H19 levels in plasma of patients, discriminate pulmonary arterial hypertension patients from controls correlated with RV function and predicted long-term survival in two independent idiopathic pulmonary artery hypertension cohorts. Moreover, H19 levels delineated subgroups of patients with differential prognosis, when combined with NT-proBNP levels or the risk score proposed by both the Reveal and the 2015 European Pulmonary Hypertension Guidelines.
So, in summary, these authors findings identify H19 as a potentially new therapeutic target to impede the development of maladaptive RV remodeling, and thus a promising biomarker as well of pulmonary arterial hypertension severity and prognosis.
Dr Carolyn Lam: Oh, Greg, I love that. Not just the paper, but the way you explained it. Thanks so much. Well, let's dip into what else there is in today's issue, shall we? First, there's Global Rounds by Dr Yacoub entitled, Towards Meeting the Challenges of Improving Cardiovascular Health in Egypt. There's a research letter by Dr Cheng on imaging the sarcoplasmic reticulum calcium signaling in intact cardiac myocytes. There's another Research Letter by Dr Angiolillo on the pharmacodynamic and pharmacokinetic effects of a low maintenance dose ticagrelor regimen, versus standard dose clopidogrel, in patients with diabetes without prior major cardiovascular events, undergoing elective PCI. And this is the OPTIMUS-6 study. There's an On my Mind paper by Dr Santos on coronary artery calcification and familial hypercholesterolemia, and an ECG Challenge by Dr Liu, which is not your uncommon electrocardiographic findings, and really looking at Q waves with post-QRS deflections. I'll let you take a look.
Dr Greg Hundley: Oh, wow, Carolyn. This issue is just jammed with really nice articles. I've got a research letter entitled, Long-Term Outcomes After Infective Endocarditis, Following Transcatheter Aortic Valve Replacement, and it's from Dr Josep Rodés-Cabau from Quebec Heart and Lung Institute. And then finally, a nice exchange of letters by Drs Rozenbaum, Kemner, and Parasuraman regarding the article Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy, and there's a very nice response by Dr Kazi. Now we get to proceed on to that feature article.
Dr Carolyn Lam: Yay! Let's go, Greg.
Dr Greg Hundley: Well listeners, we are to our feature discussion. And today we have Dr Mark Chan from the National University of Singapore, our own associate editor, Dr Wendy Post from Johns Hopkins, and Dr Thomas Wang from the University of Texas Southwestern Medical Center. Well, Mark, we'll start with you. Could you explain to us some of your thinking behind how you formulated this study and what was the hypothesis that you wanted to address?
Dr Mark Chan: The background, really, was to try to prioritize protein candidates in post myocardial infarction heart failure. We do know that there are several hundred candidates out there in the literature, but really, what we wanted to do was to try to enrich and select out what we thought would be the most biologically relevant proteins. And really, the hypothesis was that, by combining two very powerful unbiased discovery tools that have been developed in the last few years, we would be able to achieve this goal.
The two tools, I think, Tommy would be very familiar with, because he's used plasma proteomics as well in a lot of his work. That's one of the unbiased discovery tools that we used. Measuring 1300 proteins in blast mine. Second two was a single-cell transcriptomics where we're able to look at RNA sequences, genome RNA sequences, at the individual cell level.
So we first started off with cohorts of patients with acute myocardial infarction that were followed up for about five years for heart failure events, and we obtained plasma from these patients at about 30 days after myocardial infarction. So with the initial plasma proteomics, and found more than 200 candidates, actually very similar to what we actually see in the literature in terms of protein candidates predicting heart failure, in particular, post-MI heart failure.
We then thought that what we really want to do is prioritize the most important proteins, and that's when we went onto single-cell transcriptomics. And we found a total of 83 protein candidates, which were directionally similar across the human plasma proteomics and the single-cell transcriptomic data across different models of ischemic heart failure. And six candidates are the ones that we are hoping to discuss a bit more about, the top six candidates, today, which I'm sure you'll ask me about very soon.
Dr Greg Hundley: You've really led us into the next question. Tell us a little bit about the six candidates.
Dr Mark Chan: The top six candidates to all of us are really familiar with NT-proB natriuretic peptide that's been around for decades, cardiac troponin, that's the second well-known, well-established candidate, and four other candidates that seem to be really emerging as potential targets in heart failure and ischemic cardiomyopathy. Angiopoietin-2, thrombospondin-2, latent-transforming growth factor binding protein 4, and a less commonly investigated protein, FSLT3, or follistatin-like related protein 2.
The two candidates that are particularly interesting to me are angiopoietin-2 and thrombospondin-2 , and looking at a lot of Tommy Wang's work as well, we can see that these two candidates looking to be important future targets for biomarker discovery, validation, and maybe, potentially, druggable candidates to manage patients with post-MI heart failure and ischemic cardiomyopathy.
Dr Greg Hundley: Wendy, coming to you as an associate editor and really an expert in genetic epidemiology, what intrigued you about this article? Especially I heard Mark discuss differentially expressed genetics and transcriptomics. What brought you to this article and what increased its relevance to you?
Dr Wendy Post: We were very intrigued by both the importance of the problem that was being addressed, in that ischemic cardiomyopathy is a very common and major challenge that we all encounter as cardiologists, but also the unique approach that was used to handle a large amount of data. So with the plasma proteomic approach, which Mark described as the first step, you take thousands of data points and try to narrow it down, which he did, but still needed to narrow it down even more. And then use a complimentary, but different, approach to try to understand which of these hits, so to speak, maybe the ones that are important. And so using the single-cell transcriptomic approach, was able to narrow down to these six candidates.
And then it was very reassuring that two of the six were what we would have hypothesized. So if you didn't find those, we'd worry that maybe something was wrong with your approach. So on the one hand, you'd say, "Well, we already knew that. So what are you telling us?" But it actually was proof, so to speak, that your approach was working, and that these other four novel candidates might turn out to be the next BNP. So that was really a few of the things that intrigued us about this paper.
Dr Greg Hundley: So Tommy, as a practicing clinical cardiologist, and then also, really, as a clinician researcher, what do you see as relevant with Mark's work and also Wendy's description here for all of us that are seeing patients that has sustained myocardial infarction?
Dr Thomas Wang: I think as Mark and Wendy have both nicely summarized, but I'll revisit, they're really two areas in which knowledge of these biomarkers could impact patient care down the road. One is an informative set of biomarkers to tell us which among the large number of patients with myocardial infarction might be destined to develop heart failure so that we can, as clinicians, ramp up our therapies, increase our vigilance, increase our monitoring, so that we might be able to intervene on that at a very early stage, or even before the heart failures develop.
The second, which is potentially even more exciting, is the possibility that some of these biomarkers might be so informative of pathways leading to heart failure, that we could actually directly intervene on the pathways that are reflected by these biomarkers. So in other words, biomarkers would tell us not just biology, but about therapeutically effective strategies. And I think, as Mark has nicely emphasized, there are scores, if not hundreds, of biomarkers that have been looked at in this context, and there's no amount of resource in the world that allows investigators to pursue, in prospective clinical studies or experimental studies, all of these biomarkers. And so the real value of their study is to illustrate an approach for winnowing down this large number of biomarkers down to a smaller set, a much smaller set, that seem really worth pursuing in further study.
Dr Greg Hundley: Well, with that lead in, Tommy and Mark and Wendy, maybe start with you, Mark, what do you see as the next step and this area of research moving forward?
Dr Mark Chan: I think I need to sound a word of caution first with respect to the study itself. It is, at the end of the day, still a very descriptive study. Heavy in bioinformatic elucidation of targets. So careful mechanistic validation and further understanding of these highly prioritized targets will still be important.
In terms of how we can potentially get these results closer to the post-MI heart failure patients, closer to the bedside, one concept that I think it's becoming increasingly apparent is that a lot of these bioactive proteins in circulating plasma are likely a part of the secretome. Part of what we call exosomes or micro-bubbles that are secreted by cells. And we do see the origin big cells in the single-cell studies as part of this paper. We do get an idea. A lot of these cells really are within the extracellular matrix, which is the substrate in which your cardiomyocytes are embedded. We think that enriching the plasma for the exosome fraction, which one of my colleagues is now working on, could be the best way to derive a more powerful tool for prognostication. To really determine with a high level of specificity, not just sensitivity, but highly specific
to determine which patients end up with post-myocardial infarction heart failure.
So enriching plasma for exosomes and potentially looking at the proteins within these exosomes, we've already started work on that. And so far, the results, compared to the proteins just measured in free plasma, seem to predict heart failure events a lot better when we come down to the exosome fraction.
The other project, this is using exosomes to treat post-MI large animal models. So we have injected mesenchymal cell stem cell derived exosomes, and we've shown that they can reduce infarct size in large animal models, and also prevent some of the hemodynamic complications that result in heart failure. But really, trying to find which are the proteins actually are meaningfully preventing heart failure and reducing infarct size, I think that is also going to be part of the next steps.
Dr Greg Hundley: Mark, thank you for that summary. Tommy, do you have anything to add to that?
Dr Thomas Wang: I certainly agree with all that's been said. I would also emphasize that understanding the biology of some of these newer biomarkers and how they might link heart failure or active MI is going to be really important when we consider potential clinical applications. And so, further along the experimental line, I think animal models, mouse models, and other types of models, being which the biology and pathways we would manipulate it so that we can see whether these biomarkers truly do reflect etiologic pathways in heart failure would be valuable.
Dr Greg Hundley: Thank you, Tommy. Well, listeners, we've had a great presentation from Dr Mark Chan, an excellent review by both Wendy Post and Tommy Wang, emphasizing how we are discovering new protein biomarkers using plasma proteomics for identification of those that may develop heart failure after myocardial infarction. And more to come in this area. We feel very privileged to have the opportunity to work with bright young investigators like this and present this work in Circulation
For both Carolyn and myself, we wish you a great week and look forward to catching you next week on the Run. This program is copyright American Heart Association, 2020.
Dr James de Lemos: Hello, my name is James de Lemos. I'm the executive editor for Circulation, and I'm delighted to be joined here by Tim Gardner professor of surgery at University of Pennsylvania and our long-term associate editor in charge of cardiac surgical content at Circulation; and Marc Ruel, who is professor of cardiac surgery at University of Ottawa and the chair of the department there and who for many years has led the cardiac surgery supplement issue. Mark, Tim, welcome. Marc, please introduce this issue for our listeners.
Dr Marc Ruel: Thanks so much, James. It's a very exciting year academically for cardiac surgery. We've had a lot of great developments from new data on long-term patency and outcomes with radial artery graphs through the results of the ischemia trial. And I think the 2020 themed issue around cardiovascular surgery is exactly in that framework. I think it will garner wide interest.
It has a number of original papers, six original research articles, two more translational papers included in those six. We have two research letters. We have two frame of reference papers as well. And one state-of-the-art piece on exynos transplantation. We always keep in mind to have those issues very relevant to surgeons and to gather the very best cardiovascular surgery science. But in the same token we also want to make sure that they are relevant to the wider cardiovascular community. So I think, and I hope that everyone will enjoy this issue as the very best that's happened in cardiovascular surgery over the year.
Dr James de Lemos: Well, thank you, Mark. Let's get started with discussion of the first paper and one that I'm actually quite excited about. This is long-term results of the radial artery CABG in clinical outcomes trials. What did the investigators look at in the study?
Dr Marc Ruel: I think this is a very important paper, which adds to the increasing data around long-term benefits of arterial grafts, multi arterial grafts, and more specifically the radial artery. So here's a paper mostly from Australia. First author being Professor Buxton, who is a very well-known senior surgeon who has been really a grandfather in this field. And the last author is David Hare who is a cardiologist, also professor in Australia.
And essentially there were two radial artery comparative trials that have been undertaken many years ago, well over a decade ago, when we now have 10-year data on those two trials. One of the trials compared the radial artery to the right internal thoracic artery. And the second trial a little bit smaller to the saphenous is vein grafts. So it holds 400 patients in the first randomized comparison and around 225 in the second, i.e. the radial versus saphenous vein.
So it's wonderful that this is very long-term data. We have 10 year patency data, not on all patients. There was a distribution as to when the angiogram or the CT scan would be performed for patency over the course of the 10 years of the study. But the follow up is excellent and there are actually patency as well as clinical differences between the groups.
And maybe I can say a couple of things around those. So, in the radial versus right internal thoracic artery cohort, there's both a patency and a mortality as well as a major adverse cardiac events benefit for the radial artery over the right internal thoracic artery. And yes, you've heard right, the comparator is the right internal thoracic artery.
Now a couple of chatty it's all the Redis in there had to be done as a free graph. So they are connected. This is an art technique that everyone is very comfortable with and you have to use a six or seven Oh one friable internal thoracic ultra.
So it may not really provide or present the call the way at its best advantage. If you will, there may be some benefits or a loss for not having it as a pedicle, but nevertheless, and in the second comparison, looking at the radio versus 225 patients, there was a patiency advantage for the radio Herceptin in Spain.
But partly because the comparison was less power than the first, there was no major adverse cardiac event or even mortality difference. So I think again, aligns with the data that we know the arc trial, as we all know, 10 years was neutral. There was no benefit to internal thoracic arteries versus small one, which regards to anything repeat revascularization based mortality.
And we know have 10-year data recently published that shows that the radial artery in pooling patient level data from many randomized clinical trials leased their survival benefits. So I think it's fair to say based on available data now with this team issue in 2020 in the fall, that the best second RGO is very likely or radio RV and too many people surprised.
Dr Timothy Gardner: Yeah. If I could just add my perspective, there's an editorial by Steve brings on this. This really does solidify the data about long-term radial, artery patency. And that was when I came away with, it's not so much the comparison of the radial on the right internal thoracic, but the fact that the radial artery would be like held up very well.
Dr James de Lemos: If you're referring a young patient or considering a young non-diabetic patient for cabbage at this point, was you select a radial artery or right internal memory?
Dr Timothy Gardner: Well, I probably would favorite as a second graph the right internal thoracic artery rather than. As a free graph, but I certainly wouldn't hesitate to use the radial artery as the second graph there as a third grade. My competence in the radial artery continues to grow in this report reinforces that.
Dr James de Lemos: Excellent really important study for both the cardiac surgeons and the cardiologists that read our journal.
Let's switch gears and talk about bowel surgery, Tim, the camera Cardiolite study drills deep into different strategies for repairing the mitral valve. What did we learn there?
Dr Timothy Gardner: Well, first of all, this study, which comes from Mark Raul's unit Benson Chan being the first author and address the issue that repair with resection of the mitral valve made me to functional stenosis of the valve. And that has been a concern among surgeons and that has led some surgeons to prefer non-lethal the resections repair. And this study was very carefully done and actually demonstrated that the data did not support the fact that resection versus preservation is this okay with the riff? So I think that, you know, there are various ways to repair the valve. And if you go back to the original descriptions of mitral valve repair resection was a major component for many people in many studies. And this is a reassuring study that either approach appears to be effective without badly under sizing the annulus that there should not be residual mitral stenosis.
Dr James de Lemos: Tim is one of these materially easier to do in the operating room. So then it would emerge as the preferred therapy or is it really going to be surgeon dependent.
Dr Timothy Gardner: I think it’s fairly surgeons dependent. I mean, we have technical variations for a lot of operations, and I think it's when the surgeon is comfortable with Mark. You might want to comment on that point.
Dr Marc Ruel: Yeah, I agree with both of you. I think it's very reassuring because there's the orientation of where the last issue is. Small. The patient's exposure is not knowing that you can use theater technique and in some cases not have to go on to the pathway. We Muscle is a reassuring avenue. So I think every surgeon has her or his preference, but it's nice to know that both these can be used interchangeably without any drawback to the patient.
Dr Timothy Gardner: Let's switch gears and talk about a paper that I think has pretty profound implications for both of our specialties. And this is an observational analysis from the RS trial, evaluating the association of postoperative atrial fibrillation in the long-term risk of stroke. Mark, what did you think of this paper and its implications?
Dr Marc Ruel: This is a very interesting piece that comes incidentally from the heart trials. So non related to what we were
Just discussing before the 3000 patients or so of the art trial were followed at 10 years. Mostly with regards to major adverse cardiac events, et cetera, anything that's related to the question at stake at the time, which was single internal for us, incidentally, the authors have ready data regarding the incidence of stroke at 10 years. And they were able to use those and go back to those stations who have postoperative atrial fibrillation and see if there was a correlation, even when accounting for other factors in the patient profile. So interestingly about 24% of patients have had post-op and post-op you, is defined in variety of ways for this particular study, it was defined as 30 seconds at least of atrial fibrillation or atrial flutter during the index hospitalization after the operation. So I think this is a very fair and square type of definition and those patients and those who have the CBA incidents by 10 years was 6.3% versus those who did not have postoperative 3.7%.
So this is obviously a significant numerical and also statistically significant higher risk for those patients who have post-operative a-fib. So there's a number of caveats around that. All the risks for post-doc are often the same ones that may lead to the risk of stroke over the long-term. So I think we should see this not as probation. But that should be not even as an association. But certainly as a correlation, but it is really unique data that has not been produced before. Like postoperative is so common after cardiac surgery. It affects many of the patients that both the cardiology and cardiac surgery individuals have to treat.
And I think the more information on it, the better, there were a number of interesting observations warfarin, for instance, even though the incidence of post-op 24% was used in only about 8% of the overall trial. So one may debate, have these patients being anticoagulated enough also, would there be a way to provide enhanced surveillance to patients who have post-op in order to maybe catch them prior to them having a cerebral aspir event?
So I think it's really very interesting data. I would like to briefly provide one last tidbit of information, which I thought was very, very fasting. So the authors used the CHADS two score in order to kind of ascertain your overall risk attributed to which regards to stroke in those patients. So this is probably the latest and best iteration of the Chad score if you will.
And they found that in patients with a score of less than four, so it was zero to three. There was no difference with regards to the incidents of CVA or in signers versus those who have post-op after the operation. However, when the score rich four or higher. This is rare to you where the risk was concentrated. So that particular cohort of patients seemed to be the one where I think the efforts with subsequent studies should be concentrated in order to intervene and hopefully catch these patients who may have atrial fibrillation without having it.
Dr James de Lemos: Does this change your practice at all? Do you think, I mean, I guess it's interesting for me because obviously I see a lot of these patients back from surgery and I've tended to candidly ignore short episodes of peri-operative atrial fibrillation. And this really raises questions as to whether that approach is wise and needs to be revisited.
Dr Timothy Gardner: I agree completely on the other hand, I think that targeting patients, I mean, I think the last point that Mark made about the patients that ended up with problems with higher AFib and with consequences had other risk factors associated with their risk of stroke. So this continues to be a really tough group to manage. I think that one question that we all have is do the, the, the new novel oral anticoagulant agents provide better long-term protection. As a topic for another important study that should be coming down the pipe pretty soon.
Dr James de Lemos: And I'll just point out to our listeners that at the American heart association meeting in November, that late breaking trial will be presented called search AI cardio length that will evaluate extended monitoring creature fibrillation after surgery. And I think that will build off, of this theme that perhaps atrial fibrillation after cardiac surgery is a more important tissue than many of us considered.
Let's move to the next paper, Tim, this is really right in your wheelhouse in terms of surgical. So specialization. And this is an interesting paper. I thought evaluating variation and congenital heart surgery outcomes across centers in the U.S. and this group really evaluated a large proportion of dissenters doing congenital heart surgery in the U S.
Dr Timothy Gardner: Yeah, absolutely. And they made use of the STS database. They've got good data and it is a multi-institutional review group, really looking at how to optimize outcomes. And I think that, the assumption is that regionalization with more attention to high volume centers, especially for the most high risk say neonatal heart surgery is the way to go.
But this study actually while demonstrating significant hospital variations also demonstrated that and reading their conclusion. Now a substantial portion of potential improvements that could be realized on a national scale are related to variability among lower risk patients. And this makes me think back to Dr John Kirkland, who was maybe the first one in our field to actually develop a checklist of important steps and management strategies during the surgical procedure in the early post-operative period.
He worked with IBM on that. And I think that lesson here that I take away from it is that volume may be important, but not just for the high risk neonatal population, but for all congenital heart surgery patients. And it really is an important specialty. And there may be some opportunities for improvement just by standardizing sort of management of even the lower risk patients. This is one of several reports from this multi-institutional group that is focused on data from the STS database in congenital heart surgery. Good job demonstrating these variations in outcome.
Dr James de Lemos: Yeah. And I think tremendously important, right? Because these lower risk in general procedures may be more like other procedures that cardiac surgeons do. And I think you make a great point that these systems based approaches to minimizing variation do seem to matter. And I wouldn't have thought that the, this is another one of the theme really here in the issue where we have a lot of studies that are challenging the way we thought about, common medical and surgical problems, really a fascinating piece.
Let me take a moment here to introduce a new member of our team for the themed issue. Mike Fischbein, who's a surgeon scientist at Stanford, a practicing cardiac surgeon on the faculty there, but also runs a large and very successful basic science laboratory. And he has joined the surgical team for the themed issue to add his particular expertise in the evaluation of the basic science papers.
Mike, welcome to the team. I think our readers and listeners will really benefit from having your perspective. And I'd like to have you now please talk about the basic science papers here in the issue.
Dr Michael Fischbein: Thank you very much, James. It's really a pleasure to be part of a team. The paper that I'd like to discuss today is a feature of basic science paper entitled a Single cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns and Control and Aneurysm Human Aortic Tissue. This is from Scott LeMarie group from the Department of Surgery at Baylor College of Medicine. I think this study is very important. It's focusing on the ascending, thoracic aortic aneurysm, as you know, ACE and aortic aneurysms are the second most common aneurysm after abdominal aortic aneurysms. One of the risk factors of ascending aortic aneurysms is that as they grow, they can tear dissect or rupture.
Both of which are life-threatening currently the only treatment option is prophylactic surgery. And this is really based on size criteria alone. Now, while over time, we've established that smooth muscle cell loss and exhale and matrix breakdown are important during this process, really the molecular mechanisms or pathophysiology is poorly understood. Therefore, limiting development is novel drug regimen, and this manuscript, the authors use single RNA sequencing to compare the aneurysm wall to normal control. Aorta is taken from transplant recipients. One of the benefits of single cell RNA sequencing is that allows one to identify the cellular components or heterogeneity within the aortic wall. And it also allows us to see the aneurysm relevant transcriptome changes in the major vascular cell types within the aorta. The authors identified 11 major cell types in the aorta, including a number of different smooth muscle cell subtypes and to Celia's cells, fibroblasts and inflammatory cells, including T-cells and macrophages.
They found over 500 altered genes comparing the aortic wall to normal control. Mitochondrial dysfunction seemed to be altered in several gene types and they identified a transcripted factor ERG, which stands for Erythroblast Transformative, specific Related Genes to be important in maintaining the normal aortic wall function. And this was reduced specifically in smooth muscle cells, fibroblasts and endothelial cells. This is really an exciting target that may lead to drug development in the future. So thank you very much, James, for allowing me to participate in the group. And I think this will be an exciting paper for the readers.
Dr James de Lemos: So Mike, thanks so much. Really appreciate your perspectives here. Another really interesting area that is quite forward-thinking Mark is this idea of 3D printing. Theotic roots and conduits. Tell us about this paper from Joe Woo’s group.
Dr Marc Ruel: This is another great contribution from Joe's lab. Looking at the issue around bell spring, and many would call it bear hair because essentially they preserve and surgeons go to great pain and great strides to try to recreate if you will be normal slash nets, these geology and aortic root sinuses. And many of us, when we do this operation are taking great minutia and creating those. And there's a number of things that happen. And all of these techniques vary from the more approach of just taking a straight to, and essentially reinventing the native aortic valve and connecting the coronary buttons. So Joe's lab wanted to study this with regards to the translationally relevant outcome of opening velocity and closing gossip with regards to the RP pal.
And they've done this 3D printed biomechanical study, aware they have used for signing LT. Val, that'd be put into these different configurations, some including Neil, if you will, some including what we call a bell solver type of breath and using the natives or signing as a control in the same 3d biomechanical model. And essentially the conclusions of the study, which is free, elegant be performed and Bree compelling from a data point of view is that a simpler appears to be better too many.
I'm sure the investigators I'm sure what will be many readers price. These trade routes' configuration without Neil sinuses seem to have the lowest coast opening and closing velocity. So it would suggest that this may translate into longer term durability of the valve. Now, there are other reasons why someone, for instance, the one I do this operation, I like to use Valsalva graft. It's not because I so strongly believe that Neo sinus type should be there is because it also gives enhance an easier reach to the corny about adding a vertical followed by a horizontal type of pattern I find is a bit more reliable and it may not really matter what the opening and closing philosophies are because those files are not intrinsically abnormal.
So they may last for many decades going forward. But nevertheless, I think this is a very important study and series of experiments, and we're very happy to include it in the theme this year.
Dr Timothy Gardner: Yeah. And if I could just add the thing that I admire most about this study is that not just how they come up with this innovative, 3D printing way to model, but the team included mechanical engineers and bioengineers at Stanford, and that's adding real substantial science to what some surgeons have theorized about. So this is a small study, but the results are quite interesting. Let's talk now.
Dr James de Lemos: It's about this remarkable Primer that we've had on critics, transplantation. This is something I wouldn't have imagined five years ago would be something we'd have even considered close enough to clinical application to publish in circulation. But what's different about this now and what should our readers look to in the future with this technique.
Dr Timothy Gardner: This paper comes from a group at the Mass General [Hospital]. They've continued to work on Xenotransplantation as a possible solution to the need for new donor organs. And I think the most remarkable thing is after almost silence for 10 years, they have outlined the possibility much more realistically now of coming up with Xenotransplantation as a usable alternative, based on some very important basic science work that others have done in baboons and that they have model into additional experiments. This is what was a very informative article for me. And it's still some ground to cover, but they've really worked away at the science and think that they believe that they're nearing the point where they know transplantation or for cardiac replacement is a possibility. Again, amazed I sort of thought Xenotransplantation was an impossible dream 10 years ago. And here we are, perhaps at the point where it is more of a realistic possibility.
Dr James de Lemos: Really remarkable. When you think about these technologic advances that are getting so much closer to clinical application. Well.
Dr Timothy Gardner: Thank you both. I'd like to take just a moment to recognize Sara O'Brien in [the] Circulation Editorial Offices in Boston for her remarkable contributions yet again, to pulling this issue together and keeping Mark and Tim and Mike and myself on task to bring this issue home. And thank Mark Tim and Mike for pulling together. What I really believe is far and away, our finest issue. We're talking here in my opinion about multiple studies that changed the way we think about cardiovascular surgery and its complications, including atrial fibrillation that affects all of us in cardiovascular medicine.
Dr James de Lemos: Marc, would you like to make some final comments as we wrap up today?
Dr Marc Ruel: Absolutely. I could not agree more with your statement, James. I think this is a team effort and I want to be cognizant to the leadership of Circulation for as the premier cardiovascular journal, recognizing the importance of cardiovascular surgery in the field and dedicating an issue through what is best that's happened over the last academic year or so. We want this issue to continue for all time. And I think it's very well started and it's growing nicely. And thanks to the efforts of many, including of people on this call today. I hope that our readers will like it and I foresee it will garner interest even beyond the strict fields of cardiovascular surgery but to the entire cardiovascular community.
Dr Greg Hundley: This program is copyright American Heart Association, 2020.
This week’s episode includes author Finnian Mc Causland and Associate Editor Justin Ezekowitz as they discuss angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction.
TRANSCRIPT BELOW
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, we're going to be talking about RNEs and renal outcomes in HFpEF. Oh, you got to hold me back this is going to be such an interesting discussion. But maybe let's grab our coffees. Are you ready to talk about some of the papers in today's issue?
Dr Greg Hundley: You bet.
Dr Carolyn Lam: Well the first paper I have really represents a novel gene therapy approach to atrial fibrillation. So doctors led by Dr Arora from Northwestern University Feinberg School of Medicine and colleagues used a novel gene therapy approach in a canine rapid atrial pacing model of atrial fibrillation to demonstrate that NADPH oxidase-2 or NOX2 generated oxidative injury by causing upregulation of a constitutively active form of acetylcholine-dependent potassium current, or IKH is an important mechanism underlying electrical remodeling in the fibrillating atrium.
Dr Greg Hundley: Wow, Carolyn, very interesting. Tell us a little bit more about this gene therapy approach.
Dr Carolyn Lam: They performed targeted expression of anti-NOX2 short hairpin RNA in the intact atria of the dogs, and then subjected those animals to rapid atrial pacing for a period of several weeks to months. The novel atrial gene therapy approach prevented the development of electrical remodeling and sustained atrial fibrillation thus demonstrating for the first time a clearer causative role for NOX2 generated oxidative injury in the creation, as well as the maintenance of electrical remodeling in atrial fibrillation. Furthermore, they demonstrate that a likely cellular and molecular mechanism by which oxidative injury created a vulnerable substrate for atrial fibrillation, the results of this study yield therefore valuable mechanistic insights into the pathogenesis of atrial fibrillation and have important therapeutic implications for this clinical management.
Dr Greg Hundley: Very nice, Carolyn. We need more therapies for AFib. Boy, that's so informative. Well, the next paper that I have sort of merges the world of electrophysiology with the world of imaging and it comes to us from Dr Michela Casella from Centro Cardiologico Monzino. Among 162 consecutive patients, this study evaluated the combined utility of electroanatomic voltage mapping coupled with cardiovascular magnetic resonance imaging to guide endomyocardial biopsies.
Dr Carolyn Lam: Oh, so interesting. A combined noninvasive and invasive electrical guide to perform cardiac biopsies, wow. So what did they find Greg?
Dr Greg Hundley: So they found that the sensitivity of pooled electroanatomic voltage mapping and cardiovascular magnetic resonance was as high as 95%. EVM and CMR together conferred an endomyocardial biopsy positive predictive value of 89%. Endomyocardial biopsy analysis allowed to reach a new diagnosis different from the suspected diagnosis in 39% of patients, complication rates were low, mostly vascular access related, with no patients requiring urgent management. Most impressive for this manuscript are the illustrative figures that are provided. It's really a great article for those performing biopsies, doing imaging, or the EP procedures that guide the biopsy process.
Dr Carolyn Lam: Really nice, Greg, thanks. Now for the last paper, have you ever thought about atherosclerosis as an autoimmune disease?
Dr Greg Hundley: Well, I wonder, we're learning so much about our immune systems these days, perhaps.
Dr Carolyn Lam: Indeed, throughout the inflammatory response that accompanies atherosclerosis auto-reactive CD4 positive T helper cells do accumulate in the atherosclerotic plaque. Apolipoprotein B-100 or Apo B is the core protein of LDL really serves as the auto antigen that drives the generation of pathogenic T helper one cells with pro inflammatory cytokine secretion. Yet there may also exist Apo B specific CD4 positive T cells with an athero protective regulatory T cell phenotype in healthy individuals. And that relationship between the protective Apo B reactive T regulatory cells and the pathogenic T helper one cells really has remained unknown until today's paper.
And this is from Dr Ley from the La Jolla Institute for Immunology and colleagues is really the first report to characterize CD4 positive T cells recognizing Apo B in the mouse with a combination of a novel MHC II tetramer and single cell transcriptomics immuno receptor sequencing and functional evaluation, and their results demonstrated an unexpected mixed phenotype of Apo B reactive auto-immune T cells in atherosclerosis and suggest an initially protective auto immune response against Apo B with a progressive derangement in clinical disease. These findings really identify Apo B auto-reactive T regulatory cells as a novel cellular target in atherosclerosis.
Dr Greg Hundley: Very nice Carolyn, boy that was a beautiful summary. I've got in the mail bag just a couple of things to talk about before you get to the discussion of some research letters. There's an ECG challenge from Dr Gunaseelan involving a young patient with chest pain. And then Theresa Wang has a very nice case series involving pulmonary hypertension, entitled Pressures at an All Time High.
Dr Carolyn Lam: There's also an On My Mind piece by Dr Perman on overcoming fears to save lives. So COVID-19 and the threat to bystanders CPR in out-of-hospital cardiac arrest. There's a research letter by Dr Myhre on cardiovascular hospitalizations, influenza activity, and COVID-19 measures, another by Dr Gurbel on the first inhuman experience with inhaled acetylsalicylic acid for immediate platelet inhibition, the comparison with chewed and swallowed acetylsalicylic acid. A final research letter by Dr Zurek rounds us up regarding neuregulin one inducing cardiac hypertrophy and impaired cardiac performance in post myocardial infarction rats, very surprising because we thought this was protected. So there you have it for this issue, Greg, shall we go on to our future discussion?
Dr Greg Hundley: Absolutely.
Dr Carolyn Lam: In patients with heart failure, chronic kidney disease is really common and associated with a higher risk of renal events than in patients without chronic kidney disease. In fact, these renal events are really increasing in prominence in the heart failure literature. And so I'm really welcoming the discussion of today's feature paper, which looks at the renal effects of angiotensin neprilysin inhibition in patients with heart failure with preserved ejection fraction in the PARAGON trial. I'm so pleased to have with us the first and corresponding author of this paper, Dr Finnian Mc Causland from Brigham and Women's hospital, as well as our associate editor Dr Justin Ezekowitz from University of Alberta. Finnian, congratulations on this beautiful paper. Could you please tell us a little bit about the overview? What motivated it, what you found?
Dr Finnian Mc Causland: It's long been a passion of mine to look at this interaction or intersection between cardiology and renal events. And if the truth be told, I had a moment in my life where I thought about being a cardiologist but I was swayed in other directions during my training in Ireland. Well, I've always been very much interested in this intersection, like I said, and so I've had the opportunity to work very closely with Scott Solomon and others at the Brigham who lead many of the heart failure trials that you are all aware of much more than I have been.
And this particular subset of patients with heart failure with preserved ejection fraction is a very unique population that were studied in the PARAGON-HF trial. And we thought it was a unique opportunity to look at some of the pre-specified secondary end points, which were the renal outcomes in terms of trying to figure out what the effect of this was compared to valsartan therapy in this patient population. So I think looking at this intersection between heart failure and preserved ejection fraction and the deterioration of kidney function was the primary driver to look at this in the PARAGON heart failure trial, and to really
look at the comparison between sacubitril-valsartan with valsartan in this patient population.
Dr Carolyn Lam: Indeed, thanks so much Finnian, and here's a confession too. I really liked nephrology during my training. (laughs) I thought it was really cool and with all the interventions, and so I really admire the many things you think about, especially in these patients, who've got multisystem disease, but okay. Moving on with PARAGON, I know that the secondary outcomes were reported and it was really a striking effect on the renal events. And so glad that you're shedding more light in it. Could you tell us what this paper added?
Dr Finnian Mc Causland: Yeah, so here we really got into I suppose the depths of the renal composite outcome and just to remind everybody that was a composite of a 50% or greater decline in eGFR, the development of end stage renal disease, or death from renal causes, so this was the composite outcome that was examined. We really evaluated this in a lot more detailed breaking our composite down into its individual components, as well as looking at it in totality. And I think the big take away point was that we found there was an almost 50% reduction in this primary renal composite outcome for patients on sacubitril-valsartan compared with valsartan.
Dr Carolyn Lam: And what about the components and the sort of further analyses?
Dr Finnian Mc Causland: Yeah, so getting into the, I suppose the details in a little bit more granularity, the major driver of those events will be 50% or greater decline in eGFR. And that's where the majority of these events really came from over the follow-up of PARAGON. And so this was assessed that various study business throughout the course of the few years that the patients followed up with PARAGON. And I think if we look at this slope and this was clarified in terms of the overall slope analyses of the eGFR. And we thought this relatively early separation in favor of sacubitril-valsartan so that there was less decline in eGFR over time compared with valsartan. So I think this was a supportive finding from the slope analysis that really got to this 50% threshold and that many people have examined in greater detail than they had the cardiovascular literature. So it takes a fair degree of kidney function decline to really reach that threshold of 50%. And so I think this was a very repulsed finding supported by the slope analyses.
Dr Carolyn Lam: Yeah, and to the audience that's listening, you have to grab hold of figure three of this paper, and that shows the eGFR slopes, which is something that's I think really important in current heart failure literature, the concept of the eGFR decline. So really nice work. Congratulations again, Finnian. Justin, could you put these findings in context for us?
Dr Justin Ezekowitz: Finnian once again, congratulations on getting this analysis. Pretty complex area to try to analyze and analyze properly, given that there's an expansive renal literature out there about looking at eGFR and how you look at it. So I think there's a couple of questions that come to mind when we think about the PARAGON trial overall. When we think about the protection of the kidneys over three, four, five years, my sense was from your analysis and perhaps you could expand on it is there seems to be very few events in those people with pretty preserved eGFR, but a greater number of events in those less than 60 mils per minute, and I'm wondering if you think that there's more of a unique place for medications such as sacubitril-valsartan and that cohort and if so is it really, that's where all the action is, but there's no real difference? Or do you think there's an interaction there that we should explore?
Dr Finnian Mc Causland: Thinking back to the entry criteria for PARAGON-HF, one had to have an eGFR more than 30 mils per minute at baseline. And you had to go through this kind of complex running period where you didn't have elevations of creatinine or potassium that went inside the pre-specified ranges. So after you took that element of what many people would consider hemodynamic changes, acute hemodynamic changes out of it, you were left with participants who entered the double blind randomized period. And there, I think that's where again, we started to kind of see most of the end points in terms of follow-up, which again were mostly the eGFR decline. If you go to table two of the paper, you'll see the composite, the components of the renal composite broken out into those with eGFRs of less than 60 or 60 or greater at baseline.
And even in both groups, I think you'll find that again they were both driven by the 50% decline, but you only really saw the end stage renal disease events or very few deaths from renal causes in those with eGFR of less than 60 mils per minute of baseline. And I think really what that speaks to is that these are the patients with quote unquote, chronic kidney disease at baseline are the ones who have that detrimenting kidney function to begin with. And so we're more likely to progress as we know than those with more preserved kidney function. And so if you followed patients both for really good kidney function over time, it's going to take a long time before they get that really severe decline due to the compensating mechanisms that the kidney has to preserve eGFR in the face of decline. So I think once you get into the more advanced disease, you really start to see the deterioration where there's very little renal functional reserve to cope with any additional damage or hemodynamic changes.
So to me, it wasn't particularly surprising that that's where the action was. To answer your second point of should we be focusing therapy here? If you look at the median eGFR in the PARAGON heart failure study was around 63 mils per minute. So about half of these patients I suppose could be classified as having impaired kidney function. If you look at it by CKD criteria it's eGFR of less than 60. And so I think there's a huge opportunity there to really think about this population in terms of trying to look for interventional studies and potentially protect patients as we've seen with this molecule, and but also with others such as SGLT-2 inhibitors, what I'm really intrigued about is if this was persistent at eGFRs below 30, because of course, one of the most devastating icons for patients with kidney disease that we deal with is the development of end stage renal disease and those who go on to hemodialysis.
So if there was some mechanism to prevent those even higher risk patients from progressing, I think that would be a huge opportunity for further research in this area.
Dr Justin Ezekowitz: Thanks for that very complete and thorough answer Finnian, and that actually maybe leads to putting this in context for the majority of people who will read Circulation and the audience will most likely be cardiovascular specialists and understand a lot of what you said, but could you put this in context with other studies that really are nearby to this trial, such as CREDENCE where the eGFR slope might be slightly different, or even the UK HARP-III trial where the same molecule was used, but in a different population, I wonder if you could give us some context for these findings.
Dr Finnian Mc Causland: Sure, yeah. I mean, I think the UK HARP-III trial maybe is the first one to discuss since this was a comparison of sacubitril-valsartan versus irbesartan. This was a study performed in the United Kingdom and they recruited patients with chronic kidney disease, a small proportion of those patients had heart failure, but this was not any of the pre-specified entry criteria for this study. And their primary outcome was the change in measured glomerular filtration rate after 12 months. And really they found that there was no significant difference at the 12 month mark between sacubitril-valsartan versus irbesartan. And so we were asked a similar question when we presented this study in abstract form at the American Society of Nephrology meeting in Washington last year. And I think a lot of the differences potentially relate to the difference in entry criteria for the patients. But also one might argue that 12 months of follow-up may not have been enough to see these differences in eGFR slope, which tend to occur, I suppose, rather later in the course of progressive kidney disease and heart failure.
And so that may be part of the reason that we didn't see the differences with UK HARP-III. In terms of CREDENCE, obviously it's a different molecule. And if you look at our main eGFR decline over time in PARAGON-HF, it was around 0.7 mils per minute, per 1.7, three meters squared per year. And so this compares with the about 1.5 mils per minute in CREDENCE, remember CREDENCE recruited patients with chronic kidney disease. PARAGON-HF recruited patients with heart failure and preserved ejection fraction. So differences in terms of the inclusion criteria right off the bat. I think other big differences where the CREDENCE compared, and it kind of flows in versus placebo, there was an active comparator in PARAGON-HF in terms of it was sacubitril-valsartan versus valsartan. So we saw differences in eGFR slope, despite an active comparator, I think was also quite telling and that there appears to be some additional renal benefit in the additional sacubitril versus blast inhibition alone.
And so I think the mechanisms is a whole other area, right? For research, I don't think we're entirely clear of the underlying mechanisms of this potential renal benefit, but I think we're pretty excited in the kidney community. Where now we have several molecules that may have potential to slow kidney functional decline, SGLT-2 inhibitors being one class potentially sacubitril-valsartan in another, and the top line results from their number are just out as well. And so there's ongoing trials that are looking at kidney function outcomes there. So we're getting pretty excited and we're not quite as jealous of the cardiology community as we used to be.
Dr Carolyn Lam: I couldn't think of a better way to summarize those findings and to put it into context of other very hopeful medications for the cardio renal outcomes. Thank you so much Finnian for joining us today and for publishing such a great paper with us at Circulation. And thank you, Justin, for your perspectives.
Dr Justin Ezekowitz: Thanks Carolyn, and Finnian congrats to your team as well. This has been a terrific paper to be able to handle and read and look at figure three, and it tells a lot of the story of what you saw.
Dr Finnian Mc Causland: Thank you very much again for the opportunity and a big shout out to everybody that worked in PARAGON-HF and especially to the support from Scott Solomon and John McMurray for getting me involved. It's a pleasure to be part of this.
Dr Carolyn Lam: Thank you so much from Greg and I for joining us today, tune in again, next week.
Dr Greg Hundley: This program is copyright of the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, our feature paper today talks about the risks of sudden cardiac death, something that we still grapple with, and do you know what, really highlights the important emerging role of biomarkers of myocardial stress, myocardial injury, or even subclinical inflammation in predicting this risk. A really important discussion coming right up.
But before we do that, let me tell you about a paper in today's issue that really provides novel mechanistic insights into atrial fibrillation pathogenesis. In fact, this is the first paper to demonstrate that decreased expression of a striated muscle preferentially expressed protein kinase, or SPEG in atria, is causally linked to altered diastolic calcium handling and human paroxysmal atrial fibrillation.
This is from corresponding author, Dr Wehrens and colleagues from Baylor College of Medicine. And they used phosphoproteomic studies to identify S2367 on ryanodine receptor type-2 as a novel kinase substrate of SPEG. Through the study of novel ryanodine receptor type-2 phospho-mutant mouse models, they revealed that in contrast to previously characterized phosphorylation sites on this receptor, S2367 phosphorylation inhibited diastolic calcium release from the receptor, while loss of phosphorylation of the site increased atrial fibrillation susceptibility.
Dr Greg Hundley: Wow, Carolyn. So the clinical implication is that normalizing S2367 phosphorylation in SPEG activity may provide novel therapeutic opportunities for the treatment of atrial fibrillation, right?
Dr Carolyn Lam: You bet, Greg. Too smart. And this is discussed in an accompanying editorial by Drs Knollmann and Blackwell from Vanderbilt University Medical Center.
Dr Greg Hundley: Very nice, Carolyn. Well, I've got a paper pertaining to COVID-19, and it comes to us from Dr Leo Nicolai from the Klinik der Universität München in Germany. Carolyn, I really enjoyed this article about COVID-19. I found it very intriguing, and the study addresses the mechanisms by which the SARS-CoV-2 infection, associated pneumonia or COVID-19, leads to subsequent respiratory failure, complicating renal and myocardial involvement, and the prothrombotic phenotype found in some patients with COVID-19.
62 subjects were included in the study, 38 patients with RT-PCR confirmed COVID-19 and 24 non-COVID-19 controls. The investigative team performed histopathological assessments of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet-neutrophil functions and coagulation tests.
Dr Carolyn Lam: Wow, that sounds like really sort of in-depth testing. And what did they find?
Dr Greg Hundley: Several things, Carolyn. First, the authors found evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. They found that in COVID-19 patients, inflammatory microvascular thrombi are present in the lung, kidney and heart, containing neutrophil extracellular traps associated with platelets and fibrin.
Second, they observed that COVID-19 patients also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood which changes with disease severity, whereas cases of intermediate severity show an exhausted platelet and hyperreactive neutrophil phenotype. This finding differs for severely affected individuals. Among severely affected COVID-19 patients, there is excessive platelet and neutrophil activation compared to healthy controls and non-COVID-19 pneumonia.
Finally, dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability. So in conclusion, taken together, this team's data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19, and further work is suggested to identify methods to disrupt immunothrombosis in patients with COVID-19.
Dr Carolyn Lam: Wow. That makes a lot of sense and is important information. Thanks, Greg. Well, this next study really aimed to assess the current trends in US mortality related to congenital heart disease from infancy to adulthood over the last 19 years, and to determine if there were differences by sex and ethnicity.
This is from Dr Lopez from Texas Children's Hospital and Baylor College of Medicine and colleagues who conducted an analysis of death certificates from 1999 to 2017, and also used data from the National Center for Health Statistics' live birth data and US Census Bureau bridged-race estimates as denominators for these population estimates.
Dr Greg Hundley: Wow, Carolyn. Really interesting article. So what did they find here?
Dr Carolyn Lam: So overall, US mortality due to congenital heart disease throughout the lifespan has decreased over the last 19 years, with the greatest mortality rate in infants. Disparities in mortality due to congenital heart disease persists for males compared to females, with men having higher mortality than women, and for non-Hispanic blacks compared to non-Hispanic whites.
For those less than 50 years old with congenital heart disease as a contributing cause of death, associated genetic abnormalities are the leading underlying cause of death, whereas myocardial infarction was the leading cause of death in those 50 years and older.
And so, the authors also concluded that determining factors that contribute to these disparities, such as access to quality care, timely diagnosis and maintenance of insurance, will be very important moving into the next decade.
Dr Greg Hundley: Boy, that is such a timely topic. Beautiful presentation.
Dr Carolyn Lam: Thanks, Greg. And now for my last paper. We've heard a lot recently about angiotensin-converting enzyme 2, or ACE2, that’s that membrane protein that enables COVID-19 infectivity and which also converts angiotensin II, which is a potent vasoconstrictor, to angiotensin 1-7.
Now, today we've got a paper that provides novel insights into the contribution of ACE2 to the development of pulmonary arterial hypertension. And this is from Dr Shyy and Yuan as co-corresponding authors from the University of California, San Diego, as well as Dr Yuan 00:08:06 from First Affiliated Hospital of Xi'an Jiaotong University in China.
The authors used cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension to investigate the post-translational modification of ACE2 in terms of, firstly, phosphorylation by AMP-activated protein kinase, which enhances ACE2's stability, and two, ubiquitination of oncoprotein murine double minute 2, or MDM2, which is involved in ACE2 degradation.
Dr Greg Hundley: So what did they find here?
Dr Carolyn Lam: MDM2 expression was increased in lung tissues from patients with idiopathic pulmonary arterial hypertension and animals with experimental pulmonary hypertension.
On the other hand, N-kinase phosphorylates ACE2 at S680 and inhibits MDM2- mediated ubiquitination of ACE2 at K788. Functionally, ACE2 phosphorylation and deubiquitylation increases eNOS-mediated nitric oxide bioavailability in the endothelial cells.
Dr Greg Hundley: Okay, Carolyn. What are the clinical implications here?
Dr Carolyn Lam: So post-translational modification of ACE2 is a novel strategy to develop new therapies for pulmonary arterial hypertension. On the other hand, inhibition of MDM2 has great potential for pulmonary arterial hypertension by stabilizing ACE2.
Dr Greg Hundley: Wow, beautiful summary there. Let me describe some of the other articles in the issue. First, Dr Jawad Butt has a research letter regarding the impact of COVID-19 on first-time acute stroke and transient ischemic attack admission rates and prognosis in Denmark. It's from a nationwide cohort study.
Next, there's an exchange of letters regarding the article, preventive or deferred ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and an implantable defibrillator, the Berlin VT multicenter randomized trial. And that comes to us from Drs Krisai and Kuck.
Next, there's a very nice ECG challenge from Dr Arrey-Mbi wide complex QRS rhythm in a 52-year-old male with an altered mental status.
And then finally, a nice case series from Dr Oscar Cingolani, entitled, ECMO therapy for cardiac lymphoma.
Dr Carolyn Lam: Well, I've also got a research letter by Dr Verdonschot on distinct cardiac transcriptomic clustering in titin and lamin-associated dilated cardiomyopathy patients.
There's also a white paper by Dr Butler on glucagon-like peptide-1 receptor agonists and heart failure, highlighting the need for further evidence generation and practice guidelines optimization.
And finally, an On My Mind piece by myself and Dr Butler entitled, “Victims of Success and Failure,” where we really describe how, with so many effective therapies for HFrEF these days, have we become victims of our own success?
Dr Greg Hundley: Very nice, Carolyn. Well, how about we get on to that feature and hear a little bit more about myocardial stress injury and the association with sudden death?
Dr Carolyn Lam: Yes. Let's go, Greg. Sudden cardiac death is the most common cause of death in the United States but identifying individuals at risk before they suffer a fatal event remains really challenging. In fact, it's the sad truth that the majority of sudden cardiac deaths occur in low-risk populations, often as the first manifestation of cardiovascular disease.
Now, can biomarkers help us identify those at risk of sudden cardiac death? Well, you have to listen to our discussion of today's feature paper, a beautiful paper that I'm so pleased to be welcoming the first and corresponding author, who's also our associate editor, Dr Brendan Everett from Brigham and Women's Hospital, who will talk about it, as well as our guest editor, Professor Harvey White, who is director of research at the Green Lane Cardiovascular Service in Auckland, New Zealand.
So welcome, gentlemen. And Brendan, could I get you to start by telling us what you did in this study and what you found?
Dr Brendan Everett: We were interested in exploring this problem. Dr Albert, Christine Albert, who is the senior author on the paper, has years of experience looking at sudden cardiac death as an important outcome amongst patients who may not have yet been diagnosed with cardiovascular disease.
And of course, as you mentioned in your introduction, it can be the first manifestation of cardiovascular disease. And because we, as physicians, don't get a chance to then help patients recover and treat them for their cardiovascular disease, we often feel like we've missed the opportunity to help people live longer and more productive lives.
The problem, of course, with this is that there's a huge population of people who are at risk, but actually identifying tests that will work well enough and can be used in a broad population, who, in aggregate, are actually at low individual absolute risk, is very challenging.
The markers that we selected to study for this paper included measures of lipids, in this case, total cholesterol, the HDL cholesterol, NT-proBNP, a marker of myocardial stress, which is, I'm sure, familiar to many people on the podcast, high-sensitivity cardiac troponin I, which again, is increasingly used throughout the world, including here in the United States, and hsCRP, a marker of subclinical inflammation.
I think the advantage that we had is that, over the years, Dr Albert has compiled a number of cases of sudden cardiac deaths in cohorts that have been followed prospectively for a long period of time. These are NIH-funded cohorts and include studies that may be familiar to your listeners, like the Nurses' Health Study, the Physician's Health Study I and II, the Women's Health Study.
These are cohorts that have been following patients for, in some cases, decades, and of course, when you have a lot of patients or participants and you follow them over many years, some of them die suddenly. Not very many, fortunately, but enough so that if you aggregate all six cohorts together, you can have a total of, in our case, 565 cases, which is more, I think, as far as I know, anyways, than other cohorts that are out there that have studied this question.
We were able to match those two-to-one with 1090 controls, and then measure the biomarkers I mentioned earlier in all of those patients, and then look at the association between those common, relatively accessible biomarkers and the risk of sudden death.
Dr Carolyn Lam: Congratulations. I do think this is the largest collection of sudden cardiac death cases, as well as with prospectively collected blood samples. And I do believe yours is the first to really have a multi-marker approach. So now, could you tell us what you found?
Dr Brendan Everett: We first assessed each of these four markers individually and found that their risk of sudden cardiac death was relatively strong and was independent of other traditional cardiovascular risk factors, such as cigarette smoking or body mass index and those sorts of things. It appeared, at least in our analysis, that NT-proBNP and cardiac troponin might have been slightly more powerful correlates of the risk of sudden cardiac death in total to HDL cholesterol ratio in hsCRP.
But nonetheless, when we put them all together in a comprehensive model, we found that the risk estimates for each individual marker were maintained. In other words, they were independent of one another and they all remained statistically significant. So this tells me, as a cardiologist and an epidemiologist, that we're getting a sense of somebody's risk from multiple different perspectives. We're integrating that information, and then potentially, when we combine those markers together, have the opportunity to have an improved ability to identify individuals at risk.
And so, that's actually what we did, and I think this is what you're asking about. We decided to create a very simple biomarker score where we gave each participant one point if their concentration of a given biomarker was in the top core tile of that biomarker's range, so the top 25%. So just by way of example, if somebody had all normal biomarkers except for a high total cholesterol, the HDL ratio, they would get one point.
The total number of points, of course, could range from zero to four, and then we looked at what the risk of sudden cardiac death was across that scale. And what we found is that it went up in a relatively linear fashion. The odds ratio increased by about 1.6 per individual point of score increase, such that, for example, compared to those individuals with a score of zero, who of course, had normal concentrations of these four biomarkers, if you had all four be elevated, your odds ratio of sudden cardiac death was actually seven. If you just had three out of the four being abnormal, it was approximately four. So those participants with at least three or four abnormal concentrations of these biomarkers seemed to be at a high relative risk or odds ratio for sudden cardiac deaths.
Dr Carolyn Lam: Ah. Love it, Brendan. And for all of you who are listening, you have to pick up the paper and look at the figures. The story is all there, the individual biomarkers and that score. I love the simplicity and the clarity of the message.
Harvey, could you summarize for us and perhaps give us a sneak peek of the discussions that occurred behind the scenes when this paper landed on your desk?
Dr Harvey White: When I saw this paper, it was terrific. And I had to decide whether to get reviewers who are experts in sudden death, or are experts in cholesterol, or troponin, or each of the four biomarkers, and I chose to get people who are interested in sudden death. And I had three reviewers, and they all said it was absolutely terrific, elegant study, robust data.
They focused on the cut points, for example, NT-proBNP. Initially, Brendan, you looked at the median for your study, and the reviewers said, "Well, can we look at clinically relevant?" So they requested that you consider that, and I must say, your responses were just terrific. And so, you went to a cut point of 125, which is clinically relevant. I think this is extraordinarily important. The reviewers stressed that you should be careful with your conclusions. And you carefully said, "This represents only the first step in testing whether these biomarkers may serve as valuable clinical tools."
I would go further than that. I think these four tests are inexpensive, they're clinically available. I don't do them on all patients, but I do them on some. I always do lipids, and I do NT-BNP in somebody with heart failure or decreased ejection fraction. And I always do troponin, which I think is extremely important. Even in the normal range, it trebles its risk.
So a question to Brendan. I think if I found a high troponin, I want to look at CRP, look at NT-proBNP, and I'd have the cholesterol HDL ratio. So what would you think about cascade screening and the implications of that on cost effectiveness?
Dr Brendan Everett: I think that's a really excellent suggestion. We hadn't thought of that, as you know, and it doesn't come up as an idea in the discussion. I think, at least here in the United States, the standard test would be a total cholesterol to HDL ratio, and of course, with that, oftentimes in LDL cholesterol, because that's where we focus our preventative efforts with statins, as you mentioned. And we typically would not do a troponin in otherwise healthy and ambulatory patients.
I think that's a creative suggestion, the idea that if you had an abnormal cholesterol, and then an abnormal NT-proBNP, and then would you move to a CRP and a troponin as well? I think in the type of patient that we're talking about, a primary prevention patient who may have occult cardiovascular disease, CRP is probably the best validated, epidemiologically, as a marker of risk and to guide therapy.
But I think one thing that we struggled with, and I'd be interested in your view on this because you're such an expert on cardiac troponin, is, what are the therapeutic interventions that you would use for somebody with an elevated biomarkers for... And we addressed this a little bit in the discussion, and I think it's just common sense preventive therapy, but I don't know if that struck you as the right thing to do, or if you had other ideas about how to address somebody who might have, theoretically, an elevated risk of sudden cardiac death.
Dr Harvey White: I think it's challenging common sense. Do people use them? So I think the stress should be that preventive therapy should be used in these patients. So blood pressure and history of hypertension is related to sudden death. In your study, sudden death was more common in individuals who didn't exercise. Obviously, they're higher cholesterol, so you got to promote weight loss, blood pressure, nonpharmacological means diabetes is associated with, and a higher HbA1c, so you really want to get the HbA1c down.
Whenever you find an abnormal troponin, you need to go back to the patient and get an echocardiogram. Have they got left ventricular hypertrophy? Have they got underlying LV dysfunction, and so forth? And to get the patient on board, one of the things that you would challenge with doing is the drug use during follow up. And I was particularly interested in beta blockers, which of course, may reduce sudden death.
But I'm also interested in, about 30% of patients with sudden death have taken cocaine or alcohol. And so, addressing drug use is important, addressing alcohol is important. And just as an add-on in this age of COVID, don't take hydroxychloroquine, because that might cause sudden death.
Dr Carolyn Lam: Harvey and Brendan, those were just really excellent points. In fact, I was sort of thinking along the same lines of, what are the therapeutic implications of this? And I think one of the management implications addresses one of the limitations, perhaps though, because this study did not include electrocardiographic or imaging information, like left ventricular ejection fraction. I just wanted to double-check if that's the case, Brendan. And if you could, how has this impacted your own practice, or what's the next steps, you think?
Dr Brendan Everett: You are absolutely correct, that as a routine, none of the studies that we included in this research work actually had baseline electrocardiograms or echocardiograms. I think when you take the perspective of wanting to screen or thinking about screening a broad population for the risk of sudden cardiac death, an echocardiogram is probably not a feasible study. Although, to Harvey's earlier point and to your own point, using that as a subsequent test, along the lines of the cascade screening approach, when you have an abnormal cardiac troponin or an abnormal NT-proBNP, perhaps an echocardiogram is a very good study to order at that point.
The lack of electrocardiograms, I think, is another limitation of our work. Those are more commonly used, at least I think, as a screening tool, at least in the United States, when somebody has a history of hypertension, for example.
I think, with respect to your last question, "How has it changed my own practice?", I think the key thing that I wanted to emphasize, which is an important limitation of the study, is that this is a case control study. So what we're able to do is, we're able to estimate relative risks. And relative risks of seven are high. They're impressive, right?
The problem is that we can't actually estimate what the absolute population risk is of sudden death based on the patients or the participants in these studies. So it's hard to take the group of participants that we were able to look at and watch carefully prospectively, and then back-calculate what the absolute risk of sudden cardiac death would be in a broader population.
So in order to take a research finding like this, where there's a high relative risk, and start to think about population-wide screening, you have to know how that will implicate or affect the absolute risk. If your absolute risk is tremendously low, seven times tremendously low is still tremendously low.
However, if you can find a population where a relative increase of seven in your absolute risk actually becomes clinically important, then you begin to have an argument about population screening and whether or not it's worthwhile and effective, or potentially how it can reduce the occurrence of sudden death, which is our goal, after all, with a study like this.
Dr Carolyn Lam: What a balanced discussion. So thank you, Brendan. That was a very important point. Finally, are you planning next studies, or what's the next step then, you think?
Dr Brendan Everett: Well, I think the next step would be to try and figure out how to translate the data that we have here into a real sense of how this would affect absolute risk. This would then have implications for cascade screening, as Harvey mentioned earlier, potentially broader use of these biomarkers as screening tools in otherwise healthy populations, and of course, implications, both about the testing characteristics and false positives and those sorts of important issues, and then the cost and the cost effectiveness, how much it would cost to screen such and such a population to prevent one sudden cardiac death. Those would all be the next steps, I think, in terms of determining whether or not this approach could be implemented more broadly.
Dr Carolyn Lam: Thanks, Brendan, and thank you so much for this paper. It's just so beautifully and elegantly put. It's something I'm going to remember and already taken my clinical practice to recognize persons at risk and whom I want to do further work of.
Thank you so much for joining us today, Brendan. Thank you so much, Harvey. And thank you, audience, for listening today. Please tune in again next week.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
This week’s episode includes author Jeffrey Testani and Associate Editor Justin Grodin as they discuss empagliflozin heart failure, including diuretic and cardio-renal effects.
TRANSCRIPT:
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg. I'm the director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, the SGLT-2 inhibitors have really revolutionized heart failure treatment, but we still need to understand a bit better how they work. And today's feature paper is so important, talking about diuretic and cardio-renal effects of Empagliflozin. That's all I'm going to tell you though, because I want to talk about another paper in the issue very related. And it's from John McMurray from the University of Glasgow with insights from DAPA-HF. But maybe a question for you first. Have you ever wondered what to do about loop diuretics doses in patients with heart failure and whom you're thinking of initiating an SGLT-2 inhibitor, Greg?
Dr Greg Hundley: Absolutely, Carolyn. That comes up all the time and how do you make that transition.
Dr Carolyn Lam: Exactly. And so this paper is just so important, and Dr McMurray and his colleagues showed that in the DAPA-HF trial, the SGLT-2 inhibitor, dapagliflozin, first, just as a reminder, reduce the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. And in the current paper, they examined the efficacy and tolerability that dapagliflozin falls in relation to background diuretic treatment and change in diuretic therapy, following randomization to dapagliflozin or placebo. They found that 84% of patients randomized were treated with a conventional diuretic, such as the loop or thiazides diuretic. The majority of patients did not change their diuretic dose throughout follow-up. And the mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization. Although a decrease in diuretic dose was more frequent with dapagliflozin than with placebo, the between-group differences were small. So treatment with dapagliflozin is safe and effective regardless of diuretic dose or diuretic use.
Dr Greg Hundley: Very nice, Carolyn. That's such a nice practical article. I really enjoyed your presentation of that. My next article comes from Professor Karlheinz Peter, and it's investigating the reduction of shear stress and how that might impact monocyte activation in patients that undergo TAVI. So this group hypothesized that the large shear forces exerted on circulating cells, particularly in the largest circulating cells, monocytes, while passing through stenotic aortic valves results in pro-inflammatory effects that could be resolved with TAVI. So to address this, the investigative team implemented functional essays, calcium imaging, RNA gene silencing and pharmacologic agonist and antagonist to identify the key mechanical- receptor mediating the shear stress sensitivity of the monocytes. In addition, they stained for monocytes in explanted, stenotic, aortic human valves.
Dr Carolyn Lam: Lots of work done in a very translational study. So what did they find Greg?
Dr Greg Hundley: They found monocyte accumulation at the aortic side of the leaflets in the explanted aortic valves. That was the human subject study. In addition, they demonstrated that high shear stress activates multiple monocyte functions and identify PZ1 as the main responsible mechanoreceptors representing, therefore, a potentially druggable target. So reducing the shear stress from a stenotic valve promotes an anti-inflammatory effect and, therefore, could serve as a novel therapeutic benefit of those undergoing TAVI procedures.
Dr Carolyn Lam: Really nice, Greg. Thanks. We're going to switch tracks a bit, Greg. What do you remember about Noonan's syndrome?
Dr Greg Hundley: Oh boy. Impactful, congenital disease for both the probands, as well as the family.
Dr Carolyn Lam: That's truly beautifully put and you're right. Noonan syndrome is a multisystemic developmental disorder characterized by common clinically variable symptoms, such as typical facial dysmorphism, short stature, developmental delay, intellectual disability, as well as cardiac hypertrophy. Now the underlying mechanism is a gain of function of the RAs MAPK signaling pathway, kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, really remains limited. So today's paper contributes significantly to our understanding and is also notable for the methods that these authors use to uncover this novel potential therapeutic approaches. The paper is from Dr Cyganek and Wollnik as co-corresponding authors from the University Medical Center Göttingen in Germany. And they presented a family with two siblings, displaying an autosomal recessive form of Noonan syndrome with massive hypertrophic cardiomyopathy. As the clinically most prevalent symptom caused by allelic mutations within the leucine zipper like transcription regulator 1. They generated induced pluripotent STEM cell derived cardiomyocytes of the effected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level.
Dr Greg Hundley: Carolyn, is such a thorough investigative initiative. So what did they find?
Dr Carolyn Lam: They found that the patients induced, pluripotent STEM cell cardiomyocytes recapitulated the hypertrophic phenotype and uncovered, a so far not described, causal link between this leucine zipper like transcription regulator 1 dysfunction and ras map, kinase signaling hyperactivity, as well as, the hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics providing a molecular underpinning for the clinical use of these drugs in patients with Noonan syndrome. In a proof of concept approach, they further explored a clinically translatable intronic CRISPR repair and demonstrated a rescue of the hypertrophic phenotype. Massive amount of work in a beautiful paper.
Dr Greg Hundley: You bet, Carolyn, and boy giving hope to address some of that adverse phenotype in the heart. What an outstanding job.
Dr Carolyn Lam: You're right, Greg. But now switching tracks a yet again. What do you know about ischemic preconditioning? Ischemic preconditioning refers to the process in which non-lethal ischemic stress of the heart prevents subsequent lethal ischemia reperfusion injury and provides important intrinsic protection against ischemia reperfusion injury of the heart, as well as other organs. So in this paper co-corresponding authors, Doctors, Zhang, Xiao and Cao from Peking University and colleagues provided multiple lines of evidence that a multifunctional TRIM family protein, the Mitsugumin-53 or MG53 is secreted from the heart in rodents in response to ischemic, preconditioning or oxidative stress. Now this secreted MG53 protected the heart against ischemia reperfusion injury. In the human heart, MG53 was expressed at a level about 1/10th of its skeletal muscle counterpart. And MG53 secretion was triggered by oxidative stress and human embryonic STEM cell derived cardiomyocytes, while deficiency exacerbated oxidative injury in these cells.
Dr Greg Hundley: Very nice, Caroline. Tell me the take home message. How do I incorporate this information, maybe even clinically?
Dr Carolyn Lam: Well, these results really defines secreted MG53 as an essential factor, conveying ischemic preconditioning induced cardioprotection. Now, since systemic delivery of MG53 protein restored ischemic preconditioning mediated cardioprotection in deficient mice, recombinant human MG53 protein could perhaps, or potentially be developed, into a novel treatment for various diseases of the human heart in which indigenous MG53 may be low.
Dr Greg Hundley: All right, Carolyn. I'm going to tell you about a couple of letters in the mailbag. First, there's a research letter from Richard Vander Heide regarding unexpected feathers in cardiac pathology in COVID-19. And then, there's a large exchange of letters between Dr Yuji MIura, Chuanli Ren and Laurent Azoulay regarding a prior publication, entitled "Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer, A Population-Based Cohort Study." And then finally, Carolyn, there's another research letter from professor, Nilesh Samani, entitled "Genetic Associations with Plasma ACE2 Concentration: Potential Relevance to COVID-19 Risk."
Dr Carolyn Lam: Wow, interesting. There's also an "On My Mind" paper by Dr Kimura on "contextual imaging, a requisite concept for the emergence of point-of-care ultrasound." There's an ECG challenge, by Dr Dewland, with a case of an intermittent -wide QRS complexes. There's a cardiovascular case series presentation by Dr Nijjar on "a solitary left ventricular septal mass and amaurosis fugax."
Dr Greg Hundley: That's great, Carolyn. How about we move on to the feature discussion.
Dr Carolyn Lam: Let's do that.
Dr Greg Hundley: Well listeners, we are here to discuss again, another important paper related to SGLT-2 inhibition. And we have with us, Dr Jeff Testani from Yale New Haven and our own associate editor, Dr Justin Grodin from University of Texas Southwestern Medical Center. Welcome gentlemen. Jeff let's start with you. Can you describe for us some of the background behind this study, and then also the hypothesis that you wanted to address?
Dr Jeffrey Testani: Our lab is very interested in understanding volume overload and heart failure, why does the kidney retain sodium and why it stops responding to loop diuretics. Several years ago, when the SGLT-2 first came out, we saw them as a diuretic with the side effect of glucosuria. Back when they were still being thought of as primarily diabetes medications. But as the story unfolded and we saw that the SGLT-2 seemed to be doing something much more than just control blood glucose in diabetics and was demonstrating, particularly, a pronounced effect on heart failure outcomes, we got very interested in, better understanding this.
We know that loop diuretics, they're really a double-edged sword. Loop diuretics are our mainstay of therapy to relieve congestion and heart failure patients, but they do so at the expense of quite a bit of toxicity. And we know that the loop diuretics directly cause neuronal activation, elaboration of rennin, norepinephrine, etc. through their effects directly on the kidney. In addition to causing normal moral activation through the volume depletion they cause. And as we all know, blocking the neurohormonal activation is one of the primary therapies we use in heart failure. So even though it helps our patients keep the fluid off, it does that at an expense of potentially some very negative effects.
The interesting thing with the SGLT-2 inhibitors is, we've seen that in the diabetic populations, that they seem to actually improve volume status in diabetics, more so than one would really expect by the week diuretics that they are. And by and large, they were doing that without a pronounced activation of the neurohormonal system. So this led us to the conclusion that we really need to rigorously study this in heart theory and see what exactly are these effects of diuretics volume status and how much negative impact will any of those effects bring towards normal activation, kidney dysfunction, etc.
Dr Greg Hundley: Very clever, Jeff. How did you go about addressing this question? What was your study design and what was your study population? Who did you enroll?
Dr Jeffrey Testani: We wanted to have a pretty clean mechanistic study here. We weren't looking at ethnicity. We were really trying to understand a mechanism here and what are these agents doing to sodium handling in the kidney, etc.
We enrolled diabetic patients that were stable. Per their advanced heart failure position, they were at added at a stable volume status. They hadn't had recent changes in medications diuretics, and we use the crossover design where we brought the patient in for about an eight-hour rigorous GCRT type study where we administered empagliflozin in 10 milligrams and then did some pretty rigorous characterization of them. As far as body fluids spaces, renal function, normal activation, your sodium excretion. Then they would continue that therapy for two weeks, come in for a terminal visit, that was a very similar protocol. Then we'd wash them out for two weeks and cross them over to the alternative therapy. And they were randomized whether they had placebo or epilobium first in order.
Dr Greg Hundley: Very good. So a crossover design. And what were your study results, Jeff?
Dr Jeffrey Testani: We were quite interested in the overall effects and it was actually quite surprising. We know the loop diuretic resistance is common and when physicians and patients are not responding well enough, oftentimes we add thiazides. And thiazides waste potassium. They waste magnesium. They increase uric acid. They usually cause renal dysfunction and significant normal activation. That was the default hypothesis that we would see that. And to the contrary, we pretty much saw the opposite of what a thiazide did. We saw a modest, but clinically significant natriuresis. So as a monotherapy, these drugs are quite weak. Although we saw a doubling of a baseline level of sodium excretion, that's sort of a clinically irrelevant amount as an acute diarrheic. However, when we added the eplerenone to a loop diuretic, we got a 30, 40% increase in sodium excretion. And just to benchmark that, if you look at the dose trial where they compared low dose to high dose Lasix, which were one X versus two and a half X, their home loop diuretic, they got a similar increase in sodium excretion.
So even though 30, 40% increase in sodium excretion doesn't sound like a lot, it's all of our normal interventions. It's actually a pretty significant increase. We found that happened acutely. And to our surprise, that natriuretic effect had not completely gone away by two weeks. So the patient was still in a negative sodium balance at the two-week time point. And they actually had a reduction in their blood volume, in their total body water, in their weight, as a result of that kind of slow persistent, natriuresis that had happened over those two weeks.
We were unable to detect any signs of normal MAL activation with this. There was actually a statistically significant better change in norepinephrine during the dapagliflozin period versus placebo. And there's some evidence that, that might be an actual finding of saccharolytic effect of these drugs. As in many of the other trials we've seen no, despite a reduction of blood pressure and probably volume status, heart rate stays the same or even goes down. And we saw an improvement in uric acid. We saw no additional potassium wasting. We saw an improvement in serum magnesium levels. So really kind of like I started this way is the opposite, in many ways of what we see, side effect wise, with the diuretic is what we saw with addition of an SGLT-2 inhibitor.
Dr Greg Hundley: Listeners, we're going to turn now to Dr Justin Grodin, who's one of our associate editors and is also an editorialist for this paper. And Justin, we've heard some really exciting results here. The addition of a dapagliflozin to a loop diuretic enhancing the neurohormonal access and receiving some unexpected benefits on the electrolyte portfolio. Can you tell us a little bit about how you put this work in the context of everything else that we have been reading about this exciting new class of drug therapy?
Dr Justin Grodin: This certainly is exciting because with the release of the DAPA-HF clinical trial, just about a year ago, we've really come to recognize that there really are substantial, long-term beneficial effects with SGLT-2 inhibition in patients with heart failure, and as Jeff alluded to, a lot of these effects, we saw that they were beneficial in individuals that are high risk or who already had heart disease and diabetes. And we weren't sure if that was going to translate to individuals with heart failure. We really saw beneficial effects in both, individuals with heart failure, with or without diabetes. So this is an interesting paradigm because, although we saw dramatic effects in long-term survival quality of life, the mechanism was actually somewhat murky. And a lot of this was transitive based on prior works. We obviously had a strong hypothesis that they would work through reducing incident heart failure and diabetics, but then we were left questioning what is the mechanism? And I think Jeff highlighted it quite well.
There was the early thought that this was perhaps just a weak diuretic and that it was additive, and these patients were just getting long-term natiurer recess. And then others thought that there might've been, perhaps, some positive influence by some very low level, blood pressure reduction with these therapies.
So in that sense, I think Jeff's paper really is put in context and when we reviewed it, we thought it was quite fascinating because I think as Jeff showed in his paper quite elegantly and actually in a very, very careful study, which the reviewers and your editorial staff appreciated, we really saw that there was a probably more robust response to natriuresis than we had anticipated. And importantly, this was independent of glycosuria, which is a very important observation. And if I might take a 10,000-foot view of at least this therapy and how we might think about it as an incremental therapy in heart failure, it's really doing something else. So we thought that with SGLT-2 inhibition, you get a little sodium and a little natriuresis, maybe perhaps a little bit extra, as it complexes with glucose.
I think if you look at what the potential physiology would be with this therapy is that it's doing far more than that. And I think Jeff's study at least supports some of the speculation. And again, I'm going to perhaps look beyond SGLP-2 inhibitor, and then more so focus on the physiology of the proximal convoluted tubule. And given the location of the blockade, this is really priming the kidney, or at least Jeff's manuscript, and Jeff's analysis, supports the hypothesis that SGLT-2 inhibitors influence the proximal tubule environment, such that the kidney is ready to reset in natriuresis. And I think Jeff's data it at. least supports that because if we look at the proximal tubule physiology, there's really a lot more going on, then SGLT-2 inhibition.
There are other receptors that it can influence that might also promote natriuresis. It can also promote increased distal sodium delivery to other areas of the nephron. And in essence, this almost, and in Jeff has put it this way before, which I totally agree. This gives the opportunity for the kidney to taste the salt, as opposed to the more common state that we have in somebody with heart failure and congestion, where, and I talk about this on rounds all the time, the kidney's response to a failing heart is to retain salt and water. So this kidney is in this perpetual state of dehydration. And I think the idea that Jeff's analysis is at least supporting, is that somehow, we were influencing the physiology in the proximal convoluted tubule, we are actually priming the kidney and readying it. We're almost hitting reset, where the kidneys may lose this physiology, thinking that the body is dehydrated and in essence, really readying it to assist with decongestion.
Dr Greg Hundley: I love the way you explained that. It's almost as if I'm on ward rounds with you that just knocks home a lot of the message here, and the importance of Jeff's work. Understanding the physiology of the proximal tubule and then readying the kidney, instead of moving into a mode of retaining salt and water, actually allowing that to flow and facilitating a diaresis. I'll start with you, Jeff, and then come back to Justin. You might have unlocked a really special key here. What do you see as the next steps in research in this particular field?
Dr Jeffrey Testani: I think Justin really, really captured the essence of what excites us so much about this is, most diuretics are a brute force sort of approach to getting salt out of the body. They are a stick, not a carrot and SGLT-2 inhibitors, when you look at them as how they would work as a brute force diarrheic, they are really wimpy and there is every opportunity for the kidney to defeat the of a SGLT-2 inhibitor, if it wanted to buy where they work and what they block. But the reality is, is that they really seem to be the carrot almost. if you think of resetting the sodium set point of the kidney, kind of quenching some of that salt first or sodium humidity that Justin was referring to.
And the thing that's really interesting is when we look at trials like DAPA-HF. So despite the fact that they do seem to have this natural effect in blood pressure lowering effect and these different effects, they don't tend to cause hypertension, over diaresis, it's a much more of a natural, where the kidneys regulatory mechanisms are still operative. we have this duality of not causing over diaresis but causing diaresis. So it's really when the body needs to get rid of salt, it helps it do that. And so I think the next steps, at least for our research program is, we want to understand taking these drugs out of the context of stable, relatively euvolemic chronic heart failure patients. And when we put them into the acute setting of actual volume overload, do we see more robust diathesis and that natriuresis in that setting.
The second thing is we want to dig into what is the internal mechanisms that are allowing the kidney to do these things. How is it that it's able to dump out salt when it's beneficial, but not leaked over to uresis. Since we're digging into those mechanisms, I think will give us some additional insight into this class.
Dr Greg Hundley: Justin.
Dr Justin Grodin: I think Jeff really encapsulated, or at least certainly highlighted some very important points, that are largely in parallel with where I foresee this. Because really, if you look at just study, a lot of these patients were quite stable. So the questions that come along are whether or not that this synergistic effect number one, is sustained long-term. Because there are some data, at least in diabetic individuals, that this might not be the case. So Jeff's paper elegantly highlights the influence of these therapies in two weeks. Now, whether that's sustained is certainly unclear. I think the logical next step is, "Okay. We show that we have a therapy that might prime the kidney for increased natriuresis" what are its effects and individuals that might need the natriuresis even more. So as Jeff highlighted individuals with more decompensated heart failure, that are more congested and more hypervolemic.
And then obviously individuals that might be quite diarrheic resistant. This is something that I think Jeff and I have given talks on. And Jeff is clearly one of the world's experts in this space, but it's obviously a very attractive possibility that this might influence individuals whose kidneys are teased or trained into just holding onto sodium, no matter what. Or really no matter what therapies we give the kidney. I don't know if Jeff mentioned this, but at least in his analysis, they also showed through indicator dilution methods that there was a reduction in plasma volume in these individuals. And I think that's really important because we at least hypothesize that in many heart failure phenotypes, plasma volume is certainly a component of decompensation. So whether these kidneys have a more pleiotropic effect on the fluid balance from your status between the interstitium and the vascular space, long-term is really unknown.
Dr Greg Hundley: I want to thank both Jeff and Justin. What an incredible, exciting discussion. And this paper, Jeff, were so thrilled to have the opportunity to publish it in circulation. And the clarity, helping us understand some of the mechanism of the efficacy of SGLT-2 inhibition. And then this unique combination of SGLT-2 with loop diuretics, potentiating, dieresis natriuresis without some of the harmful effects on serum electrolytes. And then I really appreciate both of you giving us an insight into the future where more work is needed to understand, is this a sustainable beyond two-week effect? And then, can these therapies, this combination, be helpful in those with decompensated heart failure.
On behalf of Carolyn and myself, we wish you a great week and we look forward to catching you next week on the Run.
This program is copyright, the American Heart Association 2020.
This week’s episode includes author Charlotte Andersson and Associate Editor Naveed Sattar as they discuss familial clustering of aortic size, aneurysms, and dissections in the community.
TRANSCRIPT:
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke national University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature this week has to do with aortic size, aneurysms, and predilection to dissection. But before we get to that, how about if we grab a cup of coffee and go through some of the other articles in the issue?
Dr Carolyn Lam: I got my coffee, Greg, and you know what? I'm going to start with quiz for you.
Dr Greg Hundley: All right.
Dr Carolyn Lam: True or false, in the setting of obesity and/or diabetes, cardiac substrate metabolism shifts towards increased fatty acid oxidation, while lipid accumulates in the heart? True or false? Of course, you're right. Oh, but there's a part two. Can you guess, by increasing fatty acid oxidation, will we induce or prevent obesity-induced lipotoxic cardiomyopathy?
Dr Greg Hundley: I'm going to say, because you asked it in the way you asked it, prevent.
Dr Carolyn Lam: Wow. All right. Well, the truth is we didn't really know before today's paper. The specific link between cardiac metabolism and lipotoxic cardiomyopathy was elusive and there was no specific therapy available for this condition. And these authors, Dr Rong Tian from University of Washington and colleagues, hypothesized that cardiac pathology-associated obesity would be attributable to the imbalance of fatty acid supply and oxidation. So using a diet-induced obesity model in the current study, they demonstrated that enhancing fatty acid oxidation through deletion of acetyl-CoA carboxylase 2, was sufficient to prevent obesity-induced cardiomyopathy.
So, increasing cardiac fatty acid oxidation alone does not cause cardiac dysfunction, but instead protects against cardiomyopathy in chronically obese mice. The cardiac-protective effect of increasing fatty acid oxidation and obese mice is through maintenance of Parkin-mediated mitophagy, and thus preventing mitochondrial dysfunction. These findings indicate that impaired mitophagy contributes to mitochondrial dysfunction in obese mice, and that targeting the Parkin-dependent pathway is a viable therapeutic intervention for obesity-induced cardiomyopathy.
Dr Greg Hundley: Very nice. Carolyn.
Dr Carolyn Lam: I'm going to be greedy and go on to my next paper. So Greg, do you think cardiac regeneration is possible?
Dr Greg Hundley: Well, Carolyn, I would have said, several years ago, no, but that trip that we took to China with Joe Hill and Hesham Sadek, our Associate Editor and our Chief Editor, convinced me otherwise. So I'm going to definitely answer yes on this one.
Dr Carolyn Lam: Oh, Greg, you're just too smart. And speaking of China, this next paper is from there, from co-corresponding authors, Dr Nie and Hu, from Fuwai Hospital National Center for Cardiovascular Disease and Chinese Academy of Medical Sciences and Peking Union Medical College. So, using seven genetic mouse lines, they identify that Oncostatin M is the top upregulated cytokine during neonatal heart regeneration. Oncostatin M is a pleiotropic secretory protein that belongs to the interleukin 6 family, and associates with the pathological process of dilated cardiomyopathy.
And these authors found that macrophages promote heart regeneration by secreting Oncostatin M, which promotes cardiomyocyte proliferation via a co-receptor, gp130. Employing RNA-seq and functional screening, they further found that Src-mediated gp130 triggered cardiomyocyte proliferation by activating the downstream signaling pathway involving Yap, with Y357 phosphorylation independent of the Hippo pathway. So the last thing that they did was show that gene therapy with adenovirus-associated virus and coding this activated gp130 improved heart regeneration and pumping function, thus serving as a potential therapeutic target. An amazing paper.
Dr Greg Hundley: Very nice, Carolyn. What a great summary and so much detail. Well, Carolyn, I'm going to turn our attention to catecholaminergic polymorphic ventricular tachycardia. And this article comes to us from Dr Jason Roberts, from the Western University. Carolyn, genetic variants in calsequestrin 2 can cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia, though isolated reports have identified arrhythmogenic phenotypes among heterozygotes. So in this study, a total of 112 individuals, including 36 catecholaminergic polymorphic ventricular tachycardia probands, 24 were homozygotes for compound heterozygotes, and 12 were pure heterozygotes, against 76 family members possessing at least one presumed pathogenic calsequestrin 2 variant. These were all identified.
Dr Carolyn Lam: Wow, a very precious cohort. So what did they find, Greg?
Dr Greg Hundley: This international multicenter study of calsequestrin 2 catecholaminergic polymorphic ventricular tachycardia really redefined its heritability and confirmed that pathogenic heterozygous calsequestrin 2 variants may manifest with a catecholaminergic polymorphic ventricular tachycardia phenotype, indicating a need to clinically screen these individuals. Among individuals heterozygous for a pathogenic calsequestrin 2 rare variant, medical therapy and exercise restriction are likely not necessary in the absence of the catecholaminergic polymorphic ventricular tachycardia phenotype. Though, you have to be certain over time, an intermittent clinical screening to ensure they remain phenotype-negative should be obtained.
Dr Carolyn Lam: Wow, Greg, clinically important study there. Well, I'm going to go back to the basic science world and talk about calcineurin. Now, calcineurin has long been implicated in the induction of pathological cardiac remodeling but has not been therapeutically targetable for the prevention of heart failure because of its pleiotropy and our lack of understanding of its specific protein-protein interactions and compartmentation within the cardiomyocyte.
Dr Greg Hundley: Okay. Carolyn, do you want me to give background on calcineurin?
Dr Carolyn Lam: No, Greg, you're off the hook. I'm going to give you some background on calcineurin. So, calcineurin is the calcium-calmodulin-dependent phosphatase that exists as a heterodimer, consisting of a catalytic subunit and a regulatory subunit. Now, of the three catalytic subunit isoforms, alpha, beta, gamma, it's the beta isoform that appears to be the most important for the development of cardiac hypertrophy. Binding of calcium to the calcineurin regulatory subunit enables binding of the calcium-calmodulin complex, thereby releasing auto-inhibition and freeing the enzyme to dephosphorylate downstream substrates. That's the background.
Now, in today's issue, we have this great paper from co-corresponding authors, Dr Kapiloff from Stanford University, and Dr Nikolaev from University Medical Center Hamburg. And, with their colleagues, they described the discovery of a calcineurin catalytic subunit beta binding protein Cdc42-interacting proteins 4, and I'm going to call that CIP4, which functions as a scaffold to sequester the pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates pro-hypertrophic signaling.
These findings have really important implications for understanding how cardiac calcineurin is selectively activated by stress signals, as opposed to the pleiotropic second messenger, calcium, that really floods the cardiomyocytes during each contractile cycle. Furthermore, the data provide proof of concept for an innovative therapeutic approach, whereby CIP4-anchoring activity is selectively inhibited to block the action of a small pathogenic pool of calcineurin as a means of treating heart failure. How about that? This is really discussed in an elegant editorial by doctors, Woulfe, Travers, and McKinsey.
Dr Greg Hundley: Very interesting, Carolyn. Sounds like another possibility for treating and managing heart failure. Well, let me share with you some of the other findings in our mailbag this week. First, I've got, from Professor Lang Li and Stephen Wiviott, they swap research correspondence regarding the prior publication entitled, Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus, Insights from the DECLARE-TIMI 58 Trial. And then Professor Laszlo Littmann has a nice ECG challenge for us related to a high-risk ECG that exposed some downstream worrisome vital signs.
Dr Carolyn Lam: In addition, there's a perspective piece by Dr Nambi discussing the fact that a zero-calcium score is desirable, but isn't enough to defer therapy, given that up to one-third of events will occur in this group. There's also an In Depth paper by Dr Borlaug, entitled, “Altered Hemodynamics and End Organ Damage in Heart Failure, The Impact on the Lung and Kidney,” and oh boy, this one is so beautifully illustrated. Just a must read for the understanding of the hemodynamics in the lung and kidney and heart failure. Next is a research letter by Dr Loeys on enrichment of rare variants in the Loeys-Dietz syndrome genes in spontaneous coronary artery dissection, and not in severe fibromuscular dysplasia. And finally, another research letter by Dr Arora on racial differences in serial NT-proBNP levels in heart failure management with insights from the GUIDE-IT Trial. What a rich issue, but let's move on to our future discussion, shall we?
Dr Greg Hundley: You bet, Carolyn.
Well, listeners, we're now getting to our feature discussion and it's very interesting this week where we're going to evaluate aortic aneurysms. And we have with us one of the lead authors of this paper, Dr Charlotte Andersson from Boston Medical Center, and our own Associate Editor, Naveed Sattar from Glasgow, Scotland. Charlotte, welcome to our feature discussion. Could you tell us a little bit about the background and the hypothesis that you put forward with this study?
Dr Charlotte Andersson: The background for this study was based on clinical work and what we observed in clinic. We had a few patients where we had been stricken by the fact that they came in with an acute aortic syndrome and they had a first-degree relative themself with the condition, but they did not look syndromic at all. And we started to wonder, what is the actual risk in the community, in people without obvious syndromic features of suffering from an aortic event itself. And although there are quite a few studies out there that have, to some degree, focused on the familial clustering of aortopathies, there is not a lot of information based on communities and whole entire populations. So we wanted to, frankly, estimate what is the incidence rates of aortic dissections and aortic aneurism in the community if you have a first-degree relative that has suffered from the disease themselves.
Dr Greg Hundley: How you organize your study and what was your population and what was your design?
Dr Charlotte Andersson: This study was actually based on two independent samples. First, we used the Framingham Heart study population that is very densely phenotypes over many years of spanning three generations of participants, where we looked at people who had at least one parent who had an aortic size in the upper quartile index to body-surface area and adjusted for age and sex. And we saw what's the risk of you, as a child, having an aortic size in the same upper quartile.
And second, we looked in the general Danish population, the Danish healthcare system is, as you probably know, governmental funded and we have very good registries of all hospitalizations, all outpatient visits, and so we were able to link more hard clinical events in people with and without a first-degree relative. What we did was we started time when people had an aortic dissection, we identified all the first-degree relatives in these people, and we matched them with up to 10 sex and age match controls from the general population without a first-degree relative with the disease.
Dr Greg Hundley: What did you find?
Dr Charlotte Andersson: We found that in the Framingham sample, if you had at least one parent who belongs into the upper quartile of aortic size, you had an odds ratio of two to three, adjusted for various clinical risk factors, such as hypertension and smoking yourself. And in Danish population, we found that if you had a first-degree relative with an aortopathy, the hazard rates for you developing the disease yourself was almost a tenfold-increase compared to age and sex match controls. And importantly, seemed like hazard ratios use were, more or less, unchanged when we start adjusting various known risk factors, such as bicuspid aortic valve, Marfan syndrome, and Ehlers-Danlos syndrome, normally those kinds of things. And we also found that the younger your proband were at the time of an acute event, the higher was your relative risk yourself. So among people who were below the age of 50 when they suffered an event, the hazard ratios were up to a 50-fold increase.
Dr Greg Hundley: Very nice. Naveed, what attracted you to this article as it was coming through the editorial process? And then second, how do we take the information that Charlotte's just conveyed and will be published here today, how do we take this in the context of what we already know about aortic aneurysms?
Dr Naveed Sattar: I think it's a beautiful study, so well done, Charlotte. I think it's a beautiful fusion. As Charlotte said, an in-depth cohort study, which has got very well-measured parameters of systematic points and a fantastic population-based data set from Denmark, which Sweden shares and Scotland shares and relatively small countries like us share. So small countries like Denmark punch above their weight in these kinds of studies, which is fantastic. But there's a rich seam of research that comes from these, and this is one of them. So I think that fusion of two data sets with different strengths and limitations combined giving off same signals is good.
I think, as Charlotte said, this is the first major population study to look at this question. So there's been people around the world who have got this sense that the aortic aneurism may well be familial, this provides, probably, some of the best data to suggest, yes, it definitely is.
Now the questions going forward is, okay, at what point do you screen everybody's got a family history with a proband, or do you screen those who've got a family history of younger probands? And I think what Charlotte and the team and other people around the world thar are going to look at this say,
"Okay, we now think, in addition to screening, for example, in the UK and the US we probably screen just men above 65, where most of the disease is, do we also then implement screening in younger people with family histories? And who do we screen, and when and how? And do we need to develop some kind of risk score?" And then when we do that screening, what do we do about it? Is going to be the questions and I'm sure Charlotte and her colleagues have thought about these things and it'd be interesting to see what her view is on those things. But I think it was a beautiful study in every sense.
Dr Greg Hundley: So Charlotte, he's really set you up nicely, what study do we need to perform next in this area? What are you and your group thinking about?
Dr Charlotte Andersson: Yeah, I think there are two implications of this study. First, clinical, as Naveed says. They already had a sense that aortic diseases were heritable, and I think these data definitely support that we should probably screen first-degree relatives. And I think, at some extent, this is what the guidelines already encourage us to do. So I'm not sure it would be feasible to randomize people or do a clinical trial where we screen some but not others. I'm not sure that would be ethical. I think the evidence is too strong for familial clustering and that we should probably screen these people.
But I think also, our estimates, they are so strong that I suspect that there are likely more genetic variants associated with non-syndromic aortopathies that we are not aware of just yet. So I think the next step would be to try to disentangle the genetics a little bit more. I have seen some preliminary analysis based on the UK Biobank, for instance, and I think there are more genetic variants to come up with also, more common genetic variants, at least, that we are not aware of just yet. So that would be the next step as I see it.
Dr Naveed Sattar: And that might particularity in younger probands.
Dr Charlotte Andersson: Right.
Dr Naveed Sattar: Those with the younger probands, because it looks like, as you said, the hazard ratio, the risks, are so high, it could also potentially be monogenic, but anyway.
Dr Charlotte Andersson: I agree.
Dr Greg Hundley: Well, Charlotte, Naveed, we really appreciate your time and taking this opportunity to discuss these really interesting findings and helping us understand that, truly, there may be a familial component to understanding this disease process, particularly in patients with aortic aneurysms that may go on to develop aortic dissections.
Well listeners, we hope you have a great week and on behalf of Carolyn and myself, catch you on The Run next week. This program is copyright, the American Heart Association, 2020.
This week’s episode includes author Allan Sniderman and Associate Editor Anand Rohatgi as they discuss the expected 30-year benefits of early versus delayed primary prevention of cardiovascular disease by lipid lowering and management.
TRANSCRIPT:
Dr Greg Hundley: Welcome everyone to this September 1 issue, as we start into the fall in North America, and I guess we're getting into spring-ish in the Southern hemisphere. Today, it's just myself, Dr Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
And, I'm so sad because my good friend, Carolyn, cannot be with us today. However, we have a great feature for the latter half of this recording and discussing some of the benefits of primary prevention using lipid lowering therapy to help prevent cardiovascular disease. But, before we get to that, let's grab a cup of coffee and let's go through some of the other articles in this issue.
So, the first one is from the world of basic science and it's from Professor Eldad Tzahor, from the Weizmann Institute of Science. And, it's focusing on Agrin. So, this team previously reported that a fragment of the extracellular matrix protein, Agrin, promoted cardiac regeneration following myocardial infarction in adult mice. And, in this study the investigators propose to test the therapeutic potential of Agrin in a preclinical porcine model.
They performed ischemia reperfusion injuries using balloon occlusion for 60 minutes, followed by either a 3, 7, or 28-day reperfusion period. They demonstrated that local antegrade delivery of recombinant human Agrin, or RH Agrin, to the infarcted pig heart can target the effected regions in an efficient and clinically relevant manner. In fact, a single dose of recombinant human Agrin improved heart function, reduced infarct size, reduced fibrosis and reduced adverse remodeling parameters, 28 days post myocardial infarction.
Short-term myocardial infarction experiments, along with complementary mirroring studies, revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as aggregation mechanisms of action. So in summary, this team demonstrated that a single dose of Agrin was capable of reducing ischemia reperfusion injury and improving heart function. Demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure. So, this set the stage for future studies in human subjects.
Okay. Well, our next paper is clinical and evaluates exposure to air pollution and particle radioactivity with a risk of ventricular arrhythmias. And, it comes to us from Ms. Ajani Peralta from Harvard University. Now, individuals are exposed to air pollution and ionizing radiation from natural sources through inhalation of particles. So, in this study, the team investigated the association between cardiac arrhythmias and short-term exposures to find particulate matter, PM 2.5, and particle radioactivity.
So, ventricular arrhythmogenic events were identified among 176 patients with dual chamber implanted cardio defibrillators in Boston, Massachusetts, between the period of time of September 2006 and June 2010. And, patients were assigned exposures based on their residential addresses. So, what did they find? Well, in this high-risk population, those with these defibrillators, intermediate, 21-day parts per million, 2.5 exposure was associated with higher odds of a ventricular arrhythmia event onset among those with known cardiac disease and indication for ICD implantation. But this was independent of particle radioactivity. So, important information coming to us relating to air pollution and ionizing radiation in relation to ventricular events.
Next, let's get back to another informative study from the world of basic science. And, this one involves genomic binding patterns of forkhead box protein 01 and how that is implicated in the development of cardiac hypertrophy. The study comes to us from Walter Koch from Temple University and their co-investigators.
So, cardiac hypertrophic growth is mediated by changes in gene expression, as well as changes that underlie the increase in cardiomyocyte size. The former is regulated by ischemia reperfusion or loss, while the latter involves incremental increases in the transcriptional elongation activity of Pol II, that is preassembled at the transcription start site, or TSS.
The differential regulation of these two distinct processes, by transcription factors, really hasn't been explored. So, this group sought to investigate the forkhead box protein, and we're going to call it FOX01, which is an insulin sensitive transcription factor that is regulated by hypertrophic stimuli in the heart. To date, however, the scope of its gene regulation is also somewhat uncertain.
So, to address this, the investigators performed FOX01 chromatin immunoprecipitation deep sequencing, or ChIP-sequencing, in mouse hearts following seven-day isoproterenol injections, transverse aortic constriction, or vehicle injection by sham surgeries. The investigators found that FOX01 may mediate cardiac hypertrophic growth via regulation of Pol II de novo recruitment and pause release. As the latter represents the majority, or almost 59% of FOX01 bound Pol II regulated genes following pressure overload.
So, in conclusion, these findings demonstrate the breadth of transcriptional regulation by FOX01 during cardiac hypertrophy, which is important information that should be valuable for future therapeutic targeting.
Moving on from basic science and coming back into the world of clinical science. And, this next paper is from Professor Sripal Bangalore from New York University School of Medicine. And, it involves routine revascularization versus initial medical therapy in those with stable ischemic heart disease.
So, coronary arterial revascularization is often performed, as we know, in patients with stable ischemic heart disease. And, these authors conducted a PubMed Embase central search for randomized trials, comparing routine revascularization versus an initial conservative strategy in patients with stable ischemic heart disease. The primary outcome was death, and secondary outcomes included cardiovascular death, myocardial infarction, heart failure, stroke, unstable angina, and freedom from angina. And, the trials were stratified by percent stent use, and by percent statin use, to evaluate the outcomes across all of these trials.
So, 14 randomized clinical trials that enrolled 14,877 patients followed up for a weighted mean of 4.5 years with a total of 64,678 patient years of follow-up, were used for the study. Most of the trials enrolled patients with preserved left ventricular systolic function, low symptom burden, and they excluded patients with left main coronary artery disease.
So, here are the results, revascularization compared with medical therapy alone, was not associated with a reduced risk of death. The trial sequential analysis showed that the cumulative Z curve crossed the futility boundary indicating firm evidence for lack of a 10% or greater reduction in death. Now, revascularization was associated with a reduced non-procedural MI rate, but also with an increased procedural MI rate with, therefore, no overall difference in myocardial infarction incidents.
So, another point in this study is that there was a significant reduction in unstable angina and increase in freedom from angina was observed in those that underwent revascularization. Finally, there were no treatment related differences in the risk of heart failure or stroke. So in conclusion, in patients with stable ischemic heart disease, routine revascularization was not associated with improved survival, but was associated with a lower risk of non-procedural myocardial infarction, and unstable angina with greater freedom from angina at the expense of higher rates of peri procedural myocardial infarction. Now, longer term follow-up of trials is needed to assess whether the reduction in these non-fatal spontaneous events actually improves long-term survival.
Well, listeners what else is in the issue? Now, we refer to this as what's in the mailbox? So, we have a research letter from Jianyi Zhang regarding the apical resection prolongs the cell cycle activity and promotes myocardial regeneration, after left ventricular injury, in the neonatal pit. We have another research letter from Roger Foo, assigning distal genomic enhancers to cardiac disease-causing genes. What else is in the issue? There's a nice, On My Mind piece, from Anthony Wierzbicki on phenomics, not genomics, for cardiovascular risk assessment. And, there's a Perspective piece from Dr Dana Gal, regarding considerations for triaging elective cases in children with cardiac disease in a time of crisis.
Finally, we have an exchange of letters from Dr Daxin Wang and Dr Prabhakara Nagareddy regarding the previously published article, “Neutrophil Derived S100A8/A9 Amplification of Granulopoieses After Myocardial Infarction.” There's a very nice case series regarding an unusual reversible cause of acute high output heart failure complicated by refractory shock from Dr Matthew Durstenfeld. And then, finally, we have an ECG challenge from Mr. Alejandro Cruz-Utrilla, regarding giant T-wave inversion and dyspnea in the time of this coronavirus pandemic.
Well, listeners, what a great issue. And now, we get to look forward to that feature discussion from Dr Allan Sniderman, regarding the benefits of early versus delayed primary prevention by lipid lowering therapy.
Well, listeners, now we get to move to our feature discussion today and understand a little bit more about lipid management. And, with us, we have Dr Allan Sniderman from McGill University, and our own associate editor, Dr Anand Rohatgi from University of Texas Southwestern in Dallas. Allan, we're going to start with you. Can you give us a little bit of information pertaining to the background, or the hypothesis? Why did you want to perform this particular study?
Dr Allan Sniderman: Let us start from where we are in cardiovascular prevention now, which is the risk model. All of the major guidelines, throughout the world, select candidates for statin prevention based on their risk of a cardiovascular event over the next 10 years. Well, that's been a very positive development, but we need to appreciate what the limitations are. Because, tenure risk is so heavily based on age, what it boils down to is that if you're 60 and over, and a male you're going to be eligible. An increasing proportion of women will be eligible as they're older. But, if you're younger, regardless of your other causal factors, you may well not be eligible. And, the net result of that is, almost 50% of all cardiovascular events occur before 60, 65. So, half of the events are occurring before prevention even kicks in.
The second point is that you can't get be at risk until you have disease within your arterial tree. So, what we've done is, we're trying to prevent the disease that's already present. So, although it's been a wonderful step forward, we think it's time to start moving beyond that model, and trying to prevent disease itself, rather than preventing people who've already had disease.
So, what we decided to do, which we're shifting focus here from risk to causes. Risk, after all, is a consequence of causes. And, when you look at the pathology of atherosclerosis, with a few exceptions such as FH, up until the age of 30, 35, you don't have the complex lesions that can actually cause clinical events. So, we said, "Okay, we'll start at that time point. And, we'll try and quantitate the benefit of earlier intervention, versus later intervention, at different starting points." So, we based our analysis on NHANES, and we identified the people within the NHANES cohort, who would not have been eligible for prevention, based on the current American guidelines.
So, we had three age starting categories, 30 to 39, 40 to 49, and 50 to 59. And, we followed them out for 30 years. Our analysis has the same duration of the follow up, but the same final date. That has to be kept in mind because it limits the total benefit on the early starters. And, we further sub divided the groups based on non-HDL cholesterol, into those who had a level above 160, those who had an intermediate level, and those who had a low level because we'd previously shown that non-HDL identifies a high-risk group over 20 to 30 years.
We decided we'd look at two different models of the likelihood of the drug preventing events. One is the standard estimates that you would get from the statin clinical trials. But, if you reduce LDL cholesterol by a milli mol of 40 milligrams percent of your language, you reduce risk by about 22%. And, that's our conservative model. Then we took a model that's more biological and based on Mendelian randomization because, as you know, the Mendelian randomization analysis, the benefit, the reduction and event rate per milligram, per deciliter, lower LDL cholesterol is two or three fold greater than in the statin clinical trials.
So, Brian Friends had produced a formula in which you blend those two together, the statin estimate and the Mendelian randomization and it varies depending on how early you start. And, that was a more optimistic model, obviously. But the major point I emphasize is that both models showed that if you start early, you do better. Now, how surprising is that?
But the benefit depended on the level of non-HDL cholesterol. So starting at age 30, 35 in somebody who has a normal or low non-HDL cholesterol, doesn't really gain you all that much. Starting with somebody who has a high level, different story. In each of the categories, the conservative model, if you did the full 30-year prevention, you get a third to a half reduction in events. And, with the more optimistic model, you get half to two thirds reduction.
The closer you get to where you'd start with the guidelines, you're losing that benefit. Then you say, "Okay, well, how optimistic is the optimistic model?" And, all the optimistic model is saying, "Let's remember how we get disease." If we stop the formation of a new lesion, well, that's perfect prevention. Well, we're doing it, present is trying to stabilize existing lesions. The older we get, the more disease we have, the less new lesion we have, the less potential for the big game in prevention. So stopping new lesion formation, it seems to me is from clinical reasoning, a pretty biologically and clinically coherent way to formulate what your prevention strategy should be.
What we think we contributed, what we hope we've contributed with this analysis is saying, "Let's take a real step back, let's look at what we're doing and let's see how can we make a Magnus step forward in prevention?" And, the way we think you can do it is to start moving away from exclusively a risk paradigm, because that made sense. You want to treat people who were at risk. We get away from this 10-year duration and start focusing more on the causes, because when we look at an individual, we can measure the causes. Well, we talked about risks, that's a much slipperier concept, because it's a group. Is everybody in the group the same risk? They're clearly not. So, to try and get this to a much more concrete level, that's what we tried to do.
Dr Greg Hundley: Very nice, Allen. And so, Anand, why did you select pushing this paper forward? And, what do you think this means for patients with high cholesterols? They're in their 40s and 50s. Help expand on some of what Allan has, so elegantly, described for us.
Anand Rohatgi: First of all, Allan, thank you so much for doing this work and sending this to circulation. We were really excited to see this come across our desks, because at the end of the day, this manuscript, this study by Allan Sniderman and others, has very important public health consequences. And, that's why we were really interested in what they found and what they had to say about this topic.
And, really what it comes down to is, like Allan mentioned, the trials for statin just really never addressed what to do about risk in younger individuals and over a longer period of time. And so, it was really these genetic studies, the Mendelian randomization studies, that really strongly showed the cumulative exposure effect of higher cholesterol levels, over time, and the benefits of maintaining really low levels. And so, what I think this paper does is it translates those scientific studies, those genetic studies, into a public health concept that's easily digestible for physicians, for clinicians, for people, for patients and stakeholders about what does this all mean? How can we benefit and when?
And, I think it's very clear, the earlier you start, the more benefit you get over the life course. And, honestly, the take home message to me, it seems like for most of adulthood, the being able to maintain low risk and low cholesterol levels is the best path forward and not waiting until you find something wrong. And so, we were very, very excited about seeing that message translated in such an easy manner and compelling manner by Allan's work.
Dr Greg Hundley: Very nice, 40 to 49-year old with non-HDL cholesterols greater than 160 milligrams per deciliter, would be expected to reduce their average predicted 30-year risk by 17%. That's just amazing.
Allan, very quickly, in a minute, what do you think is the next study that needs to be performed in this area?
Dr Allan Sniderman: I don't think we're ever going to get the primary prevention trial that we want, because it's too many people, too early, and we already know too much. I think the thing that we really need to do is figure out how we're going to most accurately measure the cause within the individual. I'll put in a plug for FOV, because I think it is a more effective measure, even the non-HDL cholesterol. And, I think that when we commit people or when we invite people to take medications early in life, we ought to be doing it on the strongest ground possible.
I want to say thank you to be review process at Circulation, because the final paper that came out is not the paper that went in. The reviewers made superb, tough criticisms of this paper and not of the calculations, but of the way we were expressing it. And, they forced us to rethink and reimagine the context, in which the final form of this paper appears. So, we have a big thank you to our reviewers. We have a thank you to the patients of the editorial staff at Circulation. And, I have a big thank you to my collaborators, because they're really the strength of the paper.
Dr Greg Hundley: Very nice, well listeners, it's been another great week here at Circulation and another very important piece of information in this feature discussion regarding monitoring and evaluating non-HDL cholesterol in the earlier years, and really considering initiation of statin therapy, to prevent the atherosclerotic lesions from forming, not just stabilize them later in life afterwards.
Thanks to Anand Rohatgi and also Allan Sniderman for bringing us this wonderful article. We hope you have a great week. This program is copyright the American Heart Association 2020.
This week’s episode of Circulation on the Run has 2 Feature Discussions. Associate Editor Ntobeko Ntusi discusses the article "Prevalence of Infectove Encocarditis in Streptococcal Bloodstream Infections is Dependent on Streptococcal Species." Then, author Anumpam B. Jena and Associate Editor Sandeep Das discuss trends in new diagnoses of atrial fibrillation after the release of an ECG-capable smartwatch.
TRANSCRIPT:
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature this week involves infective endocarditis and looking at that in streptococcal bloodstream infections. Are they dependent on the different species of streptococci? But before we get to that, how about we grab a cup of coffee and start off and discuss other papers in the issue. You want to go first?
Dr Carolyn Lam: Sure, Greg. I got my coffee, but I want to start with a quick question. So do you think it's safe and efficacious to prescribe SGLT2 inhibitors to patients with Type 2 Diabetes and concomitant peripheral artery disease?
Dr Greg Hundley: Ah, Carolyn, very good question. I don't know if it's right or wrong. A little bit of controversy here.
Dr Carolyn Lam: Let's explain that controversy. So patients with peripheral artery disease are at heightened risk of cardiovascular complications. However, there's also an increased risk of amputation that was observed with canagliflozin in one prior trial. Now, the SGLT2 inhibitor dapagliflozin was shown to reduce the risk for hospitalization for heart failure and kidney events in patients with Type 2 Diabetes in the DECLARE–TIMI 58 trial. So authors Dr Bonaca from University of Colorado School of Medicine and colleagues examined the cardiovascular and kidney effects and the risk of limb related events in patients with and without peripheral artery disease in the huge DECLARE–TIMI 58 trial, including more than a thousand patients with peripheral artery disease.
Dr Greg Hundley: So this could be really helpful to answer this question. What did they find, Carolyn?
Dr Carolyn Lam: Well, patients with versus without peripheral artery disease were indeed at higher risk of major adverse cardiovascular events, cardiovascular death, or heart failure, hospitalization and kidney events. They also had consistent benefits for the outcomes of cardiovascular death or heart failure hospitalization as well as progression of kidney disease with dapagliflozin. Now ,patients with peripheral artery disease also had a higher risk of limb events, but there was no consistent pattern of incremental risk observed with dapagliflozin. So the take home, diabetes patients with peripheral artery disease are at risk of heart failure and kidney events and dapagliflozin is beneficial with no patterns of increase limb risk.
Dr Greg Hundley: Very nice, Carolyn. Boy, that is very helpful and a nice take home message for all of us administering these agents. Well, Carolyn, my first study comes from Professor Magnus Bäck from the Koralinska Institute. And the aim of this study was to identify the role of omega−3 polyunsaturated fatty acids, derived specialized pro resolving mediators, or SPMs, in relation to the development of aortic valve stenosis. The synthesis of specialized pro resolving mediators are potent beneficial anti-inflammatory agents. They have pro resolving and tissue modifying properties that are useful in managing patients with cardiovascular disease.
Dr Carolyn Lam: Interesting. So what did these authors find?
Dr Greg Hundley: This study showed that human stenotic aortic valves contain decreased levels of n-3 PUFA, and that n-3 PUFA treatment decreased aortic valve calcification, and aortic valve leaflet area in murine models’ concomitant with improved aortic valve hemodynamics. The pro resolving lipid mediator, resolvin E1, which is derived from the n-3 PUFA enoic acid, or EPA, exerted protective effects on valvular interstitial cell calcification and valvular inflammation through its receptor, chemR23. And therefore Carolyn, further clinical evaluation of n-3 PUFA treatment may open up novel therapeutic opportunities for preventing the progression of aortic valve stenosis.
Dr Carolyn Lam: Wow, really interesting, Greg. Just more and more data on these omega−3 PUFAs, huh? So cool. Well, the next paper is kind of related in the lipid world. Do you think treating to a low LDL cholesterol target of less than 70 milligrams per deciliter may impact carotid plaque evolution?
Dr Greg Hundley: I would think so. It seems like that target is beneficial in many ways.
Dr Carolyn Lam: Well, good guess, Greg. But I'm going to tell you about a study that actually looked at that. First of all, recall that the treat stroke to target, or TST trial, showed the benefit of targeting an LDL cholesterol concentration of less than 70 in terms of reducing the risk of major cardiovascular events in 2,860 patients with ischemic stroke with atherosclerotic stenosis of the cerebral vasculature. Now, today's paper describes results of the parallel TST plus study, which included 201 patients assigned to an LDL cholesterol concentration of less than 70 versus 212 patients assigned to a target of a hundred. To achieve these goals, investigators led by corresponding author, Dr Amarenco from Bichat Hospital in Paris, France, allowed investigators use the statin and dosage of their choice, and added ezetimibe as needed. After certification of ultra-sonographers, carotid ultrasound examinations were performed at baseline and at two, three, and five years, and blindly analyzed at a central core laboratory.
Dr Greg Hundley: Very nice, Carolyn. So what did they find?
Dr Carolyn Lam: After a median follow-up of 3.1 years, patients in the lower target group had a similar incidence of newly diagnosed carotid plaque compared to the higher target group, but significantly greater regression of carotid atherosclerosis as measured by the common carotid intima media thickness. So this really further strengthens the concept that the lower the LDL cholesterol, the better the clinical and atherosclerosis outcomes.
Dr Greg Hundley: Very nice, Carolyn. Another study emphasizing that very important point. Well, Carolyn, my next study comes from Professor Abdelkarim Sabri from the Temple University School of Medicine. So studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial. In this study, the authors analyzed protease activated receptor or PAR4 expression in mouse hearts with myocardial infarction, and investigated the effects of PAR4 deletion on cardiac remodeling and function post demise by echocardiography, quantitative immunohistochemistry, and flow cytometry.
Dr Carolyn Lam: Oh, okay. What did they find, Greg?
Dr Greg Hundley: Three things. First, PAR4 deficiency leads to cardiac hemorrhage and increases the rates of cardiac rupture following chronic myocardial infarction. PAR4 deficiency in neutrophils, but not in platelets, impairs inflammation resolution and myocardial healing after myocardial infarction. And finally, adoptive transfer of neutrophils can be used as a novel therapy to modulate the inflammatory response and improve cardiac remodeling and function following myocardial infarction.
Dr Carolyn Lam: Okay, what's the take home message?
Dr Greg Hundley: It's a little tricky. So acute transient administration of par four inhibitors may provide a new approach to prevent early inflammation and myocyte loss immediately after ischemic injury. The keyword is immediately. But importantly, prolonged P4 inhibition strategies could impair myocardial healing and increased cardiac hemorrhage and the rates of myocardial rupture following infarction. PAR4 inhibition therapies should be limited to the acute phases of the ischemic and fault, and it should be avoided for the chronic treatment post myocardial infarction. Really intriguing, Carolyn.
Dr Carolyn Lam: Very nice and elegant results, kind of like yin and yang, huh?
Dr Greg Hundley: You bet.
Dr Carolyn Lam: All right. Let's sum up with the other papers in the issue. There's a white paper by Dr Psotka on challenges and potential improvements to patient access to pharmaceuticals with examples from cardiology. There's a perspective by Dr Armstrong comparing the benefit of novel therapies across clinical trials, and that provides important insights from the VICTORIA trial. There's an ECG challenge by Dr Chu regarding a young male with incessantly alternating tachyarrhythmias.
Dr Greg Hundley: Very nice, Carolyn. Well, in my mail bag, I have an on my mind piece from Dr Jamil Tajik relating to, our favorite, the art and science of occultation. Well, Carolyn, how about we get on to that feature article and talk a little bit more about those little devils, the streptococci?
Dr Carolyn Lam: Yeah, let's go, Greg. Infective endocarditis is the topic of our feature paper today. Now, we all know it's a life threatening disease, and despite its relative rarity, it's still consumes a disproportionate share of healthcare resources, and its annual mortality is still really high, exceeding 20%. Now, I think we all recognize that improved outcomes are critically dependent on a timely diagnosis and early investigation. The problem is the clinical presentation is less and less likely that classical textbook presentation, and the clinical suspicion is often triggered after microbiological identification of potential causative organisms in the blood. And while we as a medical community are usually aware of the dangerous of staphylococcal bacteremia, I think there's a lot less appreciation of the propensity of different streptococcal species to cause infective endocarditis. Greg, my dear partner, greatest friend, and colleague, do you agree?
Dr Greg Hundley: Yes, Carolyn. So this paper and this feature addresses bacterial endocarditis and focuses on streptococcal infections just as you've described. Now, streptococci I frequently cause infective endocarditis. Yet, the prevalence of infective endocarditis in patients with bloodstream infections caused by different streptococcal species is unknown. So in this study, Dr Shamat and associates aim to investigate the prevalence of infective endocarditis at species level in patients with streptococcal bloodstream infections.
Dr Carolyn Lam: Now, we're taking a lot of pains to describe this paper, Greg and I, because we didn't manage to get hold of the authors this time. We certainly have our editor who managed the paper and that's Ntobeko Ntusi from University of Cape Town. So welcome Ntobeko, and thank you so much for discussing this paper with us. But before we get to that, I think Greg and I are going to try to, in our usual fashion, get to the bottom of describing. Here's something I learned that I didn't know before. That the ESC guidelines for example, are primarily based on the modified Duke criteria, which include blood cultures, mentioning viridians streptococci. Remember those? Viridians streptococcus, or strep bovis, as a diagnostic major criterion for streptococcal infective endocarditis.
And yet, the term viridians is based on bacterial culture using green hemolysis on blood agar plates, which is outdated. So I didn't realize that. It's outdated and inconsistent because some of the included streptococcal species do not even cause hemolysis, and other species are able to produce different kinds of hemolysis. And thus, we really need more details on specific streptococcal types that are much more current. And when we face these different streptococcal species, they're not mentioned in the guidelines and so we need more data. So that's why this paper is so important. So Greg, now over to you. Do you mind to describe what the authors did?
Dr Greg Hundley: Sure, Carolyn. So these investigators identified and assessed all patients with streptococcal bloodstream infections from the period of time of 2008 to 2017 in the capital region of Denmark. And data were cross-linked with Danish nationwide registries for identification of concomitant hospitalization with infective endocarditis. In multi-variable logistic regression analyses, the authors investigated the risk of infective endocarditis according to some of those species that you just mentioned. And they adjusted their analyses for age, sex, greater than or equal to three, positive blood culture bottles, native valve disease, prosthetic valves, prior episodes of infective endocarditis, and whether or not they may have had an implanted cardiac device.
Dr Carolyn Lam: Great, great. So tell us the results, Greg.
Dr Greg Hundley: So Carolyn, they had 6,500 plus cases with streptococcal bloodstream infections. And the average age of the patients was 68 years, and a little more than half. So 52% to 53% were men. The prevalence of infective endocarditis overall was 7%. Now, the lowest infective endocarditis prevalence was found with strep pneumoniae and strep pyogenes, ranging from 1.2% to 1.9%. the highest infective endocarditis prevalence, and that was found with strep mitis or oralis at 19%. Streptococcus gallolyticus, formerly known as strep bovis, at 30%. Strep sanguinis at 35%, and strep mutans at nearly 50%, at 48% overall. So in multi-variable analysis, using the strep pneumonia at 1.2% as a reference, all species except strep pyogenes were associated with a significantly higher infective endocarditis risk. Again, the highest with the odds ratio of strep gallolyticus is at an odds ratio of 31 ranging up to straight mutans with an odds ratio of 81.3.
Dr Carolyn Lam: Whoa, Greg, that was beautifully summarized, and frankly, beautifully pronounced. I don't think I could have done that with all the species. That is so cool. And in case everyone didn't get it, I strongly suggest you refer to figure three of this beautiful paper. It shows the prevalence of infective endocarditis in bloodstream infections with the different streptococcal species, all in one figure. And Ntobeko, with that introduction, if you may, by both Greg and I, could you please let us behind the scenes? Tell us what you first thought when this paper came across your desk and perhaps what the editors’ thought was so important about this paper.
Dr Ntobeko Ntusi: Thank you very much, Carolyn and Greg. So this is an important paper coming out of circulation. And while infective endocarditis may not be so harmonic in North America and western Europe, in many parts of the world, including where I come from in Sub-Saharan Africa, with a high prevalence of rheumatic heart disease, it remains an important cause of morbidity and mortality. And we forget that it's a disease with very high inpatient mortality of up to 50% in many countries. And of course in those with rheumatic heart disease, streptococcal bloodstream infections remain an important cause of infective endocarditis.
So when I saw this paper, I very much enjoyed reading it. I thought it was well written and beautifully illustrated. In some ways, even though I say it's an original paper, it has a feel of a review because the discussion, as well as the figures and tables, are quite instructive. And the comments from the reviewers were very much aligned with my own thinking that there were a number of important new learnings coming out of this paper. The first important message for me was that the distribution of streptococcal infections in the population was not uniform and I had assumed infections to be broadly the same across the population. And contrary to what I thought, the risk of infective endocarditis was inversely related to the frequency of streptococcal bloodstream infections in the population.
In other words, the most common streptococcal blood infections that are very low prevalence of infective endocarditis. And that leads to the second important learning from this paper, which is that if you are a clinician evaluating a patient with suspected infective endocarditis, the risk of infective endocarditis should be evaluated on a species level, as the species from Greg's description is probably the most important determinant of the likelihood of developing infection. And then the other important, I think, take home message from this paper, I'm looking at the results of multivariate regression analysis, is that it confirms much of what we know from studies with older patients studies focusing primarily on staphylococcal bloodstream infections as well as studies focusing on device therapies.
And that message is that the risk of developing infective endocarditis, even with streptococcal blood infections is related down to presence of native or valve disease. Those with trust that tech devices, intracardiac devices, and of course, the number of fat blood culture bottles that are positive, which is something that is well accepted and established in clinical practice. Thank you, Carolyn.
Dr Carolyn Lam: I just love those three take home messages. So beautiful. And I really also love that you invited this fantastic editorial, Dr Prendergast, Dr Allen, and Dr Klein. I thought it was wonderful the way they summarized the paper, put it into context, and perhaps, I could borrow their words and also explaining that they pointed out that we do need to be cautious about interpreting this being a retrospective series classified by diagnostic coding. And of course, by design, because of that, we can't fully attribute causal associations.
They also pointed out that this paper, I believe did not include echocardiographic data as one of the variables. And so of course, that could be something that could be further explored in future studies. And I'd love your thoughts on what they also said about before we extrapolate regional data, I mean, it's all from Denmark after all, to other regions, this work should probably be considered something that should inspire extension of further studies and prospective evaluations in other areas, and yet never losing sight of the fact that this informative paper will of course be of considerable interest to not just cardiologists, but also infectious disease specialists, because we're often called to sort of assess, "All right, how much do you need to work up for infective endocarditis if you see this specific streptococcal bacteremia?" And this paper definitely puts us strides ahead in this area. Would you agree with that, Ntobeko, and anything to add?
Dr Ntobeko Ntusi: Indeed, Carolyn. So I was delighted that the review, the editorial, was co-authored by cardiologists and infectious disease specialists. We might view as they balanced in as one of the modifications to the original submission. We actually posed that question to the office that how can we be certain in the absence of echocardiographic data that the diagnosis was in fact infective endocarditis in patients? And so they went back and performed a sensitivity analysis and triangulated the principle diagnosis of infective endocarditis with the treatment of patients in the duration in hospital. And that sensitivity analysis in fact strengthened our believe that this wasn't fit the diagnosis of infective endocarditis. And I think your point is well taken that similar studies need to be conducted in different regions of the world and this field will be strengthened by large amount of prospective studies on top of the plethora of retrospect data that we have.
Dr Greg Hundley: Well listeners, we have a second feature discussion this week. A very interesting article pertaining to the use of smartwatches and detection of atrial fibrillation. And to present this work, we have Dr Bapu Jena from the Harvard Medical School, and our own associate editor from University of Texas Southwestern Medical Center in Dallas, Dr Sandeep Das. Welcome gentlemen. And Bapu, perhaps, could you tell us a little bit about the hypothesis and the background of this material?
Dr Anupam B. Jena: Sure. So you probably are aware that in December of 2018, Apple released this new watch and this watch made a lot of buzz in part because it featured this single lead EKG that the company said would be able to detect atrial fibrillation. And there was this question among many, at least certainly among clinicians, as to whether or not we would see a large increase in atrial fibrillation diagnoses after this watch was released onto the market. And then the second question was, would we be picking up worrisome cases of atrial fibrillation that we needed to act on, or would we be picking up cases that patients probably would have been okay living with and would never have known that they were living with?
We were lucky to be able to work with a company called Athenahealth. Athenahealth is a nationwide cloud-based healthcare information technology company. What that allowed us to do was to do a very early analysis of the change in atrial fibrillation diagnosis after the Apple Watch was approved on the market. So that's the data we use is from small physician practices. It's not nationally representative, but these practices are all across the US. The data from Athenahealth have been used in other studies, including some by myself and other colleagues.
In terms of the method that we applied; it was pretty straight forward. So what you basically want to see is before and after December of 2018, do we see a market spike in the diagnosis for atrial fibrillation? Again, these are diagnoses that physicians who are in these offices would be making and that we would be seeing in the electronic health records of their practices. Now, the problem is, is suppose over time, atrial fibrillation diagnoses are going up. So if we looked at the first six months of 2019 compared to the last six months of 2018, and we saw an increase, we obviously wouldn't want to attribute that solely to the Apple Watch because atrial fibrillation diagnoses may be going up for a lot of other reasons. What we said as well, let's at least try to account for the possibility that there are seasonal trends at play in the diagnosis of atrial fibrillation.
Dr Greg Hundley: Very nice. What did you find?
Dr Anupam B. Jena: So the basic finding is as follows that we didn't really see a differential increase in atrial fibrillation diagnoses. So for example, in the months before the watch was released, in this population, about 0.4% of all visits had an atrial fibrillation diagnosis. 0.4%. If you look at the year after the app release, about 0.4% of visits have the diagnosis. If you look one year back, you also find that one year before in the pre period, there is about 0.36% of visits were for atrial fibrillation, and that increased the 0.39%. So the difference in difference change is basically about zero. Meaning, we found that there was no increase in atrial fibrillation diagnoses. The second thing that we did is we looked at high income zip codes, and we looked at zip codes with the population of individuals would be such that we might expect an increase. And we found no changes in either one of those two subgroups.
Dr Greg Hundley: Very good. Well, Sandeep, help us put this in the context of using these watches and then also using these watches to identify patients with atrial fibrillation.
Dr Sandeep Das: Absolutely. So let me first just add a comment that Bapu was a little too modest to blow his own horn, but he's really built a lovely research program of identifying and answering really interesting questions in large datasets. So the fundamental question here about whether the use of the Apple Watch and these detection algorithms would be associated with a big spike in diagnosis of atrial fibrillation was extremely important or is extremely important. So that was really the hook. I knew it was going to be something interesting. In our heart of hearts, we're all a little worried that people are going to have wearables. There's going to be an 8 million people presenting with abnormal findings on their watch and it's going to break medicine. So that was really kind of the context and the key for what made it interesting to us.
Dr Greg Hundley: Very nice. And so what do you think, maybe start with Babu, and then come back to Sandeep. What do you think will be the next study in this area using these devices as they pertain to patients with atrial fibrillation?
Dr Anupam B. Jena: Yeah. Great question. So I think there's two things that come to mind. So first is this was really an early analysis. I do expect that as the Apple Watch grows in popularity and as other similar such devices get introduced to the market, that we probably will pick up patients with atrial fibrillation who otherwise wouldn't have been diagnosed. I think that's less likely, but would be diagnosed earlier than they otherwise would have. So I think that if we look a couple of years out, we probably will find different answers that we found here. But as Sandeep said, at least in the first year after the watch was introduced to the market, we didn't break the bank. So I think this first natural question is to look longer out. And I think the second thing, which is particularly interesting to me at least, is that this potentially gives us a nice natural experiment to understand whether or not all patients with atrial fibrillation or what are the other factors that we should be thinking about in terms of benefits?
Dr Greg Hundley: Very good. Sandeep, do you have anything to add?
Dr Sandeep Das: So I agree with that answer entirely. I think that one of the things that really is going to be the $64,000 question is what does wearable diagnosed atrial fibrillation mean? So we were pretty good. As Bapu said, we have well established history of understanding what to do with patients that have atrial fibrillation that we diagnose in conventional ways. People either present with symptoms or are diagnosed externally in the hospital. But what does it mean if you're perfectly fine and you just have a watch that gives you an alarm? What are the implications of that? Because there are therapies generally revolve around anticoagulation in a large fraction of patients with atrial fibrillation. And that's the big deal.
If we're going to commit people to lifelong anticoagulation, based on what they're watch told us, is that the right thing to do? So I think that to me, the most important question going is what does a diagnosis of a-fib by wearable mean for downstream treatment implications and outcomes? And then the larger scope is also how can we then incorporate the data that we're going to continue to get from wearables into practice? So studies on sort of the practical downstream implications of wearable technology on utilization are also going to be super important and interesting.
Dr Greg Hundley: Very good. Well, I want to thank you Bapu, and also thanks Sandeep for your time today. And just sharing this new research using Apple smartwatches and trying to diagnose atrial fibrillation and compared it at least in this first year to, I guess, historical controls, not an overabundance or mass increase in the diagnosis of atrial fibrillation. And as you both have identified more to come with research on using these watches in the future for management, and then how we might improve therapeutic interventions through the use of these devices. Well, listeners, we hope that you have a great week and we look forward to catching you on the run next week. Take care. This program is copyright of the American Heart Association, 2020.
This week’s episode of Circulation on the Run features author Ami Aronheim and Associate Editor Thomas Eschenhagen as they discuss early cardiac remodeling that promotes tumor growth and metastasis.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor of the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, today we're taking a look at the cardio-oncology world in our feature discussion, but in a very interesting reverse way. Cardio-oncology, what would you think of? I suppose the effects on the heart of cardiotoxic drugs that we use in oncology, right? But this feature paper looks at it the other way around and says does the heart and its remodeling promote tumor growth and cancer? Terribly interesting data coming right up after we discuss a couple of papers, well, all the papers in today's issue.
So I want to start. Greg, do you remember what parasites are and why they're important?
Dr Greg Hundley: Well, Carolyn, this is actually one of the things that I do remember because we study the parasites when we're looking at microcirculatory dysfunction after the administration of potentially cardiotoxic agents for treatment of cancer. But how about you tell us a little bit more.
Dr Carolyn Lam: This is going to be very basic just for all of us. Now, the blood vessels are composed of endothelial cells and mural cells. Endothelial cells line the vascular lumen. Whereas the mural cells, which include faster smooth muscle cells and parasites adhere to the abluminal surface of the endothelium. Parasites regulate vessels stabilization and function, and their loss has been associated in diseases such as diabetic retinopathy, vascular malformation, stroke, and cancer. Just like you said, Greg.
Now here we have a series of elegant experiments by Dr Mariona Graupera from IDIBELL in Barcelona and colleagues who use genetic mouse models to identify the specific molecular signature of mural cells at early and late stages of the energetic process and unveil their biological relevance. Their results show that phosphatidyl inositol 3-kinase or PI3K-beta is the main regulator of parasite, proliferation and maturation in vessel growth. PI3K-beta deletion in parasites triggered early parasite maturation, whereas exacerbated PI3K signaling delayed parasite maturation, and thus vessel maturation during angiogenesis.
Dr Greg Hundley: So clinically what's the take home message here.
Dr Carolyn Lam: The proposed model of mural cell maturation together with the tools developed would be instrumental for the characterization of mural cells in pathologies associated with deregulated vessel growth, such as ischemia stroke, vascular malformation, diabetic retinopathy, and cancer. The therapeutic potential of modulating parasite biology through PI3K signaling provides a new window of clinical intervention for vascular related diseases in which parasite dysfunction contributes to their onset and or progression.
Dr Greg Hundley: Very nice, a very important cell type Carolyn. Well, my paper comes from Professor Xiang Qian Lao from The Chinese University of Hong Kong. In this paper, the authors investigated in 140,072 adults all greater than the age of 18, without hypertension who joined a standard medical screening program with 360,905 medical exams that occurred between the years of 2001 and 2016. They assess the joint associations of habitual physical activity and long-term exposure to find particulate matter with the development of hypertension in Taiwan.
Dr Carolyn Lam: Wow. A huge study. So what did they find Greg?
Dr Greg Hundley: After adjusting for a wide range of co-variants including a mutual adjustment for physical activity or particulate matter, a higher physical activity level was associated with a lower risk of hypertension. Whereas a higher level of particulate matter was associated with a higher risk of hypertension. No significant interaction was observed between physical activity and particulate matter.
So Carolyn in conclusion, a high physical activity and a low particulate matter exposure were associated with a lower risk of hypertension. What we would expect the negative association between physical activity and hypertension remain stable in people exposed to various levels of particulate matter. The positive association between particulate matter and hypertension was not modified by physical activity. Thus, Carolyn the authors believed their results indicate that physical activity is a suitable hypertension prevention strategy for people residing in relatively polluted regions.
Dr Carolyn Lam: Oh, thanks for summarizing that. So well, Greg, Hey, I've got a question for you. Do you measure a high density, lipoprotein cholesterol or HDL cholesterol? Do you measure the levels or do you measure the particle concentration in your clinical practice?
Dr Greg Hundley: I think just the levels Carolyn.
Dr Carolyn Lam: Yeah. Same, but there's a lot of data coming out about the particle concentration. Let's review a little bit about that. So the HDL cholesterol is an established athero-protective marker, particularly for coronary artery disease, but HDL particle concentration may better predict the risk. However, the associations of HDL cholesterol and HDL particle concentration with ischemic stroke and with myocardial infarction among women and blacks has not been well defined. And so Dr Rohatgi from UT Southwestern and colleagues analyzed individual level participant data in a pool cohort of four large population studies without baseline atherosclerotic cardiovascular disease. These were the Dallas Heart Study, the ERIC study and the MISA study, as well as the PREVENT study.
Dr Greg Hundley: What did they find? Were there any unique pieces of data related to either sex or those of black race?
Dr Carolyn Lam: They found that HDL particle concentration is inversely associated with the specific endpoint of ischemic stroke overall and among women. Whereas HDL cholesterol was not associated with ischemic stroke. Neither HDL particle concentration nor HDL cholesterol levels were associated with myocardial infarction in blacks. Thus HDL particle concentration, but not HDL cholesterol may be a useful risk marker for ischemic stroke. HDL particle concentration may be a useful risk marker for both myocardial infarction and ischemic stroke among women. There is likely minimal utility of HDL markers for risk prediction of myocardial infarction in the black population.
Dr Greg Hundley: Thanks Carolyn. That was such a great introduction and overview and then the results was so clear. Carolyn, my next paper comes from Dr Peter Willeit from the Medical University of Innsbrook. In this paper, the author systematically collated carotid intima-medial thickness data from randomized controlled trials. The primary outcome was a combined cardiovascular disease endpoint defined as myocardial infarction, stroke, revascularization procedures, or a fatal cardiovascular event. The authors estimated intervention effects on carotid intima-medial thickness progression and incident CVD for each trial before relating the two using a Bayesian eta- regression approach.
Dr Carolyn Lam: Oh, this is important. So what did they find?
Dr Greg Hundley: Carolyn, they're going to have 10 micrometer per year evaluations. So across all intervention, each 10 micrometer per year reduction of carotid intima-medial thickness progression resulted in a relative risk for cardiovascular disease of 0.91 with an additional relative risk for cardiovascular disease of 0.92 being achieved independent of carotid intima-medial thickness progression. So combining these results, the authors estimate that interventions reducing carotid intima-medial thickness progression by 10, 20, 30 or 40 micrometers per year would yield relative risks of 0.84, 0.76, 0.69 or 0.63 each incrementing with the magnitude of reduction in micrometers per year. Results were similar when grouping trials by type of intervention. Time of conduct, time to ultrasound follow-up, availability of individual participant data, primary versus secondary prevention trials, the type of carotid intima-medial thickness measurement, and the proportion of women in the studies.
Dr Carolyn Lam: So could you summarize that Greg?
Dr Greg Hundley: You bet, Carolyn. So the extent of intervention effects on carotid intimal-medial thickness progression predicted the degree of cardiovascular disease risk reduction. This provides a missing link supporting the usefulness of carotid intimal-medial thickness progression as a surrogate marker for cardiovascular disease risk prediction in clinical trials.
Dr Carolyn Lam: Indeed. Thanks, Greg. It's important because it also quantifies that risk reduction. Very nice. Now let's just round up with some other papers in the issue. There is a perspective paper by Dr Bunch on Dementia and atrial fibrillation, a research letter by Dr Ellinor on myocyte specific upregulation of ACE two in cardiovascular disease, the implications for our SARS-coronavirus to mediated myocarditis. There are letters to the editor regarding the article small extra cellular macrovesicles mediated, pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanism, exacerbating ischemia reperfusion injury in diabetic mice. These letters were by Dr Li with response by Dr Ma. There's a research letter by Dr Natarajan on genetic variation and cardiometabolic traits and medication targets and the risk of hypertensive disorders of pregnancy.
Dr Greg Hundley: Carolyn, I've got a couple other features to describe. Aaron Baggish and Ben Levine provide an On My Mind piece, related to sports after COVID-19. Jeffrey Smietana has an ECG challenge regarding an ELVAD artifact. Then finally, Bridget Kuhn has cardiology news related to an announcement from the Association of Black Cardiologists calling for an urgent effort to address health inequality and diversity in cardiology. Can't wait to get to that feature discussion and that really unique twist in cardio-oncology.
Dr Carolyn Lam: Here we go. Greg.
Based feature discussion. We are diving into the world of cardio-oncology. Now, usually that refers to the intersection between cancer and cardiovascular disease, where we usually talk about cancer and cancer treatment effects on the cardiovascular system. But emerging data now suggests the concept of reverse cardio-oncology, whereby heart disease potentiates cancer. Today's feature paper really provides very important and significant preclinical data to support this. I'm so pleased to have with us, the corresponding author, Dr Ami Aronheim from Israel Institute of Technology, as well as our associate editor, Dr Thomas Eschenhagen from University Hospital Hamburg Eppendorf in Germany. Ami, thank you very much for joining us today. Please. Could you walk us through your very elegance study and the results?
Prof Ami Aronheim: We used a model, which is called the transfers, all the constriction, which promotes pressure overload on the heart. Actually following this procedure, we implanted cancer cells into mice and we followed the growth of these tumors. Actually we found out that the tumors of a tuck operated mice is growing much faster. Also when we used a metastatic model, namely, when we injected cells into the tail vein, we obtained more metastatic lesions in the lungs. Actually we found out that the serum from these mice is able to promote the variation of cancer cells in vitro. Then we also identified a protein, which is potentially promoting these cell proliferation in vitro.
Dr Carolyn Lam: That is really significant. I mean, am I right that this is the first study to show that cardiac remodeling actually promotes tumor growth and metastasis and this is probably via secreted factor.
Prof Ami Aronheim: This is the first paper showing that early events of cardiac remodeling promote cancer cell proliferation. It is known that heart failure by the work of De Boer’s group, that heart failure is promoting cancer load in mice. This paper was also published in Circulation 2018.
Dr Carolyn Lam: Indeed. Thank you for reminding me about that. And I am a huge fan of Rudolph de Boer and his work. Indeed. Could I ask though, in your study, did you identify a particular secreted factor?
Prof Ami Aronheim: We looked at the RNA seq from conduct remodeled heart, and we looked for secreted factors in the heart and we focused on two secreted factors CTGF and periostin, which are known to promote cancer growth. And indeed we found in our mice models that reduced in level is increased in the serum of mice of tuck operated mice. Once we deplete the serum from periostin, we ambulated this increase in cell proliferation.
Dr Carolyn Lam: Wow. So periostin appears a culprit, but I'm sure the listeners are dying to know. Was there any human data that you had that supported the animal findings?
Prof Ami Aronheim: The model in mice, the tack operation, it's hard to find the right model in human because the operation is really rapid. When the mice wake up, they have this pressure overload, the only disease which in human correlates or is mimicked by the tag is Altucher's stenosis, which is the restriction of the outtake evolve, the right aortic valve]. And we looked in these patients and what we found out, we looked at the echo cardiography data of a lot of patients. We actually found out that for young basically patients 40 to 60 years old, if they have moderate to severe aortic stenosis, they have higher risk to develop cancer about 1.6-fold higher than our external these patients. Although I must say with caution that this size group is quite small and it should be repeated with much higher number of patients.
Dr Carolyn Lam: Wow. Thank you so much, Ami. Thomas, I have to bring you in here. Thank you for managing this very remarkable paper. Could you share some thoughts on what you think this means for the field?
Thomas Eschenhagen: We all immediately as editorial team like this paper. When it came in on the background of the different paper, it really provides significant additional evidence that this interaction between cancer and the heart is two sided. And that's, as you said in the intro, that's really very important. And it's all very interesting that apparently these two different models used by Rudolf de Boer, which wasn't ischemia myocardial injury model. And here it's a hypertrophy model with early remodeling. They both do similar things, but apparently by different mechanisms. Because the number of the factors identified in the de Boer paper do not match with, with these two factors, CTGF and periostin. And for both, I think we have now convincing evidence that they may play a role, but it also shows that this is probably a quite complex interaction between the heart and the cancer. That makes it extremely interesting.
Of course it's important because it's such a common comorbidity, I mean, cancer, cardiovascular diseases, are the most prevalent and the second most prevalent diseases is cancer. So this interaction must be very, very important. And it's very good that these two papers now focus of you on the reverse side and not only on the classic cardiac toxicity side, which me as pharmacologists, of course, we, I was always interested in.
Dr Carolyn Lam: Yeah, indeed. I mean, Thomas me too. As a heart failure clinical trial list and epidemiologists, if I may, I always thought it was just shared risk factors, you know, age being particularly one of them.
Thomas Eschenhagen: Obviously, as you said, shared risk factors do play a role must, must their role. So it's certainly not only this direct interaction, but this new paper shows that there is in addition to this risk factor model, something specific. And that of course could be, I mean, at least theoretically be addressed.
Dr Carolyn Lam: For both Thomas and Ami, what do you think are the implications now? I mean, should we be screening all patients with aortic stenosis more closely for cancers? What do you think are the clinical implications? Maybe Ami first?
Prof Ami Aronheim: I think cardiovascular disease patients are already watched very carefully beforehand. But certainly I think that they should be also observed for cancer specifically. So yes I believe it should be. Also I this cardiovascular treatment should consider to make them early as possible to avoid any interaction with cancer.
Dr Carolyn Lam: Yeah, that completely opens the field to, for example. Early aortic valve replacement, reducing subsequent cancer risk, like you mentioned in your paper, I mean, that's just mind blowing. Thomas, what do you think?
Thomas Eschenhagen: I agree, 10 years ago, we said that more cancer patients, particularly those under treatment should be sent to the cardiologist to look for the heart. Now we will say the other way around as well. We really need to look more carefully for cancer. So I think this paper and the other one have the consequences we should do more here. There's also obviously a number of very interesting questions because one of the findings I found fascinating in this paper by Ami and this group was that this mouse strain, which finally did not show the classical science of remodeling after transverse aortic striction. So no BNP, no NP, no BDMEC increase in this small strain. There was no increase in cancer growth.
Very interesting, because normally you would think somehow that these mice, which were kind of normal in the cardiac response would be worse, but in this respect they were better. So that's a very interesting aspect. The second aspect I found really fascinating is the human data suggest, I guess it's quite preliminary data, but there's a suggestion here that this interaction is mainly seen in younger patients. And I'm not quite sure what that means, but it's something to look at.
Dr Carolyn Lam: Wow. Thanks for highlighting those Thomas. So Ami maybe the last word from you. Given all of this remaining questions and so on, what are your next steps?
Prof Ami Aronheim: First, I wanted to comment something more wide view for this interaction that we find with cancer. I think all the organs actually communicate with one another. The fact that we are looking on a heart and cancer, this is due to the fact that it's easy. We have the models working in the lab and it's easy. But I'm sure if we're going to look to other diseases and other organs, there will be other connections of the heart with other organs and other diseases and maladies, which by conducting modeling, they will promote or maybe even reverse other maladies. So I'm sure that there is a communication between all organs, many organs altogether, and they will affect one another.
Our directions currently are to look more precisely for the periostin story because we follow this mainly in vitro and would like to follow it in vivo. Also I think this mice model are nice, but to look also in human, where the periostin in aortic stenosis patients, where then, we can find out earliest in, in the serum before intervention, and to look after whether this secreted factor goes down or reduced. Also we are looking in other transgenic model that we generated along the years, which are known to result in cardiac modeling. We want to see whether these mechanisms are similar or different and whether they can promote also cancer progression. The use of these transgenic mice is very nice because we can induce them and we can shut down them so we can learn more about the kinetic, which influence one another, and exactly whether they can be reversed or not.
Dr Carolyn Lam: Thank you so much Ami for sharing your thoughts on those future actions, a lot of work and such worthwhile areas to explore. Thank you too, Thomas for sharing your thoughts.
Listeners. Thank you for joining us today on circulation on the run.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, guess what we're discussing for the feature discussion? We're talking about sugar sweetened beverage tax. Isn't that interesting? We talk about sugar sweetened beverages and their health impacts, but don't actually look at how tax policies may impact cardiovascular outcomes. So this paper is super interesting, can't wait to get to it, but I really want to get my cup of coffee and discuss a couple of other really cool stuff in today's issue. I'm going to start. Do you think about factor V Leiden much?
Dr Greg Hundley: Carolyn, we are early in August and we have all new house officers rotating, and actually we do discuss factor V Leiden, and we think about Protein C and Protein S deficiencies, et cetera. But how about if you tell us about your paper and educate us a little bit more on the topic?
Dr Carolyn Lam: Okay. So first of all, it's Leiden or Leiden, I'm not sure. So I'm going to go with your pronunciation. Factor V Leiden is a genetic variant leading to alteration of the inactivation site of factor V, which in turn leads to activate a Protein C resistance and a prothrombotic state, just like you said, Greg. Affecting almost 5% of the Caucasian population, carriers of a factor V Leiden mutation have a fourfold higher risk of venous thromboembolism. However, the risk of arterial atherothrombotic events, such as myocardial infarction or stroke, conferred by the presence of this variant is less certain. So Dr Patel from University College London, and Dr Asselbergs from University Medical Center Utrecht and colleagues assess the association of the factor V Leiden polymorphism with subsequent atherothrombotic events, including mortality in individuals with established coronary heart disease using an individual level data meta-analysis of 25 prospective studies from the genetics of subsequent or GENIUS coronary heart disease consortium.
Dr Greg Hundley: Well Carolyn, what did they find?
Dr Carolyn Lam: In nearly 70,000 patients with established coronary heart disease, factor V Leiden was not associated with an increased risk of further atherothrombotic events or death compared to non-carriers. A post hoc analysis, however, suggested that factor V Leiden carriers with established coronary heart disease may gain greater protection from subsequent coronary heart disease, death, or myocardial infarction from dual antiplatelet therapy compared to non-carriers. The routine assessment of factor V Leiden genotype to improve risk stratification in secondary prevention settings is therefore unlikely to be of value and is not recommended. However, further work is required to understand if there may instead be a pharmacogenomic role for factor V Leiden status to help personalize treatment with intensive antiplatelet therapy.
Dr Greg Hundley: Very nice, Carolyn. Well, my next paper is from Dr Michelle O'Donoghue from Brigham and Women's Hospital, and creates an interesting question for you, Carolyn. Would you be comfortable discontinuing aspirin three months after PCI in lieu of continuing a P2Y12 inhibitor?
Dr Carolyn Lam: Ah, big, big question. Not until guidelines change, but tell me, tell me, tell me, Greg, what this paper said.
Dr Greg Hundley: Well, before we get some of these more randomized trial, this study included a meta-analysis of 32,145 patients, 14,095, or 43%, with stable coronary artery disease and 18,000, nearly 56%, with ACS from randomized trials during the time period of 2001 to 2020. And they had to study discontinuing aspirin one to three months after PCI with continued P2Y12 inhibitor monotherapy compared to traditional dual antiplatelet therapy. Five trials were included, and the follow-up duration range from 12 to 15 months after PCI. The primary bleeding and MACE outcomes were the pre-specified definitions in each trial.
Dr Carolyn Lam: An important study. So what did they find, Greg?
Dr Greg Hundley: Well in the experimental arm, background use of a P2Y12 inhibitor with Clopidogrel in 16.5% of cases, and prasugrel or ticagrelor in 84% of patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. So the results, discontinuation of aspirin therapy one to three months post PCI significantly reduced the risk of major bleeding by 40% compared to dual antiplatelet therapy with no observed increase in the risk of MACE, myocardial infarction, or death. The findings were consistent among patients who underwent PCI for an ACS in whom discontinuation of aspirin after one to three months reduced bleeding by 50%, to 1.78% versus 3.58%, and did not appear to increase the risk of MACE where both were 2.5% and 2.98%.
Dr Carolyn Lam: Nice, Greg. Could you summarize the take home message for us?
Dr Greg Hundley: Sure, Carolyn. So in summary, discontinuation of aspirin with continued P2Y12 inhibitor monotherapy reduced the risk of bleeding when stopped one to three months after PCI. An increased risk of MACE was not observed following discontinuation of aspirin, including patients that had previously sustained ACS.
Dr Carolyn Lam: Thanks Greg. Well, my next paper is a preclinical one showing that circular RNAs delivered via extracellular vesicles may be a new treatment for ischemic stroke.
Dr Greg Hundley: Oh my goodness. Carolyn, can you orient us to circular RNAs and these extracellular vesicles?
Dr Carolyn Lam: Sure, Greg. I decided not to quiz you on them. Circular RNAs are a type of endogenous non-coding RNA molecule characterized by back splicing and covalently closed continuous loops, hence circular. Previous studies have demonstrated that multiple circular RNAs have functional roles relating to ischemic brain injury. Although administering circulating RNAs using lentiviruses is efficient for experimental examination, this route is limited for clinical translation due, of course, to disadvantages in onset time and safety issues. So this is where the extracellular vesicles come in as a potential cargo delivering system, if you may, for brain remodeling after stroke. These extracellular vesicles are lipid membrane vesicles of 30 to 150 nanometers in diameter that are released by cells and can cross the blood brain barrier and have been shown capable of carrying proteins, lipids, and nucleotides as their cargo.
So today's co-corresponding authors, Dr Yao from Medical School of Southeast University in Nanjing, and Dr Wang from Chinese Academy of Sciences Kunming, Yunnan in China envisioned the potential of delivering candidate circular RNAs to the brain in vivo by constructing engineered extracellular vesicles bearing circular RNAs. They initially explored this circular RNA delivery strategy idea in the context of their ongoing work regarding the functional roles of circulating RNAs in ischemic brain injury. Their microarray based profiling of acute ischemic stroke patients reveal that a circular RNA generated from the SCM-polycomb group protein homolog 1, or SCMH1 gene, is decreased in plasma of acute ischemic stroke patients and confirmed that a similar decrease occurs in stroke model mice. So they successfully engineered extracellular vesicles with circular SCMH1 over-expression and were thus able to experimentally characterize the ischemia related functional benefits of this circular RNA administration in stroke models in both mice and macaque monkeys. Cool, huh?
Dr Greg Hundley: Yeah. Very nice, Carolyn. That was a great explanation. My study comes from Dr Juyong Kim from Stanford University School of Medicine, and Carolyn, this study combined RNA sequencing, chip sequencing, ATEC sequencing, and in vitro assays in human coronary artery smooth muscle cells with single cell RNA sequencing, histology, and RNA scope in a smooth muscle cell specific lineage tracing aryl hydrocarbon receptor knockout mouse model of atherosclerosis to better understand the role of the aryl hydrocarbon receptor in vascular disease. This aryl hydrocarbon receptor, heretofore AHR, is an environment sensing transcription factor that contributes to vascular development.
Dr Carolyn Lam: Wow, what a comprehensive study. So what do they find?
Dr Greg Hundley: The authors identified a novel population of cells derived from smooth muscle cells, termed condramyocytes, which have gene expression features of cartilage and bone formation within an atherosclerotic lesion. In addition, the environment sensing transcription factor aryl hydrocarbon receptor plays an important role in smooth muscle cell differentiation, ossification, and maintains the smooth muscle cell derived fibrous cap structure.
Dr Carolyn Lam: Interesting. Okay, you know what I'm going to ask. What are the clinical implications?
Dr Greg Hundley: Yeah, I knew you'd ask me that, Carolyn. So human genetics suggests a protective role of the aryl hydrocarbon receptor in the smooth muscle cell during atherosclerosis, and therapies targeted to increase the aryl hydrocarbon receptor activity in smooth muscle cells may confer protection against adverse calcific remodeling of the atherosclerotic plaque. This study also highlights a methodological advance, and further characterization of the pathways that direct the modulation of smooth muscle cells during atherosclerosis at the single cell level may be able to identify potential therapeutic targets to mitigate the risk of atherosclerosis.
Dr Carolyn Lam: Oh, I like that summary, Greg. Thanks. Now, let's move on to other things in today's issue. There's a perspective by Dr Al-Lamee on the ISCHEMIA trial asking was it worth the wait? There's also a perspective by Dr Levine on the ISCHEMIA-CKD trial, providing contemporary randomized clinical data at last in this important population. There's a white paper by Dr Emmaullee on Fontan-Associated Liver Disease, screening, management, and transplant consideration. And finally, there are letters to the editor from Dr Helgestad, Chieffo, and Waksman, with replies from Dr Amin on the article The Evolving Landscape of Impella Use in the United States Among Patients Undergoing PCI With Mechanical Circulatory Support.
Dr Greg Hundley: Very good, Carolyn. Well, I have a few other items in the mail bag. Xiang Cheng has a research letter entitled Cardiac Troponin I is an Independent Predictor for Mortality in Hospitalized Patients with Coronavirus Disease 2019. Also, Corinne Frere has a research letter regarding the Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy, and they provide insights from a perspective single center cohort study. And finally, Dr Jeffrey Wagner has an ECG challenge regarding the infamous is it VT or not VT? Well, Carolyn, how about we get on to that feature discussion.
Dr Carolyn Lam: Let's go, Greg. Beverage Texas are a promising policy approach to reduce consumption of sugar sweetened beverages. And as we know, these are linked to adverse health outcomes, such as Type 2 diabetes and obesity. Now these taxes have been adopted by seven localities in the United States, and in more than 40 countries around the world using different tax designs, but until now a critical answered question where we lack empirical data is the health impact of these beverage taxes. That is until today's feature paper, and I'm so pleased to have with us, Dr Yujin Lee from Friedman School of Nutrition Science and Policy, Tufts University, as well as our associate editor, Dr Naveed Sattar from University of Glasgow. Welcome both, and Yujin, could I start with you please? What an interesting and important idea to look at this. Could you start by perhaps first explaining to us what are the different types of tax designs?
Dr Yujin Lee: There are three types of tax design. First, the volume tax is taxing sugar sweetened beverages based on the volume. For example, a penny per owns for volume tax. So the tax rate is same whether a beverage contains 5 or 20 grams of added sugar for 8 ounces. The second design is the absolute sugar content tax, which is taxing beverages based on the sugar content regardless of the volume. So for example, one cent per one teaspoon of sugar, or one cent per one gram of sugar. Lastly, tier tax is hybrid of volume and absolute sugar content tax. For example, creating different tiers products based on the sugar content and taxing based on the volume at different rates. So for example, the American Heart Association suggested three tiers. First, no tax on beverages with less than five grams of added sugar per eight ounces. And second, 1 cent per ounce on beverages with 5 to 20 grams of added sugar per 8 ounces. And lastly, 2 cents per ounce on beverages with more than 20 grams of added sugar per 8 ounces.
Dr Carolyn Lam: Great. So thank you for explaining that. I mean, to be honest, I didn't even realize there were so many different tax designs. Now, could I understand a bit better? So in the US, are they mostly volume-based? And then perhaps you could tell us how did you go about your study of comparing these things, and looking on their impact on outcomes.
Dr Yujin Lee: Sure. So as you mentioned, all seven US locality have been implementing the volume tax, and in this study, this is the modeling study, so we're using the nationally representative data and using a microsimulation model, and we wanted to compare and estimate the health and economic impact of the volume, absolute sugar content. And the tier tax designs in the United States.
Dr Carolyn Lam: Great. And tell us what you found.
Dr Yujin Lee: What we found is we found that implementing a volume-based sugar sweetened beverage tax could prevent 850,000 cardiovascular events and 270,000 diabetes over a lifetime of current US adults aged 35 years or older. And this tax design could save tens of billions of dollars in healthcare costs. In addition, taxing sugar sweetened beverage based on their sugar content, for example, the tier or absolute sugar content based tax design, could generate about double the health and economic benefits compared to the volume tax.
Dr Carolyn Lam: Wow, that is so intriguing. Naveed, I have to bring you in here. So in the UK they use a tier tax. Do you? And what are your thoughts?
Dr Naveed Sattar: Oh, well clearly, Carolyn, I mean, I think taxation of sugar sweetened beverages is something that all of us can agree on is beneficial. I think it's really important that many other countries and states consider this. I'm surprised that only seven states in the US are currently doing this. And in some respects, this papers is very timely. It's based on modeling. I mean maybe you can come back to Yujin about how good the modeling is, but if you think about the issue we have now in terms of health inequalities and COVID related deaths, going forward we need mechanisms to help reduce health inequalities. And this particular paper will flag up that places need to think about sugar sweetened beverage taxes and how best to do them.
And I completely agree, they should be based on sugar content. I don't see why they should be more convoluted than that. And although Yujin explained it, it still seems a bit complex to me, the different mechanisms, but I think your paper is very timely and very important. And for me, the key question for Yujin is people looking at this may say well, how robust is that model? How do we know how accurate you've been in terms of the money saved, because that's going to be really important going forward, and in particular, the number of lives or cardiovascular and diabetes cases prevented?
Dr Yujin Lee: Sure. So let me explain how we estimated how many cases of cardiovascular disease and Type 2 diabetes were prevented. So we use a microsimulation model, which is a computer simulation model, which is developed by the research team, led by Dr Thomas Casiano and Harvard School of Public Health. So this model predicts the probability of an individual experiencing cardiovascular disease or diabetes based on each person's risk factor, such as sex, age, total cholesterol, or smoking or diabetes, and also their SSB-consumption also be part of this input. So it estimate the probability of one person, individual, developing the future cardiovascular disease, or Type 2 diabetes, and it estimate how this prevention can save healthcare costs associated with these diseases. So in this study, this model simulates the status quo, so the way things now stand, and also it assimilate the three different tax design. After that, we compute the health outcome and costs associated with this policy options and, by comparing this model, outputs for these three tax design with the status quo.
Dr Naveed Sattar: Has any country got long enough perspective data that have implemented such taxes to validate the model, or is that still to come? I mean it would be nice to get it validated in real life, but I think most people would accept that reducing sugar in beverages is a really good thing, and presumably the part of the mechanisms by reducing weight, and reducing all of the implications of excess calorie intake, particularly refined sugar, on a variety of different diseases. Is that fair?
Dr Yujin Lee: Yeah, and I wanted to make a point that, since this is a modeling study, so our study cannot prove the health and economic impacts of this tax design in the United States, so rather our estimates provide evidence that can be considered and incorporate into the design, and implementation, and evaluation of future SSB taxes.
Dr Carolyn Lam: That's a really good point. And maybe just to round up, Yujin, could I just ask you to were any particular individuals in the population simulated to experience larger gains? We know that it's exactly like Naveed said, it's the minorities, it's perhaps lower income region individuals who might need this more. I mean did your simulation show anything to that effect?
Dr Yujin Lee: We also investigate this tax design and how this influence in sub population. Particularly we found that the SSB taxes have a larger benefit among younger adults, minorities, and adults with the lower income. Given that these population, their SSB consumption is higher than the other group, so this SSB tax implementation gives them a greater health and economic benefit to these subpopulations.
Dr Carolyn Lam: Thank you so much, Yujin, for this really, really, I think, novel and very important data. Naveed, could I give you the last say as the associate editor who is managing this, and you even invited an editorial, which I liked very much, the title, Simple is Better for Local Beverage Tax Policy Diffusion. It's kind of in line with what you've been saying, but maybe some take home messages?
Dr Naveed Sattar: Obviously in Circulation, we get lots of beautiful papers that very molecular depth and various other factors, but actually this paper brings us back to the reality that for many of the diseases that we treat, diet and drink intake is really relevant to our diseases and the likelihood of diseases, and there are simple mechanisms whereby we can help people in the community to actually lead better lifestyles that also are actually economically beneficial. And I think that in this paper, if it was to be implemented and looked at seriously by many states in the US, by many other countries to go along this route would have huge potential benefits on health, And it's really important at this time, given what's happened with the pandemic, and as we move forward over the next 5 to 10 years. So I think it's really timely and I congratulate the authors on it.
Dr Carolyn Lam: Well, listeners, you heard it right here, novel, impactful data. That's what Circulation is about. Thank you for listening to Circulation on the Run. Don't forget to tune in again. Next week.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia.
Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains?
Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe?
Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress.
Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find?
Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease.
Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same?
Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different.
Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart.
Dr Carolyn Lam: Wow. What did they find?
Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.
Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common?
Dr Greg Hundley: I definitely need phone a friend.
Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms.
Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI.
Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg?
Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate.
Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find?
Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points.
Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19.
Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR.
Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we?
Dr Greg Hundley: You bet.
Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found.
Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock.
So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation.
Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too.
Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies?
Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease.
We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function.
Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not?
Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome.
But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease.
Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts.
Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution.
And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It’s just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them.
Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community?
Dr Damien Bonnet: And that there are clinical issues. So the first one is to see or to look at potential cardiac residual anomalies, mitochondrial or coronary arteries aneurism, because today we have not precise information of that.
The second is probably observational because it will be difficult to randomize young children, is what is the optimal treatment at baseline or what is the optimal strategy? And is it possible to stratify the strategy as I just said, but I don't have evidence for that. And for the long term, I think that trying to identify why only some children have this disease and why the other don't have, if there is any genetic susceptibility, it will be something interesting. And potentially as we discussed already together, it might give us some keys to better understand Kawasaki disease as well.
Dr Gerald Greil: Thank you so much for summarizing that. I mean, we are all very much looking forward to working together with you and other groups around the world to get a little bit more and better insight in this kind of type of disease and how to treat them best and how to follow them up best.
Dr Carolyn Lam: Thank you so much, Damien and Gerald. I mean, I'm sure I speak behalf of the entire audience that I learned a lot just listening to your very open and honest conversation of what we've seen, what we've experienced, what we don't yet know. Listeners, you have to refer to a beautiful accompanying editorial that Gerald invited, and it is by Dr John Simpson and Dr Jane Newburger from Evalina London Children's Hospital and Harvard Medical School, respectively.
Thank you so much for joining us today. And please remember, you've been listening to Circulation on the Run. Tune in again next week.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Our feature paper today discusses trans-ethnic genome-wide association studies and the insights in the genetic architecture and heritability of long QT syndrome, a massive study that we will be digging into, but only after we talk a little bit about the other papers in this week's issue. And I'm going to start, Greg. Are you ready with your coffee?
Dr Greg Hundley: I am.
Dr Carolyn Lam: The first original paper really represents seminal work, showing that the endothelium can directly regulate obesity and insulin resistance. Now, as obesity develops, there is a decline in adipose tissue vascularity, which seems counterintuitive, and an increase in fibrosis.
So authors, led by Dr Chen from the Irell and Manella Graduate School of Biological Sciences in the City of Hope, speculated that the reduction in vascularity in this adipose tissue might have an adverse effect on adipose tissue function. Now, these authors previously identified Argonaute-1, or AG01, a key component of microRNA-induced silencing complex, as a crucial regulator in hypoxia-induced angiogenesis.
So in the current study, they aim to determine the AG01-mediated endothelial cell transcriptome, the functional importance of AG01-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity.
A new mouse model with genetic deletion of AG01 in the endothelium was useful to investigate the importance of endothelial regulation of adipose tissue function. The findings were that in mice fed high fat, high sucrose diet, the suppression of endothelial AG01 promoted adipose tissue browning, and led to an anti-obesity phenotype. Endothelial cell AG01 thrombospondin-1 pathway was induced in the endothelium from human donors with insulin resistance.
In total, this study suggests a novel mechanism, by which endothelial cells through AG01 thrombospondin-1 pathway controls vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.
Dr Greg Hundley: Interesting, Carolyn. So tell me about this clinically. Where do we take this from here?
Dr Carolyn Lam: I thought you would ask. So endothelial dysfunction, per se, can cause metabolic dysregulation, rendering targeting dysfunctional endothelium, a potential therapeutic strategy to counteract obesity, and metabolic disorders. So this study really opens a door to that.
Dr Greg Hundley: Very nice. Well, I've got another basic science paper, and it evaluates single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. And it comes from Dr Jiangping Song from the State Key Laboratory of Cardiovascular Disease of Fuwai Hospital, and the National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, and Peking Union Medical College.
So Carolyn, the study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy, and to identify the genes contributing to the inflammatory response to myocarditis.
So mice were treated with myosin heavy chain alpha-peptides to generate an experimental autoimmune myocarditis model. The investigators performed single-cell RNA sequencing analysis of CD45 plus cells extracted from mouse hearts during different experimental autoimmune myocarditis phases, including normal control, acute inflammation, subacute inflammation, and then in the myopathy phase. Also, human heart tissues were collected from surgically removed hearts of patients who had undergone heart transplantation.
Dr Carolyn Lam: So what did they find, Greg?
Dr Greg Hundley: Well, Carolyn, a comparison of the single-cell RNA sequencing data from different experimental autoimmune myocarditis phases suggested that some cell clusters, such as macrophage cluster 2 and Th17 cells, were associated with the inflammatory response in the experimental autoimmune myocarditis model.
The HIF1A expression level correlated with the extent of the inflammatory response, and PX-478, a HIF1A inhibitor, alleviated the inflammation during the different experimental autoimmune myocarditis phases.
Immunohistochemical staining revealed that HIF1A expression was upregulated in autoimmune myocarditis from the tissue samples from the explanted hearts. Thus, the HIF1A inhibitor alleviated inflammatory cell infiltration, and that may serve as a potential therapeutic target in clinical practice.
Dr Carolyn Lam: Wow. That is some serious clinical implications. Well, my next paper is really the first systematic echocardiographic evaluation of consecutive patients requiring hospitalization due to COVID-19, and it comes from Dr Topilsky and colleagues from Tel Aviv Medical Center.
Dr Greg Hundley: So Carolyn, what did they find in this series?
Dr Carolyn Lam: So among a hundred consecutive patients diagnosed with COVID-19 infection who underwent complete echocardiographic evaluation, within 24 hours of admission, only 32% had a normal echocardiogram at baseline. The most frequent abnormality was right ventricular dilatation or dysfunction.
Among patients developing clinical deterioration during follow-up, which were 20% of these hospitalized patients, repeated echocardiograms showed further deterioration of the right ventricular parameters, probably related to increased pulmonary resistance. Five of these patients had deep vein thrombosis.
Dr Greg Hundley: Carolyn, my next study comes from Dr Stephen Fremes, and it's a modeling study out of the University of Toronto. It modeled TAVR versus SAVR valve durability to determine the effects on life expectancy across a broad range of age.
Dr Carolyn Lam: Interesting. And what were the results?
Dr Greg Hundley: Well, based on their simulation models, the durability of TAVR valves must be 70% shorter than that of surgically replaced valves to result in reduced life expectancy in patients with similar demographics to recent trials.
However, in younger patients, the threshold for TAVR valve durability was substantially higher. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40% and 50% shorter than surgical valves in 40, 50 or 60-year-old patients, respectively.
So Carolyn, these findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low-risk patients, based on current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors, such as life expectancy.
Dr Carolyn Lam: Thanks Greg, for that summary. Well, let me tell you about other papers in this issue. There are a pair of letters to the editor by Dr Opotowsky, and a response by Dr Goldberg regarding the paper results of the Fontan Udenafil Exercise Longitudinal, or FUEL trial.
There's a research letter by Dr Strik, Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. There are two On My Mind papers, the first, Telemedicine and Forgotten America by Dr Julien, and the second, The COVID-19 Pandemic: Ethical and Scientific Imperatives for "Natural" Experiments by Dr Lewis.
Dr Greg Hundley: Very nice. Well, Carolyn, I've got a research letter evaluating the effect of evolocumab on atherogenic lipoproteins during the peri and early post-infarction period. It's a placebo-controlled randomized trial from Dr Gary Gerstenblith.
Sarah Cuddy also worked through a tough case of cardiac amyloid when a fat biopsy was negative, but imaging studies of the heart suggested cardiac amyloid.
Carolyn, I've also got an On My Mind piece, and it's entitled, Can Old Ally Defeat a New Enemy? And it's by Dr Paul Gurbel, and he discusses the use of inhaled aspirin to treat patients with COVID-19.
And then finally, Carolyn, I have a prospective piece from Dr Robert Lefkowitz who discusses β-arrestin-biased angiotensin II receptor agonists for treatment of COVID-19. Well, Carolyn, what a great issue, and let's get onto that feature discussion.
Dr Carolyn Lam: Yay. Let's go, Greg.
Dr Greg Hundley: Well, listeners. Now we're turning to our feature discussion, and we are very fortunate to have Professor Connie Bezzina from Amsterdam University Medical Center to talk to us about her paper related to long QT syndrome.
Welcome, Connie. And I was wondering, before we get started in discussing your paper, could you tell us a little bit about the background in this area? And then, what was the hypothesis that you wanted to address?
Prof Connie Bezzina: So over the last 20 to 30 years, we've learned a lot about the genetic underpinnings of inherited cardiac disorders associated with sudden cardiac arrest. And basically, we've learned a lot about mutations in specific genes that co-segregate with these disorders within families.
However, two outstanding features have remained unresolved. Essentially, the first unresolved issue is the fact that we observe, oftentimes, a low disease penetrance and variable disease expression within families, which means that not everybody within a family that carries a familial mutation is affected by the disorder.
But two, so among those that are affected, some are affected more severely than others. So some people would have only the ECG abnormality, whereas other people, for instance, would have the ECG abnormality and arrhythmic events. And you could also have individuals, indeed, who don't even manifest any disease manifestations. This is one of the outstanding challenges.
The other outstanding challenge is the fact that, despite extensive genetic testing of the known genes in some probands and some families, they remain genetically lucid, in that we don't find a likely genetic defect in a minority of families. And of course, that hinders genetic testing and implementation of genetic testing in such families.
Dr Greg Hundley: What was the question you were going to answer with your study? And tell us a little bit about your study design and your study population.
Prof Connie Bezzina: Yeah, so essentially, we figured that assigning these disorders to one large genetic defect might be an oversimplification of biological phenomenon. So we hypothesized that even in these Mendelian disorders, the inheritance of additional genetic factors alongside the familial mutation could contribute to risk. Of course, there will be other factors such as environmental factors, which we did not tackle in the study.
The central hypothesis of the study was that common genetic variation, which is present in the germ population, could modulate the effect of the familial genetic defect of the Mendelian mutation.
So in order to do this, we assembled a large consortium of investigators from multiple centers in Europe, in North America and Japan, worldwide, to bring together about 1700 probands with the long QT syndrome. So we tested this hypothesis in the long QT syndrome because we figured, among the rare inherited rhythm disorders, it's one of the more common disorders. Also, because each individual center has too few patients. To do this locally, we put this group of investigators together to come up with 1700 probands.
The study design was a genome-wide association study with a case-control design, where we tested the association of millions of SNPs littered across the genome with susceptibility for the disorder. So this led us to identify three single-nucleotide polymorphisms that are associated with susceptibility for the long QT syndrome.
What we immediately saw is that, actually, these three SNPs, perhaps not surprisingly at all, had been previously associated with the extent of the QT interval, with QT interval in the general population. This is not surprising, of course, because repolarization is a central part of physiological mechanism in the long QT syndrome. So this basically indicated overlap between genetic control of the QT interval in the germ population and susceptibility to the long QT syndrome.
So the fact that the three SNPs that we identified as long QT syndrome susceptibility SNPs had been associated with QT interval duration in the germ population, we felt that that was pointing to assure genetic underpinnings between these two phenotypes.
So we went on to investigate that by looking at the correlation between the odds ratio for long QT syndrome susceptibility and the effect that these SNPs have on QT interval in the germ population. And in fact, we found a very high correlation between those. So essentially, this pointed to sure genetic factors between QT interval in the germ population and long QT syndrome susceptibility.
Of course, we wanted to look for disease variability. The next thing we wanted to do was whether these SNPs could actually explain disease variability. Now, this was perhaps the most disappointing part of the study, because when we constructed a polygenic risk score based on SNPs that impact on the QT in the germ population, we found no relation to QT interval among patients, and also no relation to life-threatening arrhythmic events among the patients.
We think that this is because our patients... or probrands. They're primarily probands, so they are all more sick. So we didn't have enough variability in our patient set to identify an association with disease variability. And in fact, this is at variance with previous studies that tested individual SNPs, and even our own studies with smaller polygenic risk scores that did find an association between a polygenic risk score based on QT SNPs and QT prolongation and events among patients.
So we think that this is certainly something to study further in the future, in larger patient sets where we not only have the probands, but also their relatives, their mutation-carrying relatives, which will give us a bigger variability to actually test this hypothesis. So we think that looking at probands actually was a very good design to find susceptibility variance but was not maybe a good design to find SNPs or polygenic risk scores to test their effect on disease variability.
Dr Greg Hundley: It sounds like you've found certain gene low PSI that indicate a predilection for prolongation of the QT interval, but not necessarily are those gene low PSI consistent with who's going to experience an adverse cardiovascular event as a result of their genetic constitution. Is that a fair statement?
Prof Connie Bezzina: Well, I think that the setting, because we had probands, they were the most sick people in their families. I think to have stronger conclusions on that, we need to test the polygenic risk scores in families where there are people who are differentially affected.
Dr Greg Hundley: I see. I-
Prof Connie Bezzina: We had too-narrow of a variability in a probands-only design, as opposed to a study where we would have probands who are severely affected and mutation-carrying relatives who are less severely affected.
Dr Greg Hundley: Very nice. So that puts that clearly into context. This was a massive effort. You have quite a list of investigators, and you mentioned you had to gather so many sites. How would you conduct that next study? Would you need another large collection of individuals and many sites to take that on?
Prof Connie Bezzina: Yes. I'm a geneticist, and geneticists always want larger, larger numbers, and I'm also one of those. So I'm interested in explaining as much as possible into individual variability. And I think to do that properly, I think we should go preferably for a similar design where we will approach the same centers. And hopefully, we can organize the next study, which will have these probands and their relatives.
Dr Greg Hundley: Now, just quickly, for us working in the clinic, how should we approach genetic testing in patients with long QT?
Prof Connie Bezzina: At the moment, I think our findings don't have an immediate impact. I think our findings tell us about the genetic architecture of the disorder. And actually, one thing I haven't gone into yet is the fact that what we also found is that patients who do not have mutations in the no-long QT genes, which were called mutation-negative, which are about 20% of all long QT syndrome probands, actually have a higher burden of these common variants that prolong the QT interval.
So we think, actually, that mutation-negative long QT syndrome probands will not have a Mendelian large effect variant but will have perhaps a higher burden of these QT-prolonging alleles.
Therefore, I think this has direct implications for clinical genetics of these patients, because if you have a proband in whom you don't find a mutation in the known genes, you could think that maybe it is not monogenic, which has implications because you don't have a single genetic defect to test on that family. One would need to keep follow-up of more family members until we understand more about the genetics of those individuals.
Dr Greg Hundley: So Connie, this has been just a wonderful discussion. Any additional studies examining the genetic architecture of individuals that we need to think about for the future?
Prof Connie Bezzina: Sure. So for long QT syndrome in particular, as additional SNPs that modulate the QT interval in the germ population are identified, it will be very important to incorporate these into larger polygenic risk scores, and see whether we could have a better discriminative capacity of such polygenic risk scores in discriminating between severely affected and less severely affected people, or who is more at risk for an arrhythmic event.
Outside of long QT syndrome, I think there's a lot of work to be done with respect to the likely complex inheritance of many of these disorders that we previously considered to be Mendelian. So for instance, ongoing work in our group concerns Brugada syndrome, where we're seeing the same kind of thing, and hypertrophic cardiomyopathy, where we're seeing the same kind of inheritance.
Dr Greg Hundley: Well listeners, on behalf of both Carolyn and myself, we look forward to catching you on the run next week. Take care. This program is copyright the American Heart Association 2020.
This week’s episode of Circulation on the Run features author Robert Yeh and Associate Editor Brendan Everett as they discuss the article "Use of Administrative Claims to Assess Outcomes and Treatment Effect in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings from the EXTEND Study."
TRANSCRIPT
Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week, we're going to examine outcomes in patients that have undergone transcatheter aortic valve replacement or TAVR. I can't wait to get to the results from the EXTEND study. But before we do that, how about we grab a cup of coffee and start in with some of the papers and maybe I'll go first this time.
My paper involves a validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy. And the corresponding author is Dr Seema Mital from the Hospital for Sick Children. Well, Carolyn in this study, the objective was to develop and validate a sudden cardiac death risk prediction model in pediatric hypertrophic cardiomyopathy to guide sudden cardiac death prevention strategies.
To address this, the authors performed an international multi-center observational cohort analysis. Phenotype positive patients with isolated hypertrophic cardiomyopathy, who were under the age of 18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of sudden cardiac death events at five years of follow-up. That included sudden cardiac death, resuscitated sudden cardiac arrest, and aborted sudden cardiac death, that is, an appropriate shock following primary prevention ICD.
Carolyn Lam: Nice. What did they find?
Greg Hundley: Well, overall 572 patients met the eligibility criteria with 2,855 patient years of follow-up. The five-year cumulative proportion of sudden cardiac death events was 9%. Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter Z scores, LV posterior wall diameter Z scores, LA diameter Z scores, peak LV outflow tract gradients, and the presence of a pathogenic variant.
Now, unlike adults, LV outflow tract gradient had an inverse association and family history of sudden cardiac death had no association with sudden cardiac death. The combination of clinical and genetic data were developed to predict five-year freedom from sudden cardiac death.
In conclusion, the authors study provides a validated sudden cardiac death risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. These results therefore raise the possibility that an individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for these children prior to an ICD insertion.
Carolyn Lam: Very interesting. Well, Greg, have you ever wondered what are the temporal trends in the burden of comorbidities and risk of mortality among patients with heart failure with preserved ejection fraction or HFpEF and heart failure with reduced ejection fraction or HFrEF? Well, the next paper comes from Dr Caughey and colleagues from University of North Carolina and North Carolina State University who performed an analysis of the community surveillance component of the atherosclerosis risk in communities, or ARIC study, and they found a significant increase in the burden of comorbidities among hospitalized patients with HFpEF as well as HFrEF across both sexes. Higher number of comorbidities was associated with higher risk of one-year mortality with a stronger association noted among patients with HFpEF compared to HFrEF. The one-year mortality risk associated with increasing comorbidity burden also increased over time.
Greg Hundley: Interesting, Carolyn. So more comorbidities in HFpEF versus HFrEF. How do we use this clinically?
Carolyn Lam: This study demonstrated a shift from ischemic etiology heart failure to multi morbidity heart failure over time, particularly among patients with HFpEF. This really highlights the importance of a holistic approach in targeting multimorbidity burden and guiding the management of patients with heart failure.
Greg Hundley: Very interesting. Well, Carolyn, my next paper comes from Professor Matthias Nahrendorf from Mass General Hospital and involves the relationship between bone marrow endothelial cells and myelopoiesis in those with diabetes.
Carolyn, this study investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. The authors utilized three types of mice with diabetes, including a streptozotocin model, a high fat diet model, and a genetic induction using leptin receptor deficient mice. They assayed leukocytes, hematopoietic stem cell and progenitor cells, and endothelial cells in the bone marrow with flow cytometry and expression profiling.
Carolyn Lam: What did they find?
Greg Hundley: Well in diabetes, they observed enhanced proliferation of hematopoietic stem cells leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less CXCL-12, a retention factor promoting hematopoietic stem and progenitor cell quiescence. Transcriptome wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor signaling in mice with diet induced diabetes.
In summary, Carolyn, in diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow haematopoiesis specifically diabetes reduces endothelial production of CXCL-12, a quiescence promoting niche factor that reduces stem cell proliferation. The authors also describe a previously unknown counterregulatory pathway in which protective endothelial EGFR signaling curbs hematopoietic stem cell and progenitor cell proliferation as well as myeloid cell production.
Carolyn Lam: Wow, thanks for explaining all of that, Greg. For this next paper, we're going to switch tracks a little. This comes from Dr Drakos and colleagues from University of Utah in Salt Lake City. They noted that significant improvements in myocardial structure and function have been reported in some advanced heart failure patients. This is they're going to call responders and the responders improve the myocardial structure and function following left ventricular assist device induced mechanical unloading.
This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Dr Drakos and colleagues hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, which may mediate myocardial recovery in these responders.
To test this hypothesis, they prospectively obtained paired left ventricular atypical myocardial tissue from non-failing donor hearts, as well as responders and non-responders at left ventricular assist device implant and at transplantation. They conducted protein expression and metabolic profiling and evaluated mitochondrial structure using electron microscopy.
Greg Hundley: Interesting. What did they find, Carolyn?
Carolyn Lam: The recovering heart appears to direct glycolytic metabolites into pentose phosphate pathway and one carbon metabolism, which could contribute to cardioprotection by generating NADPH to enhance biosynthesis and by reducing oxidative stress. This new information could redirect future translational investigations to efforts to identify novel therapeutic targets for myocardial recovery in patients with chronic heart failure.
Well, Greg, can I tell you a little bit more about what else is in this issue? There's a letter by Dr Wang regarding the article, A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction, and there's also a response by Dr Yan. In Cardiovascular Case Series, there's a paper by Dr Michelena on the nosology spectrum of the bicuspid aortic valve condition, the complex presentation of valvular aortopathy. That's so interesting.
There's a research letter by Dr Gaudino on the response of cardiac surgery units to COVID-19, an internationally based quantitative survey. As well as another research letter by Dr Salem on cardiovascular toxicities associated with Hydroxychloroquine and azithromycin and analysis of the World Health Organization pharmacovigilance database.
There is a perspective piece by Dr Jacobs entitled The Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA's Mission: Lifeline.
In cardiology news, Tracy Hampton reviews three papers, one, Video-Based AI for Beat-to-Beat Assessment of Cardiac Function in Nature, 2020. Two, Dynamic Transcriptional Responses to Injury of Regenerative and Non-regenerative Cardiomyocytes Revealed by single Nucleus RNA Sequencing, that is in developmental cell 2020. And three, ATP and Voltage-Dependent Electro-Metabolic Signaling Regulates Blood Flow in the Heart, the proceedings of the National Academy of Science, 2020.
Greg Hundley: Very nice. Well, I've got an in-depth review from Dr Bin Zhou regarding the heart regeneration by endogenous stem cells and cardiomyocyte proliferation, controversy, fallacy, and progress. And then there are three on my mind pieces. The first is from Dr Rashmee Shah regarding machine learning and artificial intelligence. Do we need more data, or do we need the right data? The next one is from Sharon Reimold and it discusses the importance of gathering historical information on risk factors when seeing patients with, or suspected, of COVID-19. And then finally, Dr Prateeti discusses ethical challenges in cardiology during the COVID-19 pandemic.
Well, Carolyn, what a great review. How about we proceed to that feature discussion?
Carolyn Lam: Let's go.
Greg Hundley: Well listeners, we are now turning to our feature discussion and this week we have Dr Robert Yeh, also Bobby Yeh, from Beth Israel Hospital and our own associate editor, Dr Brendan Everett from Brigham and Women's Hospital. Welcome gentlemen. Bobby let's start with you. Can you tell us a little bit about some of the background related to your study, and then what hypothesis were you trying to address?
Robert Yeh: The study that we performed is the sub study of what we're calling the EXTEND study, which is an NIH funded group of investigations meant to really examine what the value is of real world data and how it can augment clinical trial evaluations of medical devices and therapies.
We know that randomized clinical trials remain the gold standard for therapeutic evaluation, but they are expensive, difficult to do, and sometimes impractical. Real world data is cheaper, it's potentially more efficient to do observational research studies, and in fact the 21st Century Cures Act explicitly asks, among other things, that the FDA explore the use of real-world data for regulatory evaluations.
People have problems with real world data, of course, they have their own inherent challenges which are subject really to confounding. What we thought about is, well, there's probably this middle ground that we and others have proposed, which is can't real world data somehow supplement or augment randomized clinical evaluations, and in particular, in our question, can real world data be the provider of outcomes in place of adjudicated clinical trial outcomes?
What we did is we took two large pivotal randomized clinical trials of transcatheter aortic valve replacement, namely the CoreValve, high risk, and intermediate risk trials. Otherwise, the intermediate risk trials known as the SURTAVI trial. And we found those patients in those trials and then linked them with real world data from administrative claims databases in Medicare.
Our hypothesis was that had the trial been evaluated in terms of outcomes by the Medicare claims instead of the clinical trial adjudicated outcomes. Our main question was, would we have had the same findings within those trials? Would the primary hypothesis of those trials still have been met with this alternative clinical trial end point ascertainment strategy?
Greg Hundley: In your study design, how did you accomplish the comparisons? You've told us a lot about the study population. Was this everyone from those two studies or was this a subgroup of them? Maybe just expand on that a little bit.
Robert Yeh: Good question. This is a US based comparison, so we have claims for US patients, and most patients in these trials were in the United States, but the CoreValve trial and the SURTAVI trials, we took all of this patients and then tried to find those patients who we could also find in Medicare claims.
It turns out that in order to qualify for Medicare, you have to be over 65 years of age, under most circumstances. And so it's limited to really those patients over age 65, who we could then search for in Medicare and then within Medicare, there's two types of insurance, fee for service and Medicare Advantage managed care. And what we can only find are those patients who are in Medicare fee for service, which represents somewhere between two thirds and three quarters of patients age greater than 65 or older. So it is a subgroup of patients in these two large pivotal randomized trials.
We've compared those who could not be linked versus those who could, find large part, from some of the age differences, which are just inherent in looking at Medicare, there are really not that many differences between those two groups.
Greg Hundley: Bobby, what did you find?
Robert Yeh: We found those patients. So now we have this situation where we have patients in trials, and we can look at them from two lenses. The same group of patients, one lens is through the clinical trial lens and the second is through the lens of real-world data, those exact same patients.
We found that whether or not we ascertained their outcomes via claims or with clinical trial adjudication, essentially the primary hypotheses were identical, that in both scenarios, the transcatheter aortic valve was non-inferior to the traditional surgical aortic valve replacement, that the effect sizes and the hazard ratios, the confidence intervals, they were roughly the same. In fact, for the primary endpoint of the high-risk pivotal study, which was all cause mortality, it was identical. It turns out that Medicare claims and what we called the denominator file very accurately identifies exactly when a patient dies. It does so equally well compared to rigorous clinical trial adjudication.
For SURTAVI the primary endpoint was combined death or stroke in that case, stroke is reasonably accurate. There were a lot of deaths that also drove that combined end point. And the net result was that really very similar, both effect sizes and primary, P values for those comparisons.
Greg Hundley: Now how about secondary analysis?
Robert Yeh: I think the secondary analysis that's where you had some variability. There are some types of outcomes in this device specific trial that are procedure oriented. Pacemakers are a concern. Aortic valve reintervention is a concern. Those end points in billing claims turns out are quite accurate. You can understand why. I think providers and institutions, when they do a service that requires insertion of a new device, they want to get paid for those devices and they do that billing accurately.
But there are other claims which I think are a little bit more subjective, diagnoses that are more subjective, those like bleeding or cardiogenic shock, those things actually started to look different. And in fact, in some cases started to give you different inferences if you used the clinical trial data versus the real-world data. And so if I were to summarize it, I would say that mortality looked absolutely pristine identical between the two groups that some diagnoses, particularly procedural ones, looked quite good, sufficient, I think, for an accurate estimation of the treatment effect size as well as the magnitude of the risk, but then some end points, I think the softer more subjective endpoints are slightly different.
Greg Hundley: Thank you so much, Bobby. Now we're going to turn to our associate editor, Dr Brendan Everett, who has helped work this article through the entire editorial process and is also an expert epidemiologist. Brendan, we have randomized trial data versus real world data. How do you interpret these results in the context of how we're conducting studies both now and then how we will conduct them in the future?
Brendan Everett: If you think of observational research and clinical research on a spectrum with truly just observational studies on one end, where you were trying to look at an exposure and an outcome and adjusting for potential confounders, to tightly controlled randomized trials on the other, Bobby's group has managed to create a hybrid, which I think gives us some opportunity to not have to be either on one and or the other of the spectrum.
What I mean by that is that there are a couple key features of trials that are retained in the approach that Bobby used, and his group used. He mentioned those, but I want to emphasize them. I think the key thing is that there's a randomization step. From the perspective of an epidemiologist, that's key because it balances between the people who get your therapy, in this case a TAVR and don't get the new therapy…confounders that you can measure and confounders that you can't measure, the unmeasured confounders. So it allows some balance between the two treatment groups so that you can be sure, at least at baseline, that they're similar groups and what you're measuring after that point is the effect of the intervention.
The key piece that Bobby replaced is the classical trial ascertained end points where investigators are asked if their patient had one of these outcomes such as a stroke or a death, and then they're adjudicated independently.
As he pointed out, I think there are many of those outcomes, at least in this particular application, are really well collected by billing data. And in fact, some might argue that in some cases they're actually better collected. There's a higher sensitivity, if a somewhat lower specificity for the events of interest.
I think the key question, and you touched on this, Greg, is what about the outcomes that maybe are not collected quite as well by billing data? In particular, remember that any clinical trial is looking at both the efficacy of a novel treatment as well as its safety. You ultimately, at the end of the trial, want to be able to compare efficacy with safety, to make a decision, in this case from the FDA, a regulatory decision about whether to approve the device or the drug.
The question becomes, what safety events are you worried about and how reliably are you going to be able to collect them with claims data? In this case, I think Bobby mentioned that the bleeding data maybe was not quite as good as some of the other safety concerns that are common in TAVR.
I think when you look to apply this approach, which I think is ingenious, to a different research question, you have to ask whether or not the end points, the efficacy end points, and the safety end points that you're collecting will be done in a valid and consistent and sensitive way with claims data as compared with the traditional trial ascertainment process. In this case, I think they were, but that's not always the case. We can all think of examples where you might run into some trouble depending upon what your end points are.
Greg Hundley: Well, gentlemen, this has been really an informative study to present and talk about in this feature discussion. I want to ask you both just briefly, in a minute or so, what do you see as the next step forward in research in this particular area? Maybe Bobby you first and then we'll follow with Brendan.
Robert Yeh: I think that there are a couple of different areas that really need to be pushed forward. One, and Brendan alluded to this, is because these studies are really domain specific this validation does not tell us that all claims can be used to answer all questions, that in this particular question it worked, but in others it might not, so more validation work in different fields, different randomized trials, need to be done.
We're doing some of those, but they need to be done throughout so we can really get a better sense of what are the types of questions that are best answered by this type of linkage approach.
The second that is more operational, we were limited to Medicare claims data, so for questions for patients who are younger than 65, this approach just doesn't work. Whereas a place like Sweden can do a large national registry like they did in the TASTE randomized clinical trial and do this for their entire country.
We do need to develop better systems that have comprehensive real-world data collection. Maybe those involve more consolidated electronic health system, health record data that are available in big integrated health systems, for example, but a better system needs to be developed that can answer questions among more than just Medicare fee for service patients.
Greg Hundley: Very good. And Brendan?
Brendan Everett: Well, I think it's a really promising approach to trying to lower the cost of clinical trials and to do valid research on the effect of some treatments as compared to others. From my standpoint, we have to be careful that we don't try and shortcut the process too much. In particular, I think the randomization step, at least for novel treatments, is of fundamental importance. And of course, to do that, you have to collect a population that is then willing to be randomized to option A or B.
There's a lot of upfront work that is not eliminated by looking solely at the outcomes, using this technique to look at the outcomes. There's a lot of upfront work to collect the patients and then randomize them.
I think also it's important, as we saw recently, that the quality and validity of the database be ascertained and be well-established both with the investigators and the providers of the database. We can see that sometimes, if you're not careful, you can come up with outcomes that are not correct because of the example. Of course, I'm alluding to is the two papers in Lancet and the New England Journal that had to be retracted that were large database studies as well.
The quality of the underlying data remains paramount. That, of course, is where a lot of the elbow grease comes in. It's not just in the ascertainment of the events, but a lot of the stuff that leads up to counting the events at the end of the study.
Greg Hundley: Well, listeners, this has been just a superb discussion. On behalf of Carolyn and myself, we wish you another great week and look forward to catching you on the run next week. Take care.
This program is copyright, the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.
Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU Pauley Heart Center in Richmond, Virginia.
Dr Carolyn Lam: Greg, today's speaker paper is really special on a number of levels. First, it's a research letter and secondly, it's actually basic science. Now, this tells you it's got to be really special. Well, I'll just give you a hint. It talks about a new therapy for stroke. I'm going to leave it at that, leave you guessing because you've got to hang on as we tell you about the rest of the issue and then listen to the feature discussion. Now, the first original paper here, I want to describe as a basic paper focusing on PDE4B in heart failure.
Dr Greg Hundley: All right, Carolyn, I'm not even going to let you start to quiz me on this. Can you tell me what in the world is PDE4B?
Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really represent a highly diverse super family of enzymes among which PDE3 and PDE4 are the main phosphodiesterases that degrading cyclic AMP with a high affinity in the heart. The cyclic AMP hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key negative regulator of cardiac beta-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal calcium handling and PDE4B is decreased in pressure overload hypertrophy suggesting that increasing PDE4B in the heart may be beneficial in heart failure. These authors led by Dr Vandecasteele from Inserm tested this hypothesis in elegant experiments involving both human cardiac tissues and transgenic mouse lines.
Dr Greg Hundley: Carolyn, that was just a wonderful explanation and I really learned about these phosphodiesterases. Now, tell me what did they find in their study?
Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was decreased in human failing hearts. Cardiac over expression of PDE4B in mice, resulting in a 15-fold increase in cyclic AMP hydrolysis decreased cardiac contraction and protected against the cardiotoxic effects of chronic beta-adrenergic stimulation. Whereas transgenic mice with a 50-fold increase in cardiac cyclic AMP hydrolysis underwent maladaptive remodeling. Furthermore, cardiac PDE4B gene transfer with serotype nine adeno associated viruses resulted in a significantly lower increase in cardiac PDE4B and protected against chronic catecholamine stimulation and transaortic constriction without depressing basal cardiac function. These results overall suggest that a moderate increase in cardiac PDE4B is beneficial to counteract the detrimental effects of excessive sympathetic system activation in heart failure and increase in PDE4B in the human heart could be achieved by gene therapy with adeno associated viruses or by using recently developed small molecules with PDE4 activating properties.
Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps this'll work its way into heart failure management. Well, my study, our first study to describe involves the comparative efficacy and safety of oral P2Y12 inhibitors and acute coronary syndromes. It's a meta-analysis of 52,816 patients from 12 randomized trials. It comes to us from Professor Eliano Navarese from Nicholas Copernicus University. All right, Carolyn, here's your quiz. Have you wondered which PGY inhibitor is optimal for reducing risk of adverse cardiovascular events?
Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered, but you're going to tell us the results.
Dr Greg Hundley: It's getting harder and harder to trip you up Carolyn. Very clever, okay. This study aims to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in acute coronary syndrome by meta-analysis of 12 randomized clinical trials. Again, involving those 52,816 patients with ACS.
Dr Carolyn Lam: Wow. What did they find Greg?
Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly reduced cardiovascular mortality and all-cause mortality. Whereas there was no statistically significant mortality reduction with prasugrel.
Dr Greg Hundley: Next, compared with each other there were no significant differences in mortality with prasugrel versus ticagrelor. In addition, compared with clopidogrel, prasugrel reduced myocardial infarction, whereas ticagrelor showed no risk reduction.
Dr Greg Hundley: Now stint thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel. Compared with clopidogrel, both prasugrel and ticagrelor significantly increased major bleeding. There was no significant difference between prasugrel and ticagrelor for all outcomes explored.
Dr Carolyn Lam: Summarize that for us.
Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced ischemic events, but increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. So a really nice summary evaluating these P2Y12 inhibitors,
Dr Carolyn Lam: Indeed. Question for you, Greg, what is the prevalence of deep venous thrombosis, a DVT and its risk factors, prognosis and potential prophylaxis strategies for hospitalized patients with COVID-19? That's what the next paper is about. It is a single center observational study of 143 hospitalized patients confirmed of COVID-19. And this is from co-corresponding authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher Hospital for Children in Philadelphia, United States, they found that DVT was found in a high percentage of these patients. Forty-six percent of the 143 patients and was associated with adverse outcomes with CURB-65 score three to five. Padua prediction score four a more and D-dimer greater than one microgram per mil, which in combination predicted DVT with a sensitivity of more than 88.5%. Thrombo prophylaxis was associated with lower DVT in a subgroup of patients with high Padua prediction score.
Dr Greg Hundley: Now, what does this mean for all of us in this era of COVID-19?
Dr Carolyn Lam: So this suggests that DVT is more common in hospitalized patients with COVID-19. So ultrasound screening of high-risk patients, as I mentioned before, may be indicated for the more prevention of DVT with low molecular weight heparins in high risk patients, such as those with a high Padua prediction scores may reduce DVT in hospitalized patients with COVID-19. Of course more work needs to be done, but a very interesting paper.
Dr Greg Hundley: What a fantastic description. Well, my next paper is more from the world of basic science and involves phosphodiesterase 3A in arterial hypertension and comes to us from Dr Enno Klussmann from the Max Delbruck Center for Molecular Medicine. So Carolyn, autosomal dominant hypertension with brachydactyly clinically resembles salt resistant, essential hypertension and causes death by stroke before the age of 50 years. So in this study, the authors use genetic mapping, sequencing, transgenic technology, CRISPR-CAS based nine gene editing, immunoblotting, and fluorescence resonance energy transfer to identify new patients perform extensive animal phenotyping and explore new signaling pathways related to hypertension with brachydactyly.
Dr Carolyn Lam: Wow. So what did they find, Greg?
Dr Greg Hundley: Well, Carolyn, the authors described a novel mutation within a 15 BP region of the PDE3A gene, and define this segment as a mutational hotspot in hypertension with brachydactyly, the mutations cause an increase in enzyme activity, a CRISPR-Cas9 generated rat model with a nine BP deletion within the hotspot analogous to human deletion recapitulated the hypertension with brachydactyly in mice, mutant, transgenic PDE3A over expression and smooth muscle cells confirmed that mutant PDE3A caused hypertension. The afferent signaling found in these models was associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.
Dr Carolyn Lam: Gosh, so what are the clinical implications? Greg?
Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance and cause hypertension. These authors presented two new animal models that serve to elucidate these underlying mechanisms further, and their findings could facilitate the search for new anti-hypertensive treatments.
Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually one we've already discussed in our special COVID-19 edition and that was aired on 22nd, May, 2020. That's the paper from Dr Poissy and Susen from University Lille in Inserm, and they reported a case-series of COVID-19 patients with pulmonary embolism in their institution of Lille University Hospital. So, please everybody remembers to tune in to that as a refresher. Also in today's journal, the issue of COVID-19 coagulopathy in venous thromboembolism is further discussed in an editorial by Dr Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more about other papers in this week's issue. There are letters to the editor from Dr Mueller and from Dr Gulati all about the paper incidents, trends and outcomes of type two myocardial infarction in the community cohort. There's a letter from Dr Siontis on the blood pressure myocardial infarction paradox.
Dr Carolyn Lam: Does hypertension exert a protective effect in type two MI? In the ECG challenge Dr Di Cosola talks about the high, the low end, the narrow QRS in a peripartum cardiomyopathy. There's an online mind piece by Dr Kohli entitled surfing the waves of the COVID-19 pandemic as a cardiovascular clinician, a perspective piece by Dr Albert titled "The Heart of the Matter Unmasking and Addressing COVID-19's Toll on Diverse Populations". In Paths the Discovery series, Dr Rutherford talks about serial innovation to bring transformative precision medicines to people with serious diseases. And this is a conversation with Dr Jeffrey Leiden.
Dr Greg Hundley: Very nice. Carolyn, I've got a couple other papers to discuss similar to your paper on DVT, Professor Lin Cai has a research letter involving the extremely high incidents of lower extremity, deep venous thrombosis in 48 patients with severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum Saeed from University of Pittsburgh discusses reinforcing cardiology training during a pandemic. It's an open letter to our leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads to major changes for cardiologists in training. And then finally, Dr Stephen Archer from Queens University provides a nice perspective on differentiating COVID-19 pneumonia from ARDS and high-altitude pulmonary edema, and what are the therapeutic implications. And now Carolyn, how about we get onto that feature discussion, one of the unusual times where we emphasize an important point in a research letter?
Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I think one of the most impactful, basic science papers we have, and that is why we're discussing it. I am so pleased to have the first author Dr Luca Liberale from University of Zurich, as well as Dr Peipei Ping associate editor from UCLA. So welcome both. Luca, I really need your help here. Can you please explain what your experiment was and your main findings?
Dr Luca Liberale: We really happy that we could set up an experiment design, which has some kind of translation of value. So, differently from any other set up involving the tandem middle cerebral artery occlusion, which is among the most used model for ischemic stroke in basic science. In this case, the treatment is done post-ishchemically. So the mice received the neutralizing antibody against IL-1α only after they scan making salts. And we specifically thought to duties to keep the translational relevant side. As I said before, and trying to mirror the case of a patient, we think come have a stroke that goes to the emergency department, and he is eligible for revascularization therapy. And together with this revascularization therapy being at EPA or whatever for it, it received is also the kind of anti-IL-1α treatment. And another good translation of relevancy we thought this may have is that identifying of IL-1α antibody is already available in the market and being in many phase three trial. So we thought this is a ready to go, ready for the translation from the bench to the bedside, as we used to say.
Dr Carolyn Lam: It's just so interesting because when we think about ischemic stroke, you know, we think about thrombolysis as practically the only thing we can do, and forgive me I'm not in neurologist here, but this is so unique to go with an anti-inflammatory mechanism. Now, when you see that this neutralizing antibody is currently in use, do you mean in cancer in other diseases?
Dr Luca Liberale: Mainly it's cancer, but it's also other dermatological diseases. It's not only cancer, but oh yes, definitely. Cancer is one of the major fields of its application.
Dr Carolyn Lam: Wow. So with that very interesting background, could you tell us about the experiment and what you found?
Dr Luca Liberale: What we found is that after inducing ischemia in the animal for 45 minutes, we let them reperfuse for 48 hours during which the animal are under the treatment. So they received a bolus of anti-IL-1α immediately at the time of reperfusion. So when we take out from the carotid artery, the filament, and they received these volumes and they are let survive for 48 hours. So they are free to go in the cage, to seek drinks. After 48 hours, we assessed the neurological deficit and we sacrifice the animal to assess the stroke size by using the quite common PTC staining. And what we could find is that indeed the treatment with the higher dose, because we use two doses, and we could see a dose response, could that reduce the stroke size by 36% as compared to the treatment with the isotype control. And this went together with a significant reduction in that neurological impairment. So it's not only an experimental reduction, but it's also physiologically relevant for the animals.
Dr Carolyn Lam: That really is incredible, and the way you manage to convey such a lot of data in a research letters is also remarkable. So, to the audience, you have to pick this up. It's a succinct read, just this one central figure that tells the whole story, and you're about to hear from Dr Ping. Dear Peipei, if you could tell us what the significance of this paper is, maybe some of the discussions that occurred behind the doors, so to speak among the editors.
Dr Peipei Ping: We were super impressed with the fundamental message of the submitted report. Carolyn, as you are fully aware, most ischemic studies speed that in the heart or in a brain model, often select mechanisms that must be activated pre the event you bent of ischemia to induce a protective effect, a neurological protective effect in stroke or cardioprotective effect in the heart. So, as an associate editor who spent her entire 30 years career in this area of study, we often fascinated about the sentencing or the naiveness of the basic scientists in this area. Because you would have to plan an ischemia in the patient knowing when that to happen. And then before that happens, activate all these beautiful signaling and mechanisms, everything you have generated to prevent that ischemia. So the search for the possible mechanistic understanding of a post-ischemic event rescue mechanism has been going on for decades. And it's very, very challenging, Carolyn.
Dr Peipei Ping: The beauty of the study is it utilized already in clinical trial, existing human antibody inhibitor, interleukin alpha-one antibody. You said antibody. So the reagent is already bile approved. Then examine very carefully in a post-ischemic fashion to see how relevant that agent in a time window reasonable to rescue ischemic injury. You can already tell from Lucas introduction; the results are profound, and it has stimulated many discussions in the field. It's very relevant to clinical center piece, even though it's still at that translational stage. So we saw this as a beautiful representation of how clinicians and scientists capable of not only bring something from the bench to the clinic or the clinic or to the bench. This is something comes to a full circle. It went from clinic where the reagent was used and created for something to the bench, understanding mechanistic insight, have a beautiful animal of human disease stroke model to test them and then take it to the clinic again.
Dr Carolyn Lam: Goodness, Peipei. I love the way you put that. I actually didn't see that Luc[a], till you put it that way. I do have a couple of questions for Luca though. I understand you made it very clear in your paper that the human monoclonal antibody is in clinical use, but in this experiment, you had to use the rodent equivalent because the human antibody doesn't block the rodent IL-1α, which is very reasonable. But then it brings the question, how closely does this rodent model recapitulate thrombotic ischemic, or a stroke in humans? I mean, what do you think?
Dr Luca Liberale: Well, what we see when we use our usual approach, this is a model that we're using in our center for molecular cardiology here in Zurich, and this been used in that specific group of Professor Ameche for many years. And this is usually quite well accepted as a model. So that, that the timeframe is 45 minutes of ischemia and 48 hours of reperfusion. I'll got to quite mirror the acute phase of an acute ischemic stroke, which is actually where we think that the inflammatory pathways can play the major roles. Also. I mean, everybody of us know that the recent anti-inflammatory trials confirmed this, that reducing the inflammation and the inflammatory pathways is good but can also be harmful.
Dr Luca Liberale: So in the case, we can use an approach, which is limited in the time, maybe really close to that acute phase, really during the acute rates goes to the acute event. Well, maybe this can be quite useful and quite a translationally relevant that prolongs inactivation of such pathways as result. They can ask some for, so the balance in between the benefits and the harms cannot be that clear, can, I mean, needs to be quite well addressed.
Dr Carolyn Lam: And that actually brings me to the next question. You know, the word translational has been mentioned quite a number of times here. So can you give us a sneak-peak on what the translational plans that your team may have? What's the next steps?
Dr Luca Liberale: The next steps now is back to the company. So our basic findings are here. They will be published soon, and now it's all about the clinical scientist, and how they want to implement these basic findings into the clinic.
Dr Carolyn Lam: So target engagement and mechanistic information as well. Peipei, could I just give you the last word, if you don't mind, maybe a bit of a cheeky question. What would you have loved to see in this paper or in a subsequent paper that offers a step closer to translation?
Dr Peipei Ping: I think this study has shown most necessary components as a basic science research paper. I think the next level closer to the translation as Luca has already alluded to, has to do with both efficacy studies, as well as safety studies, and those actually would need to be done in the clinic because the mouse model. I think it's a fantastic model to offer these lines of information. Ischemic-wise I think it's very strong and translational value is very high and that was the predominant reason we voted to accept the paper. As you know, the accept and raise of circulation is very, very low as our bar is very high.
Dr Carolyn Lam: Very nice. So target engagement and mechanistic information as well. Congratulations, Luca. Thank you so much Peipei for your great comments. Now, listeners, you heard it first time here on Circulation on the Run. Thank you for joining us today.
Dr Greg Hundley: This program is copyright at the American Heart Association, 2020.
Dr Carolyn Lam: Well, the Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, this week's feature involves the Compass trial, and we'll be talking about a comparison of low-dose rivaroxaban plus aspirin compared to aspirin alone in patients with chronic vascular disease. But before we get to that, how about if we break away and discuss a few other papers. And I'll go first this time, because this week we're going to introduce another new feature in addition to Carolyn's Quiz.
Dr Carolyn Lam: Wait a minute. This was not on the script. What's going on, Greg?
Dr Greg Hundley: It's on the script!
Carolyn, let me get to my first paper. It's from Professor Junling Liu from Shanghai Jiao Tong University School of Medicine, and it involves branched-chain amino acid catabolism and how that may promote thrombosis risk by enhancing tropomodulin-3 propionylation in platelets.
But first, we've got a new feature to add to Carolyn's Quiz. It's called Way or No Way.
Dr Carolyn Lam: Just so everybody knows. This was a one-way decision to add this new component of Carolyn's Quiz, but okay, I'm all for it. Go, Greg!
Dr Greg Hundley: Okay. All right. It's a fast, quick question where our listeners seek your guidance regarding an important scientific discovery from one of our published manuscripts. Are you ready?
Dr Carolyn Lam: No.
Dr Greg Hundley: Okay. Here's your question. Do branched-chain amino acids promote arterial thrombosis. Way or no way?
Dr Carolyn Lam: Maybe?
Dr Greg Hundley: Okay, Carolyn.
Dr Carolyn Lam: I have a feeling you're going to tell us yes, although I wouldn't have guessed that straight away.
Dr Greg Hundley: Okay. Remember that branched-chain amino acids are essential nutrients, including leucine, isoleucine, and valine, and they serve as a resource for energy production and the regulator of important nutrient and metabolic signals.
In this study, the activity of human platelets from healthy subjects before and after ingestion of branched-chain amino acids were measured. PP2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation.
Dr Carolyn Lam: Now okay, okay. So what did they find? Way or no way?
Dr Greg Hundley: Ingestion of branched-chain amino acids significantly enhanced the activity of platelets in response to agonists and increased the risk of arterial thrombosis. The branched-chain amino acid catabolic pathway-driven propionylation of tropomodulin-3 at K255 was found to be an important mechanism underlying the branched-chain amino acid-facilitated platelet activation, and elevated levels of branched-chain amino acids and enhanced expression of positive regulators of branched-chain amino acid catabolism in platelets were found probably responsible for the high platelet activity in type 2 diabetes mellitus.
Dr Carolyn Lam: Very interesting. So yes, it is possible. And what is the clinical implications?
Dr Greg Hundley: Right, Carolyn. Branched-chain amino acids, or their catabolites, enhance the risk of arterial thrombosis in small animals, and perhaps future human subject studies, that restrict branched-chain amino acid intake or target branched-chain amino acid catabolism may serve as a novel strategy for anti-thrombosis therapy.
Dr Carolyn Lam: Interesting. Okay, Greg. Here you go. Question for me. Have you heard of Home Time?
Dr Greg Hundley: Home Time? Yes. Home Time. It's not like time out for our kids, but we've been having a lot of Home Time in this COVID-19 with our families.
Dr Carolyn Lam: All right. Touché. Touché. Home Time! Did you know it is a patient-centered outcome measure that accounts for rehospitalization mortality and post-discharge care? In the paper I want to talk about, Dr Pandey from UT Southwestern and colleagues aim to characterize risk-adjusted 30-day Home Time in patients with acute myocardial infarction as a hospital-level performance metric, and to evaluate associations with risk-standardized readmission rates. The study included almost 985,000 patients with AMI hospitalization across almost 2,400 hospitals between 2009 and 2015 derived from a hundred percent of Medicare claims data. And they found that 30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varied across hospitals, was associated with post-discharge readmission and mortality outcomes, and meaningfully reclassified hospital performance compared with the 30-day readmission and mortality metric.
Dr Greg Hundley: Very nice, Carolyn. Well, I'm coming back at you again with another quiz. But first, this paper is from Kamal Khabbaz from Beth Israel Deaconess Medical Center and the Harvard Medical School, and it's going to assess whether left atrial appendage closure or exclusion during bypass surgery has impact on short-term outcomes.
So, Carolyn, here's your quiz. Do you think that patients receiving CABG with atrial fibrillation should undergo ligation of their left atrial appendage?
Dr Carolyn Lam: Well, I think there's definitely equipoise there. On the one hand, you're already in a surgery. Why not just ligate it? It's not like we need a left atrial appendage. And then on the other hand, I suppose it extends the surgery, it involves some risk, and we don't know if it actually prevents further events. Did I answer that right?
Dr Greg Hundley: Yes. Quite the politically correct answer, I think. Now, the objective of this study was to evaluate the impact of left atrial appendage exclusion on short-term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft surgery. The study analyzed 250,287 CABG patients, of whom 7% received left atrial appendage closure. Only patients with a history of atrial fibrillation were included in the analysis, and the primary outcome was 30-day readmissions following discharge. Secondary outcomes included hospital mortality and stroke. And to assess the postoperative outcomes, the team utilized multivariable logistic regression models, and they adjusted for clinical and demographic co-variables.
Dr Carolyn Lam: Great. So what did they find, Greg?
Dr Greg Hundley: Okay. Couple of conclusions. First, left atrial appendage exclusion was associated with a greater risk of postoperative respiratory failure, acute kidney injury, but it did not significantly change the rate of blood transfusions or the occurrence of cardiac tamponade. Second, left atrial appendage exclusion was associated with a nonsignificant reduction in stroke, no difference in in-hospital mortality, and a greater risk of 30-day readmissions. Number three, after adjusting for these co-variables, left atrial appendage ligation remained a significant predictor of this 30-day readmissions. And so, Carolyn, in this study, it looks like left atrial appendage exclusion during isolated CABG in patients with AFib is associated with a higher rate of 30-day readmissions.
Dr Carolyn Lam: Thanks, Greg. Well, let me talk about what else is in this issue. First is a pair of letters, one from Kai Wu regarding the article, "Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared to Men With HFpEF: Insights From PARAGON-HF" and the response from Dr John McMurry. There are also two On My Mind pieces, one entitled "COVID-19 Arrhythmic Risk and Inflammation: Mind the Gap" by Dr Lazzerini, and another entitled, "Obesity, A Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms" by Dr Naveed Sattar.
There are two perspective pieces, "Establishment and Management of Mechanical Circulatory Support During COVID-19 Pandemic" by Dr Pham, and "The COVID-19 Pandemic: A Global Natural Experiment" by Dr Blake Thomson. There's an in-depth paper entitled "The Science Underlying COVID-19: Implications for the Cardiovascular System" by Dr Peter Liu. This is important. This one's an editor's pick, so don't forget to read this.
There's an ECG challenge by Dr Praveen Gupta on "Chest Pain with ST Elevation: Looking Behind the Masquerade." In Cardiology News by Tracy Hampton, she reviews the literature and highlights three papers, one, "A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors" in Cell 2020; two, "Noninvasive Localization of Cardiac Arrhythmias Using Electromechanical Wave Imaging" in Science and Translational Medicine 2020; and three, "Somatic Gene Editing Ameliorates Skeletal and Cardiac Muscle Failure in Pig and Human Models of Duchenne Muscular Dystrophy", and that in Nature Medicine 2020.
For the President's Page, we have a piece by Keith Churchill, who's the Executive Vice President and CEO of Yale New Haven Hospital entitled "The Compelling Need to Address Uncertainty, Anxiety, and Financial Peril for Patients".
There's Highlights from Circulation Family of Journals by Sara O'Brien, including "Factors Associated With Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results From the ORBIT-AF" from Circulation Arrhythmia and Electrophysiology. There's "Association Between Sleep Disordered Breathing and Left Ventricular Function: A Cross-Sectional Analysis of the ECHO-SOL Ancillary Study" from Circulation Cardiovascular Imaging. There's also "The Impact of a 10 Rules Protocol on COVID-19 Hospital-Related Transmission: Insights from Padua University Hospital in Italy" from Circulation Cardiovascular Interventions. There's "The Association of an AMI Readmission-Reduction Program with Mortality and Readmission" from Circulation Cardiovascular Qualities and Outcomes. And finally, "Treatment Differences in Chronic Heart Failure Patients with Reduced Ejection Fraction According to Blood Pressure" in Check HF, and that's in Circulation Heart Failure.
Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a few Research Letters that I reviewed. First is from Professor Puck Peltenburg, and the Research Letter involves children and adolescents from Brugada syndrome families in which only the SCN5A mutation carriers develop a type one ECG pattern induced by fever. And the second research letter is from Dr David Saadoun, and this evaluates the long-term outcome and prognosis factors associated with isolated aortitis. And then finally, Carolyn, there's a very nice piece related to the current status of cardiovascular medicine in Israel from Professor Ran Kornowski at the Rabin Medical Center.
Well, Carolyn, what a packed issue we have, and how about now we get on to that feature discussion?
Dr Carolyn Lam: Let's go, Greg.
Dr Greg Hundley: Well, listeners, we have a wonderful feature discussion for you in this next segment. We have Professor Keith Fox from Edinburgh and our own associate editor, Professor Stefan James from Uppsala. And we're going to discuss anticoagulation and antiplatelet therapy and rivaroxaban and aspirin and results from the COMPASS trial.
Keith, could you tell us what was the background information and what was the hypothesis that you wanted to test with your study?
Professor Keith Fox: The hypothesis was whether the combination of a very small dose, a quarter of the dose tested here, of a NOAC alongside an antiplatelet would be superior to aspirin alone, or we also tested a half dose of the NOAC by itself. And the overall trial showed that the quarter dose of rivaroxaban plus aspirin was substantially superior to aspirin alone in preventing cardiovascular death, MI, and stroke, with its biggest impact on strokes and cardiovascular death. So that's the trial as a whole.
But our specific goal here was to look at the question of net clinical benefit because clinicians are challenged by any therapy that has a balance of both potential hazard, like bleeding risk, and benefit. So what we analyzed here were the pre-specified characteristics of net clinical benefit in terms of life-threatening and major bleeding into a critical organ, plus cardiovascular death, MI, and stroke. And I asked the question, what was the net clinical benefit?
Dr Greg Hundley: Net clinical benefit. Now, tell us a little bit about what population you were looking to understand net clinical benefit, and then what was the study design?
Professor Keith Fox: This is the whole of the COMPASS trial without the arm that tested rivaroxaban alone, because that did not show significant benefit. So this is the remaining 18,000 patients, double-blind randomized trial. And the trial, as a whole, was stopped early on the recommendation of the DSMB because it met the criteria for benefit by four standard deviations. Now, what's unusual about this is the population of our patients and vascular risk. So these are people who in the past would just be treated with aspirin. So they're not post-MI. They are people with chronic vascular disease, either peripheral or coronary. And in the past, on top of standard secondary prevention care, they would only have got aspirin.
Dr Greg Hundley: And what were the results?
Professor Keith Fox: There was a 20% reduction in terms of the net clinical benefit favoring the combination of rivaroxaban and aspirin, and that net clinical benefit being the combined impact of cardiovascular death, MI, stroke, fatal bleeding, or bleeding into a critical organ.
Dr Greg Hundley: And did you find the same results in, for example, older versus some of the younger patients? Or were there any other high-risk subgroups, those with impaired renal function or those with heart failure where you saw particular differences?
Professor Keith Fox: Yes, Greg. This is a really important issue. If one looked at the whole trial, the number needed to treat to prevent one of these adverse events, N equals 52. But then if we looked at some of the higher-risk cohorts, which we defined prospectively ... For example, these were the risk factors like polyvascular disease, impaired renal function, ambulant heart failure, or diabetes. And if you had all four risk factors, the number needed to treat was nine. If you had three risk factors, it was 12. Two risk factors, 31. So I think there's clearly a message for clinicians to be able to identify people with a combination of these risk factors, one or more, in order to get the most benefit and the least hazard.
Dr Greg Hundley: Very interesting. Any speculation on mechanism?
Professor Keith Fox: Yes. One of the things that we've done in the past is we've hammered one antithrombotic pathway. Like, for example, we've used more and more potent anti-platelets or combination of anti-platelets. But perhaps one of the things that we've forgotten is the fact that the platelet activation pathway is triggered by thrombin activation and vice versa. So the concept that was new behind the whole COMPASS study was that augmentation of the antithrombotic effects by combining a very small dose of a novel anticoagulant would be beneficial. And the critical question is, would it be sufficiently beneficial without producing a lot of bleeding? So that's why we did this particular analysis.
Dr Greg Hundley: So lower doses of some of these drugs. Well, Stefan, can you help us put these study results into context with what we know today about using aspirin alone, rivaroxaban, et cetera?
Professor Stefan James: The reason I think this study's so important and interesting is that, first, it's a very common population that we see now in the practice, patients with a stable phase of atherosclerotic disease, both coronary and peripheral vascular. And we need to take care of these patients better. Until now, we have not had very great alternatives for these patients. Now, we've learned what Keith said, that if you combine a low dose of both anti-platelet and antithrombin, you can inhibit and reduce the risk of ischemic events. And the other important finding here is that, I think conceptually very interesting, that if you are able to reduce their number of ischemic complications or thrombotic complications, but not doing that to such an extent that bleeding increases too much, not to an extent that bleeding causes fatal events, then you can find a nice balance between safety and efficacy that can lead to substantial reductions and improvements in terms of the clinical benefit.
And that's what we see here in this trial. You can see that there is a reduction of thrombotic events, ischemic events, and there is also some bleeding, but not to such an extent that it affects overall survival and the overall event rate in these patients. And particularly in patients at high risk that you pointed out, these patients have a very high event rate. Although the relative benefit is similar, the absolute benefit is quite impressive.
Dr Greg Hundley: Just very exciting to me. Very low doses of some of these common drugs. What's the next study in this field, Keith?
Professor Keith Fox: We've got a big gap because we know that modern dual antiplatelet therapy works really well after an acute coronary syndrome and it's highly effective. In the longer term, we know, for example, from some of the studies with ticagrelor that there are cohorts that do well for a period of time after ACS, but really we don't know the bridge between this period and the long term and what role this therapy may have after essential dual antiplatelet therapy.
Dr Greg Hundley: Stefan, do you have any thoughts?
Professor Stefan James: I agree with Keith. This transition period, when is patient transitioned from being an acute coronary syndrome patient to a chronic coronary syndrome patient? When does that happen? And then probably it differs between individuals and type of events, and so we need to understand more of when is this patient acutely affected and when do we need potent dual antiplatelet therapy? And when can we transition to a more stable phase in which we can inhibit thrombotic events, ischemic events, but not increased bleeding to such a degree that it affects overall survival? And so I think we need to learn a lot more about that transition period and these subgroups of patients of different risks and risks of ischemic events and bleeding events.
Dr Greg Hundley: Keith, how would you go about conducting a study in that regard?
Professor Keith Fox: I think really one of the very interesting questions is whether the combination of the standard of care of, for example, aspirin and ticagrelor may be better, worse, or the same than this therapy instituted at the end of the period of essential dual antiplatelet therapy. And we need to know that.
Dr Greg Hundley: In closing and summing up, Keith, are there any concepts that we want to take home here?
Professor Keith Fox: I think that there are two key concepts. One is the synergy between the anticoagulation system and the antiplatelet system, with the potential to use very low doses, to minimize bleeding risk, yet have the benefits. That is the first concept. The second concept is that these chronic vascular disease patients Stefan has described are at continuing risk of vascular events, especially stroke, myocardial infarction, and cardiovascular death. And these can be modified.
Dr Greg Hundley: And Stefan, any thoughts from you in closing?
Professor Stefan James: I think this paper and the work that Keith has described is fantastic and fascinating to think about because these populations are incredibly large, and they are not doing well. They have a high risk of events, and we tend to forget that, and so we need to both identify them and start treating them now, as we have some evidence, but we'll also need to learn more of how to identify them, how to select them appropriately, and how to identify the transition from acute events to chronic events or current chronic phase of the disease.
Dr Greg Hundley: Well, listeners, I want to thank both Professor Keith Fox and our own associate editor, Professor Stefan James, for this very interesting presentation of lower doses of anticoagulant and antiplatelet therapy in patients with chronic vascular disease and really being able to reduce events and diminish bleeding.
On behalf of Carolyn and myself, we want to wish you a great week and look forward to catching you next week. Take care.
This program is copyright of the American Heart Association 2020.
This week’s episode is special: we have the former and current Editors-in-Chief of Circulation on Circulation on the Run. Join Dr Amit Khera, Digital Strategies Editor of Circulation, as he speaks with Dr James T. Willerson, Editor-in-Chief from 1993 to 2004; Dr Joseph Loscalzo, Editor-in-Chief from 2004 to 2016; and Dr Joseph A. Hill, the current Editor-in-Chief. They will discuss the history of Circulation and how it continues to evolve.
TRANSCRIPT
Dr Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation from UT Southwestern Medical Center in Dallas. Today we have a very special Circulation on the Run. We have three Editors-in-Chief from Circulation. First, we have Dr James Willerson, who was the Editor-in-Chief from 1993 to 2004. He's a President Emeritus at the Texas Heart Institute. We also have Dr Joseph Loscalzo, who was Editor-in-Chief from 2004 to 2016, the Chairman of Department of Medicine from Brigham and Women's Hospital. And finally, Dr Joseph Hill, the current Editor-in-Chief, the Chief of Cardiology at UT Southwestern Medical Center. Welcome, gentlemen.
Dr Joseph Hill: Thank you.
Dr James Willerson: Thank you.
Dr Joseph Loscalzo: Thank you.
Dr Amit Khera: Dr Willerson, I must say, looking over the tenure prior to Dr Loscalzo, you had one of the longest tenures ever as Editor-in-Chief of Circulation, and certainly a lot happened in the practice of cardiology during that period. It was a really formative period in cardiology. As you think back, what were some of the most important topics that you covered during that time as Editor-in-Chief, thinking about the evolution of cardiovascular care and science at that time?
Dr James Willerson: You have to remember, there have been many editors at Circulation. We all build on the shoulders of others, certainly I did. I really wanted Circulation to be the premier cardiovascular journal in the world. I wanted it to be much like the New England Journal of Medicine, but the New England Journal of Medicine Circulation of Cardiology. I wanted to publish it every week. We got permission to do that. That wasn't easy, but we were fortunate. I've been accused of wanting to publish it every day. There's actually some truth to that. I didn't make that. I didn't try very hard. I wanted to be able to present the information, important information, to everybody who cared about cardiovascular medicine: physicians, scientists, students, nurses, those who cared for people, and I wanted to do it frequently. I wanted to publish it quickly. So, we had some success with that. There are many other things that are well-known to the other editors, all of whom have built before me and after me, and I'm very proud of them.
Dr Amit Khera: Well, thanks for that. And certainly, as you pointed out, this has been an evolution where you took the gauntlet, if you will, from the people before you, and then built on that and had many advances. I guess after you, Dr Loscalzo, you I think did have the longest tenure if I saw of any of the editors and similarly, a lot of evolutions in cardiovascular care and a lot in science, particularly during your time. Tell us a little bit about any particular papers or topics that you focused on, or that really were revolutionary in the cardiovascular space during your tenure.
Dr Joseph Loscalzo: I'll pick up where Jim left off and just make the case that as you're suggesting, I mean, there's sort of been a natural transition of the kind of science that Circulation has been publishing over the tenure of the three editors here today. Before Dr Willerson, it was largely physiology and excellent clinical science. Jim really expanded the scope of what Circulation published to begin to put in press in its pages, fairly basic and translational science as well. I picked up from what he'd laid the groundwork for to expand the scope of that science. And as you know, expand it to the point that we had to develop daughter journals that would pick up the mantle in each of these increasingly subspecialized areas.
So, it's hard to think about those papers that I found have the greatest impact because every field had several of them in my several years as editor. As you know, the subspecialty journals that we established, which remain active to the current time, are also broad in their scope from outcomes based research to genomics and proteomics insistence, cardiovascular medicine, to everything in between, imaging, intervention, heart failure, and electrophysiology to arrhythmias. Each of these was led, and continues to be led, by outstanding leaders in their subspecialty fields.
I think the beauty of Circulation in contrast to even fine journals like the New England Journal of Medicine, is that Circulation has been able to put on its pages those studies that really do span quite a spectrum. We don't shy away from very basic studies. That actually began with Jim, I must say, because that wasn't the case previously. And of course, we move right through to epidemiology and outcomes based research. And the impacts have been broad in each of those fields, as witnessed by the excitement and uptake of the journal, measured however you wish, by impact factor, or citations, or the frequency with which it's referred to in the lay press. So, I think that tradition certainly continues under the current editor with papers of extraordinary impact.
Dr Amit Khera: Thanks for that. I think your point about the evolution of science over time from Dr Willerson and certainly during your tenure and beyond to the breadth of Circulation currently. You also touched on the subspecialty journals. That happened in your watch and that was quite a marked change in cardiovascular medicine to have that explosion of new journals, if you will. What do you think the impact of those subspecialty journals has been for the cardiovascular field?
Dr Joseph Loscalzo: We struggled with the idea about whether or not we should pursue that kind of fragmentation. What really pushed us was the fact that the acceptance rate remains quite low, in those days, probably eight or so percent range at its nadir. So, we were rejecting a lot of really excellent papers which wound up in competitor journal pages, that we would like to have accepted and been given the scrutiny of the careful reviews and editorials that accompany papers accepted by Circulation. We felt the best way to do that under the circumstances was to create these daughter journals. They succeeded, in many respects, beyond our wildest imagination. The numbers of papers that were published in the family increased, I think in the first two or three years, by at least 2-to 3000.
So, that really speaks to the fact that we kept the best papers in the family. We gave them the right kind of audience. Some of these would have been too technical or too highly specialized to have been published in Circulation proper, but certainly of the highest quality and of significant relevance to the subspecialist. So, we think that it was a successful experiment. Now it's sort of become tradition. I think that the question that will always come up, of course, is can we fragment things more? I would say one of the best reasons to make the case that this was a successful experiment is that if imitation's the sincerest form of flattery, the New England Journal is now going to start three subspecialty journals. In fact, in my role now as an editor of the New England Journal, editor-at-large, they asked my input in how to design those daughter journals and what to expect from them.
Dr Amit Khera: Well, I think that's a great point. It certainly has been a resounding success and as you pointed out, imitation is the best form of flattery. I'm going to pivot now to Joe Hill. Dr Hill, you have certainly been the beneficiary of all the great work that these two editors have done in the past. You've inherited a very successful journal and also have crafted your own vision for where you want Circulation to go in your mark. Tell us a little bit about some of the new initiatives you've tried to implement, leveraging on these past successes.
Dr Joseph Hill: Thank you, Amit, it's an honor and a privilege to be in this conversation, frankly. I mean, Dr Willerson made this a weekly journal. That was back in the day when FedExes were flying around. Everything was paper. That kind of volume with that technology is impressive. And Dr Loscalzo, who has been a friend and mentor for many, many years, spearheaded the subspecialty journals, as we just heard, and took the journal to yet new heights. Each of you has been a pioneer and we've been fortunate to put together a team that I think has moved in exciting directions. We've leveraged technology now, such that we have our video conference meetings. We meet in a video conference with editors from 17 different countries. We have a third of our editors in Dallas, where I live, a third in the US outside of Dallas, and another third in 16 other countries.
It turns out we alternate the time of that meeting each week because there's no single hour of the day that works around the globe, so we move it around to capture Asia or to capture California in alternating weeks. That has been a thrill and, honestly, I believe a robust success. We have leaders on the ground in all these different countries. We have a highly diverse team across the different subspecialty domains of cardiology, across different geographic regions, across race and sex and gender lines. It is an amazing team. And Amit, who leads our robust digital efforts, including this podcast and our efforts on social media, again, the opportunity now in the 21st century to take these initiatives forward has been a real privilege.
Dr Amit Khera: It's ironic that Circulation was doing Zoom before everybody else was in the modern era. I'm going to pivot back to Dr Willerson. As Dr Hill just mentioned during your tenure how the volume of papers was handled, FedEx and sort of the nature of the journal publishing process. And now in the modern era, we have so much different information. We have a huge volume of journals. We have online, we have Twitter, we have podcasts. We have people that are consuming information in so many different ways. Tell us from your perspective, what's the role of the scientific journal currently and how has it changed at all in the last few decades?
Dr James Willerson: It's always going to continue to evolve. It's about as good as it can be right now with Dr Loscalzo and Dr Hill's leadership, and I'm really proud of them. There'll be more. We can't even imagine what it will be in two or three years. Of course, it'll be better and better, faster, almost momentary. Thank you, Dr Hill.
Dr Amit Khera: Thank you for that. I think we all look forward to seeing how this evolves more rapid information, rapid turnaround. I'm certain that will change. Dr Hill, you had a comment on that?
Dr Joseph Hill: We live in an era now where peer review is under attack in many ways and pre-print journals, blogs and so forth. And one of the things that I've really seen, and we've all seen, is how the peer review process, and we're all authors, right, we live on the other end of that stick, but it really is important. It makes a big difference. And people who are anxious to accelerate that process, I totally get it. We work very hard to do that. At the same time we, following the traditions here, have an intentionally redundant review process where every paper is evaluated by multiple editors and multiple peer reviewers. On a number of occasions, we've avoided a pothole, or we've improved a paper many, many times. And that is something that has really been impressed on me that I think people who aren't on this side of the editorial fence might not appreciate as much.
Dr Amit Khera: I think that's an important point about sort of the rigor about the way that articles come out in Circulation. And Dr Loscalzo, maybe as an extension of the last question, what do you see as some of the challenges going forward or opportunities for Circulation? You think about where it's been, but what are some of the things that you look forward to for Circulation in the future and what are some of the things you're concerned about?
Dr Joseph Loscalzo: Well, I too am concerned about this issue of peer review being under attack, and I'm particularly concerned about it for papers that have direct clinical impact. A good example of that concern, of course, are papers published, or at least publicly released, on non-peer reviewed websites like the archive sites because of their importance in the COVID epidemic, potentially. We all know of cases of drugs, at least in test tubes, with cultured cells and viruses appear to be effective that have adverse clinical consequences.
So that, and more than in any other sphere of science, ensuring that proper peer review from as many perspectives as possible is always a part of the process is absolutely critical for clinical medicine. And to me, the threat that this need for acceleration and rapid peer review poses and the sort of socialization of the transmission of scientific information that we're all interested in doing really has to have the brakes put on it a bit for the clinical science that the journal represents for this very important reason. Not to say we want to slow things down, we want to make sure that the best possible reviews are performed before we release it to the public.
I know that, as Joe was pointing out, one of the most exciting parts of the role of when I led the journal was the weekly meeting. We had a face-to-face meeting because all of our associate editors, save one, was actually physically proximate and they could travel to our conference room. But it's a wonderful exercise to have people of very different perspectives, from basic scientists, to clinical electrophysiologists, to outcomes researchers, make comments on papers that were completely outside their sphere.
The argument, of course, is if one can write and transmit a thought with the clear intent in a way that's rigorous and logical, that any reasonably bright person with reasonable scientific background should be able to understand it. And often these folks with very different scientific backgrounds have perspectives that very clearly improved the paper when they were acted upon. That's a process that doesn't exist in many other journals, I have to say. And I would encourage Joe, which I know, well, he's doing this because he enjoys it and he recognizes its importance, and Joe's successors continue to do that as well because that will ensure the value of the journal through all of the challenges that it is going to have to face in the next decade or two.
Dr Amit Khera: I think that was a great point. We're certainly seeing candy bowl examples of the importance of this rigorous process of the editors looking through it carefully and, as you both mentioned, peer review. Joe Hill, I'm going to let you maybe have the last word. I know how hard the three of you have historically worked on your craft for the journal, how much effort you've put in, but I also know it's quite a rewarding job. What would you see as the best part of being Editor-in-Chief of Circulation?
Dr Joseph Hill: Oh my, I'm learning something every day. I've been on about a steep a learning curve as when I was an intern at Dr Loscalzo's hospital long ago. Under Dr Willerson's term, I imagine many, many studies came in on acute coronary syndromes and thrombolytic therapy, primary PCI, antiarrhythmic drugs. We haven't seen an antiarrhythmic drug paper except for a recent review we did, but for quite a long time. It's artificial intelligence, it's big data, it's the UK Biobank, it's Omix, it's incredibly sophisticated genetics and genomics and basic science with genetic manipulations, IPS cells.
It's a very different world now than it was 10 years ago, 20 years ago and it certainly will be again, 10 and 20 years down the road. We are now approaching, I will say, 600 COVID related papers, and they're still coming in at a record pace. The world has changed. As I said before, this is the 70th anniversary of this storied journal. And it is truly my honor to be able to stand on the shoulders of Doctors Loscalzo and Willerson.
Dr Amit Khera: Thank you. I think that's a great way to end this podcast and congratulations on the 70th anniversary. It truly has been a privilege to chat with the three of you today. I want to thank you not only for what you've done for Circulation, but for the field of cardiovascular medicine. This is Amit Khera, digital strategies editor for Circulation. Next week we're back to our usual podcast with Carolyn Lam and Greg Hundley. Take care.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
Today’s episode discusses the paper “Randomized Comparison of the Polymer-Free Biolimus-Coated Biofreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial”
Dr Carolyn Lam and Dr Greg Hundley also discuss the following:
“Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis” by Shah et al.
“Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage” by Joutel et al.
TRANSCRIPT
Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn our feature article this week, we're going to dive into evaluating stent efficacy and looking at biodegradable stents and polymer free stents, and I can't wait to get to that feature.
But before we do that, how about we get to other articles in our journal today? Would you like to start?
Dr Carolyn Lam: You bet, Greg. So this paper describes temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis in Scotland.
Dr Anoop Shah from University Center for Cardiovascular Science at University of Edinburgh, and colleagues used a Scotland wide individual level linkage approach to identify all patients hospitalized with infective endocarditis from 1990 to 2014, and linked their records in national microbiology, prescribing and morbidity and mortality datasets.
Dr Greg Hundley: Interesting, Carolyn. So what did they find in this study?
Dr Carolyn Lam: The crude incidence rate of infective endocarditis hospitalizations increased from 1990 to 1995 but has remained relatively static thereafter with both short and long-term adjusted case fatality rates showing a steady decrease over the last 25 years. However, the incidence rate has doubled in the elderly.
Importantly, there was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines. The majority of patients with endocarditis in their cohort did not have positive blood cultures. However, in those that did have positive microbiology, staphylococcus and enterococcus conferred the highest risk for all-cause mortality.
Dr Greg Hundley: Ah, very interesting. More in the world of endocarditis. Well, Carolyn, my paper is also interesting and it involves both mouse and human experiments to identify the etiology of deep intercranial hemorrhagic stroke. Now I'm not going to quiz you this week because I think you're going to want to quiz me in anticipation of some of these exciting study results.
A little bit of background. First of all, the study comes from Dr Anne Joutel from INSERM and it has been thought that smooth muscle cell degeneration at the site of arterial wall rupture may be sufficient to cause hemorrhage. However, deep intracranial hemorrhages are rare in some aggressive small vessel diseases that are characterized by significant arterial smooth muscle cell degeneration.
Therefore, the authors hypothesized that a second cellular defect may be required for the occurrence of intercranial hemorrhage. So to address this hypothesis, the author studied a genetic model of spontaneous deep intercranial hemorrhage in mice, and analyzed cerebral retinal micro vessels, performing genetic rescue experiments, vascular reactivity analysis, and computational modeling.
And in the human experiments, they examined post-mortem brain tissues from patients that had sporadic deep intercranial hemorrhage.
Dr Carolyn Lam: Wow, that's a lot of work from mice to men. Well, let's start with the mice. So what did they find there, Greg?
Dr Greg Hundley: Right, Carolyn. So the authors identified in the normal cerebral retinal vasculature, a novel segment between arterials and capillaries herein called the transitional segment, and that is covered by neural cells distinct from smooth muscle cells and parasites.
In Col4a1 mutant mice, this transitional segment was hyper muscularized with a hyperplasia of neural cells expressing more contractile proteins, whereas the upstream arterial exhibited a loss of smooth muscle cells.
Moreover, the hyper muscularization of the retinal transitional zone increased its contractility in tone and raised the intravascular pressure in the upstream feeding arterial.
Dr Carolyn Lam: Wow, masterful explaining, Greg. Okay. What about in the humans?
Dr Greg Hundley: Well, the author similarly found that hyper muscularization of the transitional segment and focal arterial or smooth muscle cell loss in brain tissues from patients were observed in those with sporadic deep intercranial hemorrhage.
Dr Carolyn Lam: Okay, so put it together for us, Greg.
Dr Greg Hundley: Right. So the results suggest that hyper muscularization of this transitional segment is involved in the incurrence of intracranial hemorrhage in these studied mice, and this hyper muscularization in this zone raises the intravascular pressure in the upstream feeding arterial and promotes its rupture at the site of smooth muscle cell loss.
The human data corroborate these findings indicating that these two mutually reinforcing vascular defects may represent a general mechanism of deep intercranial hemorrhage. Really interesting results.
Dr Carolyn Lam: Not just interesting, but very, very nicely summarized. Thanks Greg.
Well, other very interesting papers in today's issue include a research letter by Dr Tiantian Li et al, entitled Associations Between Short Term Exposure to Fine Particulate Matter and Cardiovascular Disease Hospital Admissions After Index Myocardial Infarction. A case crossover study from Beijing, China.
There's also a white paper from Dr Milton Packer on the role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient over abundance. This beautiful white paper presents a mechanistic framework that may explain the findings of large scale randomized trials of SGLT-2 inhibitors and the close association of ketogenesis and erythrocytosis with the cardio protective and renal protective benefits of these drugs. Interesting.
There's also a series of papers on COVID-19, including an online white paper by Dr Franz Messerli on COVID-19 and renin-angiotensin blockers, current evidence and recommendations.
A perspective paper by Dr Michael Givertz on the challenges in heart transplantation in the era of COVID-19. Another online paper by Dr Harsimran Singh entitled New York City innocence lost, cardiology in the COVID-19 pandemic.
Dr Greg Hundley: Wow, Carolyn, this issue is just truly full of a lot of articles in addition to our original research.
So I have an exchange of letters to the editor between Richard Sutton and Dr Ben Levine regarding Dr Levine's previously published tilt table manuscript.
Next, Dr James Byrd from the University of Michigan offers a perspective on pausing clinical research during the COVID-19 pandemic.
Dr Comilla Sasson from the American Heart Association heads a very large group of authors to provide a very nice piece on guidance for life support during the COVID-19 pandemic.
Next, Professor Guilo Stefanini from Humanitas University has a research letter regarding ST elevation myocardial infarction in patients with COVID-19, both the clinical and the angiographic outcomes.
And then finally, another ECG challenge from Dr Adrian Baranchuk entitled an ominous ECG sign in critical care.
Well, Carolyn, what a great issue, and let's get on to that feature discussion to learn a little bit more about bio resorbable intercoronary stents.
Dr Carolyn Lam: Great. Let's go, Greg.
Dr Greg Hundley: Well, listeners, We're here for our feature discussion. And today we have Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, one of our own associate editors.
Lisette, could you tell us a little bit about the background for your study of intercoronary stenting and what was the hypothesis that you wanted to address?
Prof Lisette Jensen: The overall background or aim for this program is that we want to have a quality control of what we put into the patients, what stent we put in, and also we wanted to do as much research as possible, and we want to do it if it's possible on a low budget.
For the present study, the Sort Out IX, before we did the study, we knew that the Bio Freedom stent was doing very well with a short time of dual antiplatelet therapy in patients with high bleeding risk. At the same time, we knew that the Orsiro stent was doing very well in all common populations, we used it in Sort out VII also.
We wanted to see how the Bio Freedom stent, the one you could use with a short time of dual antiplatelet therapy, how it was compared to a gold standard stent. In this study, we did not shorten the treatment time with dual antiplatelet therapy, but we followed the guidelines with six months for patients with stable angina, and 12 months for patients with acute coronary syndrome.
Dr Greg Hundley: Can you just remind our listeners, what's the difference between the Bio Freedom stent and then Orsiro stent?
Prof Lisette Jensen: There's several differences. The strut thickness of the two stents differs. The Orsiro stent is an ultra-thin stent strut and the Bio Freedom stent is 120 microns. Also, the Bio Freedom stent is free of a polymer, compared to the Orsiro stent where the polymer is biodegradable and is degraded in one to two years.
And also the drug is sirolimus in the Orsiro stent and it is released within three months compared to the Bio Freedom stent where most of the drug biolimus is released within one month.
Dr Greg Hundley: So the Bio Freedom is a stainless-steel drug coated stent, and the Orsiro stent is a biodegradable stent. So can you tell us what was the study design, and then the study population?
Prof Lisette Jensen: It was a randomized trial and we enrolled 3,151 patients. They were randomized one to one, two to two stent groups, and we followed the patients. The primary endpoint was after one year, and this is what we're going to publish now in the journal, and we plan to do up to five years follow-up in the patients.
Dr Greg Hundley: And what outcomes were you looking for?
Prof Lisette Jensen: The primary endpoint was MACE, and that was a composite endpoint of cardiac deaths, target lesion revascularization, and myocardial infarction, not clearly related to any other segment that the index listed.
Dr Greg Hundley: So 3,151 patients, so a very large study. Can you tell us a little bit about your study outcomes?
Prof Lisette Jensen: The outcome was the primary end point after one year was, we saw MACE rate in the Bio Freedom treated patients was 5.0% compared to 3.7% in the Orsiro group. And the study was designed as a non-inferiority study, so with these numbers, Bio Freedom stent did not meet the criteria for non-inferiority.
Dr Greg Hundley: And were there any particular patient populations or subgroups where you saw differences in performance from one stent versus the other?
Prof Lisette Jensen: We looked into several predefined subgroups, which are also in the paper as figure three where we did a force plot, and in all the pre-specified subgroups, including indication for PCI, acute coronary syndrome or stable angina, young patients, old patients, diabetic, non-diabetic, gender, we did not see any significant difference.
Dr Greg Hundley: Well, Dharam, I'd like to switch over to you a little bit. Can you help us put this study in perspective to the other world's literature related to intercoronary stenting?
Dr Dharam Kumbhani: You know, one of the biggest advantages of the way they enroll patients is they tend to be a lot more inclusive than many of the other trials that are done. So typically isn't all common population.
So, now and again, I think it was an important trial because as she just outlined, it compares the Bio Freedom stent, which is a polymer free stent to a biodegradable stent. And this was really the first comparison of this Bio Freedom stent with a more contemporary stent that is used in clinical practice.
There have been a couple of other trials like the industry three and industry two trial which have compared it with bare metal stents. We know that this stent has a better performance than that, but when you compare it with, especially the thin struts or Orsiro, the latest in this class of DES, it is the thinnest strut, one of the thinnest strut stents that is in the market. The strut thickness, we know it really correlates quite well in stent restenosis.
I think this really helps move the field forward in terms of having data available for this comparison, and it suggests that perhaps in this kind of pragmatic design, that this Bio Freedom stent did not necessarily in the timeframe that they studied, meet the criteria for non-inferiority compared with the Orsiro stent.
So I think there's still valuable insight. The stent is not yet approved in the US. None of the Bio Freedom stents are available in the US. This is CE Mark, but not available in the US.
So I think this does add to the overall body of literature for this group of stents.
Dr Greg Hundley: I would like to ask you both, perhaps one at a time. Lisette, you first. What do you see is the next research study that needs to be performed in this field? Lisette.
Prof Lisette Jensen: Can I just give one more comment to what Dharam mentioned with the restenosis, because that was actually what we saw in the Sort Out IX. We had a higher rate of the target lesion revascularization rate in the Bio Freedom stent group, so the efficacy was less.
It could be because of the bigger stent struts, pushing us in a direction where we should use stents with thinner stent struts. And also we saw that the safety did not differ as we saw the equal number of stent thrombosis within one year.
I think what we should do next is maybe we should continue to work on the thin stent struts, and then also for the patients, the bleeding matters a lot. So it should be better to reduce the bleeding time to develop devices where we can reduce the treatment time for dual antiplatelet therapy.
Dr Greg Hundley: Very good. Dharam, your thoughts?
Dr Dharam Kumbhani: I would definitely agree. I think one of the most appealing aspects of this group of stents, because they don't have polymer, the ability to shorten the duration of antiplatelet therapy. And over the last couple of years, we've seen an incredible change in how we think about dual antiplatelet therapy and a number of trials have really challenged that dogma.
So I really think that a stent like this, I think it will be very interesting to study this in patients who are either high bleeding risk. This does perform better than bare metal stents, we know that. So conceivably we can get away with a much shorter duration of dual antiplatelet therapy, or just a lower duration of dual antiplatelet therapy in general.
So I would think that that would be one of the next areas of research in a randomized fashion for this group of stents.
Dr Greg Hundley: Well, listeners, we've had a wonderful conversation here with Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, related to some new evolutionary thoughts in intercoronary stenting.
For all our listeners out there on behalf of Carolyn and myself, we wish you a great week and look forward to speaking with you next week.
This program is copyright of the American Heart Association 2020.
Today’s episode discusses issues pertaining to the management of ST-elevation myocardial infarction in low and middle-income countries.
Dr Carolyn Lam and Dr Greg Hundley also discuss the following:
Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation by Sadek et al.
Autoantibody Signature in Cardiac Arrest by Li et al.
Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults by Kim et al.
TRANSCRIPT
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week is a little bit different from what we've done in the past with original manuscripts, we're going to focus on issues pertaining to the management of ST-elevation myocardial infarction in low- and middle-income countries. Oh my Carolyn, there's so many different things to consider. There are knowledge gaps, how we manage patients, how we get from one center to another, even just defining those centers. And this could be a very nice blueprint for future governments to use in managing these patients. But before we get to that feature, how about we have a little bit of a chat on some of the other articles in the issue?
Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do some but not all patients with severe aortic stenosis develop otherwise unexplained reduced systolic function?
Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens to do with one of our favorite magnetic resonance spectroscopy measurements, including creatine kinase.
Dr Carolyn Lam: You are just too smart, Greg Hundley!
Dr Greg Hundley: I had the opportunity to manage this one through the whole editorial board review.
Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of Oxford hypothesized that reduce creatine kinase capacity and or flux would be associated with the transition to reduce systolic function in severe aortic stenosis. So they looked at 102 participants recruited into five groups. One, those with moderate stenosis. Two, severe aortic stenosis with ejection fraction above 55%. Three, severe aortic stenosis with ejection fraction less than 55%. Four, healthy volunteers with non-hypertrophied hearts with normal systolic function. And five, patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function who are undergoing cardiac surgery and donating left ventricular biopsies.
Now, all these groups underwent CMR, cardiac magnetic resonance imaging, and 31 phosphorous magnetic resonance spectroscopy from myocardial energetics. And they also had left ventricular biopsies. So Greg, I know you know what they found, and so let me lunge right into it. They found that total creatine kinase capacity was reduced in severe aortic stenosis with median values lowest in those with systolic failure, consistent with reduced energy supply reserve.
Despite this, in vivo magnetic resonance spectroscopy measures of resting creatine kinase flux suggested that ATP delivery was reduced earlier at the moderate aortic stenosis stage, but where left ventricular functions still remain preserved. These findings thus suggest that significant energetic impairment is already established in moderate aortic stenosis and a fall in creatine kinase flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with aortic stenosis severity, this could increase susceptibility to systolic failure. As such, targeting creatine kinase capacity and our flux may be a new therapeutic strategy to prevent or treat systolic failure in aortic stenosis.
Dr Greg Hundley: Very nice, Carolyn. That is a very challenging explanation. And boy, you walked us through it just perfectly. And I'm so glad you're here as an expert in heart failure and transplantation to get us through this next quiz. So Carolyn, can you name several of the primary causes of heart transplant related mortality?
Dr Carolyn Lam: All right. Rejection, infection, malignancy and allograph vasculopathy, of course.
Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful job. So this paper comes from Dr Alexandra Loupy, and the study focused on the etiology of transplant related vasculopathy, the last one that you just named, from a population-based perspective. So 1,310 heart transplant recipients from four academic centers spread across Europe and the United States underwent prospective protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical histological and immunological parameters. The main outcome was prediction for cardiac allograph vasculopathy trajectory.
Dr Carolyn Lam: Interesting. So what did they find?
Dr Greg Hundley: So Carolyn, over a median follow-up post-transplant of about six and a half years, 4,710 coronary angiograms were analyzed, and four distinct profiles for allograph vasculopathy trajectories were observed. These four trajectories were characterized by one, patients without allograph vasculopathy at one year and non-progression over time. And that was about 56% of the patients. Second, patients without allograph vasculopathy at one year and late onset slow allograph vasculopathy progression. And that was about seven and a half percent of patients. Third, patients with mild allograph vasculopathy at one year and mild progression over time. And that was about 23% of patients. And finally, a fourth category, patients with mild allograph vasculopathy at one year and accelerated progression. And that was about 13% of patients.
Dr Carolyn Lam: Huh? So what most predictive?
Dr Greg Hundley: Well Carolyn, six early independent predictors of these trajectories were identified. One, donor age. Second, donor male gender. Third, if the donor used tobacco. Fourth, recipient dyslipidemia. Fifth, class two anti-HLA donor-specific antibodies. And finally, acute cellular rejection greater than 2R. The four allograft trajectories manifested consistently in the US independent cohort with similar discrimination, and in different clinical scenarios, and showed gradients for all caused mortality.
Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg?
Dr Greg Hundley: Well, because this study identified these four trajectories and their respective independent predictive variables, they provide the basis for a trajectory-base assessment of heart transplant patients for early risk stratification. And therefore, we might be able to develop monitoring strategies and form clinical trials around those to determine the efficacy of perhaps these predictive models.
Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on Tet-methylcytosine dioxygenase 2, or TET2.
Dr Greg Hundley: Carolyn, what is that?
Dr Carolyn Lam: Well, I'm glad you asked me before I asked you. So TET2 is a key enzyme in DNA demethylation. And the gene TET2 encodes an epigenetic regulator that demethylates cytosine. Somatic mutations of TET2 occur in cardiovascular disease and are associated with clonal hematopoiesis inflammation and at first vascular remodeling.
The current paper by Dr Archer from Queens University Kingston in Ontario, Canada, and colleagues, is novel because it's the first to examine the role of TET2 in pulmonary arterial hypertension. And they did this by evaluating exome sequencing data from the largest PAH cohort assembled to date, including 2,572 patients in the PAH Biobank. Unlike prior genetic studies, the biobank includes patients with associated PAH. Now, this is important. This is the category that includes patients with connective tissue disease such as scleroderma. This biobank also included non-European ancestry. So these are the novel aspects.
The authors performed gene-specific rare variant association analyses using up to 1,832 cases of European origin from the PAH Biobank, and transcriptomic analysis in an independent cohort to assess TET2 expression.
Dr Greg Hundley: Carolyn, so what did they find regarding to TET2?
Dr Carolyn Lam: In the entire cohort, they identified 12 predicted deleterious variants of TET2 novel to PAH. 75% predicted germline and 25% predicted somatic variants. None of the variant carriers were responsive to acute vasodilator challenge. Now, this is the first time that putative germline TET2 mutations have been associated with a human disease. They also identify ubiquitous downregulation of the expression of TET2 in the peripheral blood mononuclear cells of idiopathic PAH and associated PAH patients.
Finally, they evaluated TET2 depleted mice and demonstrated that they spontaneously developed inflammation, pulmonary vascular obliteration and pulmonary hypertension, thus providing biological plausibility that disorders in this pathway can indeed cause PAH. This is discussed in an editorial by Dr Soubrier from INSERM, entitled, TET2: A Bridge Between DNA Methylation and Vascular Inflammation.
Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a couple other articles in our issue. First, Dr Amr Abbas has a letter to the editor regarding actuarial versus echocardiographic outcomes following TAVR, evaluating gradients, leaks, areas and mortality with responses by Flavin Vincent and from Laurent Fauchier. We have Dr Miguel A. Arias again presenting another EKG challenge for us. Next, professor Giovanni Esposito has a research letter involving PCI rates for ACS during this COVID-19 pandemic. Next, Dan Roden from Vanderbilt has a consensus report related to QTC prolongation during the coronavirus pandemic. And finally, professor Marco Roffi has an on my mind piece related to STEMI and COVID-19 pandemics.
Dr Carolyn Lam: Oh, there is a series of on my mind papers in this week's issue. “The Future of Cardiovascular Prevention: Unprecedented Times,” by Laurence Sperling. “Primary and Secondary Prevention Of Cardiovascular Disease in the Era of Coronavirus Pandemic,” by Erin Michos. “Reperfusion of STEMI in the COVID-19 Era: Is it Business as Usual?” by Dharam Kumbhani.
And finally, we also have a research letter by Dr Lili Jong, addressing immune checkpoint inhibitors which are increasingly applied to a broader range of cancers and their potential toxicity causing myocarditis. And this letter describes the association of timing and dose of cortical steroids in immune checkpoint inhibitor associated myocarditis and cardiac outcomes.
Dr Greg Hundley: How about we discuss how we might want to manage ST-elevation myocardial infarctions in low- and middle-income countries?
Dr Carolyn Lam: You bet. Let's go, Greg.
Dr Greg Hundley: Well listeners, now we get to turn to our feature article. And we're very privileged today to have Dr Chandrashekhar from The University of Minnesota. And he and a large group of authors have put together a paper discussing the resources and infrastructure really necessary to manage ST-elevation myocardial infarction in low- and middle-income countries. Welcome Chandra. So we're going to call him Chandra for short as he is known internationally. Chandra, can you tell us a little bit about this prevalence of STEMI in low- and middle-income countries, and then also about the constitution of your writing group and what you were trying to do to address this issue?
Dr Chandrashekhar: The issue we are trying to address is, as you know, the low- and middle-income countries, there are about 80 plus countries constituting this group, and they account for something like 5.8 billion people around the world. And it's so interesting that 80% of the MIs that happen on the face of this earth are probably happening there, in areas which don't have resources to effectively deal with this condition, unlike the US or European countries and developed countries.
So this group got together to create some outlines of how to optimize care in low- and middle-income countries. And we got together groups which have extensive experience in dealing with this problem. It was a coalition of frontline clinicians as well as major organizations, including the Indian Council of Medical Research, the premier research body in India, a public health foundation of India which is a nongovernmental organization extensively involved in this, The Population Health Research Institute in Canada, the Latin America Telemedicine Infarct Network called LATIN, The Pan African Society of Cardiology and The South African Society of Cardiac Interventions, and an NGO in India called STEMI India. So we took experienced people from a number of different countries and created this group.
Dr Greg Hundley: Very good. Now, were there knowledge gaps or implementation gaps, maybe help distinguish those two terms for us, that you had to address when just starting your effort?
Dr Chandrashekhar: Yeah, absolutely. So let's start with the knowledge gap. As you know, there are excellent guidelines both in the United States, as well as Europe. Of course, there are STEMI guidelines in the UK and Australia and New Zealand, but these guidelines are not very applicable to low and middle income countries due to a number of reasons, due to porosity of resources, due to poverty, overcrowding, lack of infrastructure, and a bunch of other reasons that you can imagine.
So if we recommend somebody needs total balloon time under certain threshold, it's nearly impossible to meet this in most places in the low- and middle-income countries. And so there is a significant amount of implementation gap as well as knowledge gap, because the guidelines that are tailored to Western societies don't fit very easily in low- and middle-income countries. It's like fitting a round peg in a square hole.
So that's why we thought we should create something very focused, right? And there are implementation gaps in the sense infrastructure-based as well as resource-based. And knowledge gaps, for example, we don't know what the dose of dual antiplatelet therapy is optimal in these patients, for example, ticagrelor may have a higher effect in some Asian populations with small body habitus.
Similarly, as you know, statin doses, especially in the far east are much lower than what are prescribed here. So these are the kinds of challenges that we are applying and try to suggest some solutions.
Dr Greg Hundley: It sounds like definitions could differ, management strategies could differ, pharmacologic versus invasive, even centers that would manage the patients. Can you describe some of those issues for us?
Dr Chandrashekhar: Right. So that was the biggest challenge we had. So we had to create some resource infrastructure appropriate management paradigms for low- and middle-income countries. To give you an example, primary PCI, which is something we take for granted within our milieu, if you think about it, you and I probably didn't give thrombolytic therapy in the last 15 years. So this is a day-to-day thing in low- and middle-income countries. Most of the patients either they come so late that they don't get any reperfusion therapy for STEMI, or if they do, thrombolytic therapy is are very common mode of treatment there.
And so we had to create a way for them to get the optimized care. And so we divided the localities into different levels, from level one to level five. Level one being the most remote area and five being the one which is most equipped and can implement all the Western standards and guidelines.
And so we suggest a system of hub and spoke to transfer people from the smaller centers to the big centers, and outline what therapies need to be done at what stage. And one of the things that we emphasize so much is called pharmaco-invasive therapy, where you give thrombolytic therapy if you cannot reach a PCI center in time, and then in the next three to 24 hours, you transport the patient to a center where they can do PCI. And this has been studied in a number of trials showing that it's a very effective strategy. And so these are the kinds of solutions that we try to emphasize.
Dr Greg Hundley: And how about the patients themselves and the doctors that would implement, in terms of education, does your document cover how to reach out to both patients and physicians in these countries to emphasize these new protocols that you and your group have developed?
Dr Chandrashekhar: Absolutely. That's the crucial issue, right? No matter how many guidelines we create, if we can't implement it, they're useless, right? And so we have two parts to this guideline. There's a section devoted to governmental agencies as well as NGOs interested in improving care, STEMI care in low and middle income countries, as well as a section for frontline clinicians, which includes very focused flashcards with definitions and what exactly each level of this center in the hub and spoke model should be doing and how do they transport patients and how do they ensure that adequate pharmacotherapy is instituted? And so we keep repeating this and we also provide some other options of how to communicate with the hub facilities, from the spoke facilities, including use of mobile and social media apps like WhatsApp.
Dr Greg Hundley: Do you have certain recommendations that physicians in the field and patients at home should be aware of, for example, administration of aspirin and things like that?
Dr Chandrashekhar: Absolutely. These are all codified in flashcards, which are going to be printed for distribution to the frontline physicians. And they are also created as wall posters and plastered in this peripheral health centers where essentially the only thing they may have is an old EKG machine and a few drugs like aspirin. And so we have tried to cater to each of this, both in the informational material and what basic pharmacotherapies and equipment these centers should be having. And that's where the governmental part comes. So when governments have to decide how they invest their scarce dollars, they can divide it appropriately based on these recommendations.
Dr Greg Hundley: I like that last statement, it sounds like in addition to physicians and patients that your document may even be useful for governments and organizations delivering the care in these countries, do you want to talk a little bit about where you think this document may go next in that regard?
Dr Chandrashekhar: The best use of this document would be for agencies in different parts of the countries to take this up. And at the last count, there are at least five or six governments which are actively looking at the blueprint that is provided from this document, and to see what parts of this are locally implementable within their environment. And eventually, if it appears that it's applicable to multiple jurisdictions, then perhaps something like WHO could take this and modify it suitably for different localities. We see a lot of potential in this.
Dr Greg Hundley: Well, we are very privileged to have the opportunity to publish this important work. And I wonder here, just in closing, on behalf of your entire author group, are there any words you'd like to leave us with regarding this just monumental effort?
Dr Chandrashekhar: The thing that we can say is we should thank Circulation and its editorial board for working with us. It went through, I think, three revisions and it really made the document much better. And we really thank all of you for allowing us this platform. As you know, this is going to reach a huge part of the medical establishment as an open access article. And hopefully it will help us implement some progressive changes in healthcare in the low- and middle-income countries. And so we really thank Circulation for providing us this platform.
Dr Greg Hundley: Well, listeners, we're going to wrap up here and we're most appreciative to Chandra from The University of Minnesota and his entire author group. On behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you next week. This program is copyright to The American Heart Association, 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley associated editor from the Pauly Heart Center at VCU health in Richmond, Virginia. Well Carolyn, this week's feature investigates the compass trial and is going to examine the role of combination antiplatelet and anticoagulation therapy in patients with diabetes and cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and jump in and discuss some of the other papers in the issue?
Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and I'd like to start by talking about paclitaxel containing devices. You may already know this, but it was nice to revise that these significantly reduce re intervention in patients with symptomatic femoral, popliteal, peripheral artery disease, as we may expect. However, a recent aggregate data meta-analysis reported increase late mortality in pad patients treat it with these paclitaxel containing devices. Thus today's authors, Dr Rocha-Singh from Prairie Heart Institute of Illinois at St. John's hospital and their colleagues performed an individual patient data meta-analysis to evaluate mortality using data from eight randomized controlled trials of FDA approved paclitaxel coated devices using de identified data that was provided by manufacturers.
Dr Greg Hundley: Well, Carolyn, what did they find?
Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight paclitaxel coated device trials with a four year median follow-up, there was a 4.6% absolute risk of increased mortality associated with paclitaxel coated device use compared to balloon angioplasty at a median of four years follow up, significant loss to follow up and withdrawal rates of 24% and 23% in balloon angioplasty and paclitaxel cohorts respectively through five years were observed. Recovery of lost vital status data reduced the observed paclitaxel device associated mortality rate. And there was no paclitaxel drug dose mortality relationship identified.
Dr Greg Hundley: Oh, Carolyn, I think this is really an important finding, and we have a nice editorial, don't we? So what was the take home message?
Dr Carolyn Lam: Yeah. In fact, this was discussed in an important editorial by doctors Royce, Chakraborty and Dao from the USFDA. Now listen up. So based on the prior aggregate data meta-analysis and subsequent FDA review, FDA had already communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations. They had also implemented updated labeling for this device class to communicate the risk. So in this editorial, the FDA commended the authors of the current individual patient data meta-analysis for providing important information towards signal refinement, and also commend at their collaboration with device manufacturers to work together with a shared goal of patient safety. Now, there are still many unanswered questions, including the mechanism for the observed increase in late term mortality associated with these devices and how the benefit risk profile of these devices may shift across various patient populations.
Dr Greg Hundley: Well Carolyn, my paper comes from Professor Antje Beling from Charité – Universitätsmedizin Berlin in Berlin. And it investigates heart specific immune responses in an animal model of auto immune related Meyer carditis mitigated by an immuno proteasome inhibitor and a genetic ablation. So Carolyn, this study used mouse models to understand mechanisms involved in immune checkpoint inhibitor related Maya carditis, a phenomenon that we can observe in 5% to 10% of patients that are receiving these checkpoint inhibitors for treatment of their cancer.
Dr Carolyn Lam: So what did they find, Greg?
Dr Greg Hundley: Several things, Carolyn. All immuno proteasome deficient strains of mice showed mitigated auto-immune related cardiac pathology with less inflammation, lower pro-inflammatory and chemo tactic cytokines, less interleukin 17 production and reduced fibrosis formation. The auto-immune signature during experimental proponent I auto immune carditis with high immuno proteasome expression, immunoglobulin G deposition, interleukin 17 production in heart tissue, and troponin I directed humeral auto immune responses was also present in two cases of immune mediated related my carditis. Thus demonstrating the activation of heart specific autoimmune reactions by this checkpoint inhibitor related myocarditis therapy. So Carolyn, perhaps by reversing heart specific auto immune responses, immuno proteasome inhibitors applied to these mouse models demonstrated their potential to, in the future, aid in the management of auto-immune bio carditis in humans, possibly including cases with immune mediated myocarditis heart-related specific auto-immunity.
Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a quiz? Remember what desmoplakin is Greg?
Dr Greg Hundley: I think this is going to do something with right ventricular cardiomyopathy.
Dr Carolyn Lam: Very nice. Desmoplakin is the primary force transducer between cardiac desmosomes and intermediate filaments. And mutations in Desmoplakin indeed cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of desmoplakin cardiomyopathy have been limited to small case series. Today's paper, by Dr Helms from University of Michigan and colleagues is the largest series of desmoplakin mutation carriers reported to date.
Dr Greg Hundley: So Carolyn, what did they find here?
Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin mutations and 81 patients with pathogenic Plakophilin-2 mutations as a comparison cohort, they found compelling evidence that desmoplakin cardiomyopathy is a distinct form of cardiomyopathy marked by a high proclivity for left ventricular hypertrophy and arrhythmias and associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis. Furthermore they found that diagnostic and risk stratification variables that performed well for Plakophilin-2 associated ARVC exhibited poor accuracy for the diagnosis and risk assessment of desmoplakin mutation carriers. So these results strongly indicate that a genotype specific management approach is essential for desmoplakin cardiomyopathy.
Dr Greg Hundley: Wow, Carolyn. Lots of great science in this issue. Well, just like last week, we have got a lot of other papers in this issue. So let me tell you about a few that I've had a chance to preview. The first is a research letter by our own Dr Hesham Sadek from UT Southwestern Medical Center involving the homotypic fusion generates multi nucleated cardiomyocytes in the murine heart. Next is an ECG challenge. It's from Dr G. Neil Kay at the University of Alabama at Birmingham, and really reviews an ECG in a patient that presents with pulmonary embolism. Next, there's a case series from Dr Nil Uriel from Columbia University Medical Center regarding the variety of cardiovascular presentations of COVID-19. Next there's an on my mind piece that comes to us from Dr Ersilia DeFilippis from Columbia University College of and Physicians and Surgeons. And it involves cardiopulmonary resuscitation during this COVID-19 pandemic.
And it presents a view from trainees on the front lines. Next, Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic provides an informative white paper on the description and proposed management of acute COVID-19 cardiovascular syndromes. Next is a paper from Dr Francine Marquez from Monash University, and it's a perspective piece on the impact, strategies and opportunities for early and mid-career cardiovascular researchers during the COVID-19 pandemic. So many studies have been stopped and this very nice article highlights the new opportunities in this pandemic. Next, Dr Anabel Volgman from Rush University Medical Center has a piece on the seniors on the sidelines, and it's a call to action. And then finally, Dr Andrew Chapman from University of Edinburgh and professor Christian Mueller from the University Hospital of Basel exchange letters to the editor regarding a prior article of high sensitivity cardiac troponin, and the universal definition of myocardial infarction.
Dr Carolyn Lam: Nice. There's also a research letter by Dr Sandoval and colleagues who described the transition to using high sensitivity troponin T in a United States regional healthcare system, namely the Mayo Clinic enterprise. And they really showed that a small increase in MI diagnosis in part due to an increase in type two MI diagnosis occurred without an overall increase in hospital admissions or resource utilization using the high sensitivity cardiac troponin T implementation. And if I may mention, there is also a beautiful white paper by Dr Sana Al-Khatib, whom I was very lucky to coauthor with. And it's on the advancing research on the complex interrelations between atrial fibrillation and heart failure. This a report from the National Heart Lung and Blood Institute virtual workshop. Wow. A bonanza of an issue. Thanks so much, Greg. Let's move on to our feature discussion now.
Dr Greg Hundley: Look forward to it.
Dr Carolyn Lam: Today's feature discussion was in fact a late breaking clinical trial presentation at the American College of Cardiology meeting this year, 2020. And it's all about the compass trial, this time focusing on diabetes. I'm so, so pleased to have with us, the corresponding author Dr Deepak Bhatt from Brigham and Women's Hospital, as well as Dr Gregory Lip from University of Liverpool who was not only the guest editor, but also an editorialist for this paper. So welcome gentlemen. Deepak, could I start with you? This was an incredible presentation that was very well discussed. ACC not virtually, but I'm just so glad that we can have you on this podcast to tell us again, please, the rationale, the key findings and why this paper is just so important.
Dr Deepak Bhatt: So the background really is that prior studies and particular registry studies, the reach registry, for example, have shown that patients with concomitant CAD and/or PAD, that is coronary artery disease and/or peripheral artery disease, plus diabetes, are folks that are extremely high risk of future ischemic events. This is true even if they are apparently stable outpatients. At any rate in the compass trial, these sorts of patients with CAD or PAD, stable patients, both with and without diabetes who are enrolled 27,000 plus patients randomized. And there were three arms in this study, aspirin alone, rivaroxaban alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice a day.
And that was the winner, that combination sometimes referred to as dual pathway inhibition significantly reduced the schemic events versus aspirin alone, a significant reduction in cardiovascular death MI stroke, as well a lower rate significantly so of cardiovascular death, and even all-cause mortality was lower. So the overall trial was positive, but what we wanted to examine in this analysis was specifically how to patients with diabetes fare, knowing that they're a higher risk group in general across multiple registries and studies? And indeed we found that they were higher risk, those with diabetes versus those without diabetes and compass, and indeed, though their relative risk reductions were similar, those patients with diabetes had numerically larger, absolute risk reductions than those without diabetes with this regimen of low dose rivaroxaban plus aspirin versus aspirin alone.
Dr Carolyn Lam: Thanks Deepak. And I just have to refer the listeners to those beautiful figures in your paper. I mean, just one look at it really explains exactly what you were saying and really highlights that patients with diabetes are at higher risk of adverse events and also in one of the graphs of bleeding. Greg, could I bring you in here? You mentioned that in your editorial as well, that there has to be importantly acceptable bleeding risks. Could you expand on that?
Dr Gregory Lip: The compass crowd was a game changer and in this high-risk subgroup, as Deepak elegantly has described. These are diabetic patients, and then we also have the subgroups we call with or without PCI. And those would be so of course, being the higher risk group of patients. Nonetheless, the comparison was basically a dual pathway inhibition, but a combination rivaroxaban plus aspirin compared to aspirin alone. But a high cardiovascular risk and high bleeding risk tend to track each other.
So it was important that we certainly want to reduce the adverse outcomes of cardiovascular endpoints, we should certainly individualize our assessment of our patients and make sure that a patient is not an excessive high bleeding risk. I think overall, the study is very reassuring because there was no significant access in the overall population of the subgroup, at least in relation to fatal bleeding, critical organ bleeding or intracranial hemorrhage by dual path inhibition. But I think we, as physicians, just need to assess the patient in front of us just to make sure that particular patient is not at high risk particularly of bleeding, given that high risk of bleeding also generally is high cardiovascular risk as well.
Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some words from you about this sort of risk benefit ratio? How do you see it? How do we apply these results?
Dr Deepak Bhatt: I totally agree with everything Dr Lip said. Really, the key message when we're talking about antithrombotic numbers, something Dr Brunwald had said in this context, that is, there's no free lunch. When it comes to antithrombotics, there's always bleeding risks. There's just no way around that. In any trial that is adequately powered long enough, we'll find that, and that can include bad bleeding. Now, fortunately there was no significant excess and failure endocranial bleeding within the trial or within the subgroup of patients with diabetes. But nonetheless one needs to be cautious because these of course are carefully selected patients at low bleeding risk to get into the trial. There was a run in period. So when applying to real life, of course, there's the potential for bleeding. So we need to be really cautious about that. And it's also not a stat. So if we were talking about secondary prevention, either with or without diabetes, CAD, PAD, both of them together, of course, all those patients should be on Statin assuming they don't have a real type of contraindication.
So that's kind of a no brainer. That's a matter of implementation science. A lot of patients that should be on Statin aren't, but that's not an issue of science. We already know the answer there. Here, it's not the case of everyone that is like this who has diabetes, or even who doesn't, who has CAD or PAD should be on this regimen. It needs to be carefully selected patients, patients that are a low bleeding risk. And sometimes doctors ask, "Well, how do you tell that?" Well, it's not always easy, but for sure there's some things that predict future bleeding risks such as prior bleeding. So prior bleeding, anemia, those are powerful predictors of future bleeding. And one would want to be really cautious in these largely stable outpatients that we're talking about in the compass trial in intensifying their antithrombotic regimen. But in the right patients, I think it's a really effective way of reducing important future vascular risk, whether that's cardiovascular risk consisting of MI related end points, stroke, peripheral ischemic end points, including amputation, which was significantly reduced in the trial, and within the subgroup of those with diabetes.
So it's a matter of balancing those, but I do think with careful decision-making on the part of the physician, with discussion with the patient, with their understanding of the risks and benefits of intensifying the antithrombotic regimen beyond aspirin, there are a substantial number of patients who could benefit.
Dr Gregory Lip: I whole fully agree with Deepak's comments. And we do have to bear in mind also that risk is also a fairly dynamic process and we may well be assessing the patient as the one off initially while we are initiating treatment. But of course risk, whether from cardiovascular risk or whether from bleeding risk particularly, also is influenced by increasing age and by incident comorbidities, which really means that risk reassessment should be performed in every patient we contact. With bleeding risks in particular, there are modifiable bleeding risk factors that we can mitigate. So proactive assessment or rather reassessment of risks, whether both from cardiovascular events and/or bleeding, is necessary as we follow up these patients.
Dr Carolyn Lam: Thank you, both. Deepak, I'm just going to build a bit on your analogy of no free lunch. And maybe sort of a general question do you both, because it seems like we've got a bonanza of a buffet now when it comes to diabetes, especially with the new anti-diabetic drugs. So how do you think this fits in altogether? You talked about Statins. We now talk about low dose rivaroxaban in addition to aspirin, and you think diabetic patients should be treated with all? Maybe Deepak first, then Greg.
Dr Deepak Bhatt: What a terrific question. In fact, that was asked of me by the late-breaking clinical-trial panel clinical trial panel. They said, "Well, how does it fit in? Because these data look terrific, but there's also other new diabetes drugs and approaches." So for sure, I would say again, barring a real contraindication, I would say everyone that we're talking about here should be on a statin and preferably if they can tolerate it, a high intensity statin.
And if that doesn't do the trick in terms of LDL goal, I would say zetomyde. And potentially if they're in a region of the world where it's affordable a PCSK9 inhibitor. Then beyond that, I think we've got to pay attention to triglycerides these days, not just LDL cholesterol and if it's some patient that's sort of like REDUCE IT, well then, they should be on eicosapentaenoic. So we can modify LDL related and triglyceride related risks without too much effort or too much in the way of side effects. Then beyond that, I would say, we've got to think about blood pressure, inadequate control, especially in those with diabetes, but even those without that have cardiovascular disease. And then we have to think about glycemic control. And I don't mean the old-fashioned way, but I mean with some of the newer drugs. SGLT2 inhibitors in particular have been found to be useful for both.
That's just the glycemia control part of things, more importantly, cardiovascular outcomes. In particular, heart failure and renal related outcomes. And then GLP 1 agonist as well have been shown to be very useful once more modifying cardiovascular outcomes, including atherosclerotic outcomes. So there is, as you say, quite the buffet. And assuming a patient can tolerate that polypharmacy and afford it, I do think the majority of patients with diabetes should be treated that well. And that's of course on top of lifestyle modification, weight loss is particularly important, plant-based diet, et cetera.
But on top of that, then, with all those things that are being done and a patient is still at high ischemic risk but is at low bleeding risk, that's where I think, even in the deceptively stable appearing outpatient, it's worthwhile just running a mental checklist and saying, "Okay, are they on an SGLT2 inhibitor? Check. Did In someone measured their triglycerides? Check." And then on that checklist is, "Yeah, could they tolerate being on more than just aspirin alone in terms of bleeding risk? And if the answer to that is yes, might they benefit from adding this on?" And there are a lot of patients these results apply to, and I think a proportion of those patients who are otherwise optimally treated for their risk factors are the ones to target.
Dr Carolyn Lam: Beautifully put. And Greg?
Dr Gregory Lip: Deepak does raise an increasingly applied concept in how we approach our patients at high risk of cardiovascular events. That's the so called integrated or holistic approach to management. Because we have in the past tended to just focus on one strand of management. For example, we may well just be putting a lot of focus when on the analytic reduction and ignoring the rest. Well, we can't do that these days. We have to manage the whole patient and not just the bit of the patient. And this brings in this holistic approach, this integrated approach. And I think Deepak summarized that very nicely. It may require a number of medical approaches or medication-based approaches, but we have to practically look at the comorbidities like blood pressure reduction and also the lifestyle changes that Deepak's already summarized. So a holistic and integrated approach to our care of these patients. And in fact, some of the more recent studies showed nicely how this results in better outcomes in our patients at high cardiovascular risk.
Dr Carolyn Lam: And in fact, those were exactly the last words of your editorial. A holistic and integrated care approach. Beautifully done, thank you both so much for this excellent discussion. Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again. Next week.
Dr Greg Hundley: This program is copyright the American Heart Association 2020.
In today’s episode, Dr Carolyn Lam discusses the prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease with Dr Kausik Ray (KOSH) and Dr Amit Khera.
Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg. I'm the associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia.
Dr Carolyn Lam: Greg, ever wondered what's the prevalence of familial hypercholesterolemia in the general population? It's an important question, but we're going to wait to discuss that with our feature discussion coming right up.
First, I want to tell you all about valvular heart disease. In a preclinical model, would you believe, but first let me just remind us all that primary valvular heart disease is a really prevalent cause of morbidity and mortality. And although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart disease has always centered around valve repair or replacement, rather than the prevention or reversal of myocardial dysfunction.
In fact, have you thought about this? We know very little about the mechanisms, the actual preclinical underlying mechanisms of left ventricular dysfunction and primary severe mitral regurgitation. Well, in the first paper I want to talk about today, Dr Li from First Affiliated Hospital, Sun Yat-sen, University Guangzhou, and Dr Sadek, from UT Southwestern Medical Center and their colleagues develop the first mouse model of severe mitral regurgitation. And they did this by severing the mitral valve leaflets and chords using iridectomy scissors.
Similar to the human condition, induction of mitral regurgitation was followed by gradual left ventricular dilatation and dysfunction resulting in severe systolic dysfunction. Further analysis revealed that severe mitral regurgitation resulted in a marked increase in cardiac mass, increased cardiomyocyte length, but not with, and electron microscopy evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe mitral regurgitation resulted in activation of multiple components of both the mTOR and Kelson urine pathways. Now intriguingly, inhibition of mTOR signaling even preserved sarcomeric structure and prevented left ventricular remodeling and systolic dysfunction.
Finally, immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator CRB2, along the longitudinal axis of cardiomyocytes and close to the intercalated discs, with a similar pattern of polysome localization. And all of this suggests a potential new mechanism of longitudinal cardiomyocyte growth.
Dr Greg Hundley: Well, Carolyn, there is a lot of basic science and a lot going on both histopathologically, but also mechanically with this model. What's our take home message?
Dr Carolyn Lam: Well, Greg, this mitral regurgitation mouse models suggest that cardiomyocyte hypertrophy in response to mitral regurgitation is a maladaptive process that may be pharmacologically targeted by mTOR inhibitors.
Dr Greg Hundley: Oh my, very nice Carolyn. Well, I'm going to bring you another kind of basic science paper as well. And it's from Dr Jin Li from the Institute of Biochemistry and Molecular Medicine at the University of Bern. And it really involves auto antibody signatures in cardiac arrests. So Carolyn, a quiz of what percentage of individuals sustaining out of hospital cardiac arrest have no known cause?
Dr Carolyn Lam: You said, “Oh oh!” I’m on the spot here, Greg. Okay. What about if I start with what I do know? Coronary artery disease is the most common cause. I think that may be, I don't know, large majority, 80% of it. And then we get inherited cardiomyopathy, channelopathies. So I'm going to guess less than 10%.
Dr Greg Hundley: Wow. That is why you're just the stellar extraordinaire. So it's exactly about 5% to 10%. So Carolyn this study sought to address the etiology for this out of hospital arrests in this 5% to 10% of individuals, using a peptide micro-ray designed to screen for IgG targeting epitopes from all known cardiac ion channels with extracellular domains.
So plasma samples from 23 patients with unexplained cardiac arrest were compared to 22 cardiac arrest cases of ischemic origin and a group of 29 age, sex, and BMI matched healthy subjects.
Dr Carolyn Lam: Wow. What did they find, Greg?
Dr Greg Hundley: The auto antibody against the poor domain of the L tight voltage gated calcium channel or Cav 1.2 was consistently identified as a biomarker of idiopathic cardiac arrest and functional studies on human induced pluripotent STEM cell derived cardiomyocytes demonstrated that the anti Cav 1.2 IgG purified from patients with idiopathic cardiac arrest is pro-arrhythmogenic by reducing the action potential duration through calcium channel inhibition.
Dr Carolyn Lam: Wow, that seems huge. Clinical implications?
Dr Greg Hundley: I thought you'd asked me that. So the present report addresses the concept of autoimmunity and cardiac arrest and hitherto unknown auto antibodies targeting extra cellular sequences of cardiac ion channels were detected. And so moreover, this study identifies an auto antibody signature to specific patients with cardiac arrest, thereby explaining perhaps a potential etiology for this 5% to 10% of individuals that here to for, we were uncertain of that particular ideology.
Dr Carolyn Lam: Wow. That clearly needs follow-up, but you know what? What also needs follow-up is a quiz question for you. What do you say to a young adult with stage one hypertension about his or her future health risks?
Dr Greg Hundley: Well, how about A, see a physician, B, listen to that physician and follow their recommendations?
Dr Carolyn Lam: Oh, you are brilliant. Well, guess what? I'm going to tell you a little bit more about this in the next paper from Dr Kim from Yonsei University College of Medicine and Colleagues who looked at almost six and a half million participants aged 20 to 39 years. So young, and without taking any antihypertensive medication in 2003 to 2007 in a nationwide health screening database.
Now participants were categorized according to the 2017 ACCAHA guidelines as having a normal blood pressure. That is an untreated systolic blood pressure, less than 120 and diastolic blood pressure less than 80. Or stage one, isolated diastolic hypertension. So that's when systolic is less than 130 and diastolic between 80 and 89. Or stage one isolated systolic hypertension. So that's when systolic blood pressure is between 130-139 and diastolic is less than 80. Or finally, stage one systolic and diastolic hypertension. So that's when systolic is between 130-139 and diastolic is between 80 and 89. And these were followed up for the primary outcome of composite cardiovascular disease events, including myocardial infarction, stroke, heart failure, and cardiovascular related death.
Dr Greg Hundley: Caroline, I am dying to hear what did they find?
Dr Carolyn Lam: So over a median follow-up of 13.2 years, more than 44,000 new cardiovascular disease events occurred. Among these young adults who had a median age of only 30 years stage one, isolated systolic hypertension, isolated diastolic hypertension, and systolic and diastolic hypertension were each associated with higher cardiovascular risks compared to normal blood pressure.
Cardiovascular risk of stage one systolic and diastolic hypertension was higher than the risks of stage one isolated systolic and isolated diastolic hypertension.
Dr Greg Hundley: Very good. That was an outstanding presentation and very pertinent to our younger listeners as well as young patients with hypertension. In the rest of this journal, we are jammed packed with more articles. Let me tell you about a few. First, I've got a research letter by Professor G. Kees Hovingh from Amsterdam UMC discussing Inclisiran and how that durably lowers LDLC and PCSK-9 expression in homozygous familial hypercholesterolemia. Next there's an ECG challenge from Dr Miguel Arías from Complejo Hospitalario Universitario de Toledo involving syncope and alternating QRS morphologies.
Next Professor Qing Yang from Tianjin Medical University General Hospital has a perspective piece regarding anti-platelet therapy following percutaneous coronary interventions in patients complicated by COVID-19.
One of our own associate editors, Dr Nicholas Mills, has a very nice on my mind piece related to the use of serum troponin and biomarkers, as well as their utility in managing patients with COVID-19. Next, Dr Courtney Campbell from Ohio State University and Wexner Medical Center has a perspective piece regarding will compliment inhibition be the new target in treating COVID-19 related systemic thrombosis.
And then finally, Carolyn, there's a nice exchange of research letters regarding Orai 1 channel inhibition, preserving left ventricular systolic function, and normal calcium handling after pressure overload. And the contributing authors that provided these letters are Dr Muddassir Mehmood from University of Tennessee Medical Center and Dr Jessica Sabourin from INSERM UMR S1180.
Dr Carolyn Lam: And that's not all, Greg. There's also an in-depth article on the implications of altered ketone metabolism and therapeutic ketosis in heart failure by Dr Salvaraj, Kelly, and Margulies. Now this review is a must read. It summarizes the current evidence supporting a role for ketones in heart failure and covers normal myocardial ketone utilization, alterations, and ketone metabolism in a failing heart and effects of therapeutic ketosis in both animals and humans with heart failure. There's also a research letter by Dr Susanna Larson who used the UK Biobank Cohort to perform a Mendalian Randomization investigation into the causal effects of circulating LPA levels on atherosclerotic, cerebral vascular thrombotic, and valvular disease.
There's another research letter by Dr Eliseo Guallar and that's on mitochondrial DNA copy number, which is an indirect biomarker of mitochondrial dysfunction and its association with incident heart failure in the Eric study.
Wow, such a full issue, but now let's go on to our feature discussion. Shall we, Greg?
Dr Greg Hundley: You bet.
Dr Carolyn Lam: Today's feature discussion is all about familial hypercholesterolemia. Now, recent study suggests it is more frequent than previously reported. And in fact, increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Well, today's feature paper really represents one of the most comprehensive assessments of the prevalence of familial hypercholesterolemia.
More than 7.3 million individuals from 62 studies. So pleased to have with us the corresponding author of this beautiful paper, Dr Ray Kosh from Imperial College London, as well as our editor of digital strategies, Dr Amit Khera from UT Southwestern. Kosh, if I may call you that, congratulations again on another just really important paper. This systematic review and meta-analysis is really revealing. So could you tell us a little bit more of the details of what you did and just really tell us the take home messages.
Dr Kausik Ray: We've been getting signals that familial hypercholesterolemia... So this is where essentially individuals inherited an abnormality that results in lifelong elevations of LDL cholesterol birth, increases risk of cardiovascular disease. The previous prevalence was believed to be about one in 500 and suggestions... It's actually not just a suggestion, there's a lot of data suggesting that it's a lot more prevalent than that. And one of the queries that we often have, if you think about global health is does it affect all regions of the world? And if we don't go out looking for it, you're not going to find it. So this is really why this was done. And we basically synthesize the global data and there was basically over 7 million people approximately from general population primary care settings, if you will. And the global prevalence for FH is one in 311. Confidence interval is between about one and 250 to one in 397.
If you look at WHO regions of the world, it's equally prevalent across all regions of the world. And we know there are many regions of the world where they're not going out looking for this. So if you don't look for it, you won't find it. And we think that that should inform public health policies. The other key things about this or that because this is a condition that results in premature cardiovascular disease, there's been emerging data that actually in people with early myocardial infarction, for example, the possibility of FH may be higher.
So in proportion of studies where we had participants with established cardiovascular disease, the possibility of this being present is about one in 17. Now they're not all going to be FH, but it means that actually the coronary care unit where the vast majority of these patients arose from, that's a great starting place. If you see somebody with premature MI before the age of 55, high LDL cholesterol above 190, start thinking about it. If you find one, you can think about cascade testing and finding family members because each effected individual potentially the likelihood in a first degree relative is 50%, 1 in 2. So that becomes really important. And I think those are probably where I'd stop now and maybe take a few more questions, but I think that's the take home message.
Dr Carolyn Lam: Very, very important and practical take home messages. So thanks for that, Kosh. But could I just go back with one basic question? For those of us who don't think of it every day, what is the definition of familial hypercholesterolemia? There are so many definitions out there. Could you simplify it for us?
Dr Kausik Ray: Yeah, so basically all the definitions, the common ones that have been used in making an early diagnosis. So met that criteria, looking at family history, looking at elevated cholesterol levels. There's the Simon-Broome criteria with some clinical signs, as well as family history and genetic mutations. And then there's the Dutch lipid criteria. That's probably the most used in the world, looking at the physical signs, LDL cholesterol levels, and also family history.
And they give you essentially a score of the likelihood of this. And if you like, the gold standard really is probably genetic testing. That's not available in all regions of the world. There may be cost and other issues with that, but essentially that is giving you a diagnosis of a known variant of monogenic disorder and there's over 1,800 or so variants identified. So those are the ways that you can essentially do this.
Dr Carolyn Lam: Thanks, Kosh. Amit, I have to bring you in here. Thank you so much for managing this beautiful paper and recognizing how important it is. You invited an editorial as well. Could you share some of your thoughts?
Dr Amit Khera: Sure. The one thing, Kosh, as we look at this, which is so important to understand the prevalence worldwide and really glad that your group took on this project. But if you look at your figure, what's striking is how many areas are essentially white where there's no data. I mean, huge proportions of countries around the world. Why do you think that is? And how do we close that gap?
Dr Kausik Ray: That becomes really important. So what I would say is this was looking at prevalence and those are areas of the world where prevalence has not been reported. So if I were to overlap that with countries, for example, where we are starting to get definitive diagnosis through gene mutations, for example, there would be fewer gaps. We don't yet have enough data in terms of prevalence in those areas. But if you look, there's a huge gap, for example, in Africa. You've got a few countries that we know that haven't reported prevalent but have published on FH. So we do know it's there. And then you've got South Africa at the bottom and you've got Nigeria now also collecting data.
But part of it is, I guess, one important thing is misclassification. So if somebody dies in those regions of the world, often it's attributed to other causes. And because there is little public health information, because there hasn't been investments on thinking about cholesterol, for example, is it common in our population? If you were in sub Saharan Africa, maybe you think about infectious disease or other things, right? So it's not on the agenda. So there hasn't been that investment and therefore data is then lacking. We starting to see shifts in that, and hopefully this will move the needle a little bit more. And I think once that is done, what will then happen is we will get more reliable estimates from that part of the world. I think we've all got patients from that part of the world. And when I think about my clinical practice, I have patients from the middle of Africa, West, East, Sri Lanka, none of which is represented on that map.
Dr Amit Khera: I think that's a great point. And you know, there's no reason to think that the prevalence is much different. We just have a gap in knowledge there. And I guess the next part comes to implications. As you rightfully discussed many times in your paper, less than 1% of people are diagnosed. And even if someone publishes prevalence data, a diagnosis could involve genetic testing, it could involve broad limpid screening, a combination of both. What do you think is the next step?
Dr Kausik Ray: That's incredibly important. And I think you have to think about two different approaches. They're are the populations already out there living with this condition. So how do we picture those? It's going to be very difficult to think about universal screening in everybody 40-60, for example. So one way is to look at those people, the index case who comes in premature myocardial infarction in particular and use that as a source for cascade testing.
We know that that is cost-effective. There've been formal evaluations of that approach. I do think with the cost of genetic testing, for example, that will make life a lot easier. And I think that that point in CCU, the elevated LDL premature MI should be the start of that thought process. What we tend to do is we have a whole list of medications. We start people on that and it's an afterthought, depending upon the post-treatment cholesterol levels. It shouldn't be.
The other thing I think that you could do, there are lots of opportunities for screening. If you think about those people now, who are under the age of 10, 11, and you think about vaccination programs, you think about pre-college, pre-university health assessments that are often done in many parts of the world. Those offer opportunities to get a blood sample. David Wall did a lovely piece several years ago, looking at child parents screening, reverse cascade, if you will. And that showed that it could be cost effective. You don't need a small sample of blood. You can use DNA. And each of those interactions gives you an opportunity for screening.
What I'd love to see is we all think that there will be or there could be an update of the WHO recommendations for cholesterol management. And that might advocate, for example, universal screening for cholesterol before the age of 29. If that is done, then if you think of low middle-income countries, a lot of those white gap, we will start to see those things being or this condition being picked up and potentially huge numbers of lives being saved. And because this is a genetic condition which is ultimately dominant, you find one, you can either exclude or find other people early and early diagnosis changes prognosis as you well know.
Dr Amit Khera: Thank you for that, the implications and the potential profound if one could implement that broad screening. And as you pointed out early treatment, and I have one last question for you and it has to do with other part of the coin, which you touched on, which is the ASCBD. You know, your estimates of one and 17 were really helpful. I think many people aren't appreciative of how relatively common FH is in patients with coronary artery disease. And you talked about the implications being cascade screening of family members, but I know you work in therapeutics as well. There've been some data about maybe even earlier intervention or more aggressive intervention once someone's diagnosed with FH and after cardiovascular disease. What are your thoughts on that part of the investigation?
Dr Kausik Ray: Yeah, no, that's a really important question. So most of the studies that have actually looked at ACVD, they didn't utilize, for example, a genetic diagnosis. So it's largely the clinical phenotype. And remember, you have an A priority bias in terms of scoring on the Dutch Lipid Network Criteria, by virtue of the fact that you've had premature disease. Some of these people will probably have elevations in LP(a) and others it could be polygenic hypercholesterolemia, which does carry an increased risk, but not as much as FA.
If you could separate those three out the implications really are if you think about the ACVD patient population with true FA, you basically missed 40 years of unexposed exposure. And so in these people, I think those are people that we should be thinking about mainly more aggressive intervention with either lower LDL targets, because the absolute benefit is likely to be much, much greater. So I think that's the key implication I think of these findings.
Dr Carolyn Lam: Thanks so much, Amit. Thanks so much, Kosh. As someone living in an area where there is... It's white on that map as well, but no available data in Southeast Asia, I've learned a lot.
Thank you, listeners, for joining us this week. You've been listening to Circulation On the Run. Please tune in again next week.
Dr Greg Hundley: This program is copyright the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: I'm Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Today's feature discussion is the first huge look at the global, regional and national burden of calcific aortic valve disease and degenerative mitral valve disease over a huge period, from 1990 to 2017. Very important discussion coming right up after this coffee chat.
Greg, do you mind if I go first?
Dr Greg Hundley: Go ahead, Carolyn.
Dr Carolyn Lam: The first paper I want to talk about applies novel single cell transcriptomics to unveil new insights into pressure overload cardiac hypertrophy. Here's your quiz, Greg, ready?
Dr Greg Hundley: Well, I'm choking on my coffee here, but go ahead.
Dr Carolyn Lam: All right, I was thinking of asking you about single cell transcriptomics but let me just tell you the results. Single cell RNA sequencing is a new and rapidly advancing technique that can comprehensively characterize gene expression and relationships among individual cells.
Dr Wang from Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, and Peking Union Medical College and colleagues analyze the transcriptomes of 11,492 single cells and identified major cell types, including both cardiomyocytes and non-cardiomyocytes based on their molecular signatures. They did this at different stages during the progression of pressure overload induced cardiac hypertrophy in a mouse model.
Their findings not only illustrated dynamically changing cell type crosstalk doing pathological cardiac hypertrophy, but also shed light on strategies for cell type and stage specific interventions in cardiac disease. For example, subtype switching of macrophages was found to be a key event underlying the transition from normal to decline dejection fraction in cardiac hypertrophy.
Thus, targeting macrophages in hypertrophy for example, during the switch could attenuate disease progression. All of this is discussed in an editorial by doctors, Zhang and Zhou from University of Alabama in Birmingham.
Dr Greg Hundley: Oh wow. Carolyn very important macrophage infiltration and another role for those, that cell type. Well, my first paper gets at the topic of reversal of these factor Xa inhibitors.
In this particular patient population, it's the situation where we're dealing with intracranial hemorrhage. The article comes from Dr G Morgan Jones and colleagues from the University of Tennessee Health Sciences Center. Since the approval of oral factor Xa inhibitors, there have been few papers published really regarding the ability to neutralize the anti-coagulate effects of these agents, particularly after intercranial hemorrhage.
Dr Carolyn, this is a multi-center, retrospective, observational cohort study of 433 patients. Then it received apixaban, or rivaroxaban, and then developed an intercranial hemorrhage. They then subsequently received prothrombin complex concentrates in that period of time between 2015 and 2019.
Dr Carolyn Lam: Wow. How did these participants who had intracranial hemorrhage, how did they fare after receiving these prothrombin concentrates?
Dr Greg Hundley: Yeah, well, administration of the prothrombin complex concentrates after, apixaban or rivaroxaban in the setting of intracranial hemorrhage, provided a high rate of excellent or good hemostasis. That was in nearly 82%, coupled with an adverse consequence of 3.8% of those experiencing a thrombosis.
Thrombosis occurred in 25 patients who had a total of 26 thrombotic events of which 22 occurred in the first 14 days, following the prothrombin complex concentrate administration. One patient had documentation of an infusion related reaction. For the full cohort of patients, in the hospital mortality was 19% and the median ICU care and hospital length of stay were two and six days respectively.
Carolyn, these cohort analyses seemed to demonstrate the possibility of success and similar to other observational cohort studies. The results of this study suggest that future randomized control trials evaluating the clinical efficacy of these prothrombin complex concentrates in patients with factor Xa inhibitor related intercranial hemorrhage are needed.
Dr Carolyn Lam: Nice, Greg. You know what? I'm going to start with a quiz. True or false, heart failure with reduced ejection fraction is characterized by blunting of the positive relationship between heart rate and left ventricular contractility known as the force frequency relationship?
Dr Greg Hundley: Well, Carolyn, this is one of those where if I go 50/50, you'll knock out the wrong answer. Let's say, I'm going to go, true.
Dr Carolyn Lam: You're so right, Greg. This next paper really deals with this. It's from corresponding author, Dr Witt from Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds in UK and colleagues who previously described that, tailoring the rate responsive programming of cardiac implantable electronic devices in patients with HFrEF based upon individuals noninvasive force frequency relationship data, really improves exercise capacity. Addressing this reduce force frequency relationship and HFrEF.
Now in the current paper, they sought to examine whether using force frequency relationship data to tailor heart rate response in HFrEF with inpatients, with HFrEF and cardiac implantable electronic devices would favorably influence exercise capacity and left ventricular function six months later.
They conducted a single center, double blind, randomized parallel group trial in 83 patients with HFrEF. With a cardiac implantable electronic device and randomized to tailored rate response programming based on these individuals force frequency relationship versus conventional age guided rate response programming. The primary outcome measure was changed in walk time on a treadmill walk test.
Dr Greg Hundley: Wow, Carolyn. So this is a really detailed analysis. What did they find?
Dr Carolyn Lam: They found that rate adaptive cardiac implantable electronic device programming taking into account the at normal force frequency relationship in these patients, was associated with improved exercise time.
Force frequency relationship guided heart rate settings had no adverse effects on left ventricular structure and function. While conventional settings were associated with a reduction in left ventricular ejection fraction.
Out of the box age guided rate adaptive pacing, might be a sub optimal choice in patients with heart failure and an assessment of the force frequency relationship might be of clinical benefit in facilitating personalized rate adaptive programming.
Dr Greg Hundley: Very nice.
Dr Carolyn Lam: Thanks Greg, but there's other stuff I want to tell you about in this issue. There's a research letter by Dr Gambier on Molecular Imaging of Infective Endocarditis with Floral Multiple Trials PET-CT. This is the first time that a Florine 18 PET tracer has been used to specifically image bacterial infection of the heart valves with high sensitivity and specificity in an animal model.
Dr Greg Hundley: Oh, good job, Carolyn. Those flooring tracers, very interesting. Another application perhaps. Well, in a perspective piece, I have an article Carolyn from Dr Orly Vardeny from University of Minnesota Medical School in Minneapolis and remembers the prior cardiovascular complications from influenza. And how those experiences may be useful in anticipating some of the cardiovascular complications that we may see from SARS-CoV-2.
In a separate article, Dr Aatish Garg and collaborators from VCU Health, present an ECG case of syncope in an individual with severe aortic stenosis status post bioprosthetic aortic valve replacement and coronary artery bypass grassing. Who also has paroxysmal AV block?
Then finally, Carolyn, Professor Concepcion Peiró from Universidad Autónoma in Madrid. Has an on my mind pace discusses ACE inhibition and our abuse in relation to the SARS-CoV-2 to virus bonding to ACE two binding sites within the respiratory epithelium.
Well, Carolyn, how about we get on to that feature discussion? I can't wait to hear about aortic and mitral valve disease over nearly 30 years.
Dr Carolyn Lam: Let's go Greg. Nondramatic valvular heart disease is really common throughout the world. However, no studies have previously estimated their global or national burden, that is until today's feature paper. That's part of the Global Burden of Disease, or GBD, 2017 study. I am so pleased to have with us a corresponding author, Dr Greg Roth from University of Washington. As well as Victoria Delgado, our associate editor from Leighton University Medical Center.
What a great topic to discuss. Nondramatic valvular heart disease, meaning calcific aortic valve disease, degenerative module valve disease, all the stuff we see and have to deal with now. Greg, could you please tell us about this GBD effort and really what you found?
Dr Greg Roth: Let me tell you a little bit about the Global Burden of Disease Study and then why we wanted to explore this question and then what we found. I am the lead for cardiovascular research at the Institute for Health Metrics and Evaluation in Seattle at the University of Washington. We're the coordinating center for the Global Burden of Disease Study. It's now in its second decade, and it's a large-scale effort to quantify the lost health due to early death and disability for every country in the world.
This is a huge effort with over 5,000 people around the world working on it. We work closely with governments around the world, as well as the World Health Organization, as well as county, state, and other authorities in the US.
Our goal is really to bring together all of the evidence in the world to bear on important health policy questions. One of the areas that I've had a long interest in is valve disease.
I'm a practicing cardiologist at our county hospital here in Seattle, as well as an echocardiographer. I was really excited by the idea of bringing together my passion for taking care of patients with valve disease and looking at how to use diagnostic imaging to take better care of them and the disease modeling research that I do at the institute.
We decided a couple of years ago after exploring the global patterns of rheumatic heart disease, that we would turn our focus towards these really important questions of non-rheumatic valve disease. There's obviously a very large literature and lots of active research around the clinical pathways that we need to follow for patients with calcific valve disease and mitral valve disease that's not due to rheumatic causes. Obviously in recent years, we've got amazing technologies and interventions that we're using more and more frequently like percutaneous interventions.
However, we had not done the work to turn this really interesting tool, the Global Burden of Disease Study, towards looking at these important causes. We pulled together every data source we could find on the population level burden of nonrheumatic valve disease and then using a range of techniques, and we rely heavily on tools that come out of data science.
These include computer disease modeling tools that we've developed as well as ensemble models and other sort of big data approaches to pull all of this together into comparable, consistent estimates of death and prevalence. Then we're also really interested in using those to estimate what we call summary metrics of health, like disability adjusted life years. We do this for a very long time series. So we went back all the way to 1990 and we looked all the way to 2017.
Then we're able to get a really good sense of not only what the impact of these diseases are, but how they compare to the 350 other diseases that we estimated in exactly the same way for the Global Burden of Disease Study. Also, where is the burden of these particular conditions going up? Where is it going down?
We're really excited to be able to pull that together into this paper. In which we report the global, regional, and national burdens of calcific aortic valve disease and degenerative mitral valve disease. As well as a right sided valve disease that's not due to congenital endocarditis causes, which we estimate separately in the study.
Dr Carolyn Lam: Greg, you say, you're excited. I can definitely speak, I think on behalf of both Victoria and Augie, that we're the ones excited publishing this really great piece of work here in circulation. You know personally, I'm a great fan of your work in GBD. Tell us the results.
Dr Greg Roth: What we found was that in 2017, there was an estimated 12.6 million cases of calcific aortic valve disease in the world and 18.1 million cases of degenerative valve disease globally. With higher rates of calcific valve disease, among men and higher rates of degenerative valve disease among women. Now that is an aggregate.
We've produced estimates for every country in the world and for larger countries with more than 200 million people, we've gone down to what we call the first administrative level. So, US states, Chinese provinces, and we do this in the larger countries, but when you add it all up, you get those numbers.
We also found that there were just over a hundred thousand deaths globally each year due to calcific aortic valve disease and about 35,000 deaths reported due to degenerative mitral valve disease. I think this is really interesting because of course, as clinicians, we have a lot of experience with sources like cohort studies, and trials, and registries, but we have not actually looked at what's actually the world's largest public health reporting system, which is vital registration, meaning death certificates.
Now, most of us have filled out that certificates and we always wonder, how reliable are there? And there's clearly limitations. In fact, a huge amount of our work at the Global Burden of Disease Study is dealing with the limitations of death certificates, looking for bias, and adjusting that bias when we can, but these are death certificates where somebody's entered these causes as the underlying cause of death.
I think when that actually shows up on a death certificate, that's actually a real signal to us that there was a physician out there who felt pretty strongly that that was the sort of trigger that led to the patient's death.
We also found that aging and population growth are leading to about a hundred percent increase over this period of time over the last 25 years in the number of deaths due to these nonrheumatic valve diseases. If we age standardized, we see that the trend is flat, but if you're running a health system or a minister of health, you need to hear that message that with aging and population growth affecting almost every country in the world, you're going to see dramatic rises in the number of cases of both of these conditions showing up on the doorstep of all of your hospitals.
Dr Carolyn Lam: Fantastic Victoria, could you put these findings in context for us and maybe take us behind the scenes a little bit at what the editors thought?
Dr Victoria Delgado: These are very important data, because so far, for example, we have, as Greg said, registries and one of the most known registries was for example, in Europe, The Valvular Heart Survey that was done in 2001, if I remember well. Has been redone recently, it was last year published in circulation. The other one with a very large data is coming from counties. With similar data to the results that are publishing now.
For example, if you compare those two registries with much smaller populations, in US, they always report much, much frequently the genetic mitral valve regurgitation. While in Europe, aortic stenosis is the most frequent one, calcific aortic stenosis. Here, I was again surprised with in the global population that again, degenerative mitral valve regurgitation is much more prevalent than calcific aortic stenosis, but you can see that there was an increase of 124% in the prevalence of calcific aortic valve disease in 2017.
I wonder if this is related to the awareness of the risk associated with aortic stenosis and they invent of a new therapies, transcatheter therapies, with the TAVI for example, or transcatheter aortic valve replacement, which has opened the door for an effective treatment for many patients that before were simply denied for surgery. I don't know if you have further insights into that.
Dr Greg Roth: Yes. I think that's a really important point, that we see a lot of variation in the data. While we have millions of death certificates to look at all around the world. Really scores of millions, where we can look for trends and patterns. The population level data on nonrheumatic valve disease is actually quite limited compared to most diseases.
We did a very aggressive perspective review of the published and gray literature and found about 50 sources reporting prevalence for these conditions that were usable in our study. For the most part, those studies are not long time series. We have to estimate trends, piecing together data from different populations.
Now, there are a couple of places in the world where you can get a long trend of time where they've gone back repeatedly in the same population and looked with echo, which you obviously need here to make these diagnoses.
As far as we can tell, and these are just a handful of studies, the trend is flat. We don't see large increases. Now, the increases in our study were completely driven by aging and population growth and the age standardized rates. The epidemiologic pattern for this disease is that it's flat and for mitral valve disease, maybe trending down a little bit.
I think it's clear that in places where there's been a lot of attention paid either because of new therapies, like TAVR or new access to diagnostic screening with the growth of echo cardiography and other screening methods, that is a limitation of the study, for sure. I think what it really focuses me on is the idea that we need better data. We need to think about ways and probably more cost effective ways of surveilling for these conditions, but I'll tell you something that was really interesting, that we found is that, in the United States where we relied heavily on administratively coded data, because we have that in a uniform format for every state and we have a long time series for that, and we have complete vital registration.
We looked at the state level and we found that the all ages rate, was actually going up. Meaning it wasn't just population growth and aging, but in about a third of the states, the true epidemiologic rate of the disease was going up. Meaning it's becoming more common even if you control for the change in age structure of a country like the United States over time.
I think that given the fact that we're seeing this explosion of obesity around the world, and we know that atherosclerotic risk factors can be a major driver of let's say calcific aortic valve disease. I mean, an interesting question is, is valve disease going to be sort of a canary in the coal mine? Are we going to see more of it at younger ages?
Traditionally it's been the oldest patients who actually survived the longest and tend to be healthier, who we can actually find having the disease, but I wonder, are we going to see more of that as patients present with more obesity. Unfortunately we know that reversing or controlling those atherosclerotic risk factors hasn't paid off in big ways for preventing calcific aortic valve disease. It's complex and like mitral valve disease, clearly there's likely to be a very strong genetic component as well.
Dr Carolyn Lam: Greg, you mentioned a little bit more about the age effect, but you did mention some sex differences. Could you just clarify a little bit about that and maybe the interaction between the two?
Dr Greg Roth: What we've all been taught, or at least what I was always taught, was that there was more mitral valve disease in women. We actually did find that in the study and that was reassuring because when we went back to look for the source of that sort of common teaching, actually, it's pretty hard to find.
I think it actually comes, my guess is, from a lot of people's clinical practice. To see that match-up between what we thought was going to be true in terms of the relative prevalence by sex for these two major diseases, calcific aortic valve disease and degenerative mitral valve disease was reassuring. It suggested that the data we have is actually picking up on real patterns and patterns that match sort of our clinical experience as well.
One of the interesting things about the interaction between age and sex, is that women live much longer on average than men. As women age into those oldest years, what we actually see is a decline in the burden of disease. There's an increase in stroke, but for everything else, those women are truly survivors. Actually we see less bowel disease and cardiovascular disease in general, in the oldest old women.
What we do see is a massive rise in cognitive impairment and dementia. That's a very active area of research for us right now. The interaction between atherosclerotic risks, which can drive things like valve disease and of course, coronary disease and stroke and then the cognitive impact is a really important area of research. There are a couple of great papers that have come out even just in the last few weeks.
I think this question of how risk is going to impact people in those oldest age groups? Is really important. We know the population is aging. We know that in some places, life expectancy is increasing to the point where we really need to rethink what the disease patterns are going to be in the oldest old.
Dr Carolyn Lam: Indeed. So the feminization of aging is kind of what I like to call it, but yikes Victoria. Could I maybe ask you to please give the final words of advice and maybe the take home messages?
Dr Victoria Delgado: I think that this data are really welcomed because as Greg said, we need to understand better how we can modify the prognosis of these prevalent and how we can tackle it and for that we need data. I think that these are very welcomed data.
Now, how we are going to do it in the future? That's a great question. I don't have the answer right now, but I think that increasing the awareness that nonrheumatic valvular heart disease can impact as well on the outcomes of the population, is important to know. I think that people need to have access to diagnostics best particularly echo cardiography is very available imaging technique and very feasible. We can have right now developments where we can do the echo cardiography with our phone by adding one of the probes.
I think that in the future, we may see more and more valvular heart disease that probably was already there, but we just need to increase the awareness. From those data, learn how we can treat those individuals if they need and how we can improve the outcome of these individuals.
Dr Carolyn Lam: Thank you, Victoria. Thank you, Greg. More awareness and more good data needed.
Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal
and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National
University of Singapore.
Dr. Greg Hundley:
I'm Dr. Greg Hundley, the director of the Pauley Heart Center at VCU health in Richmond, Virginia.
Dr. Carolyn Lam:
Oh, Greg. Today we have a special episode focused on COVID‐19 pandemic, something that has just
affected us so severely worldwide, it really needs no introduction. Why are we doing a special issue?
Well, I think it very quickly got recognized that patients with cardiovascular disease do seem
predisposed to severe COVID‐19 syndrome, and that these patients can have an acute COVID‐19
cardiovascular syndrome, in fact. We're going to be talking all about this in a series of interviews about
the syndrome, the clinical presentations, what this implies for management. Is the pulmonary embolism
involved in the pathophysiology of all of it? And what are ways that we should use to monitor or even
screen these patient?, For example, what's the role of troponins?
Dr. Greg Hundley:
Yes, Carolyn. I am excited, just as well as you, and our first paper today is from Dr. Leslie Cooper, from
the Mayo Clinic. He's really done a nice review describing the disease process and the management of
acute COVID‐19 and the cardiovascular syndromes.
Dr. Greg Hundley:
Leslie, we'd like to welcome you to Circulation on the Run and just to get started, I'm wondering, could
you tell us a little bit about the genesis of your paper and then also perhaps some of the mechanism,
how does this virus affect our systems and promote cardiovascular disease?
Dr. Leslie Cooper:
In mid‐March as the COVID, crisis was taking off in this country, I was on a telephone call with Dr.
[Biykem] Bozkurt and [Dr. Mark] Drazner, from Texas. We realized that there was a terrific need for
clinicians to have an overview of how to manage the COVID‐19 impact on the heart. There was also, at
that point, very little clinical data about the mechanisms and what the real pathogenesis was. We set
about and the rapidly put together the available world's literature. That is what was ultimately
published here in Circulation about two weeks ago.
Dr. Greg Hundley:
Tell us a little bit about that mechanism.
Dr. Leslie Cooper:
It became apparent that there is not one specific mechanism. We initially thought that like the Coxsackie
viruses, this could be a direct cardiac damage, but clinically as we reviewed the literature, it became
clear that it's more systemic. The older patients who have preexisting cardiac disease, hypertension,
coronary disease, other risk factors, such as diabetes or obesity have a much greater risk of cardiac
involvement and the consequences of that cardiac involvement are very substantial.
Dr. Leslie Cooper:
In addition, when you get a profound cytokine storm from the systemic infection, that can depress
cardiac function. A combination, in individuals, of cytokine mediated damage from systemic
inflammation, stress induced cardiomyopathy, as you would see in takotsubo, as well as hypoxia and
perhaps increased pressures in the lung from, as Carolyn mentioned, pulmonary emboli, and finally
direct viral damage. Viruses can infect macrophages in the heart. There is a growing body of literature
that there can be a direct effect independent of the systemic infection. The answer is there are multiple
factors each of which may have its own therapeutic target.
Dr. Carolyn Lam:
Oh, I love the way you explained that so clearly Leslie, and in fact, this is really bringing back sweet
memories of when I was training under you at Mayo Clinic. I won't say how many years ago, but there
comes the question, you know so much about myocarditis, in general, and a different viral myocarditis.
Could you maybe tell us a little bit about how this one may or may not differ and also how this impacts
management?
Dr. Leslie Cooper:
The coronaviruses have a very different mechanism of cell entry and propagation. It does not appear
that this particular infection in the heart is causing the kind of antigen specific immune reaction that you
see classically with a Coxsackie virus. We're not seeing necessarily a lot of auto‐antibody, molecular
mimicry. We're not seeing a lot of T‐cell infiltrate. We are seeing some infection of macrophages, and
it's not yet clear how many of those were infected peripherally and then migrated to the heart. The
histology is quite different and the acute damage is therefore, more subtle. You're not seeing sheets of
lymphocytes and the targeted therapies would not be necessarily directed at those cells.
Dr. Leslie Cooper:
Having said that, inflammation more broadly, for example, anti‐IL‐6, anti‐IL‐1 type, anti‐cytokine
mechanisms are currently under evaluation in clinical trials, and they may be quite meaningful. Quite
meaningful in the setting of the systemic inflammation. When you compare this to a SARS and other
coronavirus infections, I'd like to say, we have known that occasionally a coronavirus can cause
myocarditis, for 40 years. It's simply not very common. It predisposes the individual or makes the
particular virus more cardiovirulent at this point.
Dr. Carolyn Lam:
All listeners, you have to get ahold of this beautiful paper. As Greg was actually suggesting a little bit
earlier, they're this beautiful figure that you have to refer to that shows a management pathway and
considerations. Also, very lovely illustrations of potential mechanisms. Leslie, could you also let us know
then, in the overall management, not just treatment, where is the place then, for things like myocardial
biopsy?
Dr. Leslie Cooper:
I think you have to start with the clinical presentation. COVID‐19 as a syndrome, and SARS‐CoV‐2 as a
virus, can present with multiple cardiac syndromes. The first would be ST segment elevation, like
myocardial infarction with normal coronary arteries. In that setting, it may be microvascular obstruction,
or it could be myocarditis or stress cardiomyopathy, perhaps in a younger person who doesn't have risk
factors.
Dr. Leslie Cooper:
Can also present with a primary cardiomyopathy, a heart failure presentation, shortness of breath,
systolic dysfunction. And finally it can present as a pericardial effusion, not the most common
presentation, but it's important to realize that just like other viruses, this can cause an epicardial or
pericardial inflammation.
Dr. Leslie Cooper:
Management really depends on the clinical syndrome and I'd emphasize guideline‐directed medical
management. If it's an arrhythmia, a ventricular tachycardia or heart block, manage that per the current
guidelines. The same is true for systolic heart failure.
Dr. Leslie Cooper:
In addition, I would say that since most patients with COVID infection do not have cardiac involvement,
you should first treat the whole patient. First, see the clinical syndrome. What is the dominant problem?
Is it a lung problem? Is it kidneys? Then, if there is a cardiac manifestation, we recommend starting with
a troponin. If the troponin is elevated, proceed to a point of care echo.
Dr. Leslie Cooper:
We do want to minimize exposure of allied health staff and physicians to the virus. We do not
recommend multimodality imaging or heart biopsy upfront. Having said that, if the patient has
substantial left ventricular systolic dysfunction, and they're already in the cath lab, because you're
excluding coronary disease, our paper does recommend that you consider an endomyocardial biopsy to
find the mechanism of left ventricular dysfunction.
Dr. Greg Hundley:
Very good, Leslie.
Dr. Greg Hundley:
Could you close this out, a little bit about therapy when we have patients with this severe hypertension,
respiratory abnormalities requiring ventilation, and then also these devastating cardiovascular effects.
Are we looking at anti‐inflammation is primarily the target as opposed to antiviral therapy?
Dr. Leslie Cooper:
Right now, there are a couple of clinical pearls. Number one, as in all cardiogenic shock, you don't
have... Sinus tachycardia is not a therapeutic target. You may need that because of low stroke volume.
You want to allow when it's compensatory for the tachycardia. Once you've treated with guideline
directed therapy, the arrhythmias and the cardiomyopathy appropriately, specific mechanistic
interventions, such as antiviral therapy or anticytokine therapy should be given within the context of a
clinical trial, wherever possible.
Dr. Leslie Cooper:
Our article recommends that if you have access to a clinical trial and in this country, the convalescent
plasma trial, is up and running. Mayo is leading that for the country. It's available at approximately 600
sites. We would recommend, first of all, enrollment in a trial because we then will understand the
mechanisms and the best treatment. If you don't have access, it really depends on the clinical syndrome
and how sick the patient is. Patients who are less sick have been treated with things like
hydroxychloroquine. People who are more sick, we move on to a convalescent plasma and anticytokine
therapy such as tocilizumab.
Dr. Greg Hundley:
Very good. Well, Leslie, we want to thank you for sharing this wonderful review with us at Circulation.
We feel very privileged to have the opportunity to publish this and also to share it with our readership.
Again, thank you for all of your frontline work at the Mayo clinic and helping participate in trials and
things of this nature to combat this terrible disease.
Dr. Leslie Cooper:
Thank you so much.
Dr. Carolyn Lam:
Greg, from acute COVID‐19 cardiovascular syndrome to now, all about troponins. I am so, so thrilled that
Dr. Nicholas Mills is here with us, not only our associate editor, but also corresponding author of the
next paper. He's from University of Edinburgh in UK. Nick, I love the question that you asked in your
title, "Are troponins an ally or a foe in the fight against COVID?" Explain, please.
Dr. Nicholas Mills:
I strongly believe that they can be an ally, but I recognize amongst cardiologists and clinicians around
the world that are grappling with this new condition, that the use of biomarkers can be contentious.
We're still learning very much about this condition and how it affects the heart. Therefore, it's difficult
to provide very clear guidelines. It's how you interpret the cardiac biomarkers in this condition. The
reason I feel strongly that they can be an ally is, they're easy to measure, they're cheap, and you don't
require a direct patient contact to obtain the result of the test. It gives us some fundamental
information about whether the heart is involved or not.
Dr. Greg Hundley:
Nick, can you tell us which biomarkers do you favor and is it high sensitivity troponin? Is it regular
troponin? For our listeners in many different hospitals across the world, what would you suggest?
Dr. Nicholas Mills:
The evidence that has that merged very rapidly over the last few weeks and months suggests that our
range of cardiac markers have very, very high prediction for poor outcome. Whether that's predicting a
patient that might deteriorate and require admission to an intensive care unit for ventilation, or
develop complications such as acute kidney injury or death.
Dr. Nicholas Mills:
There are a number of biomarkers that look very useful for predicting the course of a patient. The
strongest, in most studies, is cardiac troponin. I think it's because we do have such sensitive assays now.
High sensitive assays are such a fabulous way of getting a barometer of your heart health. The heart of
course, is a fairly fundamental organ. If this condition is going to affect to any other organ out with the
lungs. If it's the heart, you're going to be in trouble. I think high sensitive troponins, in particular, give us
such exquisite information about the systemic complications of this virus that they are perhaps above all
other markers, the most useful for predicting outcomes. Now, that clinical question goes beyond that.
We need to understand how this virus is affecting the heart and whether we can intervene in any shape
or form in response to these results in order to try and improve the course for these patients. That is a
more challenging question.
Dr. Greg Hundley:
Nick, you've got a wonderful figure and we just heard from Leslie Cooper about the different
cardiovascular disorders. Once we have elevation or experience, we see elevation in a patient with a
biomarker, whether that be high sensitivity, proponent, BNP, et cetera. How does that point us in a
direction of where our next move is, clinically, to combat this disease process in patients?
Dr. Nicholas Mills:
I think the first thing to say is that biomarkers do need to be interpreted in the clinical context and to
understand that the pre‐test probability of having underlying structural chronic disease in your patient
who presents with COVID‐19. That will very much influence your interpretation. If you think about the
spectrum of conditions that you might see, and in fact, that we are seeing, there are a number that I
would highlight. In particular, we know from many years of looking after patients with bacterial or viral
pneumonia, that the pro inflammatory state of those conditions in patients who are vulnerable, older,
and have underlying coronary heart disease is a really powerful risk factor for acute coronary syndrome
and type one myocardial infarction.
Dr. Nicholas Mills:
Often in ventilated patients or patients who have clearly an alternative diagnosis, these important
conditions, which are treatable, are overlooked. I think in considering the potential causes of myocardial
injury of these patients, we should not overlook the probability that vulnerable patients have triggered
acute cornea events in the context of their illness.
Dr. Nicholas Mills:
The other group that I think are really important are type two myocardial infarcts. They are an
increasingly well‐recognized group of patients with the use of high sensitive tests in critical care units
around the world. In the context of profound hypoxia or hypotension in sepsis, it gives the clinician
managing the patient an idea about the vulnerability of the patient and their susceptibility and risk. I
think that is also important.
Dr. Nicholas Mills:
Then, I think there's a separate group of conditions that are a direct consequence of the exposure to
coronavirus and the clinical syndrome of COVID‐19. We are seeing case reports and have our own
experience locally, of patients who develop myocarditis in this condition. I think it is rare, but it is real.
When it occurs, it can be particularly severe and associated with prothrombotic complications. The
other conditions that we are seeing are stress cardiomyopathies in relation to profound breathlessness,
and that is not uncommon.
Dr. Nicholas Mills:
We are trying to systematically scan our more critically unwell patients in the intensive care unit to look
for evidence of cardiomyopathy.
Dr. Nicholas Mills:
The final group that I would highlight is in those that are more severely unwell. Right ventricular
dysfunction as a cost of either prothrombotic changes or of ARDS itself, is a really important observation
that an elevated cardiac biomarker may be the first clue that that patient is developing cardiac
decompensation. Although there's a range of different, important underlying conditions and the
biomarker in itself cannot differentiate between these, I think recognizing that the patient is at risk of
these underlying cardiac artery disease is an important first step.
Dr. Carolyn Lam:
Nick, really nicely explained. I'm going to read one of the lines from, I think, one of the concluding
paragraphs from your paper, because it's really interesting. "Clinicians must recognize that troponin is
not a test for myocardial infarction and it never was." Now, that's very interesting. I know in many ways
you've explained it in what you said earlier, but could you maybe just end by hammering home what you
meant there?
Dr. Nicholas Mills:
Myocardial infarction is a clinical diagnosis. It is not a test, one test. It's a combination of clinical
features, a variety of different tests that help you arrive at that final diagnosis. Unfortunately, when
troponin was introduced into clinical practice a number of years ago, as a replacement for CKMB, it
became a sort of de facto. This is the test we use to differentiate people with myocardial infarction,
without it, and that has become perpetuated in our clinical practice.
Dr. Nicholas Mills:
As the technologies move forward and we've developed really high sensitive tests that allow us to
measure proponent accurately in almost all patients, it's become abundantly clear that it is a marker of
heart injury in a very wide range of clinical conditions. We need to almost unlearn that original teaching,
but this was a marker used exclusively to rule in and rule out myocardial infarction and embrace it as a
test that tells us about your heart health and how it is affected in a wide range of conditions.
Dr. Nicholas Mills:
For me, it's never really been high sensitivity troponin in any way, a test exclusively of myocardial
infarction. I use it very widely. I always find it informative in the clinical setting in order to guide
decisions that I make for my patients. In a patient with ischemic chest pain and an elevated troponin,
the default is, this is a type one myocardial infarction until proven otherwise. In all other settings, this is
evidence of acute myocardial injury. Some careful consideration is required to determine what the
mechanism is that underpins that.
Dr. Carolyn Lam:
There, you heard it, ladies and gentlemen. That kind of wisdom is going to last beyond COVID‐19. Thank
you so much, Nick, for joining us today. That was awesome.
Dr. Nicholas Mills:
Pleasure.
Dr. Greg Hundley:
Well, listeners, now we're going to switch and talk a little bit about pulmonary emboli and to introduce
that topic. We have Dr. Sophie Susan from Lille, France, who has performed a study in France, looking
for this disorder.
Dr. Greg Hundley:
Welcome Sophie. I was wondering, could you start us off, tell us a little bit about the background for
your study, the hypothesis and the question you were going to address, and then what was the study
population and some of your results?
Dr. Sophie Susan:
I work in Lille University Hospital, which is in the North of France. During the early days of March, we
had the first patients with COVID‐19 and we were very surprised. High number of patients with sudden
aggravation of the respiratory symptoms. We were suspecting high numbers of, I would rather say
pulmonary thrombi or pulmonary embolisms. We looked back to medical records of patients admitted
in our institution last year, in the same period of time, to look at the frequency of these pulmonary
embolism or pulmonary thrombi. We also looked at all the patients admitted for influenza, ARDS in our
institution last year.
Dr. Sophie Susan:
What we observed is that there was a higher frequency of pulmonary embolism during COVID‐19. We
observed 22 patients. At the moment we sent the [Research] Letter to Circulation. That means 20% of
patients admitted in ICU. And by comparison, there were only 6% of patients in the same period of time
in ICU last year. To be sure to avoid any bias in the data collection, we looked also at the CTPA, the
angiograms, of the angiography of those patients. We observed that in influenza patients, they were
much more investigation with CTPA than in COVID‐19 patients. Despite this higher number of CTPA
perform, they were less pulmonary embolism or thrombi identified. Our conclusion was at that moment,
that there was an awareness on the new increase frequency in thrombotic pulmonary complications in
COVID‐19 patients.
Dr. Greg Hundley:
Thank you so much, Sophie. You've got a beautiful table in your article. Were there any particular
patient characteristics that you could identify in this patient population that you think may make
patients predisposed to this?
Dr. Sophie Susan:
Yes, we were very surprised in my region. My area is a metabolic area and we were very surprised to
observe the high number of obese patients in our ICU. There was a publication from our group on the
subject. We looked at the BMI of those patients and on our table, you can see that almost all of them
were above 25, and the large majority about 30 BMI. They were also all receiving thromboprophylaxis at
baseline at the entrance in ICU. Although all the patients were at least receiving 40 milligrams of
Heparin, or even more, and some of them were also on their particular levels of low molecular weight or
unfractionated heparin therapy.
Dr. Carolyn Lam:
That is a very important point that you just made, that some of these patients, or a lot of them, had
background prophylaxis already. Sophie, could you end by telling us how have these results perhaps
influence your management? Or what do you think are the implications?
Dr. Sophie Susan:
It's a difficult question. The first issue is that regarding the population admitted in ICU, we've got a lot of
weight patients and there are no current guidelines adapting thromboprophylaxis to weight. The first
question was that 40 milligram of heparin is good for everyone. Do we need to increase this regimen in
obese patients?
Dr. Sophie Susan:
There was a proposal of ESC two years ago, and we adapted these proposals for COVID‐19 patients. We
do believe that 40 milligrams of heparin is not enough for patients in ICU, for overweight patients in ICU.
So for a BMI above 30, we think that we should increase the regimen of low molecular weight or
unfractionated heparin. That's the first point.
Dr. Sophie Susan:
We've got also, a disease that is random, very difficult sometimes to perform CTPA, difficult, to move
patients to those exams. Sometimes we've got to give a probabilistic treatment and in case of acute
worsening of the respiratory status and in particular, in case of repositioning patients, when they are
under high‐positive and expiratory pressure, sometimes they get sudden aggravation. We must think
about probabilistic therapeutic approach with heparin on those patients. That's the two main
conclusions we made for the adaptation of protocols.
Dr. Carolyn Lam:
Well, thank you so much, Sophie. I really am so grateful that you published this work here at Circulation.
You very, very, fairly pointed out what you found. I thought that your inclusion of the control groups was
really the best that we could do, and therefore your data represent the best available evidence for a
very important question that we've all been asking. Are these patients at higher risk of pulmonary
embolism?
Dr. Carolyn Lam:
Thank you so much for sharing that with us.
Dr. Sophie Susan:
Thank you very much for the invitation.
Dr. Carolyn Lam:
What an amazing series of papers that we have on COVID‐19. Guess what? These three that we talked
about today are not the only ones. We really strongly encourage you to look at
ahajournals.org/coronavirus where you can see many more papers published in Circulation, relevant to
COVID‐19 as well as some commentary from experts on the front lines.
Dr. Carolyn Lam:
Thank you very much, once again, everyone for joining us today.
Dr. Greg Hundley:
Have a great week.
Dr. Greg Hundley:
This program is copyright, the American Heart Association, 2020
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: We've got a juicy, juicy feature discussion coming up. It's on a pre-specified analysis of the ODYSSEY OUTCOMES randomized clinical trial, this time to ascertain whether PCSK9 inhibition reduces the risk of peripheral arterial disease events or venous thromboembolism after acute coronary syndrome. And, also to answer, these effects are related to levels of lipoprotein(a) or LDL cholesterol. I'm going to keep everyone guessing, as we get on our coffee chat and talk about the other papers in this issue.
And I want to go first, because the first original paper I want to discuss is really quite related to the feature discussion too. And it asks the question, what is the relationship between cholesterol levels and risk of venous thromboembolism? And, what is the effect of PCSK9 inhibition on the risk of venous thromboembolism? So this is from Dr Marston from the TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts, and colleagues who performed a post hoc analysis of the FOURIER trial, testing whether evolocumab reduces the risk of venous thromboembolic events. That is, deep venous thrombosis, a pulmonary embolism. The authors then looked at data from FOURIER and the ODYSSEY OUTCOMES trial and combined them in a meta-analysis to assess whether there was a class effect of PCSK9 inhibition on the risk of venous thromboembolism. As a reminder, the ODYSSEY OUTCOMES trial tested alirocumab as the PCSK9 inhibitor.
Dr Greg Hundley: Well, Carolyn, what did they find?
Dr Carolyn Lam: Well, first Greg, remember, this is the first study to demonstrate a significant reduction in venous thromboembolism with PCSK9 inhibition. Interestingly, the reduction in venous thromboembolism was associated with the degree of lipoprotein(a) lowering and not LDL cholesterol lowering, suggesting that lipoprotein(a) may be the mediator of venous thromboembolic risk. More coming up in our feature discussion.
Dr Greg Hundley: Wow, Carolyn. Well, I'm going to go into the world of PCSKs, but talk about PCSK6. So this study involves a secretome analysis of cardiomyocytes as novel players in cardiac remodeling after myocardial infarction and the corresponding author is Dr Florian Leuschner from Heidelberg University. So Carolyn, we know that acute occlusion of coronary artery results in swift tissue necrosis and bordering areas of the infarcted myocardium may also experience impaired blood supply and reduced oxygen delivery leading to altered metabolic and mechanical processes. While transcriptional changes in hypoxic cardiomyocytes are well-studied, little is known about the proteins that are actively secreted from these bordering cells.
So in this study, the authors established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis.
Dr Carolyn Lam: Wow, sounds like very advanced methods and what did they find?
Dr Greg Hundley: Okay. Carolyn lots of results here. They found that PCSK6 expression was elevated in hearts of mice, following three days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements and human serum also indicated distinct kinetics for PCSK6 in patients suffering from acute myocardial infarction with a peak on day three post infarction.
One of these beautiful studies combining basic science and human subjects in the same paper. In addition, adeno-associated virus nine mediated cardiomyocyte specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis as well as decreased left ventricular function after MI. So Carolyn, this study demonstrates how novel mass spectrometry-based approach allows the investigation of the secretome of primary cardiomyocytes. That's a first for that technique. And then analysis of hypoxia-induced secretion led to the identification of PCSK6 to be crucially involved in cardiac remodeling after MI, demonstrating increased collagen expression and cardiac fibrosis in those border zones.
Dr Carolyn Lam: Wow, fascinating, Greg. Well, I want to switch tracks here. Maybe ask, when you're choosing between antithrombotic therapies for patients with atrial fibrillation and a recent acute coronary syndrome, have you ever wondered what is the tradeoff of risk? Risk of bleeding and benefit that would be in terms of prevention of ischemic events over time? Well, guess what, I'm not going to put you on the spot here because our next paper addresses this very question. And it's from corresponding author, Dr Alexander from Duke Clinical Research Institute and colleagues who performed a post hoc analysis of the AUGUSTUS trial.
Dr Greg Hundley: Okay, Carolyn. I'm going to digress for just a minute here. We have this wonderful producer, Augie Rivera, and he's just fantastic and we should give him accolades because he really helps put all these together. Now I'm not going to ask him this time, but maybe in one of our future discussions, we may need to bring him into one of these because of his expanded knowledge of all of science, but getting back, Carolyn, can you remind us what is the AUGUSTUS trial?
Dr Carolyn Lam: All right, so in the AUGUSTUS trial, patients with AF and a recent ACS and/or PCI taking a P2Y12 inhibitor had less bleeding and rehospitalization with apixaban, than vitamin K antagonists and less bleeding with placebo than aspirin. The composite of death or hospitalization was also reduced with placebo compared to aspirin. However, the risk of several recurrent ischemic events, including stent thrombosis, where numerically higher in patients assigned placebo. Further analysis of the stent thrombosis outcomes suggested that most of the increase in risk was early within 30 days of randomization.
And hence the objective of the current paper, which is a post hoc analysis to explore the balance of risk and benefit using a variety of composite outcomes between randomization and 30 days and between 30 days and six months over time comparing apixaban versus vitamin K antagonists and aspirin versus placebo. So, here's what they found. Apixaban caused fewer ischemic and bleeding events than warfarin in the first 30 days after ACS and/or PCI and similar or fewer ischemic and bleeding events from day 30 to six months. Use of aspirin acutely, and for up to 30 days, resulted in an equal tradeoff between an increase in severe bleeding and reduction in severe ischemic events. However, after 30 days aspirin continued to increase bleeding without significantly reducing the ischemic events. So these results really informed shared patient-centric decision making regarding the ideal duration of use of aspirin after an ACS and/or PCI in patients with AF already receiving oral anticoagulation.
Dr Greg Hundley: Very nice, Carolyn. You know, lots of data coming out about how we perform anticoagulation, the administration of aspirin, both an atrial fibrillation, ischemic events, those with stents and this is just another piece of important data that we're so fortunate to have published in circulation. Well in the rest of the issue Carolyn, there's a lot of information. I want to talk about a research letter from Dr Armand Killick from the University of Pittsburgh, and he describes the outcomes of the first 1300 adult heart transplants in the United States following a policy change in the U S related to allocation of hearts.
In an EKG challenge, Dr Nobuhiro Takasugi from Gifu University and colleagues reviewed the etiology of wide complexes. Are they aberrantly conducted supraventricular beats? Are they premature ventricular complexes or intermittent ventricular prereq citation in an individual 70 years old presenting with symptoms of palpitations? Then Carolyn, in one of our COVID-19 articles, there's an in-depth piece by Dr Kevin Clerkin and associates from Columbia University. And they review coronavirus disease that is caused by severe acute respiratory syndrome, coronavirus 2 or SARS-CoV-2, which invades cells through the angiotensin converting enzyme or ACE-2 receptor. Among those with COVID-19, they note there is a higher prevalence of cardiovascular disease and more than 7% of patients suffer myocardial injury as evidence from elevated cardiac troponin values from the infection and in 22% of those that were critically ill.
And despite ACE-2 serving as a portal for infection, the role of ACE inhibitors or angiotensin receptor blockers requires further investigation. And right now, as you know, in your field is a heart failure expert, they are not recommendations to consider discontinuation for those drugs. And then lastly, in a prospective piece, Professor Gianluigi Condorelli from Humanitas University in Milan, presents critical organizational issues for cardiologists in this COVID-19 outbreak, including prioritization of unstable patients with cardiovascular disorders by postponing visits, and in this situation they did so by 80%, reorganizing clinical activities in terms of ward, ICU beds and outpatient visits, using a hub-and-spoke model to prioritize management acute MI, and then finally rapidly acquiring and training physicians and staff in the correct use of PPE. All very valuable lessons from Italy that was so hard hit by this devastating disease.
Dr Carolyn Lam: Indeed, and you know what, Greg, I just want to tell everybody about our circulation YouTube channel, where we have frontline interviews with people dealing with this from all over the world. Thank you to Augie and his team for making all of this happen. Let's go on to our future discussion, shall we?
Dr Greg Hundley: Absolutely.
Dr Carolyn Lam: Patients with acute coronary syndrome are at risk of peripheral artery disease events and venous thromboembolic events. Now we've heard a lot about PCSK9 inhibitors in patients with acute coronary syndrome, but what is the effect of PCSK9 inhibition on the risk of PAD or venous thromboembolic events? Well, we're about to find out. The feature paper is a pre specified analysis of the ODYSSEY OUTCOMES trial. And I'm so pleased to have the first and corresponding author, Dr Greg Schwartz with us from the University of Colorado, School of Medicine, as well as our guest editor, Dr Erin Michos from Johns Hopkins School of Medicine. So welcome. And Greg, could I ask you to start us off. Tell us why you looked at this in ODYSSEY OUTCOMES and what you found.
Dr Gregory Schwartz: All of our patients or nearly all of our patients with acute coronary syndrome have had an atherothrombotic event and most of them also have a heightened inflammatory state. These factors are also thought to have a role in the pathogenesis of peripheral artery disease events, and perhaps also venous thromboembolism. We typically think of the risk factors for peripheral artery disease as being diabetes and smoking, and less so dyslipidemia, although dyslipidemia may play a role in PAD events as well. And although the association of LDL cholesterol levels with PAD events has been inconsistent in the literature, there's more consistency actually with levels of lipoprotein(a) and the risk of PAD events.
And that kind of makes sense because we think that Lp(a) has both atherogenic and pro-inflammatory and perhaps also prothrombotic properties. So elevated levels of that lipoprotein might promote the risk of PAD events. Now statins, which are obviously the mainstay of our treatment of patients with atherosclerosis, lower levels of LDL cholesterol, but they don't affect the levels of Lp(a). In contrast, inhibitors of PCSK9 lower the levels of both of those key lipoproteins. So we looked at the relationship of baseline and on treatment levels of both LDL cholesterol and lipoprotein(a) on the risk of PAD events and also venous thromboembolism, which has been associated with lipoprotein(a) in some observational studies.
Dr Carolyn Lam: Nice. So, could you tell us what were the results?
Dr Gregory Schwartz: So first, we used data from the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in nearly 19,000 patients with a recent acute coronary syndrome. And as you mentioned, Carolyn, those patients may be at elevated risk for other types of arterial and venous atherothrombotic or thrombotic events. We had three goals in our analysis. First, we looked at the relationship of PAD and venous thromboembolic events to the baseline levels of lipoprotein(a) and LDL in the trial cohort. Second, we looked at the effects of randomized treatment on both of those types of events, PAD events, and venous thromboembolism. And lastly, we determined the relationship of treatment effects on lipoproteins to the risk of those events in the alirocumab active treatment group. What we found are four principle findings. First, although this was an acute coronary syndrome cohort, and there were only four percent of the trial cohort who had a prior history of PAD, there was nonetheless a substantial risk of PAD events. About two percent of the placebo group suffered a PAD event during the trial and about one percent had a venous thromboembolic event.
In the placebo group. We found that there was a very strong association between baseline lipoprotein(a) concentration and the risk of PAD events. So to put that in a quantitative framework, if we compared the highest quartile of baseline lipoprotein(a) with patients in the lowest quartile of baseline lipoprotein(a), there was a more than twofold elevated risk of PAD events. And by that, I mean, critical limb ischemia, revascularization, or amputation for ischemia, more than a twofold elevated risk in the highest quartile of baseline lipoprotein(a). There was a non-significant relationship of venous thromboembolic events to the baseline concentration of lipoprotein(a). The patients who were treated with alirocumab, the PCSK9 inhibitor, achieved the expected approximately 50 percent reduction in LDL cholesterol and a median 23 percent reduction in lipoprotein(a) concentration.
And those effects were associated with significant reduction in PAD events, a hazard ratio of point six nine, and a nearly significant peak, well point zero six reduction in the risk of venous thromboembolic events with a hazard ratio of point six seven. And incidentally, in the same issue of circulation, there is a companion paper from the FOURIER study, which looked at the risk of venous thromboembolic events with another PCSK9 inhibitor, evolocumab. They found something very, very similar. And again, the results of that trial individually were kind of on the margins of statistical significance, but putting the two trials together in their analysis, there was a highly significant reduction in the risk of venous thromboembolic events with PCSK9 inhibition, compared with placebo. They also related those effects to lipoprotein(a), but not to LDL cholesterol levels.
So we found that the magnitude of the reduction in lipoprotein(a) was related to the reduced risk of PAD and VTE events, but a similar relationship between the magnitude of LDL cholesterol reduction and the risk of those events was not found. So to put it all together, lipoprotein(a) may be the stone that we haven't turned over, but should, when we encounter patients with PAD events or VTE events that we can't otherwise explain. And although these two trials were not purposed primarily to look at PAD events, the findings certainly suggest that treating elevated levels of lipoprotein(a) might be an effective strategy to reduce risk of PAD events and VTE.
Dr Carolyn Lam: Wow. Congratulations, Greg, that was beautifully summarized. A novel on at least two levels, right? One is the PCSK9 inhibition effects on these two outcomes that we never thought of before. And second, that role of lipoprotein(a). Erin, could I bring you into this discussion? You were guest editor when this paper came across your desk. Could you tell us what were the considerations and frame how novel these findings are for us?
Dr Erin Michos: Oh, Carolyn excited to be the associate editor for this paper. People who know me know; I love all things lipids. So as a preventive cardiologist, I'm very excited to have drugs like PCSK9 inhibitors in my toolbox. They are certainly known for their powerful LDL lowering effects, but also further lipoprotein little a reducing effect who these combined data show the PCSK9 inhibitors, not only reduced incident major adverse cardiovascular events and PAD events, but potentially can reduce VTE events as well in patients prescribed this therapy. So I thought it was really interesting and this new analysis from ODYSSEY, that it was the levels of lipoprotein little a, but not LDL cholesterol that predicted the risk of future PAD event and we saw a similar trend with VTE. And then furthermore, on treatment with alirocumab. It was the magnitude of Lp(a) little a reduction, but not LDL reduction that was associated with reduced PAD and VTE events.
And so this suggests that the reduction of PAD events is mediated by the lipoprotein little a lowering and not the LDL lowering. You know, lipoprotein(a) is a particularly risky type of LDL. It's strongly inheritable it's atherogenic similar to LDL, but prothrombotic, so it's this double whammy of badness due to its structural homology with plasminogen competes with berberine binding and inhibits tissue plasminogen activator and ultimately inhibits fibrinolysis. And so that's why lipoprotein(a) may be a mediator of this apparent effect of PCSK9 inhibitors with PAD and VTE incidents. So how do I put this in practice? Prior to PCSK9 inhibitors, we really didn't have any lipid modifying therapies to actually lower lipoprotein little a, except niacin, which we don't really use. This was mentioned by Greg, statins don't really lower lipoprotein(a) and they actually increase lipoprotein little as levels.
Although we do know that statins of course reduce ASCBD risk. So, I'm checking lipoprotein little a now in all my secondary prevention patients with established CVD and in high risk primary prevention with those with family history. While we're all anxiously awaiting outcome trials, such as the antisense oligonucleotides that can lower lipoprotein(a) by 80 percent, that therapy is not here now, we don't have that available in practice. But we do have PCSK9 inhibitors now, which can reduce lipoprotein little a by 20 to 25 percent and have meaningful outcome data like the alirocumab data we see here in this ODYSSEY OUTCOMES study.
With a 31 percent reduction of PAD, that is really meaningful. So I'm particularly excited about PCSK9 inhibitors and my patients with PAD who often have concomitant CAD, polyvascular disease, and then regarding the VTE effects, I think we should point out that the absolute risk reduction of VTE was pretty modest. We didn't really see significance until we combined it with the FOURIER data. So I think given the cost of the drug, it's not warranted to prescribe PCSK9 inhibitors to the general population, specifically for VTE prevention alone. But in patients with ASCBD, who would be recommended for a PCSK9 inhibitor to reduce incident CBD, you know, there may be this added special benefit of reducing risk of VTE as well.
Dr Gregory Schwartz: I just wanted to comment on a few things that Erin said, I think we’re really important. All of these patients were on intensive statin therapy in the background. So although we did not see a relationship between the further reduction in LDL cholesterol with alirocumab and the risk of these events, it doesn't mean that lowering LDL cholesterol has nothing to do with the risk of those events because everybody was on background statin therapy, 90 plus percent. So, I think that's important to point out. And I think the comment that was made about when to check a lipoprotein(a) level is very pertinent. And, in the European guidelines, they direct us to check lipoprotein(a) at least once in a lifetime for everyone, even if there's no other signs or risk factors for cardiovascular disease.
So I think as Erin indicated, with some tools in the toolbox now, and more tools, perhaps on the way with both the antisense, and also there are small interfering RNA approaches to lower lipoprotein(a), we should get more accustomed to looking at this, to turning over that stone. Even if we're not a hundred percent certain what to do with what we find underneath it, we should still look because there may be some things we can do in the interim.
Dr Carolyn Lam: Thanks, Greg. Erin, can I give you the last word? Any take home messages?
Dr Erin Michos: I definitely think that as we move forward with other therapies such as the small interfering RNA and the antisense oligonucleotides, we need really more phase three clinical trials specifically assessing VTE. And then I just want to mention, although I didn't write an editorial for this study, I did have the pleasure of writing an editorial for another ODYSSEY OUTCOMES analysis that was published in December. You know, my editorial was entitled, "Achievement, a Very Low LDL. Is it Time to Unlearn the Concern for Hemorrhagic Stroke?" And I mention this because one of the barriers I get in clinical practices, people get very worried about the very low LDL levels that we see with PCSK9 inhibitors and I think important to point out from ODYSSEY that, with the reduction in ischemic stroke, that there was no signal for increased hemorrhagic stroke and that provides additional reassurance.
So I think that's important to mention, I think this PCSK9 therapy is being under-utilized in clinical practice and ASCBD and PAD, these are really high-risk patients who have really high risk of recurrent events and our efforts to ward off these devastating consequences. We need to make sure that we're appropriately utilizing this important therapy.
Dr Carolyn Lam: Thank you so much, Erin. Thank you so much, Greg. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr Greg Hundley: This program is copyright, The American Heart Association, 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.
Well, our feature article this week, Carolyn, is really interesting and evaluates management of patients that are suspected to have atrial fibrillation and how we should screen them, what kind of monitoring and the like, very interesting discussion that will be coming up.
But before we get to that, how about we start into the papers and would you like to go first?
Dr Carolyn Lam: I would love to. And the first one is a basic paper on regenerative therapy, very important topic. Now remember that mammalian adult hearts have limited regenerative capacity. However, a transient regenerative capacity is maintained in the neonatal heart.
So co-corresponding authors, Dr Wang and Dr Guo from Nanjing Medical University hypothesize that by analyzing systemic phosphorylation signaling in ischemic neonatal myocardium, they may unlock key pathways involved in heart regeneration.
They therefore used quantitative phosphorylation proteomics to analyze the kinase substrate network of regenerative myocardium post MI in neonatal mice. And they found that activated Chk1 kinase was responsible for neonatal regeneration and could enhance cardiac regeneration in adult hearts post MI via activating the mTORC1 P70-S6K axis.
Dr Greg Hundley: Wow, Carolyn. Sounds like this could have a lot of clinical application several years down the road. So what are your thoughts on that?
Dr Carolyn Lam: I thought you may ask. Well, potentiation of Chk1 kinase, therefore, may be a promising regenerative therapy and authors gave this example that Chk1 injection could for example, in the form of a hydrogel, be injected into the myocardial infarction region and surrounding areas and may even be a novel therapeutic option to promote cardiac regeneration post MI.
Dr Greg Hundley: Very good, Carolyn. Well, my paper comes from the PARTNER 3 trial and remember PARTNER 3 is a comparison of transcatheter versus surgical aortic-valve replacement in low risk patients.
The corresponding author is Dr Philippe Pibarot from Quebec. The placement of aortic transcatheter valve three or PARTNER 3 trial randomized a thousand patients with severe aortic stenosis and low surgical risk at 71 centers to undergo either transfemoral TAVR with the balloon expandable SAPIEN 3 valve versus undergoing SAVR or surgical aortic valve replacement.
Transthoracic echocardiograms were obtained at baseline and at 30 days and one-year post procedure and they were analyzed by a consortium of two echocardiography core labs.
The objective of this study is to compare echocardiographic findings in low risk patients with severe aortic stenosis following surgical or transcatheter aortic valve replacement.
Dr Carolyn Lam: Important topic, very hot. So what did they find?
Dr Greg Hundley: In patients with severe aortic stenosis and low surgical risk, TAVR with the SAPIEN 3 valve was associated with a similar percentage of moderate to severe AR compared with SAVR, but a higher percentage of mild AR with no association between any grade of AR and outcomes.
Trans-prosthetic gradients, valve areas and LV mass regression were similar in TAVR versus SAVR. And SAVR was associated with a significant deterioration of RV systolic function and greater tricuspid regurgitation, which persisted at one year.
So Carolyn, very interesting results. Another study from PARTNER 3 comparing TAVR versus SAVR for patients with severe aortic stenosis.
Dr Carolyn Lam: Nice. So going from PARTNER 3, I want to talk about MESA and this time focusing on coronary artery calcium. Now we know that the recent ACC/AHA primary prevention guidelines recommend considering low dose aspirin therapy only among adults who are at high atherosclerotic cardiovascular risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified.
So the current study aimed to assess the value of coronary artery calcium for guiding aspirin allocation in primary prevention using the 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk.
So corresponding author Dr Cainzos-Achirica from Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and colleagues studied 6,470 participants from MESA all of whom underwent coronary artery calcium scoring at baseline to assess benefit versus harm.
A 12% relative risk reduction in cardiovascular disease events was used for five-year number needed to treat calculations, while a 42% relative risk increase in major bleeding events was used for the five-year number needed to harm estimations.
And now here are the results. Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the ACC/AHA guidelines and using more than 20% estimated atherosclerotic cardiovascular disease risk to define higher risk.
Among the 3,540 aspirin naive participants less than 70 years old and not at high risk of bleeding, the overall number needed to treat in five years with aspirin to prevent one cardiovascular disease event was 476, while the number needed to harm in five years was 355.
The numbers needed to treat in five years was also greater than or similar to the numbers needed to harm among estimated ASCVD risk strata by pool cohort equations.
Conversely, with a coronary artery calcium score of more than a hundred or more than 400, both these cutoffs identified subgroups in which the number needed to treat in five years was lower than the number needed to harm in five years.
Also, coronary calcium score of zero identified subgroups in which the number needed to treat was much higher than the number needed to harm.
Dr Greg Hundley: Lots of data. So we're mixing aspirin and MESA coronary calcium scores. What do we take home from this?
Dr Carolyn Lam: So here's the take home message. Coronary artery calcium may be superior to the pool cohort equations to inform the allocation of aspirin in primary prevention.
Individuals with a coronary artery calcium score above hundred and particularly above 400 may be good candidates for aspirin therapy for primary prevention. Although the net expected benefit will likely be modest.
In the presence of zero coronary artery calcium, the risk of bleeding is greater than the potential benefit and aspirin therapy for primary prevention should probably be avoided.
Overall, implementation of the current 2019 ACC/AHA guideline recommendations together with the use of coronary artery calcium scoring for further risk assessment may result in a more personalized, safer allocation of aspirin for primary prevention. Although ,of course, confirmation and external settings are required.
Dr Greg Hundley: That was really interesting. Combining coronary calcium scores, if you happen to have it, if someone's considering primary prevention with aspirin, it looks like those calcium scores could really be helpful there.
Well, I've got a couple other papers to talk about in this week's issue. There's an ECG challenge from Abdulhamied Alfaddagh from Johns Hopkins reviewing the quote unquote de Winter EKG pattern in a truck driver presenting with chest pain.
Second, there's an in-depth article from Alexander Fletcher from Edinburgh in the United Kingdom who discusses the metabolic pathways involved in inherited aortopathies trying to move beyond just diameter assessments to predict risk above future dilation and rupture.
And then lastly, there's a research letter from Petra Frings-Meuthen from the German Aerospace Center, the reports on how weightlessness shifts intravascular volumes and concentration of natriuretic peptides in astronauts.
Dr Carolyn Lam: Huh. And I would like one on my mind by Dr Kowey and it talks about the relentless pursuit of new drugs to treat cardiac arrhythmias.
Wow. What a nice issue. Let's move on now to our feature discussion.
Dr Greg Hundley: Welcome everyone to our feature discussion. In this particular paper will focus on atrial fibrillation and we're delighted to have Dr Søren Diederichsen from Copenhagen presenting this work and Dr Changsheng Ma, one of our associate editors from Beijing, China to have nice discussion.
Søren, I was wondering if we could get started with you. Could you tell us a little bit about what was the background related to this study and perhaps even a little bit about the hypothesis that you wanted to test?
Dr Søren Diederichsen: The background for this study is that, as we all know, atrial fibrillation is actually big and it's a growing health problem throughout the world and we also know that AF is often asymptomatic. So many cases of atrial fibrillation go undetected until complications occur.
And, of course, one of the most feared complications from AFib is a disabling stroke. And there's more and more evidence growing that a large proportion of people with risk factors for stroke do have some subclinical atrial fibrillation when they investigated or when they are followed, for instance, with a pacemaker.
So there has been a recent meta-analysis that found that the at risk of stroke in patients with subclinical AFib was fairly large compared to the risk of stroke in patients without subclinical AFib.
So, in this study, we want to look at the subclinical AFib in patients from the general population using loop recorders to follow these patients. And we want to sort of look at how could we screen the patients to find those with subclinical AFib using different screening scenarios which are less intensive than using a loop recorder for everyone.
Dr Greg Hundley: Søren, could you tell us a little bit about your study population and your study design?
Dr Søren Diederichsen: First of all, this study is part of an ongoing randomized control trial called the loop study. And in the loop study we recruited study participants from the general population.
The participants had to be at least 70 years old. And besides age as a stroke risk factor, they also had to have at least one additional stroke risk factor, hypertension, diabetes, heart failure or previous stroke. And importantly, they could not have AFib.
And the included participants were then randomized to control or screening for AFib using implantable loop recorder with remote monitoring and adjudication of new onset AF episodes.
In this particular study, we looked at the first participants in the loop recorder group who had been monitored for the entirety of the device's battery life, which is approximately three and a half years. So for these persons, we know whether or not they actually have AFib and we know exactly when they were in AFib and when they were in sinus rhythm.
So we use this data from the loop recorders to reconstruct full heart rhythm histories for each person, including exact time of onset and termination of each episode after exclusion of any clinically detected AF in the patients.
And it's a bit complicated study design because we have these heart rhythm histories. Now you can imagine where we have a string of data which is approximately three and a half years long and we know exactly when is AFib present and when a sinus rhythm present in this patient.
So we could use that data to simulate that the persons had been invited to an AFib screening by the health care service and had undergone a different type of screening at a random time. And these screenings that we investigated were time-point screening using standard ten second ECG during office hours and intermittent screening using single list devices, for instance, and short term continuous screening using external devices such as Holter or event recorder.
So we simulated that the patients had undergone such screenings and we could also assimilate that the patients were screened several times on a monthly or annual basis such as, for instance, taking an ECG every year.
And this simulation was then used to evaluate the sensitivity and negative predictive value of various screening regiments using the loop recorders' gold standard.
Dr Greg Hundley: What were your study results?
Dr Søren Diederichsen: All of this data comprised, as I told you, the first participant in our trial that had been monitored for the full battery life of the device.
So that was 590 participants entering nearly 700,000 days of continuous monitoring. So that was our data. And one third of those participants actually had previously unknown AFib and the number of AF episodes in our data was more than 20,000 AF episodes.
The main results were that if we simulate the pseudo-random daytime ECG in those patients, we would have identified only 1.5% of those who had AFib while performing by daily 32nd ECGs during 14 days, we would have identified 8% of those with AFib.
And if we took a 72-hour Holter, we would have identified 15% or a longer, for instance, a 30-day event recorder, we would have identified about a third of all those with AFib.
So that was actually our main results. We were able to see how many would we have identified of those with AFib if we'd done anything from taking a daytime ECG to performing a rather long event recorder.
Dr Greg Hundley: Were you able to put together maybe a combination of other variables along with the more lengthy recordings that could forecast future atrial fibrillation?
Dr Søren Diederichsen: One of the things we wanted to do with this study was not only did we want to see what is actually the diagnostic performance of doing an ECG or screening patients at risk with different kinds of screening, we also want to look at specific subgroups of the population who were more likely to maybe benefit from the screening in terms of having their AFib diagnosed.
So we looked at some population characteristics, age, sex and NT-proBNP. And we saw that the sensitivity of the screening was consistently higher among those who were older with a cutoff at 75 years, and also among males and among those with a high NT-proBNP.
So we could see that if we had screened one of those risk factor groups, age, male sex or high NT-proBNP, we would have been more or less likely to identify if AF was actually present.
Dr Greg Hundley: Changsheng, I'd like to turn to you. Can you help us put this results into perspective? How should we use this information in managing patients with atrial fibrillation?
Dr Changsheng: The AI for screening is a very important clinical problem and a hot topic issue. The heart rate monitoring is a cornerstone for detecting suspected AF patients. And then emerging new technology make monitoring more convenient than before.
But however the best screening strategy for those at higher risk of future AF stroke. And probably the strategy for the general population screening remain undetermined.
On the contrary, they evaluated the performance of a large panel of AF screening strategy among the 600 persons with a stroke risk factor that was not known yet.
The study used as an implantable loop recorder as a gold standard to assess the detection or difference in simulating a screening model.
I've got to say, the method employed in this study is quite exquisite and there's a key finding our clients tried to forward.
The time-point screening or the short-term monitoring could only identify a very small fraction of AFIB as compared for long-term loop recording screening. And diagnostic yield increased with duration, number and the dispersion of screenings.
So this is done to provide important clinical implications that every relatively intense screening such as even now I knew 30-day monitoring would need more than four in ten with AF.
And about one in six which are underlying more than 24 hours episode of AF. So the authors also gave the practical dispersion concept that when screening for AF, three times 24 hour monitoring are superior to one time 72 hour monitoring.
So I think this is a very important study to understand the condition, to understand the screening of AF patient for the general population.
Dr Greg Hundley: So really, helping us put these results in perspective. Maybe I'll ask each of you Søren first and then Changsheng. What do you think is the next research that needs to be performed after taking your results into account?
Dr Søren Diederichsen: In terms of what we should do next, I agree with Changsheng that there's a lot of attention towards AF screening at the moment, but we still really don't know if widespread screening in the population is actually something that could prevent heart endpoints.
So the next thing we need to know is, first of all, if we screen, will we have fewer of those events or will we have more side effects from the screening such as anticoagulant-mediated bleedings? It's very important to keep in mind that we don't yet know if screening is something that would prevent heart endpoints.
Second of all, we want to know more about what is actually the relationship between AF burden or amount of AF and risk of stroke. There's some evidences coming up that it's growing.
Is it, for instance, from the CERT study that the amount of AF and the pattern of AF that you have might tell us a little bit about what is your risk of stroke? For instance, if you have long AF episodes, your risk of stroke is higher than if you have all the short AF episodes.
And so that would be two of the next things I would think we should look at.
Dr Greg Hundley: Very good. Changsheng, do you have something to add to that?
Dr Changsheng: Yes, I agree with Søren. Now, on the detection, it's important but as a burden, even more important. So in practice in future, wouldn't we need more advanced technology and the patients or the participants frontally the monitoring device, which has the same ability to loop record them.
But this is more easy to use because when we use frontal monitoring for the patients, the longer duration of your monitoring period. So worse complains to the patients, not as our study because we have a simulation methodology, that 100% of patient accomplishments.
So I think in future, the watch with a diagnostic function of AF differentiation based on not ECG, but only based on the pulse.
So, the watch diagnostic function, not by ECG that are by pulse, like a detection of pulse. And then depend on the artificial intelligence, the AI function, to make a diagnosis of atrial fibrillation, not by ECG. That would be the future.
Dr Søren Diederichsen: And if you don't mind, I would like to add to that because I think that Changsheng raises an excellent point here with the smartwatch and how could they contribute to our prevention of stroke and in society.
So the current smartwatches work by looking at the pulse by photoplethysmography. And they cannot look at the pulse continuously as we do with the loop recorder looking at the ECG continuously.
This like with the photoplethysmography turns on when the patient is at risk and builds up an algorithm to look at what is actually the likelihood that the patient is an AF at this moment or today.
So at this point it'll only detect fairly long AF episodes, but in this study, we also looked at the longer AF episodes and the AAF burden. How does that impact the likelihood of detecting AF and of course it's more easy to detect it in patients with long AF episodes.
And if we find out in the future that a larger AF burden or longer AF episodes are actually required to increase the risk of stroke, then I believe that technology such as smartwatches could be a very feasible way to screen or to detect that kind of AF in patients at risk.
Dr Greg Hundley: Well listeners we've had a wonderful discussion here with Dr Søren Diederichsen from Copenhagen and our associate editor, Changsheng Ma from Beijing, China.
And really reviewing some important results related to screening for atrial fibrillation and the three 24-hour monitoring sessions combined with risk factors really help us identify who may be experiencing atrial fibrillation in our patients.
And then also, very interesting projections for the future, both using technology to try to identify atrial fibrillation perhaps through watches.
And then also how we could incorporate the duration, the time, et cetera of atrial fibrillation occurrences and how they may relate to adverse events.
Thank you so much Søren. Thank you Changsheng. And to all our listeners, we wish you a very safe week and look forward to meeting with you next week. Take care.
This program is copyright the American Heart Association 2020.
Dr Carolyn Lam: Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia. Well Carolyn, our feature this week really examines long-term efficacy of drug eluting stents versus coronary artery bypass grafting in those patients with left main disease. Really looking at long-term extended follow up from the PRECOMBAT trial but before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And I'll start off. My first article is a basic science paper looking at catecholamine sensitive and ventricular tachycardia in ARVC. And it comes from Dr Long-Sheng Song from the University of Iowa Carver College of Medicine.
So, the study from Dr Song used protein mass spectrometry analyses and that identified integrin beta one is downregulated in those patients with arrhythmogenic right ventricular cardiomyopathy hearts without changes to calcium handling proteins as adult cardiomyocytes express only the beta-1 D isoform, they generated a cardiac specific beta-1 D knockout mouse model and perform functional imaging and biochemical analyses to determine the consequences from integrin beta-1 D loss of function in hearts in vivo and in vitro.
Dr Carolyn Lam: Nice, very elegant design. So what were the results Greg?
Dr Greg Hundley: Well Carolyn, the authors found that integrin beta- 1D deficiency and RyR2 serine 2030 hyper phosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. And in the mouse experiments, beta-1 D negative or knockout mice exhibited normal cardiac function and morphology, but presented with catacholamines sensitive polymorphic ventricular tachycardia consistent with increased RyR2 serine 2030 phosphorylation and apparent calcium handling in beta-1 D knockout cardiomyocytes.
So Carolyn, in conclusion, the authors found their data suggest that integrin beta-1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.
Dr Carolyn Lam: Okay. You told us about integrin beta-1 D and I'm going to tell you about apolipoprotein M. So Greg, what do you know about apolipoprotein M?
Dr Greg Hundley: Well, Carolyn, at seven o'clock the morning, I seem to have forgotten a little bit about that. Can you remind me what apolipoprotein M is?
Dr Carolyn Lam: Sure Greg, very happy to. So apolipoprotein M or apoM mediates the physical interaction between high density lipoprotein particles and sphingosine 1-phosphate and exerts an anti-inflammatory and cardio-protective effects in animal models. Now listen on, listen on. So authors, Dr Chirinos from Perelman Center for Advanced Medicine, University of Pennsylvania and Dr Javaheri from Washington University School of Medicine and co-authors hypothesized that reduced levels of apoM would be associated with worse outcomes in human heart failure.
Specifically, they tested the hypothesis that reduced circulating apoM would be associated with the risk of death, a composite of death, ventricular assist, device implantation or heart transplantation and a composite of death, heart failure related hospitalization among adults with heart failure and rolled in a large multicenter Penn heart failure study. They did stratified analysis in patients with heart failure with reduced and preserved ejection fraction and even replicated these findings in two independent cohorts, the Washington University heart failure registry and a subset of the TOPCAT trial. What they found was that reduced apoM plasma protein levels indeed were associated with adverse outcomes in heart failure including both HFpF and HFrF. The relationship between reduced apoM and outcomes and heart failure was particularly pronounced when concentrations of its binding partner sphingosine 1-phosphate were also reduced. ApoM protein levels were associated with inflammation in human heart failure and thus the conclusion being that apoM represents a risk marker in human heart failure.
Further studies are of course needed to assess whether it could be a therapeutic target as well.
Dr Greg Hundley: Very good. Carolyn. So more information for the world of heart failure isn't it. I'm going to sort of switch over to coronary artery disease and talk about low attenuation non-calcified plaques that are sometimes appreciated on cardiac computed tomography scans. And in this study, Dr Michelle Williams from the University of Edinburg evaluated the results from the multi-center SCOT-HEART trial or the Scottish computed tomography of the heart. So Carolyn, the future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score or coronary artery stenosis severity and the authors assessed in 1,769 patients about 56% men and the average age 58 years and they followed them up for a median of 4.7 years and looked at whether noncalcified low attenuation plaque burden on coronary CT angiography might be a better predictor of the future risk of myocardial infarction.
Dr Carolyn Lam: Interesting. So what did they find?
Dr Greg Hundley: Well, low attenuation plaque burden was the strongest predictor of myocardial infarction irrespective of cardiovascular risk score, coronary artery calcium score or coronary artery area stenosis. And patients with low attenuation plaque burden greater than 4% were nearly five times more likely to have subsequent myocardial infarction and the hazard ratio was 4.65 with a confidence interval of two to more than 10 and a half. So in conclusion, Carolyn in patients presenting with stable chest pain, low attenuation plaque burden is the strongest predictor of fatal or nonfatal myocardial infarction and these findings may add to classical risk predictors of myocardial infarction.
Dr Carolyn Lam: Wow. Important findings. Okay, let's go onto what else is in this week's journal issue. There's an online mind by Dr Jaffe. It's on the universal definition of myocardial infarction. It talks about both present and future considerations. There's an ECG challenge by Dr Arias and what's described as spontaneous wide QRS complex rhythm in a patient with wide QRS complex tachycardia.
Dr Greg Hundley: Very good, Carolyn. Well, I've got two other articles. Another on my mind piece from Professor Peter Nagele from the University of Chicago Medicine and it discusses a simplified proposal to redefine acute MI versus acute myocardial injury. Looking at that troponin question. And then finally Dr Fabian Hoffman from the Heart Center and University of Cologne has a research letter on providing new data regarding the evolution of pulmonary hypertension during severe sustained hypoxia.
Well Carolyn, how about we get onto that feature discussion looking at left main disease and whether we should place an intercoronary stent or undergo coronary artery bypass grafting.
Dr Carolyn Lam: Important question. Let's go, Greg.
Dr Greg Hundley: Welcome everyone to our feature discussion today that really pertains to interventional cardiology and we're very fortunate to have Duk-Woo Park from Asian Medical Center in Seoul, South Korea and our own associate editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Well Duk-Woo, we'd like to get started with you and could you tell us a little bit about the background data and the hypothesis related to your research study?
Dr Duk-Woo Park: Our research, it was the 10-year report of the PRECOMBAT trial. If I'm going to first introduce the background over the last half of a century bypass surgery, it was a mainstream, the number one choice of on protecting the main disease. Yeah. Did you know unprotected left main disease, the one were very high risk of coronary artery disease and owing two and the supply, the large burden of myocardium. But the last two decades, 20 years. Their remarkable evolution in PCI field including development adaption of a drug eluting stent and the adaption of intravascular ultrasound as well as experience of intervention or catalyst expertise. So on the basis of such evolution, many interventional cardiologists think about that, a PCI with a drug eluting stent. Will it be non-inferior to a standard type A surgery? Sometime for single region PCI could be very nice alternative option for unprotected left main disease that the reason why we're going to start quick on the trial. This trial already done 15 years ago at the time. We designed this PRECOMBAT trial on the basis of that background.
Dr Greg Hundley: Very good. Well can you tell us a little bit about the study population of this trial and what was your study design?
Dr Duk-Woo Park: This is a open library trial design and we at first time we evaluated the noble unprotected left main disease and the for considerable for clinical and ethic eligibility, initially assessed by intervention or cardiologists as you as a cardiac surgeon and the reason why we try to pick up the post treatment eligible population and then at the screening initial re-screen the nearly 1,400 patient and then finally 600 of patient who was our individuation one arm is drug eluting stent, first-generation ciphers 10 versus another arm is convention or a coronary artery bypass stent grafting.
Dr Greg Hundley: What were you looking for your outcome measures and how long did you follow these patients?
Dr Duk-Woo Park: Initially and the BDN two year follow and are published in England, the journal of medicine nearly eight years ago. And then we did five year follow-up at the publish the JAG in five years ago and the this time is a, we did complete that 10 year follow up all the render mutation population and the median follow-up duration is nearly more than 11 years and we complete 10 year follow-up and the key outcome was PCI is a comparable apart from surgery for treatment of left main disease.
Dr Greg Hundley: And were there other outcomes that you were looking for?
Dr Duk-Woo Park: We evaluated several important clinical outcomes. We primary end the point we select competent outcome compass of all cause of mortality by myocardial infarction, stroke, or ischemia-driven target vessel revascularization. Secondary outcome was each component of a primary outcome all-cause mortality as you raise the harder clinical and the point like compost outcome like this am I sure. So finally we did not any statistical difference with the regard to primary composite outcome as well as a hard clinical compost outcome as death or stroke. Finally, we did not detect all-cause mortality. One exception or difference was a target vascularization as well as a repeat rebase collateralization was a much higher after PCI than after bypass surgery.
Dr Greg Hundley: So overall, in this more lengthy follow up of 10 years. The primary outcomes were similar between the two interventional arms, but there was a difference in target vessel revascularization. With that being more frequent after PCI as compared to bypass, were there any other subgroups that tended to have distinctions or discrepancies between your primary outcome?
Dr Duk-Woo Park: As the sensitive to analysis, in circulation we supply the subgroup analysis or more, we did not find any differential treatment. IPEC according to subgroup in age group, diabetes and clean-cut presentation or in environmental coronary embolism shock versus application. We didn't find any interaction effect, just the except the extent of disease vessel, left or main. We the three best three digit bypass surgery was better than PCI. However we did not do any P value. Adjust them on. So interpretation is should it be cautious.
Dr Greg Hundley: Well you know as an interventional cardiologist, what new information does this bring and how do you interpret the results of this study relative to other studies that have been published in the past?
Dr Emmanouil Brilakis: I think this is a very timely study, especially since about a year ago we did have the five-year outcomes from two other similar trials, the Excel file and the Nobel trial which say randomized patients with unprotected left main disease to either PCI or bypass. And actually those studies had some differences which are also relevant to the present study. So for example, Excel overall the outcomes were similar. There was a higher all-cause mortality in the PCI where normal had better outcomes in terms of death, MIT VR, but there was no difference in mortality. So I think the natural question that comes up from the studies was whether mortality is different with PCI versus coronary bypass and you know the PRECOMBAT, the 10 years. It's really suiting in that respect because it doesn't show any difference in the overall mortality. So I think this comes very timely and the answers a lot of questions. Of course there's limitations with the sample size and the number of patients treated, but I think although it's a very timely result.
Dr Greg Hundley: Maybe I'll start first with you, Manos and then I'll circle back to you. Duk-Woo. Manos what do you see is the next important study to perform in this field?
Dr Emmanouil Brilakis: I think the natural question here is these outcomes which are similar but use first generation drug eluting stents, which we no longer use. He did use high proportion of five which is an excellent feature in, again congratulate Duk-Woo and the other co-investigators for doing such a high rate of follow-up. But we now know that the techniques, for example, for bifurcations, maybe the DK crush or double DK crush might be a better technique to do. So in my mind, the next question would be if who use the current, a much improved the drug eluting stent and state of the art bifurcation techniques. For example, DK crush where the double-kiss crush bifurcation would, the outcomes have been different and perhaps PCI will be similar, even better than bypass in long-term outcomes. So for me this next study will be state of the art techniques, state of the art materials and long-term for follow-up as in frequently.
Dr Greg Hundley: Duk-Woo. How about from your perspective?
Dr Duk-Woo Park: You know, a future perspective is a very difficult to expect. Our trial is the longest to follow-up trial. We have the nation are insurance support and we nearly a hundred percent pop picked up fighters status, but I think most of them interventional cardiologists as well as a cardiac surgeon. One true additional longest follow-up Excel and Noble trial. The reason why we didn't do additional random trial using additional second generation drug eluting stent. We already do exit trial approximately 2000 and noble trial and more than thousand patients we already do and the two trial a complete five-year follow and most of the trial is as well as the clinician want to extend the follow-up of Excel and Noble trial but I don't know how much that extended of a follow-up would be possible.
Dr Duk-Woo Park: The next step as you know the intervention or cardiac surgeon still debate about the long-term mortality issue after release of exited five-year-old research and the data peak issue, European association cardiac thoracic group. We did draw the endorsement of a guideline so I think an additional stem we require the individual patient level data analysis involving, Excel, Nobel, Syntech and PRECOMBAT trial would be required to provide the more definite compelling evidence for mortality difference as well as the have the end point and including or so some end point to repeat revascularization. We do allow individual patient data analysis. That would be next. The short step, next the long step, we definitely require extended follow-up, Excel and Noble trial.
Dr Greg Hundley: Very good. Well listeners, this has been another very informative feature discussion where we've compared PCI and coronary artery bypass grafting in those with left main disease. And now from this PRECOMBAT trial, 10 years of follow up showing very similar outcomes related to death, myocardial infarction and stroke in the two randomized arms. We want to thank Dr Duk-Woo Park and Dr Manos Brilakis for presenting this information and as we move forward, their insights as to next studies with newer technologies and different examinations of stents. More long-term follow-up from ongoing trials and then individualized patient assessments.
Listeners, we hope you have a great week and hope everyone is staying safe in this COVID crisis. Take care.
This program is copyright of the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today looks at the use of Apixaban versus Warfarin, so a trial between the two in patients with atrial fibrillation and advanced kidney disease. But before we get to that, how about if we break away, grab a cup of coffee and go through some of the other important papers in this issue?
Dr Carolyn Lam: Yeah, and why not start with talking about our gut and fiber in the diet. Now, we know that a diet poor in fiber is associated with the prevalence of hypertension, but what are the underlying mechanisms? Well, this first paper I want to talk about is from Dr Marques from Baker Heart and Diabetes Institute in Australia and colleagues who basically performed a nice series of mouse experiments and found that a diet lacking prebiotic fiber led to a gut microbiome that was pro hypertenenogenic facilitated the development of cardiac hypertrophy in germ free mice.
Even in the absence of fiber, gut metabolites called short chain fatty acids usually produce from the fermentation of prebiotic fiber by the gut microbiota, but they were able to protect against the development of hypertension, cardiac hypertrophy and fibrosis in a preclinical model. This cardioprotection involved short chain fatty acid receptors, and a decrease in the ratio of sodium to potassium excretion and changes in genome white methylation that supported higher levels of T regulatory cells.
Dr Greg Hundley: Oh my goodness, Carolyn. So I need to know what I eat for lunch? What's the take home message here?
Dr Carolyn Lam: Lots of fiber and definitely not the low fiber westernized diet, which may underlie hypertension. And how? Through deficient short chain fatty acid production and thus the take home is maintaining a healthy, short chain fatty acid producing microbiome is important for the cardiovascular health.
Dr Greg Hundley: Wow, Carolyn. I love that article because it really helps provide some perspective on all the diet information that we've been receiving lately. Well, my paper is from doctor ... another Carolyn, but this is Carolyn Ho from Brigham and Women's Hospital-
Dr Carolyn Lam: I love her.
Dr Greg Hundley: ... And it involves hypertrophic cardiomyopathy and left ventricular systolic dysfunction. So Carolyn, the term end-stage has been used to describe hypertrophic cardiomyopathy with left ventricular systolic dysfunction. And that's defined when someone has hypertrophic cardiomyopathy and the LVEF is less than 50%. The prognosis of patients with this condition has been reportedly poor, but it's very rare in occurrence and therefore, the natural history really remains incompletely characterized. So what did the authors do in this study? They evaluated more than 500 patients from 11 high volume hypertrophic cardiomyopathy specialty centers comprising the international Sarcomeric Human Cardiomyopathy Registry or SHaRe registry. And they were used to describe the natural history of patients with hypertrophic cardiomyopathy and left ventricular systolic dysfunction.
Dr Carolyn Lam: Interesting. So what did they find, Greg?
Dr Greg Hundley: Number one, first overall, this group of patients, hypertrophic cardiomyopathy with left ventricular systolic dysfunction occurs in about 8% of those with hypertrophic cardiomyopathy. Although the natural history of left ventricular systolic function and hypertrophic cardiomyopathy is variable, 75% of those that have this condition experience adverse events including 35% experiencing a death equivalent at a medium of 8.4 years after developing their systolic dysfunction. In addition to clinical features, the genetic substrate appears to play a role in both prognosis, so there are multiple sarcomeric variants, and in the risk for incident development of left ventricular systolic function with hypertrophic cardiomyopathy due to variance in the thin filaments within those myocytes.
Dr Carolyn Lam: Nice. Thanks for that Greg. My next paper is a really interesting secondary analysis if you may, of the EXSCEL study. As a reminder, the Exenatide Study of Cardiovascular Event Lowering or EXSCEL assessed the impact of once weekly exenatide versus placebo in patients with type two diabetes and showed non-inferiority but not superiority for the primary MACE outcome.
Now, during this trial, while aiming for glycemic echo-poise, a greater drop-in of open label glucose lowering medications occurred in the placebo group, thus prompting the current authors, which is Dr Rury Holman from University of Oxford and their colleagues to really explore the possible impact of unbalanced open labeled drop-in of glucose lowering medication on EXSCEL outcomes. To our modern diabetes trial, they used three methodologies. One, drop-in visit, right censoring. Two, inverse probability for treatment waiting. And three, applying drug class risk reductions. Now, Greg, I could either quiz you on these methods or summarize the results, which would you prefer?
Dr Greg Hundley: Well, Carolyn, this calls for the infamous phone a friend. So one of the nice things we have at Circulation is a wonderful group of statisticians that really help us go through all the papers. But I sure would like to pick up the phone and call one of those folks now. But I think what I'm going to do ... maybe just give me the results of this study. That's what I prefer.
Dr Carolyn Lam: I thought you might say that. So the EXSCEL observed has its ratios for MACE remained robust after right censoring or application of the literature derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by the inverse probability treatment waiting approach. So I think the take home is that effects of open label drop in cardioprotective medications do need to be considered carefully when designing, conducting and analyzing cardiovascular outcome trials of glucose lowering agents. Do we have the perfect solution? Perhaps not, but this was a really important paper to just look at and study. So Greg, I can see that you are stats out, so I'm going to tell you a little bit more about other papers in this week's issue.
There's a research letter by Dr Zhang on transcription factor Kruppel-like factor 15 and how it regulates the circadian susceptibility to ischemia-reperfusion injury in the heart.
Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple of other papers. There's a nice in-depth piece from Dr Gregory Marcus from the University of California, San Francisco on how we evaluate and manage patients that have premature ventricular contractions. Dr Mori Krantz from Denver Health and Hospital Authority gives us an EKG challenge in someone that's had a needle stick. And then finally, there's a nice perspective piece from Dr Paul Armstrong from the Canadian VIGOUR Centre, department of medicine cardiology at the University of Alberta. And he really goes over nicely how we're going to do global collaboration to enhance cardiovascular care. What a great issue. And now onto that feature where we're going to hear a little bit about Apixaban and Warfarin in those individuals with atrial fibrillation and chronic kidney disease.
Dr Carolyn Lam: Let's go, Greg.
Today's feature paper really represents the first randomized data on NOAC versus warfarin in a very important group of patients, that is those with atrial fibrillation and advanced chronic kidney disease. So happy to have with us the corresponding author, Dr John Stanifer from Munson Healthcare, Traverse, Michigan. As well as our associate editor, Dr Chang-Sheng Ma from Beijing Anzhen Hospital in China. Welcome, welcome. So John, could you tell us the inspiration if you may, or the rationale, for doing this study?
Dr John Stanifer: This is a population that's near and dear to my heart as a practicing nephrologist. We care for so many patients with atrial fibrillation, particularly those on dialysis or those with advanced kidney disease. And as other practitioners and people taking care of this population will tell you, this is just such a confusing and challenging clinical problem to try to deal with. And then really this stems from that important clinical need that we recognize almost on a daily basis.
Dr Carolyn Lam: I just love that you shared that John, because coming from a nephrologist, and we're usually talking to cardiologists where we think about this all the time and have no idea what to do. So tell us about your study and what you found.
Dr John Stanifer: As you know, these were data that were taken from the Aristotle trial that was finished in 2011, that was really a landmark study that established the real superiority of Apixaban compared with Warfarin and the general population.
And it happened that within the study, there were several patients, 269 that had a creatinine clearance of between 25 and 30 milliliters per minute. We then took those data from those patients and compared really in this study, the safety of Apixaban compared with Warfarin within that subpopulation, and then compared that as an interaction with the safety of Apixaban versus Warfarin in patients with creatinine clearance of greater than 30.
Dr Carolyn Lam: And what did you find?
Dr John Stanifer: Well, in conclusion, we really found that among these patients with a creatine clearance of 25 to 30 MLs per minute in atrial fibrillation that Apixaban did cause less bleeding than Warfarin. And it appeared to be an even greater relative risk reduction when you compare that with the safety of Apixaban versus Warfarin and those with a less severe kidney disease.
Dr Carolyn Lam: It's truly the first time I've seen data like this. So congratulations John and thank you so much for publishing this paper with us at Circulation. Chang-Sheng, Circulation seems to be publishing a lot in the space of combined renal and cardiac disease, which is very interesting. Why was this paper so important to us as well?
Dr Changsheng Ma: It's a very important question for a clinical practice. The anticoagulation therapy in patient with advanced CKD. And observation or analysis have demonstrated inconsistent of findings regarding the net clinical benefit of warfarin in reducing the risk for stroke in patients with advanced CKD. The problem of Warfarin treatments in this patient group is dramatically higher bleeding risk. The current study also show that the bleeding risk was three- to four-fold higher in patient with advanced CKD compared to that in patient with creatinine clearance more than 30 milliliters per minute when treated with a Warfarin.
So these studies are our first randomized data for NOAC compared with warfarin in patients with advanced CKD. The results provide important information as to the safety of Apixaban in this special patient group with high risk of bleeding. With reduced risk of bleeding, we may expect net clinical benefits of Apixaban in preventing stroke in patients with advanced CKD.
Dr Carolyn Lam: Indeed. John, did you demonstrate that net clinical benefit or could you perhaps explain if future steps are needed to look at that a bit better?
Dr John Stanifer: Well, I think absolutely future studies are needed. You have to keep in mind that these were pre-specified groups within Aristotle. These are still post-trial data from this study and that absolutely we need studies that are powered to really compare the safety. I would add not just apixaban with warfarin, but I would also add placebo to that.
Dr Carolyn Lam: Interesting. Changsheng, you had some questions for John as well.
Dr Changsheng Ma: Yes. John, I had questions for you. If you take a randomized trial for the answer for this question, how many cases do you think?
Dr Carolyn Lam: How many cases of?
Dr Changsheng Ma: How many cases should there be for a sample size for a trial?
Dr John Stanifer: Well, you're really putting me on the spot here. I'll have to go back to my statistical days. Well, I think the easy part in the design of a trial for a question like this is that the event rates are so high. Whether that be for both safety outcomes related to hemorrhage and bleeding risks or primary benefit outcomes. So that would be very beneficial with that respect. But I think the key to designing a study ... and I know that there are several ongoing RENAL-AF and several others that are trying to examine this very question, but I think as a nephrologist, what we would kind of push back on a little bit is that there's no placebo arm to these trials. And I actually think that that would be a step forward even though that would be a very challenging thing, I think at this point to push for ... I think the nephrologist has kind of continued to push for that a little bit.
Dr Carolyn Lam: So John, that was beautifully answered. If I could ask you then, have these results influenced your practice even now?
Dr John Stanifer: Well, prior to this, we've been a little bit nervous with Apixaban, even though observational data may suggest that it would be safer or potentially usable in patients with advanced kidney disease. But part of the real conundrum and some of the challenges that come up are really around dosing of Apixaban. And they say, "Well, gosh, if they're in stage renal disease, yeah, maybe it's too bad. Maybe the kidney function is way too low and we need to kind of reduce it based just on that one criterion as opposed to the three criteria laid out in Aristotle." So I think that was some of the challenges. but I think after seeing these data and seeing the safety relative to Warfarin was really there in this patient group, yeah, it has influenced me a little bit. I am a little more adamant about switching patients.
Dr Carolyn Lam: Yep. Chang-Sheng, do you agree with that? What do you think are next steps here?
Dr Changsheng Ma: Because clinical practice is different, apparently, more evidence is badly needed to guide the future clinical practice because the patients with creatinine clearance even less than 25 milliliters per minute. And those in dialysis were not included in any of the pivotal studies of NOAC.
Dr John Stanifer: Absolutely.
Dr Changsheng Ma: It is still uncertain whether this patient will benefit from Apixaban or other NOACs. So in this study, even the significant less measured bleeding events were observed. I think the all-cause mortality was not different between the two groups. So the next step we should design a new trial to confirm whether Apixaban will really improve the prognosis of the patient with advanced CKD and AF.
Dr John Stanifer: I will second that. For sure we want to answer that very important efficacy question related to this class of medications.
Dr Carolyn Lam: Efficacy and patients on hemodialysis. Wow. This really just opens up a lot, but you're right. It's such tantalizing information that you see in ... so thank you so much John, for publishing this paper with us. Chang-Sheng, it's such a great paper. I remember the discussions we had during our editors’ discussions and it's so nice to see it out in print. I'm telling you, audience, you have to get hold of this paper. It will change this field I think and will lead to further trials exactly like you've heard here, and that we've put John on the spot to describe.
Dr Carolyn Lam: Thank you very much gentlemen for a wonderful discussion. Thank you, audience, for joining us. You've been listening to Circulation On The Run. Join us again next week.
Dr Greg Hundley: This program is copyright the American Heart Association, 2020.
Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. But I am running to hide today, because I am going to get quizzed by the master in the feature discussion. And listeners, it's really interesting. It involves quantitative myocardial perfusion using magnetic resonance imaging, but also adding the twist that artificial intelligence computer algorithms are being used to read the stress test images without any physician interference. Oh, my goodness. I don't know what she's going to quiz me about.
Dr Carolyn Lam: Absolutely about all the AI algorithms and exactly how you derive them. But why don't you tell us what you want to describe first and the rest of the issue.
Dr Greg Hundley: Carolyn, I'm going to start with a paper on peroxynitrite and as you know, that's a very short-lived free radical produced in cells, part of the both oxidative and nitrosative stress pathways. And this article comes from Dr Swapnil Sonkusare from the University of Virginia School of Medicine. Well, Carolyn, this study is involving mouse models, and the investigators evaluated the relationship between peroxynitrite, that powerful oxidative nitrosative stress molecule, and obesity and hypertension.
Dr Carolyn Lam: Nice. And before you ask me anything more about peroxynitrite, because I think you just summarize everything I know. What did the authors find, Greg?
Dr Greg Hundley: What that found is that obesity induced impairment of endothelial AKAP150-TRPV4 channel signaling contributes to the loss of endothelial function and elevated blood pressure. And lowering the levels of this oxidant molecule of peroxynitrite reduces endothelial AKAP150-TRPV4 channel signaling, vasodilation and blood pressure and obesity.
Dr Carolyn Lam: And what are the implications?
Dr Greg Hundley: Well, endothelial TRPV4 channels are essential regulators of resting blood pressure and impairment of endothelial TRPV4 channel activity contributes to obesity induced hypertension. And therefore, therapeutic strategies, perhaps in the future, that lower peroxynitrite levels can be used to rescue endothelial TRPV4 channel activity, endothelial function and blood pressure in obese individuals.
Dr Carolyn Lam: Nice, Greg. Well, I want to tell you a little bit more about plain old hypertension. Now, we know that blood pressure is regulated by the function of the kidney vasculature and sympathetic nervous system, but do immune cells play a role?
Well, Dr Guzik from University Medical College, Krakow, Poland, and University of Glasgow and his colleagues, studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and employed a Mendelian randomization analysis to examine which leukocyte populations maybe causally linked to blood pressure.
Dr Greg Hundley: So we've got another blood pressure article. What did they find?
Dr Carolyn Lam: They found potentially causal positive effects of total blood lymphocyte count with blood pressure. Among the mechanisms that might mediate this relationship, they found evidence that blood lymphocyte count might influence albuminuria. The study may additionally support a reverse, potentially causal positive effect of blood pressure indices on blood neutrophil monocyte and you sit a full count. So fairly interesting.
Dr Greg Hundley: Very nice. So I'm going to switch over and talk a little bit about lifestyle interventions. I know you're a big fitness buff. So this paper is about fitness, body mass index and the risk of heart failure in overweight, obese individuals with type two diabetes mellitus. It's an analysis from The Look AHEAD Trial. The corresponding author is Dr Ambarish Pandey from the University of Texas Southwestern Medical Center. And a little bit of background Carolyn. Type two diabetes is associated with a higher risk of heart failure and the impact of a lifestyle intervention and changes in cardiorespiratory fitness and body mass index on the risk of heart failure in this population is not well established.
So what are the authors do? They had 5,109 participants from The Look AHEAD or The Action for Health in Diabetes Trial, without prevalent heart failure at the time of their inclusion. They implemented time to event analysis to compare the risk of incident heart failure between an intensive lifestyle intervention versus a diabetes support and education group. The association of baseline measures of cardiorespiratory fitness estimated from a maximal treadmill test. The participants, BMI and longitudinal changes in these parameters with the risk of heart failure were evaluated using multi variable models.
Dr Carolyn Lam: Wow. What did they find?
Dr Greg Hundley: Carolyn, very surprising. Among participants with type two diabetes mellitus. In The Look AHEAD Trial, the intensive lifestyle intervention did not, did not appear to modify the risk of heart failure. What they also found is that higher baseline cardiorespiratory fitness and sustained improvements in cardiorespiratory fitness and weight loss were associated with a lower risk of heart failure.
So even that education group where patients started doing things more, had more cardiorespiratory fitness and baseline and sustain that with weight loss, those were the ones that had lower risk of heart failure.
Dr Carolyn Lam: Nice summary. Well let's go through what else is in today's issue. There's a research letter by Dr Eitel on the impact of morphine treatment within without metoclopramide co-administration on ticagrelor-inducted platelet inhibition in AMI and that's the randomized MonAMI trial. There's also an in-depth paper by Dr Eijsvogels on exercise and coronary atherosclerosis. So, this interesting review describes the effects of physical activity and exercise training on coronary atherosclerosis in middle aged and older athletes and really aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries. Very interesting.
Dr Greg Hundley: And Carolyn, I've got a perspective piece and it comes from Dr Robert Stravitz, as well as Dr George Vetrovec from VCU, and it evaluates the risk of invasive cardiac procedures in patients that have liver cirrhosis.
Then finally there's a very nice ECG challenge. It's the anterior STEMI without S T elevation in lead one and it comes from Dr Yun-Tao Zhao from the Peking University Aerospace School of Clinical Medicine. Oh no. Oh, I've got to run.
Dr Carolyn Lam: Now, we're going straight into the prolonged Dr Hundley quiz.
Dr Greg Hundley: Very good.
Dr Carolyn Lam: Oh boy. Today's feature paper is really a biggie. It talks about AI and its approach in quantitative myocardial perfusion by cardiac magnetic resonance imaging. Now, I know we've been building up to this discussion already right from the start because I've got my beloved cohost, Greg Hundley talking about this, but wearing the hat as the editor who managed this paper and also so pleased to have with us the corresponding author, Dr James Moon from University College, London and Barts Heart Centre in UK, as well as from across the other side of the world. We have Dr Peter Kellman from the National Heart, Lung and Blood Institute of NIH. So welcome gentlemen, what a great paper. I think in Greg's words he said earlier just really landmark. I'm almost paradigm shifting in this area. So let's dive straight into it. And so maybe James, could you start by telling us how does CMR quantitative myocardial perfusion usually work in today's world without the AI and perhaps you know what the study showed that it can do. What can AI help us do?
Dr James Moon: If we want to understand where chest pain comes from, we can sometimes use cardiac CT, or we can use a functional test and a different function test. But a particular test with bandages is chronic MRI. And what we do is we give a dye into a vein and track that through the heart. And the upslope can tell us about a fusion. And if you do that during vasodilators stress, you can see regional differences visually. Now, the interesting thing is that if you take those signals and using a team such as Peter Kamina, NIH, you can make that constative and, in fact, do that inline on the scanner, so you get color maps where the pixels of valid in mils per gram per minute. So you can see exactly how much facilitation there is. And what we share in here is that if you quantify that, literally, automatically on the scanner using artificial intelligence approaches from the NIH, those values are incrementally prognostic predicting outcomes for patients.
Dr Carolyn Lam: Wow. Okay. So give us a little bit more here, James. What do you mean by incrementally prognostic? Did you compare it with the best human readers and perhaps have a subset and I think you did, of course, who the human readers can see something, and AI did, right? Could you tell us a little bit more about that?
Dr James Moon: We've been doing a lot of the sort of technical development papers after the common initiatives from the NIH. So we've been doing the correlations across a number of sensors with, for example, pets and animal models. And really what we did here was we overlaid our clinical service with the AI and in more than a thousand patients actually at two sites, we were able to follow up patients and a number of those of course, and sadly underwent an event, death, or mace. And what we are able to see is that the stress flow and the ratio stress to rest flow, were independently associated by death and base and mace. So for each mil decrease in stress flow that has a great share went up. And that was as you say, something that you just can't do viscerally because you can't get that global background change.
Dr Carolyn Lam: Oh this is scary. So AI beating out humans, I suppose is what you're saying, not quite maybe. Or is it right?
Dr Greg Hundley: You know, we have to do a number of things in health care and we're often drawing circles, drawing consoles, identifying regions of interest and these are quite mundane tasks and if you can train your AI correctly, then that can do that for you, leaving you and freeing you up to higher executive functions, like discussing the results with patients. And I wouldn't be scared of the AI here because the way PISA implemented this, the contours are all drawn, so it's completely explicable.
Dr Carolyn Lam: I really liked that explanation. And so what most people fear when AI comes about is, they fear this black box approach that they cannot understand. And what you're saying here is it something understandable and it will facilitate efficiency, which is beautifully done, and what you've shown as well. So Peter, it sounds to me that it took a long time to develop this. Could you describe what it takes to get an algorithm and AI algorithms like this?
Dr Peter Kellman: This is quantitative perfusion and perfusion in general using cardiac mechanisms has been in development by a lot of labs around the world over the past 20 years. And the specific objectives we had were to get it out of the laboratory into the hands of the clinicians and do that, we chose to implement everything fully, automatically and integrated onto a clinical scanner so that the clinicians would get the answers on the fly.
That is to say they would perform a scan and it would be transparent. They'd run the scan the way they normally do today, and the results of the myocardial blood flow would appear on the scanner within a minute. So, we probably worked on this, myself and Dr Wie Wzei at NIH, for the past five years. Gradually building this up to the state where it is now at sites like The Barts Heart Centre can use it.
Dr Carolyn Lam: Just really hats off. This is amazing because you've summarized it in a few sentences, but you know I kind of personally know what it takes. Just getting an algorithm is one thing but making it clinically usable and then James demonstrating it clinically are all huge achievements. So congratulations. I don't think anyone can say it better than Greg. Greg, tell us why is this paper so important? And see that was an easy question.
Dr Greg Hundley: This is really dramatic in the field of cardiovascular magnetic resonance, but also for stress testing related to patients with cardiovascular disease. As many of our listeners know today, the majority of studies are interpreted visually and while the spatial and temporal resolution is just beautiful like high definition television of the inside of our bodies, the artifacts that sometimes occur and then some of the interobserver variability remains problematic. What I love about this, is this is now a quantitative. It's not a visual interpretation of signal intensity. What both Dr's. Kellman and Moon have developed is something that measures the blood flow in mls per minute, per gram of tissue regionally throughout the heart and then color codes that so that all of us can interpret it readily. I think another big piece of this is that they have created the artificial intelligence that helps interpret that for us and just think now we'll be able standardize readings across medical centers.
That's an enormous advance for this field and combining this information and putting it into, both national as well as international registries, could be very important for identifying abnormalities that would forecast prognosis. And these gentlemen have laid the framework for that because they have a large number of subjects, two centers, and they had comprehensive follow up that looked at heart events and this technology was able to forecast that on the backdrop of all the other parameters, demographic variables, risk factors, etc., that we find in patients that present to us with cardiovascular disease and are symptomatic with chest pain syndromes. So boy, what an outstanding imaging paper and feel so fortunate to actually have this in circulation.
Dr Carolyn Lam: Greg, no one can say it better than you. I would like to emphasize that this just doesn't hold the implications for MR imaging. I think it holds implications for many forms of cardiac imaging if we have AI to assist us. So James, how do you see this helping the patients? These are prospectively performed cardiac MR scans, but you know, what about surveillance of MR databases? What are the implications for perhaps detecting microvascular abnormalities? Another pet topic on my own. If you don't mind, you know, tell us, what do you think are the clinical implications?
Dr James Moon: Quite a lot of clinical implications. We're really starting a journey here. So, one of the things I'm interested in is that we have been in an era of thinking about the epicardial cone use only. We were seeing significance between patient differences in peak hyperemia related to, for example, age and presence of diabetes, but must be reflecting the microvasculature and of course, that may be a key biomarker for the future and understanding what happens to patients. So naturally, of course, when we're assessing the epicardial arteries, we're going to have to understand that those assessments, especially if it's measuring wall flow, will be influenced by the microvasculature because it's a circulation. So, this may just bring that microvasculature into the mainstream as potentially therapeutic target.
If you think about this AI and observe a variation. So what we do is measure things clinically and that sounds like boring old science, but metrology and accuracy and precision translate into something that cascades down. So that key dots the patient relationship where we're making the decisions on what therapies together might influence outcome. And if you can rely on those results and if the results that scanner one in one place and another scan at another place always read the same, then your healthcare system just gets a boost because everything is more reliable.
Dr Carolyn Lam: That's beautifully put. And Peter, thank you to you and your group for developing such AI and James for demonstrating this. Now if I may, this is an amazing collaboration. I understand the British Heart Foundation had a role in supporting this. How did you get together to decide to work across regions and so on, on this? Could you just give us a little bit about that?
Dr Peter Kellman: Our working together was an outgrowth of prior collaborations in areas such as T one map and for tissue characterization and Barts Heart Centre represents the largest cardiac MR site in the world, in terms of volume. And when you have a quantitative method, it was the perfect place to evaluate this kind of ischemic heart disease. And furthermore, when you talk about AI, you need to train the algorithms and develop the models. You need a large volume of data. So, right now we're probably doing on the order of 150 stress tests a week. And so, after a year we had a large volume of data to train the algorithms for segmenting the myocardium. So the collaboration has been ongoing for about five years.
Dr Carolyn Lam: That's great. Greg, you know what, because I adore you, I'm going to ask you to give us the final words. Tell us your thoughts on where this is all heading.
Dr Greg Hundley: I think Peter astutely identified that Barts Heart Centre and you're seeing really in the United Kingdom the primary use of magnetic resonance imaging for cardiovascular stress testing with its accuracy. And now, adding to this these quantitative assessments that can reflect, not only epicardial disease, but as we've heard, have the potential to identify micro circulatory disease. I see this growing and extending worldwide. And I think the next studies will involve the use of this type of technology and multiple different manufacturers of scanners and across different field strengths, 1.5 and three T, and multi-center initiatives using this technology to try to forecast cardiovascular prognosis in patients that present with chest pain syndromes as well as other disease processes that involve both epicardial coronary arteries and micro circulation.
Dr Carolyn Lam: Wow. And we're so pleased and proud to be publishing then this paper here in circulation this week. Thank you so much, gentleman. It's been awesome discussing this with you.
And thank you, audience for joining us this week. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr Greg Hundley: This program is copyright, The American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia.
Dr Carolyn Lam: Greg, amyloid cardiomyopathy is the rage. I cannot tell you the number of discussions I've had on the topic. Of course, it was tafamidis, the amazing results with that trial that really made us realize we need to pick this up. But have you ever thought about the cost effectiveness of tafamidis for amyloid cardiomyopathy? Well, guess what? We're going to have a whole feature discussion just about that. But first let's go to our summary, shall we?
Dr Greg Hundley: You bet, Carolyn. Well, let me get started. I'm going to talk about regulation of cell cycle growth as well as division in regard to cardiac regeneration. My first paper comes from Dr Lior Zangi from the Mount Sinai School of Medicine. Well, Carolyn, have you ever wondered why the adult mammalian heart has limited regenerative capacity?
Dr Carolyn Lam: All the time, Greg.
Dr Greg Hundley: Well, of course you have. It's mostly due to postnatal cardiomyocyte cell cycle arrest. In this study the investigators evaluated the effect of pyruvate kinase muscle isozyme 2 and cardiomyocytes through models of loss, that is cardiomyocyte specific PKM2 deletion during cardiac development or gain using cardiomyocytes specific PKM to modified mRNA to evaluate PKM to function and regenerative effects post-acute or chronic MI in mice.
Dr Carolyn Lam: Nicely described. What did they find, Greg?
Dr Greg Hundley: What they found is that PKM2 is expressed in cardiomyocytes during development and immediately after birth, but not during adulthood. Using cardiomyocytes PKM to modified RNA, they found that cardiomyocyte targeted strategy following acute or chronic MI resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. They found that PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and beta-catenin.
Dr Carolyn Lam: Cool, Greg. Man, this cardiac regeneration really, really is a hot area.
Dr Greg Hundley: Carolyn, that is so insightful because these results really impact research toward unlocking pathways that could be involved in induction of myocyte cell division and regeneration in those sustaining MI or conditions like MI.
Dr Carolyn Lam: Nice. Well, Greg, I'm going to change tones here and ask you, can we prevent atrial fibrillation with treatments for diabetes? Well, guess what? We have a paper next. It's from Dr Wiviott from the TIMI Study Group and his colleagues who really reason that since atrial fibrillation is associated with hypertension, obesity and heart failure in patients with diabetes and SGLT2 inhibitors have been shown to lower blood pressure, reduce weight, and reduce hospitalization for heart failure in these patients, perhaps SGLT2 inhibitors may also reduce the risk of atrial fibrillation. They explored the effect of Dapagliflozin on the first and total number of atrial fibrillation and atrial flutter events in patients from the DECLARE-TIMI 58. As a reminder, they had type two diabetes with either multiple risk factors for or known atherosclerotic cardiovascular disease.
Now importantly, atrial fibrillation events were identified by a search of the safety database using these MedDAR preferred terms. Now what they found was Dapagliflozin reduced the risk of atrial fibrillation events during follow-up as well as the total number of atrial fibrillation events in patients with type two diabetes. These reductions were consistent across major subgroups including sex, presence of atherosclerotic cardiovascular disease, history of atrial fibrillation, history of heart failure, history of ischemic stroke, HBA1C groups, body mass index groups, blood pressure or EGFR. They looked at all these subgroups because these are all clinical factors, well established, with associations with the risk of atrial fibrillation.
Dr Greg Hundley: Wow, Carolyn. Another sort of feather in the cap for the SGLT2 inhibitors. What does this mean for clinical practice?
Dr Carolyn Lam: Ah. I'm not going to answer it here. I am going to say everybody has to read the excellent editorial by Dr Granger from Duke University and Dr Mahaffey from Stanford University School of Medicine. But what I will tell you is their concluding sentences. They said, "This report provides evidence that Dapagliflozin appears to reduce atrial fibrillation events in patients with diabetes and coronary disease and multiple risk factors. It also raises the issue of how to determine when effects on a secondary outcome, particularly one collected without the rigor of systematic collection using perspective definitions and case report forms, whether or not these are reliable." So must read.
Dr Greg Hundley: Absolutely. Carolyn, my next study comes and evaluates arrhythmogenic right ventricular cardiomyopathy and is really investigating the concept of auto immunity, looking at associations of circulating anti heart and anti intercalated disc auto antibodies with disease severity and family history. The paper comes from Professor Alida Caforio from the University of Padova. Again, looking at the role of auto antibodies in patients with ARVC. An interesting topic.
Dr Carolyn Lam: Yeah, that's really novel. What did they find?
Dr Greg Hundley: They investigated ARVC pro bands, so those that sort of started with the disease process in a family and noted an increased frequency of serum organ specific anti heart autoantibodies and anti-intercalated disc autoantibodies in a sizeable arrhythmogenic RVC cohort as compared to controls. They found that positive AHA status.
Dr Carolyn Lam: Anti-heart antibodies.
Dr Greg Hundley: Yep. Was associated with lower left ventricular ejection fraction, a higher frequency of cardiac symptoms and implantable cardioverter defibrillator implantation. Positive AIDA was associated with lower ejection fractions in both the right and the left ventricle.
Dr Carolyn Lam: AIDA being the anti-intercalated disc auto antibodies. Wow. That is interesting. But what are the clinical implications?
Dr Greg Hundley: Well, the presence of both these organ specific AHA and AIDA antibodies provides evidence of autoimmunity in the majority, so 85% of familiar, and almost half, 45%, of sporadic ARVC. In programs and in effective relatives, these antibodies were associated with the disease severity features. So really a link with this auto immunity and ARVC.
Dr Carolyn Lam: Yeah. I never thought of ARVC as an autoimmune disease. Very interesting. But let me also tell you what else is in this week's issue. There are letters to the editors, one from Dr Kaski regarding the mag STEMI randomized control trial questioning whether improving coronary vasal motion can be equated to restoring patient's cardiovascular health. Interestingly with a letter in response from Dr Sabatine. There's also a research letter by Dr Alahmad on the cardiovascular mortality and exposure to heat in an inherently hot region and where they were was Kuwait. They also drew some implications for climate change. Very interesting piece. There's also an ECG challenged by Dr Verma describing conduction abnormalities and ischemic cardiomyopathy in an 84-year-old man.
Dr Greg Hundley: Very nice. Carolyn, in the mailbag, there's a nice research letter from Dr Nicholas Leeper from Stanford University School of Medicine. It's entitled “The 9p21 locus promotes calcific atherosclerosis.” Our own Josh Beckman has an on my mind piece regarding “The Big Mac Attack on Peripheral Arterial Disease.”
Dr Carolyn Lam: I love that. I just love the titles Josh comes up with.
Dr Greg Hundley: Then finally Bridget Kuehn has a very nice sort of correspondence on Cardiovascular News regarding cardiac imaging on the cusp of artificial intelligence. What a revolution we have ahead, Carolyn, and I know that's a topic that's true to your heart.
Dr Carolyn Lam: It is. I loved her paper.
Dr Greg Hundley: Okay. Carolyn, how about we get onto that feature article? I'm waiting to hear about the cost effectiveness of tafamidis.
Dr Carolyn Lam: Me too.
Dr Greg Hundley: Well listeners, we have got a great discussion for our feature publication today and we have Dr Dhruv Kazi from Beth Israel Deaconess in Boston and our own associate editor, Dr Justin Ezekowitz from University of Alberta. Well, as we get started, Kazi, can you tell us a little bit what was the hypothesis that you wanted to test with this study and maybe even before that a little bit of background with transthyretin amyloid and tafamidis?
Dr Dhruv Kazi: Yeah. Transthyretin amyloidosis is a subgroup of patients who present with heart failure with preserved ejection fraction, which we know is a heterogeneous condition that has been pretty resilient to effective guideline directed therapies over the past decade. It's a subgroup of patients generally presenting in their 70s with slowly declining quality of life and a median survival of about three years. It hadn't had an effective therapy before and so when tafamidis, which is a stabilizer of transthyretin and prevents its deposition in the myocardium, was developed and tested in a randomized clinical trial that showed an improvement in survival, a reduction in heart failure hospitalizations and a slowing of decline and quality of life. It was viewed as a really big win for the heart failure community.
What came as a surprise though is the pricing. It was launched in 2019 at $225,000 a year. We set out to ask, given that this is a severe disease without alternative treatments, is this price tag generating enough value? Is this a cost-effective therapy? The background here again is that oncologic therapies have had a long history of very high prices for rare diseases and severe diseases. But this is the first time we're seeing this in cardiology. Can we think more broadly about how we're going to tackle this issue? Not just for tafamidis but also for other drugs that come down the pipe.
Dr Greg Hundley: Wow. $225,000 per year. Tell us what was your study design, and how did you go about evaluating this issue?
Dr Dhruv Kazi: We started off with the one phase three trial of the drug that has been published and simulated in a mathematical model the population that would be eligible for this therapy, reproduced the events, heart failure hospitalizations, debts, quality of life that were seen in the trial for the first three years, and then extrapolated beyond the trial based on what we know about HFpEF and what we know about transthyretin amyloidosis. It's a mathematical model that first reproduces what was seen in the trial and then extrapolates beyond what we think is the best guess of what happens to these patients. We tested a variety of scenarios whether the drug continues to be effective, whether the effectiveness declines over time or the effectiveness ceases immediately after three years.
Dr Greg Hundley: What did you find?
Dr Dhruv Kazi: What we found was interesting and it surprised us a little bit, which is that in the base case, which is assuming that the drug stays effective beyond three years, the drug is actually very effective in the traditional sense. It added 1.3 quality adjusted life years. For context here, this is about twice the effect size you expect to see with Entresto, and the HFpEF patients. So here's a drug that we've accepted and HFpEF has part of guideline directed medical therapy. Tafamidis in that best-case scenario is about twice as effective, but it is not cost effective. Because you're paying $225,000 for every year that the patient is on the medication, its incremental cost effectiveness ratio compared with usual care was $880,000, so well above what we would consider value for money. That's the best-case scenario assuming that the drug is permanently effective, if the drug's effect wanes over time, which is very likely as these patients get older and sicker, then the drug gets even less economically attractive.
Dr Greg Hundley: You've pointed out in your article, if you had 120,000 transthyretin patients in the United States, that would translate to how many dollars?
Dr Dhruv Kazi: We estimate that if all of those 120,000 patients received tafamidis, the healthcare spending would go up by $32 billion a year and most of it is towards the drug. But the caveat is that we think 120,000 patients in the US is a very conservative number because the diagnostic technology for amyloid cardiomyopathy has improved substantially over the last five years so that we no longer need biopsies. We can use nuclear scans to diagnose the disease and we have pretty good to genetic testing to identify the genetic variant of the disease. We think that number is probably closer to 200,000 or even higher because the healthcare expenditure is almost entirely driven by drug costs. The more patients we diagnosed, the bigger the budget's impact on healthcare spending.
Dr Greg Hundley: Oh my. Well Justin, for our listeners, Justin resides in Canada. Justin, what do we do with these results? I mean this is quite a sticker shock for probably an important therapy for this patient population.
Dr Justin Ezekowitz: Greg, it's a great issue and Kazi, thank you very much for this terrific, easily understandable manuscript that I think everybody should read as it's very well written and easy to understand for us non-health economists. The sticker shock is a bit of a tricky one because we always want to do what's best for our patients. When we look at that budget impact analysis, the challenge is what do we think internationally? The US is critical in terms of understanding this, but then for the rest of the world, there's certainly almost no willingness to pay at this threshold and with an uncertain incidence of amyloidosis globally, but also within the US and Canada and the difficult in diagnosis already, I think we're going to have to realize what can we do for our patients and who benefits the most with this drug given its importance and its efficacy?
Kazi, you mentioned another thing which I think is critical is what happens after 30 months if the effect wanes and where does that take us for the impact on cost and effectiveness over time but also the budget impact analysis? Because the second drug or third drug may very well come along that may fill that niche.
Dr Dhruv Kazi: Justin, that's a really good question. I mean the study only goes to 30 months and that's the only one randomized trial for tafamidis that we're working off of. So there's substantial uncertainty about what happens to this drug beyond 30 months. It's reasonable to assume that some of the effect persists, that as patients get older, get sicker, that effectiveness will wane over time. Which ties very closely to the cost effectiveness. So if the patients continue to take the drug but it's not as effective as you can imagine, it becomes less cost effective.
This also has implications for other drugs coming down the pike, which may or may not be more effective than tafamidis. They may or may not be tested head to head with tafamidis. Physicians are going to be left with the question, very clinically relevant question, of which drug to start with, how do you switch on them the next generation or more expensive drugs that come down the pike? We'll have to rely on both real-world evidence and to some extent mathematical modeling to use our best judgment on developing a treatment strategy for these patients. But rest assured that our current regulatory framework means that the drugs coming down in the future will be more expensive than tafamidis and hence, this is a good time to have the conversation about cost effectiveness and our willingness to pay for innovation.
Dr Greg Hundley: What needs to happen next to help either lower cost or develop some sort of competition in the treatment of this disease to lower the cost?
Dr Dhruv Kazi: I can take a stab at that. Greg, I think the findings of this particular drug in transthyretin amyloidosis is illustrative of the challenges that lie ahead. I think there are clinical research and policy implications. As clinicians, it's really important for us to know that this high cost of the drug is not a theoretical challenge. It's a practical challenge for our patients. The majority of these patients are going to be on Medicare part D. We estimate that the out of pocket costs is going to be in the range of $8,000 to $9,000 a year even with Medicare part D, which is a big amount of money for our fixed income seniors. I encourage our clinicians to have this conversation about out-of-pocket costs with patients, not just when you start the therapy but throughout the year. We know that the Medicare part D copays change over the course of the year based on where they are in the insurance plan.
Having this conversation may help preclude costs related non-adherence. We might be able to identify patients early or at risk, put them into patient support programs or switch them to alternate therapies that may not be as effective but at least are likely to offer the patient some support.
From a research perspective, we really need to figure out what subgroup of patients are more likely to benefit. Let's say we have 200,000 patients with transthyretin amyloidosis in the US. We need more research, and the company is not going to be vested in doing this research, it's going to have to be NIH funded research to identify subgroups of patients who benefit most from this drug, both in the short term and over the long term.
From a policy perspective, what this drug pricing issue is telling us is that we provided incentives for companies to innovate in the rare disease orphan drug program. These incentives are working. More than half of the drugs that are coming out now or have in the past year are under this rare disease umbrella. But these drugs, once they're approved, are super expensive.
We need to figure out a regulatory framework where we continue to incentivize innovation for rare diseases for orphan drugs, but at the same time tie those incentives to the final pricing to ensure that the patients get access to the drug and not just the wealthy patients who can afford the copays, but all patients who would benefit from the drug.
One of the things that comes to mind as clinicians and researchers is that particularly in cardiology, we are obsessed with innovating, with regards to new molecules and new technology. I would like us as a community to focus not just on molecules but also on markets because the innovation is not meaningful if our patients cannot have access to them. This year being the presidential election year, we're going to hear a lot about drug pricing. What I hope that this example shines a light on is that drug pricing is complicated and trying to figure out the right framework to incentivize innovation while it's still ensuring access is going to take thoughtful interventions, regulatory interventions, and clinicians should very much be a part of that process.
Dr Greg Hundley: Well listeners, we've heard a wonderful discussion here highlighting a new therapy for a disease process that's being increasingly diagnosed with our aging population and new technologies, magnetic resonance, echocardiography that identify this condition. But then how are we going to afford some of the therapies that are moving forward and design a system that emphasizes not only scientific discovery, but cost effectiveness?
We want to thank Dr Dhruv Kazi from Beth Israel Deaconess and also Justin Ezekowitz from the University of Alberta. We hope you have a great week and look forward to speaking with you next week. This program is copyright the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia.
Dr Carolyn Lam: Greg today's speaker paper is all about soy products and whether or not there is a benefit with them with regards to risk of coronary heart disease. Now, this has been extremely controversial and today's speech or paper is really important in its findings. Ha ha, I bet you want to get to it right now but I'm going to say, hold on let's get to some other really interesting papers in this series first. Can I start off? You got your coffee?
Dr Greg Hundley: Yes. Let's get going Carolyn.
Dr Carolyn Lam: So the first paper I want to highlight really talks about myocardial energetics in obesity, and you're going to love this one Greg it's got some really cool MRI techniques. We know that obesity is strongly associated with exercise intolerance and the development of heart failure particularly HFpEF. Well Dr Rayner from University of Oxford and colleagues looked at this carefully in 80 volunteers, which included 35 controls with an average BMI of 24 and 45 obese individuals with an average BMI of 35, who did not have coexisting cardiovascular disease. Now, these participants underwent body composition analysis and MRI of the abdominal liver and myocardial fat content, left ventricular function and 31 Phosphorus Magnetic Resonance Spectroscopy to assess Phosphocreatine ATP and Creatine Kinase Kinetics at rest and during Dobutamine Stress.
Dr Greg Hundley: Oh, wow Carolyn, this is right up my alley. You've got MRI imaging for body composition coupled with MR spectroscopy for metabolism, so what did they find?
Dr Carolyn Lam: Thanks for putting that simply for us Greg. They found that in the obese resting heart, the myocardial creatine kinase reaction rate is increase, maintaining ATP delivery despite reduced energy stores during increased workload. While the non obese heart increases ATP delivery through creatine kinase the obese heart does not, and this is associated with reduced systolic augmentation and exercise tolerance. Weight Loss reversed these energetic changes, so these findings really highlight myocardial energy delivery via creatine kinase as a potential therapeutic strategy to improve symptoms in obesity related heart disease, as well as a fascinating modifiable pathway involved in the progression to heart failure. Now with this paper the central illustration is so critical, everybody has to pick up that issue and have a look. Furthermore, you must read the elegant editorial by Barry Borlaug and Craig Malloy.
Dr Greg Hundley: Oh, you bet Carolyn. Craig always puts these MR spectroscopy papers in such fantastic perspective, really looking forward to that read and such an elegant study. Now, we haven't had Carolyn's quiz in weeks and we're going to get into one. This paper comes from Professor Nina Wettschureck, from the Max-Planck-Institute for Heart and Lung research, and it pertains to the infamous G-protein coupled receptors. Now, Carolyn here's your quiz and guess what, it's just multiple choice. All you have to do is fill in the blank.
Dr Carolyn Lam: On G-protein coupled receptors?
Dr Greg Hundley: Yeah, I know it's... we know a lot about these, but we're going to learn. So, G-protein coupled receptors are the largest family of transmembrane receptors in eukaryotes. They transduce signals of numerous physio-chemical stimuli including... and Carolyn you have to complete this sentence. So it's neurotransmitters, hormones, local mediators, metabolic or olfactory cues and got to complete the sentence. Is it air resistance? Time? Or light?
Dr Carolyn Lam: Space.
Dr Greg Hundley: That's not a choice.
Dr Carolyn Lam: All right, all right let me guess light.
Dr Greg Hundley: That's awesome. Fantastic, great job Carolyn. So in the vascular system the contract alternative vessels is crucially regulated by these GPCRs, including basic constrictors such as Angiotensin two and Endothelin one. In this study the investigators studied the role of GPRC5B, and the regulation of contractility and differentiation in human and murine smooth muscle cells in vitro, as well as in tamoxifen inducible smooth muscle cells Pacific knockout mice under conditions of arterial hypertension and atherosclerosis, and these experiments were done in vivo.
Dr Carolyn Lam: Okay, so what were the results?
Dr Greg Hundley: They found that GPRC5B regulates vascular smooth muscle tone and differentiation by negatively regulating prostate cycling receptor signaling. Thus, Carolyn inhibition of the interaction between GPRC5B and the prostacyclin receptor might be beneficial in human arterial hypertension and vascular remodeling. What a great new insight into basic science. Well, let me get on I have a clinical paper, and this is on the infamous topic from the COMPASS-PCI trial, Rivaroxaban plus Aspirin versus Aspirin alone in patients with Prior Percutaneous Coronary Intervention from Dr Kevin Bainey at the Canadian VIGOUR Center in University of Alberta.
So Carolyn, the cardiovascular outcomes for people using anticoagulation strategies or COMPASS trial demonstrated dual pathway intervention with Rivaroxaban 2.5 milligrams twice daily plus aspirin, and 100 milligrams once daily versus aspirin 100 milligrams once daily, reduced the primary major adverse cardiovascular event outcome of cardiovascular death, MI or stroke as well as mortality in patients with chronic coronary syndromes or peripheral arterial disease. Now, whether this remains true in patients with a history of PCI is unknown.
Dr Carolyn Lam: Oh, Greg I'm so disappointed. Why didn't you give me a quiz here? I know about the COMPASS trial. Okay, so what did the author's find?
Dr Greg Hundley: So Carolyn of the 27,000 plus patients in COMPASS 16,500 plus patients had chronic coronary syndrome, were randomized to DPI or aspirin and of these 9,862 had prior PCI. So here are the results, DPI compared with aspirin produce consistent reductions in MACE mortality, but with increased major bleeding with or without prior PCI. So among those with prior PCI one year and beyond, the effects on MACE and mortality were consistent irrespective of time since the last PCI.
Dr Carolyn Lam: Mm-hmm (affirmative) Interesting implications on dual platelet inhibition. Well, let me tell you a little bit about what's in the mailbag in the rest of this issue. There's a research letter by Dr Joseph Wu on molecular signatures of beneficial class effects of statins on human induced pluripotent stem cell derived cardiomyocytes. We have global rounds by Dr Annika Rosengren and Dr Lars Wallentin on the cardiovascular medicine in Sweden. We have a White Paper by Dr Abhinav Saxena and colleagues on the value of hemodynamic monitoring in patients with cardiogenic shock undergoing mechanical circulatory support. And we also have paired perspective pieces, one by Dr Salim Virani and colleagues on secondary prevention of atherosclerotic cardiovascular disease comparing recent United States and European guidelines on dyslipidemia, and another by Dr Neil Stone and colleagues on comparing primary prevention recommendations with the focus look at the US versus European guidelines on dyslipidemia.
Dr Greg Hundley: Very good, Carolyn. Well, I've got a research letter Professor Do-Young Kwon from the Korea University of Ansan Hospital, Korea University College of Medicine and discusses the association of Parkinson's disease with the risk of cardiovascular disease and all-cause mortality, and a nationwide population-based cohort study. In addition, different series of letters Dr Seung-Jung Park from Asan Medical Center at the University of Ulsan College of Medicine, and Professor Lang Li of The First Affiliated Hospital of Guangxi Medical University exchanged letters regarding the article, Clinically Significant Bleeding With Ticagrelor versus Clopidogrel in Korean patients with Acute Coronary Syndromes Intended for Invasive Management, that previously published randomized clinical trial. Then finally one of those great ECG investigations from Dr Miguel Arias, and they have an ECG quiz entitled The Hidden Reveals the Hidden, but really, it's referring to a Brugada ECG pattern and a patient with Wolff-Parkinson-White. I can't wait to get onto that feature article discussing the potential benefits or harms of soy in men and women as it relates to cardiovascular disease.
Dr Carolyn Lam: Yeah, you and I Greg let's go. Oh, boy today's feature paper really literally cuts close to the heart for me talking about soy products, and whether or not there's a relationship with cardiovascular health. This remains controversial but thankfully we've got really great data just published in this week's issue, so proud to have the first author with us Dr Qi Sun from Brigham and Women's Hospital, as well as our associate editor who's also an editorialist for this paper and that's Dr Mercedes Carnethon from Northwestern University Feinberg School of Medicine. So welcome both I cannot wait to just jump right into it. Please, Qi, tell us what you found about soy products.
Dr Qi Sun: First off this is a prospective cohort study that included three cohort studies, the Nurses’ Health Study and the Nurses’ Health Study II and Health Professionals Follow-Up Study. So those three big prospective cohort follow up studies. Now over the years we have collected much data of diet which has been repeated, reviewed, and assessed over the years, and we have accumulated many cases of cardinal heart disease the numbers are a solid. Now what we found is that the intake isoflavones which are the big family are flavonoids, the higher intake of isoflavones were associated with a lower risk of developing coronary heart disease in those three cohorts of men and women. And in addition because tofu and soy milk are the primary contributor in our guide of isoflavones, we also examine the tofu and soy milk in relation to the risk of cardinal heart disease What we found is that tofu intake is significantly associated with lower risk of developing heart disease, and soy milk is also associated with lower risk of developing heart disease. It's just the association for soy milk, soy milk is not significant. And I think very interestingly we also found that the menopausal status and the postmenopausal hormone use somewhat also modulated association primarily for coffee intake with heart disease risk, in that we found younger women who were before their menopause and also postmenopausal women who did not use hormone will benefit more from tofu intake.
In contrast, for postmenopausal women who are using hormone the association was not significant. I think those are the primary findings of our prospective cohort study.
Dr Carolyn Lam: Oh my goodness, hallelujah. That's really marvelous and beautifully summarized, Mercedes please explain why was this such a controversial area before? And what does this paper add? Love your editorial by the way.
Mercedes Carnethon: We hear a lot about nutritional epidemiology studies, and we have a lot of debates about what we should believe, whether we should change our behavior based on these observational studies and quite often we have discussions about what's new. And I lean on that final point about why I like this particular paper so much, and that's because I found the topic of isoflavones, tofu intake and soy to be extremely relevant to a large proportion of the world's population, whose primary protein intake may be something made from a soybean, heavy and isoflavones. Within the United States it's also relevant even though a smaller proportion of our population relies primarily on vegetarian diet, there is a very large and interested group wondering whether soy intake is safe. There have been discussions about whether there's harm associated with it, and the possibility that it could have beneficial influence on our leading causes of death of coronary heart disease.
So I was most thrilled about the innovation of this particular topic, and its methodological rigor. When we think about what we lean on, we lean on large studies, we lean on multiple events and the size of the study allowed the investigators to explore numerous subtleties. Subtleties such as that reported related to the moderation by menopausal status, and that was the point I was most curious about and why I'm really excited to have an opportunity to talk to you today Chi. Can you tell me a little more about the menopausal status finding?
Dr Qi Sun: So first off as I mentioned tofu intake was more strongly associated with lower risk of developing heart disease among younger pre-menopausal women, or postmenopausal women who did not use ham. Before that I want to also mention for isoflavones intake where I also found a similar pattern in that isoflavones are more. Appear to be more strongly associated with lower risk also in those two groups of women, although the past by interaction was non-significant. Now in terms of why I think there are a couple reasons why is that, among postmenopausal female or in our use hormone, the isoflavone can function as estrogen and provide at least partially the estrogenic effects that were calculated in postmenopausal women who do not use hormone, and for premenopausal women we think that's probably because before menopausal, the activity of estrogen receptor may be higher than the estrogen receptor after menopausal. So, in reality, the other variables of isoflavones may provide estrogen effects after menopausal. So those are the hypotheses although I have to mention that those hypotheses, we need more evidence to really shed light on the mechanisms underlying those interactions between menopausal status, postmenopausal hormonal use, where's the intake of isoflavones and tofu.
Dr Carolyn Lam: So Chi I love that explanation and giving it some biological possibility, although as you said it's a postulation. But may I ask so what's the implication for men? I lived with a man who thinks if he takes soy he's going to grow boobs. So what... did you see any sex differences and do studies like this and able looking for the downsides of eating soy?
Dr Qi Sun: As a scientist I'm open to any kind of new findings as long as the findings are from well conducted, rigorously designed study. But having said that I couldn't exclude the possibility that maybe soy intake is associated with certain adverse health outcomes, but so far based on my experience I didn't see any such evidence. But having said this I always say I wouldn't risk any possibility, but coming... circling back to the coronary heart disease we really didn't see much difference between men and women. It's true for the younger women we saw a stronger association but for men I also see a lower risk of heart disease. So there's a kind of interesting image on soy intake or isoflavones intake in the United States that people believe they are estrogen so a man shouldn't take it, but if you look at the group of vegetarians, the vegans. There are a lot of guys they practice vegetarian, they practice vegan diets and we also publish on plant-based diet in relation to coronary heart disease and lot of men eat very healthy. And we found those people who practice those kinds of healthy diets, soy is often mouthful of primary sources of proteins and if you look at their risk of developing heart disease, type two diabetes is quite low. Something lower than other normal women who practice otherwise omnivore diet.
Dr Carolyn Lam: It's true Qi soy intake could also be a marker of a healthier lifestyle in general, by extension of what you just said. But Mercedes I love that you discuss quite a number of these issues in your editorial and at the end of the day you asked the most important question, what does this mean for us? Should we all be increasing our intake of soy products? Could you give us your synthesis of that?
Mercedes Carnethon: Yes, a point that I've definitely tried to make here, and this is really in response to what I expect to be the media fear surrounding new dietary findings. One of the first questions that I know that she and his colleagues will be asked is, should I change my diet? Can I extend my life? And that's because the media is really looking for a lot of sensational headlines in this topic, and I think we have to focus on what we learn from these observational studies. They're a very important step in the scientific process that helps us provide a justification for later clinical trials, that helps us think about the multiple components that work together to promote overall excellent health. And the point you were making right before this about the individuals who eat plant based diets that are heavily based in soy. In the paper it also describes that those individuals exercise more, they may have lower intakes of saturated fat, and so I think ultimately what I take from this at least for myself and for people who would ask is that an overall healthy diet seems to stand up very well in these well done observational studies. And that soy in particular may be a part of an overall healthy diet given what we're seeing here in this very well done study.
Dr Carolyn Lam: Oh, that's beautifully put Mercedes and Chi perhaps I can give you the last word. What would you say is the take home message and what are next steps?
Dr Qi Sun: I think the core message is this as Mercedes very well discussed, I think soy and especially tofu can be really good components of the overall healthy plant based diet, and by practicing that I think we can significantly reduce the risk of developing coronary heart disease for both men and the women. I think moving forward we would like to see evidence from clinical trials that target cardiometabolic risk factors as outcome, and to see whether increased consumption of tofu and isoflavones can really reduce those risk markers so that they have ample evidence to support the mechanisms. As you mentioned Carolyn that this is an initial study, and it could be soy, intake could be just macro how is it, through clinical trials, we can really control those confounding factors and really provide good evidence to support our findings.
Dr Carolyn Lam: Well, in the meantime I just have to say you made my day this is coming from a soy eating vegetarian, so thank you so, so much. Thank you, listeners for joining us today.
Dr Greg Hundley: This program is copyright the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Dr Greg Hundley from the VCU Health Pauley Heart Center in Richmond, Virginia. Well, Carolyn, we've got a great feature article this week, evaluating do we wait or do we do now ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and implantable defibrillators? But before we get to that, how about if we grab our coffee or whatever it may be and jump into the other articles?
Dr Carolyn Lam: Sure. Well, Greg, have you ever wondered what the outcomes are of transcatheter aortic valve replacement, or TAVR, in patients with bicuspid aortic valve stenosis? Now, remember, patients with bicuspid aortic valve stenosis were excluded from the pivotal evaluations of TAVR.
Dr Greg Hundley: I wondered that yesterday, Carolyn.
Dr Carolyn Lam: Well, guess what, Greg, it's your lucky day because we're going to get answers now from corresponding author Dr Brennan from DCRI and coauthors who use data from the Society of Thoracic Surgeons, American College of Cardiology, TAVR registry from 2011 to 2018 to determine the device success procedural outcomes, post-TAVR valve performance and in-hospital clinical outcomes in almost 171,000 eligible procedures, of which 5,412 TAVR procedures were performed in bicuspid aortic valve patients, including 3,705 with current generation devices.
Dr Greg Hundley: Wow. Carolyn, this sounds to me like probably one of the largest collections of patients that have had TAVR and bicuspid valves. What did they find?
Dr Carolyn Lam: Well, compared to patients with tricuspid aortic valves, bicuspid aortic valve patients were younger and had a lower STS predicted risk of operative mortality score, so you have to bear that in mind first. With the current generation TAVR devices, the incidence of device success was only slightly lower for bicuspid versus tricuspid aortic valve patients and residual two-plus aortic insufficiency remains slightly higher, though, for bicuspid versus tricuspid aortic valve patients.
There was no difference in adjusted one-year hazard of stroke in patients with bicuspid versus tricuspid valves, but the adjusted one-year hazard of mortality was lower among bicuspid aortic valve patients. Thus, using current generation technology, TAVR appears both safe and effective for the treatment of bicuspid aortic valve stenosis, although there remains a low incidence of moderate or greater aortic insufficiency among both bicuspid and tricuspid aortic valve patients.
Dr Greg Hundley: Very nice. Well, Carolyn, do you ever wonder how white cells are recruited into areas of the heart that have sustained a myocardial infarction?
Dr Carolyn Lam: Every day, Greg. Every day I think about that.
Dr Greg Hundley: You know, we've got so much wondering on your side of the world and on my side of the world, but if we connect that we will solve a lot of things. Well, this paper is from Dr Prabhakara Nagareddy from Ohio State University. This group of investigators used a mouse model involving ligation of the LAD and flow cytometry to characterize the temporal and spatial effects of myocardial infarction on different myeloid cell types, a process termed myelopoiesis, that results in heightened production of neutrophils.
The investigators sought to understand the mechanisms that sustain white blood cell production in recruitment to the injured heart using global transcriptome analysis of different cardiac cell types within the infarct. In addition, just as these clever circulation papers do, also a human subject study was performed utilizing a combination of genetic and pharmacologic strategies. The authors identified the sequela of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography and the association of early indices of neutrophilia with major cardiac events, or MACE, was studied in those patients sustaining an MI.
Dr Carolyn Lam: Wow, that's a huge amount of work. What was the bottom line results?
Dr Greg Hundley: So, first, in the patients with acute coronary syndromes, a higher neutrophil count on admission and post-revascularization correlated positively with major adverse cardiovascular disease outcomes. And then, second, from the basic science component, the study identified novel evidence for the primary role of neutrophil-derived alarmins and, in particular in this study, S100A8-A9 in dictating the nature of the ensuing inflammatory response following myocardial injury.
Therapeutic strategies aimed at disruption of this S100A8-A9 signaling, or its downstream mediators in neutrophils, were shown to suppress granulopoiesis and therefore, perhaps in the future, could improve cardiac function in those patients sustaining an acute coronary syndrome. Really elegant work. That combination of the basic science in the animal model and then the translational work in the human subject model.
Dr Carolyn Lam: Exactly what I was going to say. Translational work. Well, hold onto your seat because this next one is super cool, too. It is the first time a pre-clinical development and first in human proof-of-concept of peritoneal direct sodium removal using a zero-sodium solution as a candidate therapy for volume overload. So, as a background, remember that loop diuretics have been well described to have toxicities and that loss of response to these agents are common when we try to treat volume overload. So alternative strategies are clearly needed for the maintenance of euvolemia in heart failure.
These authors, led by Dr Testani from Yale University hypothesized that non-renal removal of sodium directly across the peritoneal membrane, that is called direct sodium removal, using a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal. So what they did is they performed porcine experiments followed by a human study in which participants with end-stage renal failure on peritoneal dialysis underwent randomization and crossover to either a two-hour dwell with one liter of this direct sodium removal solution or a standard peritoneal dialysis solution. Sodium-free 10% dextrose, by the way, was utilized as the direct sodium removal solution.
Dr Greg Hundley: Boy, Carolyn, this is really another one of these elegant translational studies. So we have the animal model, we have the human subjects and then we have different concentrations of these peritoneal fluid that are injected and then extracted for dialysis. I can't wait to hear. So what did they find?
Dr Carolyn Lam: First, cycling a sodium-free osmotic solution that's a 10% dextrose across the peritoneal cavity of swine resulted in substantial sodium removal. So, proof of principle there. The sodium removal increased proportionately as the volume of 10% dextrose cycled across the peritoneum increased. Experimental elevation of right-sided cardiac filling pressures also resulted in substantial increased sodium removal with this technique. Now, in the humans, a single dose of sodium-free 10% dextrose was well tolerated in human subjects and resulted in over four-fold greater sodium removal than the strongest commercially available peritoneal dialysis solution.
So, direct sodium removal with a sodium-free osmotic peritoneum solution represents a new potential therapy for non-renal sodium and fluid removal in edematous disorders such as heart failure. However, there is a long way to go in deploying such a procedure in the heart failure population. And this is really highlighted and discussed in an accompanying editorial by Dr Robert Toto from UT Southwestern.
Dr Greg Hundley: Fantastic. Carolyn. Bob Toto always puts things really in perspective. That'll be a great read. Well, let me tell you about a couple other articles in this issue. Dr Bina Ahmed from Santa Barbara Cardiovascular Group has a very nice on-my-mind piece getting at this issue of how we should, as physicians, be reacting to the healthcare issues. Also, particularly in cardiovascular disease, as they occur in the face of climate crisis. A great read. Then there's a beautiful adult learning excerpt put together by Dr Daniel Kramer from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center.
It involves a patient that presents with some symptomatology associated with their thoracic spine. They have to undergo an MRI. They've got an implanted device. How do you work through that? What do we need to do with anticoagulation? It turns out the patient also may need a Watchman device. Who is a candidate for that? Boy, it's just a great educational read.
Carolyn, there is a lot in the mailbag this week. Professor John Madias from the Icahn School of Medicine at Mount Sinai and Dr Adaya Weissler-Snir from the Hartford Hospital and University of Connecticut exchanged some letters regarding the article previously published on hypertrophic cardiomyopathy-related sudden cardiac death in young people in Ontario.
Robin Woods from Monash University has a research letter involving no modulation of aspirins effect by body weight in healthy older men and women. And then Myra Lipes from the Joslin Diabetes Center Harvard Medical School has a research letter entitled the Cardiac Autoimmunity is Associated with Subclinical Myocardial Dysfunction in Patients with Type 1 Diabetes.
Dr Carolyn Lam: And I'll add one more research letter by Dr Dempsey on prospective associations of accelerometer-measured physical activity and sedentary time with incident cardiovascular disease, cancer and all-cause mortality. So something that's really a hot topic now. Man, that has been a great issue. But let's move on to our feature discussion, shall we?
Dr Greg Hundley: You bet. Well, listeners, welcome to this feature discussion where we're going to understand a little bit more about ICDs and ventricular tachycardia and we have Dr Karl-Heinz Kuck from the University Hospital of Lübeck. We have Francis Marchlinski from the University of Pennsylvania and we have Dr Sammy Viskin, our own associate editor from the Tel Aviv Medical Center. What a great study. So, Karl, I'd like to start with you. Can you give us a little bit of background about why you wanted to perform the study and what was your hypothesis?
Dr Karl-Heinz Kuck: There is an ongoing debate in clinical electrophysiology, what would be the optimal timing of catheter ablation in patients with ventricular tachycardia and ventricular fibrillation. Now, until today, most patients come to catheter ablation at a very late stage of the disease, mostly after multiple ICD shocks. So the patients are in a very bad condition and our strong feeling is the patients should undergo, much early, a successful catheter ablation.
The study was initiated with the background that we, and others, have shown that a very catheter ablation, which is before any ICTD shock, a so-called preventative ablation, is superior with respect to clinical endpoints as compared to optimal medical treatment. That's number one. And number two is that we know from retrospective analysis of multiple ICD studies that ICD shocks increase mortality as compared to patients with ICDs that have no shocks.
So, on one side we have the benefit of a preventive ablation which has been shown in three randomized trials, and on the other side we know that ICD shocks increase mortality. So somewhere in between multiple ICD shocks and no shock should be the benefit of catheter ablation and this, exactly, was the background of the BERLIN-VT Trial to investigate whether a very only catheter ablation study, which is after the first episode of VT/VF, before any ICD shock, would be superior as compared to having an ICD implanted and follow the patients and then ablate the patients after an arbitrary taken number that we set to three ICD shocks. We were looking then for a combined clinical endpoint to see whether there is any benefit of prophylactic, or preventative, ablation versus what we call deferred catheter ablation.
Dr Greg Hundley: Can you tell us about the BERLIN-VT? What was your study population? A little bit about the design.
Dr Karl-Heinz Kuck: Yeah. The patients that we investigated were patients only with ischemic cardiomyopathy who would had a previous myocardial infarct, to reduce the number of interventions that would require an epicardial access in that patient population. That's number one. And number two, the patients should have an ejection fraction above 35 because a previous study that we have done, the VTACH Study showed that there was no benefit of catheter ablation in patients with a very low ejection fraction, so this was the patient population that we were looking. And then patients had to have had at least one episode of VT/VF before they were randomized either into preventive ablation or into deferred ablation.
Dr Greg Hundley: How many participants were in your study? And then tell us a little bit about the study results.
Dr Karl-Heinz Kuck: We randomized the 76 patients to preventive ablation, and 83 patients do differed ablation. The number, we originally thought to be higher, but we had redesigned interim analysis and after the second interim analysis at the DSMV, we commanded to terminate the trial for futility. And at that point in time when the study was terminated, these numbers were included, which was almost two thirds of the patients which were originally included in to the front.
Dr Greg Hundley: What were your results?
Dr Karl-Heinz Kuck: Now, which respect to the endpoint of the trial, which was the primary endpoint, which was a composite endpoint of all-cause mortality and unplanned re-hospitalizations for worsening of heart failure or ventricular arrhythmias, we did not find any significant difference between the preventive and the deferred ablation group. Actually, after 12 months, there were 21% of patients in the differed, and 27% in the preventive ablation group, and these numbers almost doubled over two years but didn't show any difference.
So with respect to the components of the combined endpoint, we also didn't see any significant difference with respect to overall mortality, hospitalization for worsening of heart failure and hospitalization for worsening of ventricular tachycardia or ventricular fibrillation, despite the fact that there was a strong trend to a reduction of hospitalization for VT/VF in the preventive group as compared to the deferred group.
But this was fully compensated for the primary endpoint by an increase of hospitalizations, early hospitalizations after ablation for worsening of heart failure and a somewhat higher mortality rate in the preventive group as compared to the deferred group, which I believe was really bad luck because almost none of the six [inaudible 00:17:12] in the preventive group died due to cardiovascular reasons. Whereas most patients in the deferred group died because of ventricular tachycardia, ventricular fibrillation.
Now, what is interesting to mention is that with respect to the secondary endpoint, which is sustained VT and VF and appropriate ICD therapy, there was a significant benefit of preventive catheter ablation as compared to deferred catheter ablation but, as I mentioned before, this could not be translated into a benefit with respect to clinical outcome in the trial.
Dr Greg Hundley: Thank you, Dr Kuck. Dr Marchlinski, could you help us put this in perspective as we're thinking about patients with ischemic heart disease that we are considering implantation of an ICD?
Dr Frank Marchlinski: Yes, definitely. First, I like to congratulate the investigators. This is a real tour de force, a lot of effort, multiple centers involved. Dr Willems, Dr Kuck, congratulations because this is an important effort. I think that one needs to realize, of course, that it is our goal to try to eliminate VT with the hope that we're going to improve mortality outcome in addition to improving quality of life. It's a worthwhile goal. I hope someday we will achieve it and that we'll be able to use ablative therapy very early in the course, even in advance of ICD implantation and potentially even to prevent ICDs. That's a worthwhile goal and something that we all need to target as investigators in this area.
But Dr Kuck's study demonstrated that we're not there yet to use it as very early in the course of a disease before patients manifest a lot of arrhythmia recurrences. One thing is for certain, though. This study, although important in suggesting that we need to take our time in terms of planning to do the ablation procedure, we don't want to delay. There's enough evidence to say that repeated shocks can increase mortality, as Dr Kuck pointed out, and enhance a bad outcome.
It certainly provides a very poor quality of life for the patient to experience these shocks, so we need to consider the timing of when it's appropriate, when patients begin to experience ICD shocks after receiving a defibrillator and not wait for repeated shocks, not wait for excessive dosing with Amiodarone, but rather to intervene in a timely fashion after a patient begins to get the shock therapy. It was clear that even the BERLIN-VT investigators didn't wait for multiple additional shocks. As soon as patients received one or two shocks, they got enrolled in this study, this is the deferred limb, and took advantage of the effectiveness of ablation to reduce the number of VT episodes.
Dr Greg Hundley: Sammy, now back to you. What study do we need to perform next in this field? How do you think the results here guide us moving forward with research in this area?
Sammy Viskin: As Frank said, in [inaudible 00:20:25], it is very important that patients are not referred too late for ablation when they arrive after many shocks and they're already, sometimes even encouraged to getting shocks. The present study shows that perhaps they should not be referred for ablation too early at this point, at least not until we get better with our ablation techniques. So we need studies on how to improve our ablation techniques. They keep getting better, but they still have a long way to go. And then we should be able to define the optimal time when it's not too early and when it's not too late to perform the ablation procedure.
Dr Karl-Heinz Kuck: I agree with all of what had been said. I just would like to mention that the study, the BERLIN-VT Study compared, actually, very early catheter ablation versus early catheter ablation. We just wanted to know whether very early ablation is better than early because I think that all the three physicians here, the three electrophysiologists, would agree that we would be happy if most of the patients would even be sent after the second or third shock. Many patients having multiple more shocks before they are sent for catheter ablation.
So, in this sense, the BERLIN-VT Study was an aggressive study because they did not allow patients to be sent after the 10th shock, after the 15th shock, after an electrical storm. So we are comparing very early versus early ablation and I'm not giving up, like Frank Marchlinski was saying. I'm not giving up on the idea.
Sammy is saying we are not yet there, but we should continue to prove that an early ablation is superior to a late ablation. But BERLIN-VT did not look at the very late ablation component of the strategy here. I think what this study shows and what all the other studies also show how difficult it is, in the field of VT/VF and severely diseased patients, to do such a randomized trial. We have a lot of problems to enroll these patients and therefore, I was glad that we could at least get some information out of the trial.
I'm still supporting the idea that the international community should work closer together in the field of catheter ablation of ventricular tachycardia and ventricular fibrillation so that we could increase the number of patients within a rather short period of time that should be included in these VT ablation trials. That's, I think, another learning that I've done from this trial but also from some of the other trials that we and others have done in the field.
Dr Greg Hundley: Well, listeners, we want to thank Dr Karl Kuck from University of Lübeck in Germany, Dr Frank Marchlinski from University of Pennsylvania, and Dr Sammy Viskin from Tel Aviv Medical Center. We've really heard some insightful results related to ICD placement and those with ischemic heart disease from the BERLIN-VT Study. It really emphasizes the importance of, as we move forward, international collaborations when we're trying to study this patient population.
Well, on behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you and grabbing a cup of coffee next week. Take care. Of this program is copyright of the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast soiree and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor for the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week we're going to talk about carotid stenosis, and you remember how we measure those a lot with ultrasound, and what that thickness is, and IMT? Well, we're going to talk about getting some thresholds and an update in that with our feature discussion today. But before we get there, how about grab a cup of coffee and we get started with other papers.
Dr Carolyn Lam: All right. Well, I've got my coffee and I'm ready to tell you about two papers. They're both on left ventricular hypertrophy. One is basic and one is clinical. I will start with the basic paper because it is a super cool one that uncovers a novel mechanism underlying myocardial hypertrophy. And this involves S-nitrosylation, a prototypic, redux-based post-translational modification, S-nitrosylation.
So this is from co-corresponding authors, Drs Xie, Han, and Ji from Nanjing Medical University, who performed a series of elegant experiments using myocardial samples from patients and animal models exhibiting myocardial hypertrophy, and they demonstrated that S-nitrosylation of muscle limb protein plays a crucial role in myocardial hypertrophy.
This muscle limb protein modification enhanced binding to toll-like receptor 3 and receptor interacting protein kinase 3, which stimulated NOD-like receptor pyrin domain containing 3 or NLRP3 inflammasome activation and consequent caspace-1 and interleukin 1 beta activation, ultimately promoting myocardial hypertrophy. They further showed that the deficiency of S-nitrosylated muscle limb protein governed toll-like receptor 3 really alleviates pathological myocardial hypertrophy.
Okay Greg, I can see the look on your face. You're like what? That was a lot. What are the clinical implications, right?
Dr Greg Hundley: Yeah, Carolyn, you are taking me back to molecular biology course 410, that I would take as a senior in college. Wow. So tell me what are the clinical implications?
Dr Carolyn Lam: All right, here's a take-home. The data really identify that S-nitrosylated muscle limb protein is a key regulator, which together with toll-like receptor 3 made therefore serve as putative therapeutic targets in treating pathological myocardial hypertrophy in heart failure. That's the take-home. Before any further comments, let's go to the clinical study.
Now, this one focuses on a malignant subphenotype of left ventricular hypertrophy in which minimal elevations of cardiac biomarkers identify individuals with left ventricular hypertrophy at high risk for developing heart failure. And this is from corresponding author Dr James de Lemos from UT Southwestern. He and his colleagues tested the hypothesis that a higher prevalence of the malignant left ventricular hypertrophy phenotype among blacks may contribute to racial disparities in heart failure risk. So they pooled data from three large multi-ethnic cohorts, that is Eric, Dallas Heart Study, and MESA, totaling more than 15,700 participants. These participants were then classified into three groups: One, those without ECG left ventricular hypertrophy; two, those with ECG left ventricular hypertrophy but normal biomarkers; and three, those with ECG left ventricular hypertrophy and at normal levels of two biomarkers, high sensitivity troponin T above six nanogram per liters, or NT-proBNP above 100 picograms per milliliter. And that last group were the malignant left ventricular hypertrophy group.
They found that the prevalence of malignant left ventricular hypertrophy was threefold higher among black men and women versus white men and women. Compared to participants without left ventricular hypertrophy, the adjusted hazard ratio for heart failure was 2.8 in those with malignant ventricular hypertrophy and only 0.9 in those with left ventricular hypertrophy and normal biomarkers. And these were similar findings in each race and sex subgroups.
Mediation analysis indicated that 33% of the access hazard of heart failure among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant left ventricular hypertrophy in blacks.
Dr Greg Hundley: So Carolyn, race could be a really important issue in left ventricular hypertrophy. What did the authors conclude? I mean, how should this help us perhaps manage these patients? What was the take-home?
Dr Carolyn Lam: So this really shows that a higher prevalence of the malignant hypertrophy phenotype may in part, explain the higher risk of heart failure among blacks compared to whites. And what it means too is that when left ventricle hypertrophy is detected by ECG or cardiac imaging, perhaps we should consider measuring high sensitive troponin T or NT-proBNP, which will help distinguish those in whom risk for heart failure is favorable from those at a much higher risk.
Dr Greg Hundley: Very, very interesting. Well Carolyn, I'm going to switch. I've got a basic paper and it's going to focus on dysfunctional adipocytes and how they might talk to cardiomyocytes in the situation of ischemia reperfusion injury. And the corresponding author is Xin-Liang Ma, from Thomas Jefferson University in Pennsylvania.
So Carolyn, do you have any thoughts regarding how patients with diabetes might experience a greater degree of myocardial ischemia reperfusion injury in the setting of an MI?
Dr Carolyn Lam: Oh my goodness, you're really putting me on this spot here. Well, I know things that come to mind would be oxidative stress, microvascular disease.
Dr Greg Hundley: Very good. Open-ended questions for Carolyn's quiz. I'm going to give you a 90. That was very good. So Carolyn, this current study attempted to clarify whether and how small extracellular vesicles may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating myocardial ischemia reperfusion injury. And to do this, adult male mice were fed a normal or high fat diet for 12 weeks.
The small extracellular vesicles from diabetic serum, diabetic adipocytes, high glucose, high lipid-challenged, non-diabetic adipocytes were injected then, intramyocardially, distal of the site of a coronary ligation.
Dr Carolyn Lam: Okay. So Greg, I would not have guessed it was about extracellular vesicles, but very interesting. What did they find?
Dr Greg Hundley: Intramyocardial injection of diabetic serum small extracellular vesicles or these SEVs, in the nondiabetic heart, significantly exacerbated myocardial ischemia reperfusion injury, as evidenced by poor cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. And administration of small extracellular vesicles, biogenesis inhibitors, significantly mitigated the myocardial ischemia reperfusion injury in diabetic mice. And mechanistic investigations in these studies identified that MIR 130B3P is a common molecule, significantly increased in diabetic serum of small extracellular vesicles and mediated the pathological communication between the dysfunctional adipocytes and the cardiomyocytes. Therefore, if in the future, we could interfere with this molecule, that could perhaps be a novel strategy for attenuating diabetic exacerbation of myocardial ischemia reperfusion injury. Really, a clever study, I think. What else did you find in this issue of the journal?
Dr Carolyn Lam: Yeah, Greg, this week's issue is packed with other papers too. For example, there's the research priorities for HFpEF by NHLBI working group summary by Dr Shah, et al. There's a research letter by Dr Kaltman on the disparities in congenital heart disease mortality based on proximity to a specialized pediatric cardiac center. There's also another research letter by Dr Irisawa, on the impact of low-flow duration on favorable neurological outcomes of extracorporeal CPR, after out-of-hospital cardiac arrest, and this is a multicenter prospective study.
Dr Greg Hundley: It sounds like a lot's in the mailbag. In the couple of things that I wanted to talk about, Dr Giulia Rivasi from the University of Florence, and William White from University of Connecticut, exchange a series of letters back and forth regarding a previous publication on the effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older individuals.
I have another research letter entitled, The Cardiac Cell Therapy Rejuvenates the Infarcted Rodent Heart via Direct Injection, but not by Vascular Infusions. And that is from Dr Jeffrey Molkentin from Cincinnati Children's Hospital Medical Center.
Finally, though Carolyn, there's a very interesting piece from Dr Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of Chicago, discussing are we now in a time, in the United States, where congenital heart surgery should be coalesced or regionalized? And that really comes on the back of a discussion of there have been several high-profile articles in the national media, reporting on US congenital heart surgery programs. And that's led to, the author describes, some closure of several centers and at least in five programs. So a great discussion on, should this be regionalized? But we've got a great feature article coming ahead and how about if we head to that.
Dr Carolyn Lam: Let's go, Greg.
Dr Greg Hundley: Welcome everyone, to this feature discussion where we are going to discuss the use of diagnostic ultrasound in the carotid arteries and how that pertains to selection of patients for vascular surgery. And with us today, we have Dr Jesse Columbo from the Geisel School of Medicine at Dartmouth University in Hanover, New Hampshire. We also have Dr Bob Zwolak, from the Manchester VA at the Dartmouth School of Medicine and we have our own Josh Beckman from Vanderbilt University, one of our associate editors at Circulation. And Bob, let's get started with you. Could you tell us a little bit, what was the background of this study and what hypothesis were you looking to test?
Dr Robert Zwolak: It goes without saying that stroke is still a huge health problem in the United States. If there is any good news, it's that stroke incidence is falling slightly, but there are still over 100,000 deaths from stroke each year in United States and as many as 700,000 new strokes each year, and a significant proportion of those derive from atherosclerotic plaque in the carotid bifurcations.
Carotid duplex ultrasound is a fantastic way to assess the presence of plaque in the carotid bifurcations because it does not use any ionizing radiation, does not require any contrast. Ultrasound is a relatively less expensive technology than CT or MR, and the study can be repeated so we can follow people over time, who are found to have significant atherosclerotic plaque in their bifurcations.
The hypothesis of our study though, was that there is variation in the diagnostic thresholds used by various carotid ultrasound testing laboratories, such that it may impact the healthcare and the treatment plans of people who undergo the studies. Jesse will tell you the details, but specifically, we hypothesized that people who undergo this carotid ultrasound test may or may not be inducted into a surveillance program and intensive therapy based on the diagnostic criteria that were used by the individuals conducting their ultrasound study. And even more substantially, we hypothesized that individuals who undergo carotid endarterectomy or potentially carotid stenting, could also have their procedure influenced, whether or not they undergo surgery or stenting based on the carotid ultrasound results. It might vary from one facility to another. So it potentially could be that an individual would be inducted into ultrasound surveillance or even undergo carotid surgery, depending on the vascular laboratory in which they were tested.
Dr Greg Hundley: Jesse, could you tell us a little bit, what was your study population and how did you design this to address the hypothesis that Bob just stated?
Dr Jesse Columbo: Sure. A review of the published literature really shows a variability in that ultrasound criteria that's used for diagnosing carotid stenosis. And so our first objective was to see if we could obtain as many in-use criteria as possible. Our first step was to partner with the Intersocietal Accreditation Commission, the commission that accredits vascular labs. We partnered with them and obtained a 25% random sample of ultrasound criteria in use across the US. And so that kind of gave us the starting point for the criteria upon which to look at.
We then wanted to apply those to a couple of different groups. As Dr Zwolak mentioned, there's really two primary breakpoints here. One, you either have mild stenosis, where you get medical therapy, but no further surveillance, or moderate stenosis, at which point you then are dedicated to long-term surveillance per the AAJ recommendations, or then, the break point between moderate and severe stenosis where surgery is considered.
What we wanted to do is examine the impact of moderate and severe stenosis thresholds. For the severe stenosis thresholds, we use the Vascular Quality Initiative Registry, which collects information on patients who underwent carotid endarterectomy. When we studied patients specifically that we thought the percent stenosis would be the major deciding factor in who got surgery, those are the asymptomatic stenosis and we applied the range of severe stenosis criteria from the IAC to those patients. We then wanted to study other individuals who might be committed to long-term surveillance based on the criteria used. And so for that, we used participants in the Cardiovascular Health Study, which had their induction into the study, had baseline data on carotid stenosis collected. And so that kind of formed our basis of the study, applying the criteria to those two different groups of individuals.
Dr Greg Hundley: And so how many subjects did you have in the two cohorts? And then tell us what were your study results?
Dr Jesse Columbo: Sure. Once we narrowed down that patients in the vascular quality initiative to those who underwent surgery for asymptomatic carotid stenosis, we had about 28,000 patients. And then when we examined the Cardiovascular Health Study, we had about 4,800 or 5,000 patients in that group. What we found was pretty interesting.
If you look at individuals who underwent surgery, and you take the carotid threshold criteria and apply it to them, and if you say, "Well, we're going to take criteria in the fifth percentile versus criteria in the 95th percentile," what you'll find is that 10% of patients who got surgery, fall between that range. And what that means is that there are patients, approximately 10% of patients, who are undergoing surgery that may not have been offered surgery if they had gone to a different institution, which we thought a pretty important finding.
The second part was studying patients who maybe committed to long-term surveillance. And if we took centers that were in the fifth percentile versus those in the 95th percentile for their carotid stenosis thresholds, we found a twofold difference in the number of patients that would be committed to long-term surveillance. And remember, this is the difference between getting aspirin and a statin and medical therapy, but no longer surveillance and getting carotid ultrasound every six months to a year for a long period of time. That twofold difference really could have a meaningful impact on patients.
Dr Greg Hundley: It sounds like we've got a variance issue here and that could really impact clinical care. So while ultrasound's very portable and advantageous, how do we use these results to more effectively select how we're going to implement ultrasound to monitor these patients?
Dr Joshua Beckman: I have to say the results of this study, when I read them the first time were eye opening. One point that doesn't come out clearly to those folks who aren't necessarily in the field, is that these are the labs that have been accredited and they are the top labs in the United States. This doesn't include at least half of the rest of the labs in the United States and suggest that if there's variation in the very best of labs, you know that there's even more variation that's being practiced routinely around the United States. So when I read this, I thought that there was a huge problem that they were uncovering. There are many, many millions of patients with atherosclerosis.
And so what we have to figure out now is how to standardize the measurement and reading of these studies so that ultrasound can be deployed routinely, without a fear of your treatment varying based on which doctor you decide to see and where you decided to go. And I think the fact that these guys highlighted that in such a nice and clear way, really raises the alarm and raises the flag that attention needs to be paid here quite soon because it's quite important.
Dr Greg Hundley: So what study could we perform next? And maybe I'll ask, Bob, you just start off. What study could we perform next to help clarify and guide us to the better use of ultrasound in this situation?
Dr Robert Zwolak: Well, I think there are two issues. The first issue that this manuscript points out is the one of variation and it's real and the results speak for themselves. The second issue is the one of accuracy, and the question of what are the best thresholds? And there are several ways that this can be standardized. I'm pleased to say that the Intersocietal Accreditation Commission, the IAC, that Jesse mentioned, is actually tackling this problem.
Dr Robert Zwolak: But what's the gold standard? 40 years ago when ultrasound was developed, these thresholds that people are discussing, were related to measurements on contrast arteriograms. And the catheter-based contrast arteriogram, a relatively invasive study, was the source and we compared ultrasound velocities to the measurements on the contrast arteriograms to determine these thresholds that Jesse has investigated. That resulted in substantial variation depending on the individual authors. The question is, over time, have the machines changed? Is there really a central focus that we can look at? Most of these studies were very small and so it accounts for the variation in recommendations.
Dr Robert Zwolak: The IAC now, is going back and collecting contemporary contrast arteriograms, not so many of which are done anymore and so, it's taken a very substantial multicenter effort. But trying to look again, to see if there are more accurate results that could be published, studied in a way such that they would be universally accepted and potentially promulgated by professional societies within guidelines. And standardized such that various specialties, whether it's vascular surgeons who run the labs, or a cardiologist, or radiologist, would agree on a set of both accurate and reproducible and constant velocity thresholds to standardize this technology, which is otherwise a very, very good technology and eliminate this variation that we've seen.
Dr Greg Hundley: Well, this has been a phenomenal discussion in a very interesting piece of research. Jesse, can you give us sort of a point forward from here, how do we move forward with some of these results and what you anticipate seeing going forward?
Dr Jesse Columbo: Well, a duplex ultrasound for carotid stenosis is really important. There are lots of studies done. It's a great way to follow patients over time, in a noninvasive manner. And I might hope that this paper would open the eyes of some of the listeners as to what the carotid ultrasound really means. Instead of just looking at the percent stenosis on the report, to perhaps look at the raw velocities and interpret them in the context of the patient, because I think that has really important impact on how we might manage some of these individuals, for each person that you see.
Dr Greg Hundley: Well, listeners, we want to thank Dr Jesse Columbo, Dr Bob Zwolak, also Dr Josh Beckman, for discussing this very informative research related to the use of ultrasound for assessing carotid stenosis.
Dr Greg Hundley: On behalf of both Carolyn and myself, we wish you a great week and see you next week. This program is copyright, the American Heart Association 2020.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start.
Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients?
Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial.
They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival.
Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study?
Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt.
Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation.
Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find?
Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality.
Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus.
Dr Greg Hundley: Coated, remember, coated stents.
Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction.
Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights?
Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational?
Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI.
Dr Carolyn Lam: Whoa, so what did they find?
Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal.
Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy.
Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania.
I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute.
Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG?
Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone?
Dr Carolyn Lam: Let's go.
Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population.
I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find?
Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population.
At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population.
Dr Carolyn Lam: What did you find?
Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy.
Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important?
Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects.
While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting.
Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study.
Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study.
In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results.
That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion.
Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population?
Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country.
Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country.
Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there.
Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience?
Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah.
Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but most of them, the vast majority of them, so of course they are not so well prepared and that may have an impact on the follow-up. We try to talk to the family; we try to talk to the general practitioner.
Dr Mark Drazner: Of the 10 patients, it's very interesting that patients are being implanted and not knowing they're being implanted in and say waking up with an LVAD. I don't know if you have the granular detail, but do you know, of these 10 patients, how many of them were in that situation?
Dr Vincent Galand: The patients were implanted in cardiogenic shock, so I think it's four patients, but six patients were implanted without cardiogenic shock. They received this kind of information before the LVAD implantation, so it's not a big part of the population, but it's some patients.
Dr Mark Drazner: Could you, just for our readers, it's a little goory, I will admit, but in terms of how these patients attempted or actually committed suicide, just to explain in terms of, it was oftentimes related to a mechanism through the LVAD. If you could just summarize that and how they tried to commit suicide or commit suicide.
Dr Vincent Galand: That was the case. The suicide was with drive line disconnection or drive line section. In two patients, it was drug suicides, but in most of the patients the drive line is the main way for suicide.
Dr Mark Drazner: It's interesting that the mechanism that these patients tried to commit suicide was directly through the LVAD.
Dr Erwan Flécher: Of course it's the easiest way to terminate their life and they just cut off it. Just don't plug the battery and they are alone and that was the main way to practice their suicide.
Dr Mark Drazner: I know we don't have the initial report, we probably don't have all those, but in terms of you postulating in the paper why patients might get to the state where they would try or commit suicide with the LVAD. If you just want to throw out some of your hypotheses so that our listeners can hear those as well.
Dr Erwan Flécher: I've got in mind two or three points in order to improve our results. First of all, we should implant maybe earlier patients in France in order to have a better way to prepare and to invest the VAD implantation.
The second point would be to have a better organization of care and I think we should develop that VAD nurse coordinators program like in many countries. We still have some but not in all the hospitals implanting that.
The third point would be also to get the better LVADs. I mean, probably the drive line in sections, batteries, the controller, this of course it's much better than it was 10 years ago. There is no noise. It's less big than it was, but still, I think if we can improve the device itself, I think we may observe maybe the decrease in the risk of a system in society, especially the drive line, if there is no drive line, the quality of life should be better. We may suggest that the risk of suicide would decrease.
Dr Carolyn Lam: A very somber topic, but those last take home messages, leaving hope for improvement, were really important. Thank you everyone for sharing with us today, and thank you, audience, for joining us today.
Dr Greg Hundley: This program is copyright, the American Heart Association 2020.