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CardioNerds (Dr. Apoorva Gangavelli, Dr. Rebecca Garber, and Dr. Tina Reddy), discuss pre-pregnancy risk stratification and counseling with Dr. Katy Young across a range of risks.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds. This discussion was planned in collaboration with the Mayo Clinic Cardiovascular Board Review Course.

Audio editing by CardioNerds intern, Dr. Patrick Pekyi-Boateng.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Notes: 1. Why is pregnancy considered a “physiologic stress test,” and why does risk extend beyond delivery? * Blood volume, heart rate, and cardiac output rise while systemic vascular resistance falls, peaking in the late second/early third trimester; underlying (even undiagnosed) heart disease can be unmasked or worsened. * Postpartum (“fourth trimester”) is a high-risk period, not a safe zone – fluid shifts, rising SVR, and bleeding risk can precipitate decompensation in patients with heart failure, pulmonary hypertension, valvular disease, or aortopathy. * Adverse pregnancy outcomes (hypertensive disorders, gestational diabetes, preterm birth, fetal growth restriction, peripartum cardiomyopathy) are markers of future cardiovascular risk and warrant long-term preventive follow-up. 2. What is the practical framework for approaching pre-pregnancy cardiovascular risk? * Four broad categories: (1) patients who may need cardiac screening before pregnancy, (2) patients needing risk-factor/medication optimization, (3) known cardiovascular disease where pregnancy is reasonable with structured risk stratification, and (4) high-risk disease where pregnancy may need to be delayed, modified by intervention, or discouraged. * Testing should be targeted, not blanket – reserved for symptoms, abnormal exam, concerning family history, or reduced functional capacity. 3. How is risk stratified in patients with known cardiovascular disease? * Use a combination of tools per 2025 ESC guidelines: mWHO 2.0 (broad maternal risk category), CARPREG II (additional predictors of maternal cardiac events), and ZAHARA (useful in congenital heart disease). * Key lesion-specific factors: aortic size/growth, valve severity, ventricular function, symptoms, blood pressure, and family history of dissection. * Translate risk into practical terms for patients rather than leading with a numerical score. 4. Which cardiovascular medications require review before conception? * ACE inhibitors, ARBs, and ARNIs should be transitioned off before pregnancy; statins, MRAs, and SGLT2 inhibitors also need review. * DOACs are contraindicated in pregnancy and lactation; mechanical valve anticoagulation requires individualized shared decision-making, as no strategy is risk-free for mother and fetus. * Medication changes are best made proactively, before conception, rather than reactively. * This is not an exhaustive list! The medication list needs to be reviewed carefully. 5. Which conditions carry high or prohibitive risk in pregnancy? * Pulmonary arterial hypertension, Eisenmenger syndrome, severe ventricular dysfunction, prior peripartum cardiomyopathy with residual LV dysfunction, severe left-sided obstructive valve disease (e.g., severe mitral stenosis), mechanical valves, significant aortopathy, cyanotic congenital heart disease, and Fontan physiology. * Common theme: limited cardiovascular reserve and high risk of decompensation, thrombosis, arrhythmia, heart failure, aortic dissection, or death. These patients need expert multidisciplinary evaluation before pregnancy. * Severe mitral stenosis is poorly tolerated because tachycardia shortens diastolic filling time and raises left atrial pressure, risking pulmonary edema and decompensation. 6. When should genetic testing or counseling be offered? * Consider when a diagnosis may be inherited or affect the patient, pregnancy, or family members: inherited cardiomyopathies, aortopathies, channelopathies, select congenital heart disease, and some pulmonary hypertension syndromes. * Recurrence risk of congenital heart disease in offspring is roughly 6-10% when the mother has CHD; fetal echocardiography should be offered. 7. How should contraception be approached in high-risk cardiac patients? * Frame contraception as part of the cardiac care and reproductive safety plan to prevent unplanned high-risk pregnancy. * Long-acting reversible contraception is often preferred; progestin-only methods are generally safer than estrogen-containing options with thrombosis risk, pulmonary hypertension, or mechanical valves. 8. What are key delivery-planning considerations for cardiac patients? * Vaginal delivery is preferred unless there is an obstetric indication for cesarean or a specific cardiac reason (e.g., unstable maternal status, therapeutic INR) to avoid labor. * Planning should address delivery location, anesthesia involvement, telemetry needs, fluid management, and postpartum monitoring, clearly communicated across the multidisciplinary team in advance. 9. How should clinicians counsel patients when pregnancy is discouraged but strongly desired? * Acknowledge the patient’s goals and the emotional weight of the conversation; separate the goal (family building) from the timeline (safety now vs. after optimization). * If pregnancy remains prohibitively risky, discuss alternatives for family building and ensure adequate patient support. 10. What are the key gaps and future directions in cardio-obstetric risk stratification? * Current risk tools (mWHO, CARPREG II, ZAHARA) provide common language but do not fully capture functional status, prior pregnancy history, or how risk evolves over time. * Future direction: individualized, dynamic risk prediction incorporating imaging, biomarkers, exercise capacity, and social drivers of health, with better long-term links between pregnancy complications and cardiovascular prevention.

References1. European Society of Cardiology. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy.

1. Mehta LS, et al. Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement From the American Heart Association. Circulation. 2020;141:e884-e903. PMID: 32362133. doi:https://doi.org/10.1161/CIR.0000000000000772

2. ACOG Practice Bulletin No. 212. Pregnancy and Heart Disease. Obstet Gynecol. 2019;133(5):e320-e356. PMID: 31022123. doi:https://doi.org/10.1097/AOG.0000000000003243

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CardioNerds Dr. Rohit Nathani, Dr. Atefeh Ghorbanzadeh, and Dr. Mariam Riad, discuss Obesity-related Heart Failure with Preserved Ejection Fraction (HFpEF) with Dr. John Ostrominski.

This episode was produced as part of the CardioNerds Academy curriculum by House Jones under the guidance of House Chief, Dr. Mariam Riad and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds.

This episode highlights the diverse clinical phenotypes and complex, multifaceted pathophysiology of HFpEF. We take a deep dive into the therapeutic advances that represent paradigm shift in metabolic modulation aimed at improving outcomes in patients with HFpEF and metabolic syndrome.

Audio editing by CardioNerds intern Pacey Wetstein.

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey.

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Pearls1. HFpEF is a constellation of symptoms often with different underlying pathophenotypes; cardiometabolic type is rising in incidence. 2. Diagnosis is predominantly based on the clinical scenario along with supporting evidence from imaging modalities such as echocardiogram, cardiac MRI, and right heart catheterization. 3. Cardiometabolic HFpEF is a complex syndrome characterized by dysregulated lipid metabolism, systemic inflammation, and hemodynamic abnormalities, all of which contribute to exercise intolerance and frailty. 4. Lifestyle interventions, comorbidities management, and HFpEF therapeutics go hand in hand for comprehensive HFpEF care and offer opportunities for multispecialty collaboration to achieve optimal patient outcomes.

References1. Ostrominski, J, Højbjerg Lassen, M, Butt, J. et al. Adiposity-Related Anthropometrics and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Participant-Level Pooled Analysis of Randomized Clinical Trials. JACC. 2025 Nov, 86 (20) 1760–1777.https://doi.org/10.1016/j.jacc.2025.08.012 2. Packer, M. The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment. JACC. 2025 Oct, 86 (16) 1269–1373.https://doi.org/10.1016/j.jacc.2025.06.055 3. Ahmed, N., Dalmasso, C., Turner, M.B. et al. From fat to filter: the effect of adipose tissue-derived signals on kidney function. Nat Rev Nephrol 21, 417–434 (2025). https://doi.org/10.1038/s41581-025-00950-5 4. Alicic, R.Z., Neumiller, J.J. & Tuttle, K.R. GLP-1 receptor agonists and next-generation metabolic hormone therapies in chronic kidney disease. Nat Rev Nephrol 22, 265–282 (2026). https://doi.org/10.1038/s41581-025-01036-y 5. Ostrominski, J, Harrington, J, Claggett, B. et al. Anthropometric Measures, Cardiovascular Outcomes, and Treatment Effects of Finerenone in Cardiovascular-Kidney-Metabolic Disease: Pooled Participant-Level Analysis of 3 Global Trials. JACC. 2025 Nov, 86 (20) 1781–1801.https://doi.org/10.1016/j.jacc.2025.08.039

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CardioNerds (Drs. Apoorva Gangavelli, Jenna Skowronski, and Hannah Every) discuss the continuum of prevention and heart failure with Drs. Anu Lala and Martha Gulati. Grounded in a clinical case of a 55-year-old woman with uncontrolled hypertension, type 2 diabetes, and obesity who is on the trajectory toward heart failure, this episode unpacks a paradigm-shifting framework from a joint HFSA/ASPC Scientific Statement. The discussion explores how prevention should not be siloed from heart failure management but rather integrated across a patient’s lifespan—from primary prevention in at-risk individuals, to secondary prevention in those with established heart failure, to tertiary prevention in patients with advanced therapies such as LVADs and heart transplantation. The experts highlight the importance of aggressive risk factor management, biomarker-guided screening, the AHA’s Life’s Essential 8, and the need for multidisciplinary collaboration and systems-level change to shift heart failure care from reactive to proactive. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls1. Systemic inflammatory diseases are associated with an elevated CVD risk that has significant implications for early detection, risk Heart failure prevention is a continuum, not a checkpoint. Prevention applies at every stage—from at-risk (Stage A) through advanced/post-transplant care—and every clinical encounter is an opportunity to intervene. The AHA’s Life’s Essential 8 (diet, physical activity, nicotine exposure, sleep, BMI, blood lipids, blood glucose, blood pressure) forms the foundation at every stage. 2. Hypertension carries the highest population-attributable risk for heart failure of any modifiable risk factor. In the Framingham Heart Study, 91% of patients with newly diagnosed HF had pre-existing hypertension. The SPRINT trial demonstrated a 38% reduction in HF incidence with intensive blood pressure targets (<120 mm Hg systolic). Agent selection matters: ACE inhibitors, ARBs, and thiazide diuretics should be prioritized for HF prevention. 3. Overlapping risk factors should prompt parallel, not sequential, intervention. Pharmacotherapies such as SGLT2 inhibitors and GLP-1 receptor agonists target multiple pathways simultaneously (diabetes, obesity, CKD, HF risk), making them ideal for patients with cardiometabolic multimorbidity. The cardio-kidney-metabolic (CKM) syndrome framework reinforces this integrated approach. 4. Biomarker screening with BNP/NT-proBNP should be used proactively in high-risk populations, not just reactively in the emergency department. Even modestly elevated natriuretic peptide levels (e.g., BNP >30 ng/L or NT-proBNP >125 ng/L) identify individuals at heightened risk for progression to symptomatic HF. The ACC/AHA/HFSA guidelines give a Class IIa recommendation for natriuretic peptide screening in at-risk patients. Urine albumin-to-creatinine ratio (UACR) is an underutilized screening tool that provides additional insight into CKM risk. 5. The heart failure label does not close the prevention window—it accentuates it. Secondary prevention through GDMT optimization (quadruple therapy in HFrEF) and continued risk factor management remains critical. Tertiary prevention extends to post-LVAD and post-transplant patients, where hypertension, diabetes, obesity, and CKD management remain essential to long-term outcomes.

Show notesFor a comprehensive review, please review the full HFSA/ASPC Joint Scientific Statement: Lala A, Beavers C, Blumer V, et al. The Continuum of Prevention and Heart Failure in Cardiovascular Medicine. J Card Fail. 2026;32:75-105. doi:10.1016/j.cardfail.2025.06.013

1. What is the “continuum of prevention” framework, and how does it differ from traditional approaches to heart failure prevention?

• Historically, prevention and heart failure management have been treated as separate disciplines—primary prevention handled by preventive cardiologists and treatment managed by heart failure specialists. This joint HFSA/ASPC Scientific Statement reframes prevention as a dynamic, continuous process that spans a patient’s entire lifespan, regardless of HF stage or ejection fraction.
• The framework maps onto the ACC/AHA HF staging system:
  • Primary prevention targets Stage A (“at risk”) and Stage B (“pre-HF”) patients to reduce the burden of incident HF.
  • Secondary prevention targets Stage C (symptomatic) and Stage D (advanced) patients to reduce the impact of established HF through GDMT optimization and ongoing risk factor management.
  • Tertiary prevention encompasses risk factor management in patients with LVADs or heart transplants—populations where hypertension, diabetes, and obesity still drive outcomes.
• The Central Figure of the statement illustrates that Life’s Essential 8 (blood pressure and lipid control, diabetes management, exercise, sleep, smoking cessation, weight management, and diet/nutrition counseling) forms the foundation at every stage, with pharmacologic and device-based therapies layered on top as disease progresses (Figure)

2. How do traditional risk factors drive heart failure, and what should clinicians prioritize?

• Hypertension carries the greatest population-attributable risk for HF. In the Framingham Heart Study (N=5,143), HTN was associated with a 2- to 3-fold increased risk of HF, with a population-attributable risk of 39% in men and 59% in women. The SPRINT trial showed a 38% reduction in HF incidence and 25% reduction in the primary composite outcome with intensive BP targets (<120 mm Hg). Not all antihypertensives are equal for HF prevention: the ALLHAT trial showed that amlodipine carried a 38% higher risk and lisinopril a 19% higher risk of incident HF compared with chlorthalidone. The statement recommends prioritizing ACE inhibitors, ARBs, or thiazide diuretics as first-line agents when HF prevention is a goal.
• Type 2 diabetes confers a 5-fold risk of HF in women and 2-fold in men. Each 5-year increment in diabetes duration is associated with a 17% increased risk of incident HF. SGLT2 inhibitors have a Class 1 recommendation for HF prevention in patients with T2DM and established CVD or high cardiovascular risk. Finerenone (nonsteroidal MRA) reduced new-onset HF by 32% in the FIGARO-DKD trial among patients with T2DM and CKD. GLP-1 receptor agonists reduce CV events in patients with T2DM and ASCVD and are recommended in current guidelines.
• Obesity independently leads to myocardial dysfunction through the leptin-aldosterone-neprilysin framework, ectopic fat deposition, and neurohormonal dysregulation. The SELECT trial demonstrated that semaglutide reduced HF composite endpoint events (HR 0.84; 95% CI 0.74–0.97) in patients with obesity and established CVD without T2DM. Women with obesity are at highest risk for HFpEF, while men with obesity are at highest risk for HFrEF.
• Chronic kidney disease with albuminuria is deliberately included as a traditional risk factor in this statement. Albuminuria confers a 2- to 3-fold increased risk of incident HF. UACR screening is recommended for patients with T2DM and those at risk for CKD.

3. How can risk stratification tools and biomarkers be used to identify patients on the trajectory toward heart failure?

• Natriuretic peptides (BNP/NT-proBNP): The ACC/AHA/HFSA guidelines give a Class IIa recommendation for BNP or NT-proBNP screening in patients at risk for HF. Even modestly elevated levels (BNP >30 ng/L or NT-proBNP >125 ng/L) are associated with heightened risk for progression to symptomatic HF. In the ARIC study, incorporating NT-proBNP reclassified 20% of older adults without HF into Stage B. Factors that affect interpretation include age, sex, obesity (lower values), and CKD (higher values).
• High-sensitivity cardiac troponin (hs-cTn): Concentrations above the 99th percentile are now included in the definition of Stage B HF. Troponin testing may complement natriuretic peptides, particularly when BNP/NT-proBNP values are ambiguous.
• Risk scores: The PCP-HF equation predicts 10-year HF risk using traditional risk factors plus QRS duration. The AHA PREVENT score incorporates HF risk calculation and includes markers of kidney function (albuminuria, eGFR), though it may underestimate risk in men and Black adults. The CKM syndrome staging framework (Stages 0–4) provides a holistic approach to assessing systemic cardiovascular-kidney-metabolic risk.

4. What are the key nontraditional risk factors and cross-cutting themes in heart failure prevention?

• Genetics: Pathogenic cardiomyopathy variants exist in ~1 in 200 individuals in the general population. The HFSA and ACMG recommend cascade testing to identify at-risk family members. Polygenic risk scores for dilated cardiomyopathy show a 3.8-fold risk for DCM in the top 10th percentile compared with the median.
• Sex-specific considerations: Women have 2.8 times the odds of developing HFpEF, while men have similarly increased odds of HFrEF. A complete obstetric/gynecologic history is essential—preeclampsia is associated with a 4-fold increased risk of HF. Peripartum cardiomyopathy requires intentional screening in high-risk populations.
• Cardiotoxic exposures: Clinicians should be aware of medications that cause direct myocardial toxicity (e.g., anthracyclines, trastuzumab, tyrosine kinase inhibitors). A team-based approach with pharmacists can help optimize medication selection and risk factor modification.
• Social determinants of health: Environmental exposures (air pollution, arsenic, lead, cadmium), food insecurity, financial instability, and limited healthcare access contribute to HF risk and progression. Equity-focused, risk-based prevention strategies are needed.
• Psychological health: Depression is common in HF and independently associated with worse outcomes. Screening with brief questionnaires (e.g., PHQ-2) is recommended. Meditation, spirituality, and holistic wellness approaches remain underutilized.

5. What systems-level and policy changes are needed to move the needle on heart failure prevention?

• Multidisciplinary HF prevention clinics that bring together preventive cardiologists, HF specialists, endocrinologists, nephrologists, dietitians, pharmacists, exercise physiologists, and genetic counselors are advocated by the statement.
• EHR-embedded risk stratification could proactively flag patients on a trajectory toward HF—analogous to sepsis alerts or fall risk flags—enabling earlier intervention, particularly for patients who may not reach a cardiologist.
• Cardiac rehabilitation remains underutilized, particularly in HFrEF (Class 2b recommendation) and HFpEF (not yet covered by Medicare). The HF-ACTION trial showed quality-of-life benefits, and the REHAB-HF trial showed particular benefit in older patients with HFpEF.
• Policy priorities include expanding insurance coverage for preventive screening and novel therapies (SGLT2i, GLP-1 RAs, nsMRAs), reducing clinical inertia through team-based care models with closer follow-up intervals, and ensuring equitable access to evidence-based therapies across diverse populations.
• Digital health and AI hold promise for personalized risk prediction, remote monitoring (e.g., wearable devices, implantable PA pressure monitors), and virtual cardiac rehabilitation to overcome access barriers.

Figure

Lala A, Beavers C, Blumer V, et al. The continuum of prevention and heart failure in cardiovascular medicine: a joint scientific statement from the Heart Failure Society of America and the American Society for Preventive Cardiology. J Card Fail. 2026;32(1):75-105. doi:10.1016/j.cardfail.2025.06.013)

References Key references are bolded.

1. Lala A, Beavers C, Blumer V, et al. The continuum of prevention and heart failure in cardiovascular medicine: a joint scientific statement from the Heart Failure Society of America and the American Society for Preventive Cardiology. J Card Fail. 2026;32(1):75-105. doi:10.1016/j.cardfail.2025.06.013
2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
3. Lloyd-Jones DM, Allen NB, Anderson CAM, et al. Life’s Essential 8: updating and enhancing the American Heart Association’s construct of cardiovascular health: a presidential advisory from the American Heart Association. Circulation. 2022;146(5):e18-e43. doi:10.1161/CIR.0000000000001078
4. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116. doi:10.1056/NEJMoa1511939
5. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275(20):1557-1562. doi:10.1001/jama.1996.03530440037034
6. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997. doi:10.1001/jama.288.23.2981
7. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145-153. doi:10.1056/NEJM200001203420301
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
9. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038
10. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-1098. doi:10.1056/NEJMoa2206286
11. Filippatos G, Anker SD, Agarwal R, et al. Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial. Circulation. 2022;145(6):437-447. doi:10.1161/CIRCULATIONAHA.121.057983
12. Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024;391(16):1475-1485. doi:10.1056/NEJMoa2407107
13. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
14. Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet. 2024;404(10454):773-786. doi:10.1016/S0140-6736(24)01498-3
15. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963
16. Ndumele CE, Neeland IJ, Tuttle KR, et al. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation. 2023;148(20):1636-1664. doi:10.1161/CIR.0000000000001175
17. Khan SS, Matsushita K, Sang Y, et al. Development and validation of the American Heart Association’s PREVENT equations. Circulation. 2024;149(6):430-449. doi:10.1161/CIRCULATIONAHA.123.067626
18. Khan SS, Ning H, Shah SJ, et al. 10-year risk equations for incident heart failure in the general population. J Am Coll Cardiol. 2019;73(19):2388-2397. doi:10.1016/j.jacc.2019.02.057
19. Bozkurt B, Fonarow GC, Goldberg LR, et al. Cardiac rehabilitation for patients with heart failure: JACC expert panel. J Am Coll Cardiol. 2021;77(11):1454-1469. doi:10.1016/j.jacc.2021.01.030
20. Packer M. Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity. Circulation. 2018;137(15):1614-1631. doi:10.1161/CIRCULATIONAHA.117.032474
21. Lala A, Tayal U, Hamo CE, et al. Sex differences in heart failure. J Card Fail. 2022;28(3):477-498. doi:10.1016/j.cardfail.2021.10.006
22. Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure. Eur J Heart Fail. 2021;23(3):352-380. doi:10.1002/ejhf.2115
23. Hershberger RE, Givertz MM, Ho CY, et al. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail. 2018;24(5):281-302. doi:10.1016/j.cardfail.2018.03.004
24. Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological health, well-being, and the mind-heart-body connection: a scientific statement from the American Heart Association. Circulation. 2021;143(10):e763-e783. doi:10.1161/CIR.0000000000000947
25. Ezekowitz JA, Colin-Ramirez E, Ross H, et al. Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial. Lancet. 2022;399(10333):1391-1400. doi:10.1016/S0140-6736(22)00369-5

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CardioNerds co-chairs Dr. Dinu Balanescu and Dr. Billy Joe Mullinax, along with FIT lead Dr. Shiavax Rao, discuss the evolving landscape of randomized controlled trials in pulmonary embolism with Dr. Jay Giri, interventional cardiologist, Associate Professor of Medicine, and Director of the Cardiovascular Catheterization Laboratories at the Hospital of the University of Pennsylvania. This episode examines the historical evidence behind systemic thrombolysis, the emergence of catheter-directed therapies and mechanical thrombectomy, and the landmark RCTs – STORM-PE, PEERLESS, HI-PEITHO, and PEERLESS II – that are reshaping intermediate-risk PE management. The discussion highlights challenges in PE trial design, the critical importance of clinical deterioration as an endpoint, and why this era represents an unprecedented wave of evidence generation in PE. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

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Pearls: Systemic thrombolysis in intermediate-risk PE reduces hemodynamic decompensation but at the cost of ~1.5–2% intracranial hemorrhage risk – a near-zero net benefit that has driven the search for safer catheter-based alternatives. * “Focus on clinical deterioration, not mortality” – Due to crossover design in contemporary PE RCTs, control-arm patients who decompensate are rescued with advanced therapies, biasing mortality toward the null. Clinical deterioration is the most informative endpoint to watch in HI-PEITHO, PRAGUE-26, and PEERLESS II. * HI-PEITHO is the first large RCT to demonstrate that catheter-directed fibrinolysis plus anticoagulation significantly reduces the composite of PE-related death, cardiorespiratory decompensation, or PE recurrence versus anticoagulation alone (RR 0.39; 95% CI 0.20–0.77; P=0.005), with no intracranial hemorrhage in either arm. * The four major upcoming/recently reported PE RCTs (HI-PEITHO, PRAGUE-26, PEERLESS II, PE-TRACT) enroll progressively different risk populations – from the most enriched (HI-PEITHO) to the most permissive (PE-TRACT, which includes intermediate-low risk patients) – enabling a nuanced understanding of which patients benefit most from intervention. * PE device clearance follows a fundamentally different FDA pathway than structural heart devices* (single-arm safety/efficacy studies vs. mandated RCTs), yet market forces and clinical need have ultimately driven industry and government to sponsor large-scale RCTs – a lesson in how evidence development can evolve organically alongside regulatory frameworks.

Notes: Notes drafted by Dr. Shiavax Rao.

Question #1: What is the current evidence behind advanced PE therapies?

• Systemic thrombolysis: Sixteen RCTs over 40 years (1972–2014) enrolling nearly 2,000 patients have studied systemic thrombolysis in intermediate-risk PE. The landmark PEITHO trial (n=1,006) showed that tenecteplase reduced the composite of death or hemodynamic collapse (2.6% vs. 5.6%; P=0.015), driven primarily by reduced hemodynamic decompensation (1.6% vs. 5.0%; P=0.002). However, this came at the cost of increased major bleeding (6.3% vs. 1.5%; P<0.001) and a ~2% rate of intracranial hemorrhage. Meta-analyses of systemic thrombolysis trials show a small absolute mortality benefit (~1–2%) that is closely offset by bleeding risk, explaining why guidelines have not broadly recommended systemic thrombolysis for intermediate-risk PE.
• Catheter-directed thrombolysis (CDT): The ULTIMA trial (n=59) was the first RCT of ultrasound-assisted CDT (EkoSonic/EKOS system) vs. anticoagulation alone in intermediate-risk PE. CDT showed superior RV/LV ratio improvement at 24 hours (decrease of 0.30 ± 0.20 vs. 0.03 ± 0.16; P<0.001), but this difference was no longer significant at 90 days. The CANARY trial, initiated in Iran in 2019, was halted prematurely due to the COVID-19 pandemic but largely verified ULTIMA’s findings, with a signal that RV benefits may persist at 90 days.
• Mechanical thrombectomy – single-arm data: The FLARE trial demonstrated a 25% reduction in RV/LV ratio at 48 hours with large-bore aspiration thrombectomy (FlowTriever). The EXTRACT-PE trial showed significant RV/LV ratio reduction with the Indigo aspiration system with a low major adverse event rate. The FLASH registry (FlowTriever) reported a mean 7.6 mmHg drop in mean PA pressure and RV/LV ratio decrease from 1.23 to 0.98 at 48 hours.
• STORM-PE (2025): The first RCT of mechanical thrombectomy (computer-assisted vacuum thrombectomy [CAVT] with the Indigo/Penumbra system) vs. anticoagulation alone. One hundred patients were randomized across 22 sites. CAVT was superior for the primary endpoint of 48-hour RV/LV ratio reduction (0.52 vs. 0.24; difference 0.27; P<0.001), with earlier normalization of vital signs and comparable major adverse event rates (4.3% vs. 7.5%; P=0.681). Two PE-related deaths occurred in the CAVT arm. The trial was not powered for mortality or longer-term outcomes.
• PEERLESS (2025): The first RCT comparing two interventional strategies head-to-head – large-bore mechanical thrombectomy (FlowTriever) vs. CDT – in 550 patients with intermediate-risk PE. The primary hierarchical win ratio composite favored LBMT (win ratio 5.01; 95% CI 3.68–6.97; P<0.001), driven primarily by fewer clinical deterioration/bailout events (1.8% vs. 5.4%; P=0.04) and substantially less post-procedural ICU use (41.6% vs. 98.6% admission rates). No significant differences in mortality, intracranial hemorrhage, or major bleeding were observed. RV/LV ratio reduction was similar between arms. LBMT was associated with shorter hospital stays and fewer 30-day readmissions.

Question #2: What are the challenges with conducting RCTs in PE?

• Crossover and rescue therapy: Unlike early TAVR trials where control-arm patients could not cross over to the device arm, contemporary PE trials allow crossover upon clinical deterioration. This is ethically necessary given available therapies but biases mortality toward the null, making it unlikely that any individual trial – or even a meta-analysis of the four major trials (~2,400–3,000 patients combined) – will demonstrate a mortality difference.
• Heterogeneity of intermediate-risk PE: Two patients meeting ESC intermediate-high risk criteria (RV dysfunction + elevated troponin) can look clinically very different – one may be tachypneic on 5 liters of oxygen, while another is comfortable on room air. This heterogeneity complicates enrollment, endpoint detection, and generalizability.
• Endpoint selection: Early PE trials relied on surrogate imaging endpoints (RV/LV ratio, PA pressure reduction, Miller score). While these demonstrate proof-of-concept, they have not moved guidelines. Clinically relevant endpoints – mortality, clinical deterioration, functional status, quality of life – are needed but require larger sample sizes and longer follow-up.
• Funding and maturation of the field: Trials require buy-in from government or industry funders. It took time for the field to mature enough to estimate effect sizes for trial powering, accumulate sufficient operator experience to ensure internal validity, and for industry to recognize that market adoption required randomized evidence despite existing FDA clearance.
• FDA regulatory pathway: PE devices are cleared via a 510(k) pathway requiring single-arm studies (~100–150 patients) demonstrating safety and RV/LV ratio improvement – a much lower bar than the pre-market approval pathway requiring RCTs mandated for structural heart devices (e.g., TAVR, MitraClip). While this has enabled rapid innovation and market competition, it initially reduced the incentive for industry-sponsored RCTs.

Question #3: What are the upcoming/recently reported RCT trials in PE?

• HI-PEITHO (published 2026, NEJM): Multinational adaptive-design RCT of ultrasound-facilitated CDT (EkoSonic system, alteplase 2 mg bolus + 1 mg/hr/catheter × 7 hours) plus anticoagulation vs. anticoagulation alone in 544 patients with enriched intermediate-high risk PE (RV/LV ≥1.0, elevated troponin, plus ≥2 of: SBP ≤110, HR ≥100, RR >20). Primary composite of PE-related death, cardiorespiratory decompensation/collapse, or symptomatic PE recurrence within 7 days: 4.0% intervention vs. 10.3% control (RR 0.39; 95% CI 0.20–0.77; P=0.005). Effect driven by reduced cardiorespiratory decompensation. Major bleeding at 7 days: 4.1% vs. 2.2% (P=0.32). No intracranial hemorrhage in either arm. Clinical deterioration measured using the National Early Warning Score (NEWS), a validated ordinal scoring system incorporating vital signs – more sensitive at detecting decompensation than binary clinical criteria.
• PRAGUE-26: Czech Republic government-sponsored RCT with a design essentially identical to HI-PEITHO in terms of sample size and primary endpoint, but using standard (non-ultrasound-assisted) CDT catheters in the interventional arm. Enrolling well; results anticipated in the near term.
• PEERLESS II: Industry-sponsored (Inari/Boston Scientific) RCT of large-bore mechanical thrombectomy (FlowTriever) plus anticoagulation vs. anticoagulation alone in up to 1,200 patients with enriched intermediate-high risk PE (enrichment criteria slightly less stringent than HI-PEITHO). Five-component hierarchical primary endpoint assessed via win ratio: (1) mortality, (2) clinical deterioration (defined by binary clinical criteria – pressor initiation, SBP <90 for sustained period, mechanical circulatory support, or significant respiratory decompensation/intubation – a less sensitive measure than NEWS), (3) recurrent PE admission, (4) non-deterioration-based bailout crossover at day 3, and (5) 48-hour dyspnea score. The larger sample size compensates for the less sensitive clinical deterioration definition.
• PE-TRACT: NIH-sponsored, open-label, assessor-blinded RCT of CDT (any FDA-cleared device – CDT or mechanical thrombectomy, strategy trial) plus anticoagulation vs. anticoagulation alone in 500 patients with intermediate-risk PE (most permissive enrollment – includes intermediate-low risk patients). Co-primary endpoints at 3 months (peak VO₂ on cardiopulmonary exercise testing) and 12 months (NYHA functional class), analyzed sequentially. Designed to answer the longer-term functional question rather than early clinical deterioration.

Question #4: What does the future of PE research look like?

• Unprecedented evidence generation: Across STORM-PE, PEERLESS, HI-PEITHO, PEERLESS II, PE-TRACT, PRAGUE-26, PEITHO-3, and high-risk PE trials (PERSEVERE, TORPEDO-NL), approximately 8–9 RCTs are enrolling or recently completed – an unparalleled volume of comparative evidence in any cardiovascular subspecialty over such a short period.
• Guideline impact: The 2026 AHA/ACC PE Guideline already reflects the evolving evidence landscape, with Class 2a–2b recommendations for CDT and MT in select PE categories. Results from HI-PEITHO, PEERLESS II, PRAGUE-26, and PE-TRACT have the potential to substantially strengthen these recommendations, particularly if clinical deterioration endpoints are positive.
• PERT evolution: As evidence clarifies which patients benefit from intervention, PERT programs may transition from primarily clinical decision-making bodies to systems-of-care delivery engines – analogous to STEMI systems – focused on efficient, protocol-driven care and real-world evidence generation for quality improvement.
• Innovation ecosystem: The relatively permissive FDA clearance pathway has fostered a competitive device landscape with multiple manufacturers and device types, contrasting with the prolonged duopoly in the TAVR space. This competition may drive technological improvement and more favorable economics.
• Caution with real-world evidence: While real-world evidence is valuable for quality improvement and systems-of-care assessment, it should be used cautiously for comparative effectiveness analyses due to irreconcilable confounding and limitations in causal inference. RCTs remain the gold standard for comparative questions.

References:1. ★ Rosenfield K, Klok FA, Piazza G, et al. Ultrasound-facilitated, catheter-directed fibrinolysis for acute pulmonary embolism. N Engl J Med. 2026;394(22):2131-2141. doi:10.1056/NEJMoa2503539 2. ★ Lookstein RA, Konstantinides SV, Weinberg I, et al. 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. Circulation. 2026;153(1):21-34. doi:10.1161/CIRCULATIONAHA.125.077232 3. ★ Jaber WA, Gonsalves CF, Stortecky S, et al. Large-bore mechanical thrombectomy versus catheter-directed thrombolysis in the management of intermediate-risk pulmonary embolism: primary results of the PEERLESS randomized controlled trial. Circulation. 2025;151(5):260-273. doi:10.1161/CIRCULATIONAHA.124.072364 4. ★ Gonsalves CF, Gibson CM, Stortecky S, et al. Randomized controlled trial of mechanical thrombectomy vs catheter-directed thrombolysis for acute hemodynamically stable pulmonary embolism: rationale and design of the PEERLESS study. Am Heart J. 2023;266:128-137. doi:10.1016/j.ahj.2023.09.002 5. ★ Sista AK, Troxel AB, Tarpey T, et al. Rationale and design of the PE-TRACT trial: a multicenter randomized trial to evaluate catheter-directed therapy for the treatment of intermediate-risk pulmonary embolism. Am Heart J. 2025;281:112-122. doi:10.1016/j.ahj.2024.11.016 6. ★ Giri J, Sista AK, Weinberg I, et al. Interventional therapies for acute pulmonary embolism: current status and principles for the development of novel evidence: a scientific statement from the American Heart Association. Circulation. 2019;140(20):e774-e801. doi:10.1161/CIR.0000000000000707 7. ★ Zhang RS, Maqsood MH, Sharp ASP, et al. Efficacy and safety of anticoagulation, catheter-directed thrombolysis, or systemic thrombolysis in acute pulmonary embolism. JACC Cardiovasc Interv. 2023;16(22):2781-2793. doi:10.1016/j.jcin.2023.09.014

Additional References 8. Rosovsky RP, Konstantinides SV, Moriarty JM, et al. A prospective, multicenter, randomized controlled trial evaluating anticoagulation alone vs anticoagulation plus computer assisted vacuum thrombectomy for the treatment of intermediate-high-risk acute pulmonary embolism: rationale and design of the STORM-PE study. Am Heart J. 2025;288:1-14. doi:10.1016/j.ahj.2025.03.018 9. Klok FA, Piazza G, Sharp ASP, et al. Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: rationale and design of the HI-PEITHO study. Am Heart J. 2022;251:43-53. doi:10.1016/j.ahj.2022.05.011 10. Creager MA, Barnes GD, Giri J, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN guideline for the evaluation and management of acute pulmonary embolism in adults. J Am Coll Cardiol. 2026;87(7):e77-e206. doi:10.1016/j.jacc.2025.11.027 11. Piazza G. Advanced management of intermediate- and high-risk pulmonary embolism: JACC focus seminar. J Am Coll Cardiol. 2020;76(18):2117-2127. doi:10.1016/j.jacc.2020.05.028 12. Zuo Z, Yue J, Dong BR, et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2021;4(4):CD004437. doi:10.1002/14651858.CD004437.pub6 13. Kroupa J, Buk M, Weichet J, et al. A pilot randomised trial of catheter-directed thrombolysis or standard anticoagulation for patients with intermediate-high risk acute pulmonary embolism (CANARY). EuroIntervention. 2022;18(8):e657-e665. doi:10.4244/EIJ-D-22-00194 14. Zuin M, Lang I, Chopard R, et al. Innovation in catheter-directed therapy for intermediate-high-risk and high-risk pulmonary embolism. JACC Cardiovasc Interv. 2024;17(20):2390-2408. doi:10.1016/j.jcin.2024.07.037 15. Harvey JJ, Huang S, Uberoi R. Catheter-directed therapies for the treatment of high risk (massive) and intermediate risk (submassive) acute pulmonary embolism. Cochrane Database Syst Rev. 2022;8(8):CD013083. doi:10.1002/14651858.CD013083.pub2 16. Kim JM, Horbal SR, Mewaldt C, et al. Mechanical thrombectomy and catheter-directed thrombolysis in acute pulmonary embolism: trends and practice patterns in the PERT Consortium Registry (2016-2024). J Am Coll Cardiol. 2026;87(13):1271-1283. doi:10.1016/j.jacc.2025.12.044 17. Planer D, Yanko S, Matok I, et al. Catheter-directed thrombolysis compared with systemic thrombolysis and anticoagulation in patients with intermediate- or high-risk pulmonary embolism: systematic review and network meta-analysis. CMAJ. 2023;195(24):E833-E843. doi:10.1503/cmaj.221655 18. Farmakis IT, Binder H, Chopard R, et al. Reperfusion strategies for acute pulmonary embolism: design and rationale of RECONNECT-PE – a living systematic review and meta-analysis. Am Heart J. 2026;295:107365. doi:10.1016/j.ahj.2026.107365 19. Rashedi S, Leyva H, Hamade N, et al. Fibrinolytic therapy for thromboembolic diseases: approved indications and future directions. J Am Coll Cardiol. 2025;86(14):1395-1416. doi:10.1016/j.jacc.2025.07.048 20. Creager MA, Barnes GD, Giri J. A field in transition: catheter-based therapy in the 2026 AHA/ACC acute pulmonary embolism guideline. J Am Coll Cardiol. 2026;87(13):1284-1288. doi:10.1016/j.jacc.2026.01.024

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CardioNerds (Drs. Apoorva Gangavelli, Rebecca Garber, and Tina Reddy discuss INOCA with Dr. Claire Raphael. Audio editing by CardioNerds Academy intern, student doctor Pacey Wetstein.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli, and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds.

Non-obstructive coronary artery disease (CAD) is more common than often recognized, particularly in women and individuals with risk factors like diabetes or hypertension. Conditions such as INOCA, ANOCA, and MINOCA can cause ischemia and chest pain despite “clean” angiograms, often due to microvascular dysfunction, coronary spasms, or subtle plaque. Diagnosing these conditions requires advanced imaging or invasive studies to assess blood flow and vessel function. Treatment focuses on reducing cardiovascular risk with aspirin, statins, ACE inhibitors, or ARBs, and managing symptoms with beta-blockers or calcium channel blockers. The key takeaway: A normal angiogram doesn’t rule out disease, and these patients need a comprehensive, evidence-based approach to care.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:1. When patients present with chest pain but do not have obstructive coronary artery disease, the story does not end there! Other pathologies that must be ruled out include spontaneous coronary artery disease (SCAD), coronary vasospasm, microvascular disease, Takotsubo, and cardiomyopathy. A TTE can help rule out other pathologies. Cardiac MRI can help identify myocardial fibrosis, scarring, or edema that may suggest prior events or alternative diagnoses. 2. About 60-70% of INOCA cases are in women. However, it is estimated that about half of the patients with so-called “normal” angiograms actually have positive stress tests. Patients with elevated troponins are more likely to have recurrent events. Patients with INOCA are more likely to come back to the ER multiple times before getting diagnosed. These patients have a 1.4x increased risk of adverse cardiovascular events (such as HFpEF, MI, and recurrent hospitalizations for cardiac chest pain). 3. INOCA is a complex condition with a variety of causes, primarily linked to microvascular disease. Within microvascular disease, there are different “endotypes” (types or subcategories) classified by specific characteristics. In centers that conduct microvascular testing, patients are categorized as endothelium-independent or endothelium-dependent, based on their responses to adenosine or acetylcholine during testing. Additionally, microvascular disease can be classified as either structural or functional, depending on the results of tests measuring microvascular resistance. 4. The field is moving towards the term ANOCA, or angina with non-obstructive coronary arteries, to include patients with anginal symptoms without objective ischemia. 5. The field is moving toward using genotyping and hemodynamic testing to guide first-line therapies for microvascular disease, a heterogeneous condition. Current treatments mostly come from obstructive coronary artery disease, but specialized approaches—like the coronary sinus reducer—may offer unique benefits for microvascular disease. 6. Treatment includes sublingual nitroglycerin, ACE inhibitors/ARBs, and beta-blockers. Remember to also treat any additional comorbidities, such as diabetes, hypertension, and hyperlipidemia. Unfortunately, many of these patients may still have refractory chest pain, so it is important to reassure them. These patients can still exercise, but they may be hesitant to do so for fear of having chest pain. Cardiac rehab may be helpful for these patients as it helps them build up their tolerance.

References* Lawton JS, Tamis-Holland JE, Bangalore S, et al; Writing Committee Members. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(3):e18-e114. doi:10.1161/CIR.0000000000001039 * Hwang D, Park S, Koo B-K. Ischemia with nonobstructive coronary artery disease. JACC: Asia. 2023;3(2):169-180. doi:10.1016/j.jacasi.2023.01.004 * Yukselen Z, Majmundar V, Dasari M, Kumar PA, Singh Y. Chest pain risk stratification in the emergency department: current perspectives. Open Access Emerg Med. 2024;16:29-43. doi:10.2147/OAEM.S419657

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This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 5.2.1 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Henry Ford Interventional cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Li Pang, and then by expert faculty Dr. Michelle O’Donoghue.

Dr. O’Donoghue is a cardiologist, senior investigator with the TIMI Study Group, and Associate Professor of Medicine at Harvard Medical School who holds the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital. She was the Vice Chair of the Writing Committee for the 2025 ACS Guidelines.

Question #2

| A 63-year-old woman presented to the emergency room for chest pain. She described having exertional chest pain for the past two months and had an episode of severe pain after dinner 3 days ago. She went to bed and slept it off. She told her children today at a family gathering, and was immediately brought to the ED by her daughter. She has a history of hypertension and hyperlipidemia. She was asymptomatic and normotensive in the ED. Labs show a down-trending troponin and an elevated NT-proBNP but are otherwise unremarkable. Her ECG showed Q waves with ST elevation in V2-V4. She was treated with aspirin and heparin drip, and taken to the cath lab. Coronary angiogram showed complete proximal LAD occlusion with right-to-left collaterals, without significant residual disease elsewhere. She remains asymptomatic and is stable, both hemodynamically and electrically.What is the next best step with regard to reperfusion and anti-thrombotic management? | | A | Proceed with primary PCI to LAD | | B | Medical management with aspirin and enoxaparin | | C | Medical management with aspirin and clopidogrel | | D | Medical management with aspirin and ticagrelor |

Answer #2

| Explanation | The Correct answer is DIn patients who are stable with STEMI and have a totally occluded infarct-related artery >24 hours after symptom onset and are without evidence of ongoing ischemia, acute severe HF, or life-threatening arrhythmia, PPCI should not be performed due to lack of benefit. (Class 3, LOE B-R)The benefit of PPCI begins to diminish after >12 hours from symptom onset, but there appears to be continued benefit through approximately 24 hours. In stable asymptomatic patients with an occluded artery >48 hours after symptom onset, routine PCI has not been shown to be beneficial in the absence of ongoing ischemia. The relative utility of routine PCI for asymptomatic patients with STEMI between 24 and 48 hours from symptom onset is less rigorously tested.PCI is not recommended for an occluded infarct-related artery if the patient is asymptomatic and has a completed infarct. MACE outcomes were similar in those with an occluded infarct-related artery who underwent medical therapy versus those who underwent PCI 3 to 28 days after an MI (Occluded Artery Trial [OAT]), and results were no different at 7-year follow-up. Similar findings were noted in the DECOPI (Desobstruction Coronaire en Post-Infarctus) trial, which enrolled patients with an occluded artery and Q waves on the ECG presenting 2 to 15 days after symptom onset.However, coronary revascularization should be considered for patients with late presentations with continued signs and symptoms of ischemia, including cardiogenic shock, acute severe HF, persistent angina, and life-threatening arrhythmias. | | Main Takeaway | In patients who are stable with STEMI who have a totally occluded infarct-related artery >24 hours after symptom onset and are without evidence of ongoing ischemia, acute severe HF, or life-threatening arrhythmia, PPCI should not be performed due to lack of benefit. | | Guideline Loc. | Section 5.2.1 |

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CardioNerds (Amit and Dan), Billy Joe Mullinax, and Saahil Jumkhawala discuss the long term management of pulmonary embolism with Dr. Soophia Naydenov. The episode focuses on the approach to patients who struggle with persistent symptoms like dyspnea and fatigue even after completing the acute phase of anticoagulation. This spectrum of disease, ranging from mild post-PE impairment to chronic thromboembolic pulmonary hypertension (CTEPH), requires a structured follow-up. The discussion covers the critical importance of identifying CTEPH early, the necessary timelines for follow-up, and the appropriate objective screening tools and invasive testing to guide patient care toward full functional recovery. Audio editing by CardioNerds academy intern, Grace Qiu.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Acronyms PE: Pulmonary Embolism * PERT: Pulmonary Embolism Response Team * CTEPH: Chronic Thromboembolic Pulmonary Hypertension * QL: Quality of Life * VTE: Venous Thromboembolism * DASH: D-dimer, Age, Sex, History of non-provoked PE (a risk score) * CPET: Cardiopulmonary Exercise Testing * PFTs: Pulmonary Function Tests * VQ Scan: Ventilation-Perfusion Scan * DOACs: Direct Oral Anticoagulants * TPA: Tissue Plasminogen Activator (Thrombolytics) * ECMO:* Extracorporeal Membrane Oxygenation

Pearls: Post-PE “Syndrome” is a Spectrum: It is more accurately a spectrum of disease (sequelae of PE) rather than a single syndrome, ranging from mild fatigue/dyspnea to the most severe form, CTEPH. * Structured Follow-up is Mandatory: All PE survivors need a structured follow-up, typically with checkpoints at 3, 6, 12, and 16–24 months, with the primary goal being to detect CTEPH, the deadliest, yet potentially curable, disease on the spectrum. * Screening Should Be Objective and Practical: When screening for persistent symptoms, use objective assessment tools like the Post-VTE Functional Status (PVFS) scale or the Modified Medical Research Council (MMR-C) scale, as highly comprehensive but cumbersome tools (like the PE Quality of Life questionnaire) may not be practical for routine clinical use. Recurrence Risk Scores Aid in Anticoagulation Duration: Simple scores like the DASH score or the HERDO2 score (for women) can provide guidance when considering the continuation versus discontinuation of anticoagulation after the initial treatment phase. * Invasive Testing for Persistent Symptoms:* If a patient remains symptomatic at the 6-month mark despite normal non-invasive testing (chest X-ray, ECG, PFTs, six-minute walk, echo, VQ scan, CPET), consider invasive testing such as Right Heart Catheterization (RHC) at rest or with exercise, or an invasive CPET.

Notes: Notes drafted by Saahil Jumkhawala.

1. The Spectrum of Post-PE Disease The term “post-PE syndrome” should be used with caution, as it refers to a spectrum of disease rather than a single entity. * This spectrum includes symptoms (sequelae) that exist in a patient’s life following an incidental PE event that they did not have before. * On one extreme is Chronic Thromboembolic Pulmonary Hypertension (CTEPH): + The definition is clear, but it is the most deadly type, though thankfully rare (2% to 4%). + It involves a residual clot and pulmonary hypertension identifiable at rest. * In the middle is Chronic Thromboembolic Disease (CTED): + Patients may have residual defects seen on a VQ or CT scan, but they do not have pulmonary hypertension. * On the other side* is a milder disease, which can include fatigue, dyspnea, or a patient’s perceived impairment, where the definitions of CTEPH and CTED are not met, but the patient remains symptomatic.

2. Structured Follow-up and Screening for Post-PE Symptoms Structured follow-up is key for all PE survivors, though the structure may vary based on available resources (PCP, Cardiology, Pulmonary, or multidisciplinary clinic). * Recommended Timeline for Follow-up: Data from studies like ELOPE and FOCUS suggest checkpoints at 3, 6, 12, and up to 16 to 24 months. + This timeline is designed to identify patients who may develop CTEPH. + 88% of patients who develop CTEPH will be identified within about a year. + A structured follow-up can reduce the delay in CTEPH diagnosis from 10–12 months to 4–6 months. + Personal Practice Note: A quick 2–3 week/30-day check-in is recommended for severely ill patients (e.g., those who had TPA, profound shock, or ECMO support) to ensure medication compliance, manage symptoms, and identify red flags. * Screening Tools (Objective Assessment): + The first step is an inventory of patient symptoms, leaning toward objective rather than subjective assessment. + Recommended Simple Tools: - Modified Medical Research Council (MMR-C) for dyspnea evaluation. - Post-VTE Functional Status (PVFS) scale. + The Pulmonary Embolism Quality of Life (QL) questionnaire is comprehensive but long, making it tedious and better suited for research. + Future Utility:* Technology (AI/electronic tools) may assist in administering these questionnaires before the clinic visit, presenting the information as a “dashboard” for the provider.

3. Management of Persistent Symptoms and Further Testing Initial Non-Invasive Tests (Often done at 3 months): + Echocardiogram + VQ Scan + Full PFTs + Six-minute walk + CPET * Further Evaluation for Persistent Symptoms (e.g., at 6 months):* If non-invasive tests (Chest X-ray, ECG, CPET) are normal but symptoms persist, more invasive testing should be considered as the patient has not returned to baseline. + Repeat VQ scan or echocardiogram if symptoms have changed. + Right Heart Catheterization (RHC) at rest or with exercise. + Invasive CPET. + PA gram (Pulmonary Angiogram) to assess vasculature.

4. Recurrence Risk and Anticoagulation Duration The decision to continue or discontinue anticoagulation depends on the patient’s risk factors, the situation of the PE (provoked or unprovoked), presence of active cancer, and patient preference. * Recurrence Risk Scores: + Simple scores are preferred for practicality. + DASH Score. + HERDO2 Score (particularly for women). + The Vienna Score can be considered if the question is whether to restart anticoagulation after a disruption. * Role of D-dimer in Abbreviation: While D-dimer can be used to guide the decision to restart anticoagulation after a planned pause (if D-dimer is high, resume), patient symptoms are preferable* to guide management decisions like early abbreviation.

5. Prevention of Post-PE Syndrome Currently, there is no clear tool known to prevent the post-PE syndrome/spectrum of disease. * Best Current Advice for Prevention/Recovery: + Anticoagulation compliance. + Pulmonary rehabilitation, which aids in faster recovery. + General precautions, such as smoking cessation and body weight management. * Future Research:* Ongoing trials are investigating whether acute management strategies (e.g., using thrombolytics in intermediate-risk PE) can prevent long-term sequelae. (The PYTHO trial did not show a reduced rate of CTEPH in intermediate-risk PE patients who received thrombolytics).

References:1. Khan, F., Tritschler, T., Kahn, S. R., & Rodger, M. A. “Venous Thromboembolism.” The Lancet, vol. 398, no. 10294, 2021, pp. 64-77. doi:10.1016/S0140-6736(20)32658-1. 2. Kearon, C., & Kahn, S. R. “Long-Term Treatment of Venous Thromboembolism.” Blood, vol. 135, no. 5, 2020, pp. 317-325. doi:10.1182/blood.2019002364. 3. Kahn, S. R., & de Wit, K. “Pulmonary Embolism.” The New England Journal of Medicine, vol. 387, no. 1, 2022, pp. 45-57. doi:10.1056/NEJMcp2116489. 4. Di Nisio, M., van Es, N., & Büller, H. R. “Deep Vein Thrombosis and Pulmonary Embolism.” The Lancet, vol. 388, no. 10063, 2016, pp. 3060-3073. doi:10.1016/S0140-6736(16)30514-1. 5. Chopard, R., Albertsen, I. E., & Piazza, G. “Diagnosis and Treatment of Lower Extremity Venous Thromboembolism: A Review.” JAMA, vol. 324, no. 17, 2020, pp. 1765-1776. doi:10.1001/jama.2020.17272.

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CardioNerds (Drs. Rawan Amir, Tripti Gupta, and Alysha Joseph) discuss the fundamentals of adult congenital heart disease (ACHD) surgery with Dr. Elizabeth Stephens. Audio editing by CardioNerds academy intern, Grace Qiu.

Using a case of a young adult undergoing a Ross procedure, the episode walks through what happens in the operating room—from induction and intraoperative transesophageal echocardiography (TEE) to cardiopulmonary bypass (CPB), myocardial protection, and surgical repair. The discussion highlights key concepts including cardioplegia, cross-clamp and bypass times, hypothermic circulatory arrest, and the complexity of redo sternotomy. This episode provides learners with a practical framework to interpret operative reports, anticipate postoperative physiology, and better collaborate with surgical teams.

This episode was produced by the CardioNerds ACHD Council and planned by Dr. Rawan Amir.

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Pearls1. “LV distension kills patients.”
Preventing left ventricular distension with appropriate venting and awareness of aortic insufficiency is critical to intraoperative safety. 2. TEE can change the surgical plan in real time.
Findings such as underestimated aortic regurgitation, mitral pathology, or a PFO may directly alter cannulation and cardioplegia strategy. 3. Cross-clamp time = myocardial ischemic time; bypass time = systemic stress.
Both are key predictors of postoperative complications including renal injury, bleeding, and ventricular dysfunction. 4. Redo sternotomy risk is driven by anatomy, not just number.
Aorta adherent to the sternum, conduit position, and chamber pressurization define risk more than the number of prior surgeries. 5. Think longitudinally—ACHD surgery is lifetime planning.
Surgical materials and strategies must account for future interventions, especially in younger patients.

Notes: Notes drafted by Dr. Alysha Joseph, aided by generative artificial intelligence.

1. What are the key steps in congenital cardiac surgery from incision to closure?
2. Preoperative planning is multidisciplinary, involving surgeon, anesthesia, cardiology, and ICU teams; high-risk inductions (e.g., critical AS, Williams syndrome) are identified early
3. TEE is performed immediately after induction to reassess anatomy and may reveal new findings (e.g., underestimated AI, mitral disease, PFO)
4. Median sternotomy is performed, followed by creation of a pericardial well to optimize exposure
5. Heparin is administered prior to cannulation; arterial and venous cannulas are placed for initiation of CPB
6. Cross-clamp is applied and cardioplegia delivered to arrest the heart, allowing a still and protected operative field
7. Surgical repair (e.g., Ross procedure) is performed, followed by de-airing, cross-clamp removal, and reperfusion
8. Patient is weaned from bypass with TEE reassessment, hemostasis achieved, and chest closed
9. What is cardioplegia and how is it delivered?
10. Cardioplegia is a potassium-rich solution that arrests myocardial activity and reduces metabolic demand
11. Most commonly used solution in the U.S. is Del Nido cardioplegia, originally developed for pediatric myocardium
12. Delivery strategies include:
13. Antegrade (via aortic root) – standard approach
14. Ostial (direct coronary delivery) – used when aortic root cannot be relied upon
15. Retrograde (via coronary sinus) – useful in severe AI or coronary disease

NOTE: Severe aortic regurgitation can impair antegrade delivery and requires alternative strategies and LV venting

1. What do cross-clamp time and bypass time represent clinically?
2. Cross-clamp time = duration of myocardial ischemia while the heart is arrested
3. Bypass time = total duration on CPB, reflecting systemic exposure to non-physiologic circulation
4. Prolonged cross-clamp time (>2–3 hours) increases risk of myocardial dysfunction, especially with poor baseline function
5. Longer bypass time is associated with increased risk of renal injury, coagulopathy, and bleeding
6. These metrics often reflect both case complexity and intraoperative challenges
7. What is hypothermic circulatory arrest (HCA) and when is it used?
8. HCA involves complete cessation of blood flow to allow a bloodless surgical field
9. Typically used in complex aortic arch repairs
10. Patients are cooled to ~18°C to reduce metabolic demand and protect organs
11. Duration is ideally limited to <30 minutes to minimize neurologic injury
12. Adjuncts include:
    • Antegrade cerebral perfusion (ACP) – provides targeted brain perfusion
    • Retrograde cerebral perfusion (RCP) – less effective for oxygen delivery
13. What makes redo congenital cardiac surgery high risk?
14. Re-entry risk depends on anatomical relationships:
    • Aorta adherent to sternum (especially midline) poses high risk of catastrophic bleeding
    • RVOT conduits or pressurized chambers near sternum increase injury risk
15. Loss of peripheral vascular access from prior procedures limits bailout options
16. Accumulated comorbidities (renal, hepatic dysfunction) increase perioperative risk
17. Diastolic dysfunction and ventricular impairment complicate weaning from bypass
18. Complexity of planned repair and institutional/surgeon experience significantly influence outcomes
19. What does “venting the ventricle” mean and why is it important?
20. Venting refers to decompression of the left ventricle using a cannula (often via right superior pulmonary vein)
21. Prevents LV distension, which can impair myocardial protection and lead to hemodynamic collapse
22. Particularly important in the presence of aortic insufficiency or inadequate forward flow
23. Failure to adequately vent can result in arrhythmias, poor recovery, and adverse outcomes
24. What materials are used in congenital surgery and how do they impact long-term care?
25. Common patch materials include bovine pericardium (durable, non-stretch), Dacron, Gore-Tex, and autologous pericardium
26. Conduits (e.g., homografts, Contegra, Hancock) are used to connect cardiac structures and often contain valves
27. Most materials do not grow with the patient and are prone to calcification over time
28. Surgical decisions must consider future transcatheter or surgical interventions
29. Limited availability of certain graft sizes (e.g., pulmonary homografts) impacts real-world decision-making

References:1. Salis, S. et al. Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth. 2008;22(6):814-822. doi:10.1053/j.jvca.2008.08.004

1. Al-Sarraf, N. et al. Cross-clamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. International journal of surgery (London, England). 2011; 9(1):104–109. https://doi.org/10.1016/j.ijsu.2010.10.007

2. Weiland, A. P. et al. Physiologic principles and clinical sequelae of cardiopulmonary bypass. Heart & lung : the journal of critical care. 1986;15(1):34–39.

3. Park, C. B. et al. Identifying patients at particular risk of injury during repeat sternotomy: analysis of 2555 cardiac reoperations. The Journal of thoracic and cardiovascular surgery. 2010;140(5):1028–1035. https://doi.org/10.1016/j.jtcvs.2010.07.086

4. Morales, D. L. et al. Repeat sternotomy in congenital heart surgery: no longer a risk factor. The Annals of thoracic surgery. 2008; 86(3):897–902. https://doi.org/10.1016/j.athoracsur.2008.04.044

5. Francica, A. et al. Cardioplegia between Evolution and Revolution: From Depolarized to Polarized Cardiac Arrest in Adult Cardiac Surgery. Journal of clinical medicine. 2021;10(19):4485. https://doi.org/10.3390/jcm10194485

6. Ghia, S. et al. Hypothermic Circulatory Arrest in Adult Aortic Arch Surgery: A Review of Hypothermic Circulatory Arrest and its Anesthetic Implications. Journal of cardiothoracic and vascular anesthesia. 2023; 37(12): 2634–2645. https://doi.org/10.1053/j.jvca.2023.08.139

7. Peivandi, A. D. et al. Grafts and Patches: Optimized but Not Optimal Materials for Congenital Heart Surgery. Pediatric cardiology. 2023;44(5):996–1002. https://doi.org/10.1007/s00246-023-03153-6

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The following question refers to Section 7.1 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by University of Michigan fellow and CardioNerds FIT Ambassador Dr. Kayla Secrest, and then by expert faculty Dr. Sunil Rao.

Dr. Rao is an interventional cardiologist, Professor of Medicine at NYU Grossman School of Medicine, Deputy Director of the Leon H. Charney Division of Cardiology, and the Director of Interventional Cardiology for the NYU Langone Health System. He is the Editor-in-Chief for Circulation Cardiovascular Interventions and was the Chair of the Writing Committee for the 2025 ACS Guidelines.

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

Question #1

| A 68-year-old man with a history of hypertension, hyperlipidemia, stage III chronic kidney disease, and prior tobacco use presents to a local emergency department with reports of chest pain while raking leaves at home. Upon arrival, he is hemodynamically stable with a heart rate of 86 beats per minute and a blood pressure of 133/85 mmHg. His EKG reveals ST elevations in the septal and anterior leads (V1-V4). He is given 324mg of aspirin and is promptly evaluated by the interventional cardiology team, who elects to take him emergently to the catheterization lab. Upon arrival to the catheterization lab, the nurse asks the interventional fellow which access sites they should prep for this case? How should the interventional fellow respond? | | A | Right radial artery only | | B | Radial + bilateral femoral | | C | Bilateral femoral only |

Answer #1

| Explanation | The correct answer is B. Radial and bilateral femoralRadial artery access is the preferred vascular access site for coronary angiography and PCI in patients with ACS. Transradial access has been shown to reduce mortality, bleeding, and vascular complications compared with transfemoral access (Class I, LOE A). Radial access also allows earlier ambulation and is associated with greater patient comfort.Although the right radial artery is the most widely studied upper-extremity access site, alternative sites such as the ulnar and distal radial arteries have demonstrated similar outcomes.However, the radial artery may be required as a bypass conduit for CABG. In institutions where the radial artery is routinely used for surgical grafting, this potential future use should be considered when selecting vascular access.In addition, transfemoral access—preferably performed with ultrasound guidance—should be considered in patients in whom temporary mechanical circulatory support (MCS) is anticipated or in those for whom radial access is not feasible due to anatomical or technical constraints. Prepping bilateral groins in addition to the radial artery provides a backup strategy for urgent MCS placement or for transition to femoral access should radial access fail.For these reasons, prepping both the radial artery and bilateral groins is the most appropriate response.Radial-only preparation is incorrect because, although radial access is preferred, patients with STEMI may still require emergent MCS or alternative access if the radial artery is unsuitable. Preparing only the wrist without backup femoral access may delay care should hemodynamic instability occur.Femoral-only preparation is incorrect because transradial access provides superior outcomes in ACS, including significant reductions in all-cause mortality, major bleeding, and vascular complications. RCTs and meta-analyses, including MATRIX (which showed lower MACE and net adverse clinical events with radial access) and SAFARI-STEMI (which showed no difference in mortality but was underpowered)—support radial as first-line access when feasible. | | Main Takeaway | For patients with ACS undergoing PCI, radial access is strongly preferred to reduce mortality, bleeding, and vascular complications. | | Guideline Loc. | Section 7.1 |

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CardioNerds (Dr. Billy-Joe Mullinax, Dr. Dinu Balanescu, and Dr. Jane Ehret) discuss risk stratification in acute pulmonary embolism with Dr. Stavros Konstantinides, Chair of the 2019 ESC Pulmonary Embolism Guidelines. Using a real-world case, this episode explores how modern PE care has moved beyond “massive” and “submassive” labels toward a dynamic, physiology-based approach. The discussion highlights the limitations of static risk scores, the importance of right ventricular dysfunction and biomarkers, and why normotension does not imply stability. Special emphasis is placed on intermediate-high risk PE, early identification of impending hemodynamic collapse, and the role of lactate, serial reassessment, and PERT teams in guiding escalation of care. Audio editing by CardioNerds intern, Joshua Khorsandi.
The 2026 American multi-society PE guidelines were published after this episode was recorded.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

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Pearls1. Stable blood pressure does not mean low risk in PE
Hypotension is a late finding. Patients may have severe RV failure, hypoxia, and tissue hypoperfusion while remaining normotensive — a key concept behind “normotensive shock.” 2. Risk stratification in PE must be dynamic, not static
Legacy scores like PESI and Bova provide a snapshot and predict 30-day mortality, but they do not capture short-term trajectory or impending hemodynamic collapse. 3. Intermediate-high risk PE is a dangerous and heterogeneous group
Patients with RV dysfunction, positive biomarkers, tachycardia, hypoxemia, and elevated lactate may have in-hospital mortality approaching 15%, rivaling STEMI. 4. Lactate is a critical but underutilized marker in PE
Elevated lactate reflects tissue hypoxia and early circulatory failure and may identify patients at risk for collapse before blood pressure declines. 5. PERT enables physiology-driven, patient-centered PE care
PERT teams operationalize continuous reassessment, integrate imaging, labs, and clinical trajectory, and allow timely escalation — shifting PE management from rigid categories to real-time decision-making.

NotesDrafted by Dr. Jane Ehret.

1. What is the contemporary framework for risk stratification in acute pulmonary embolism?

• Modern PE risk stratification prioritizes hemodynamics and right ventricular (RV) function rather than clot burden.
• The 2019 ESC Guidelines classify PE into high risk, intermediate risk (low vs high), and low risk, based on: Hemodynamic status, RV dysfunction on imaging, and Cardiac biomarkers.
• This framework emphasizes early mortality risk but requires clinical context to guide escalation decisions.

2. Why is normotension insufficient to define “stability” in PE?

• Blood pressure is a late marker of circulatory failure in PE.
• Patients can maintain normal BP through Tachycardia, Increased sympathetic tone, and RV compensation.
• Many patients with preserved BP may already have shock physiology, including hypoxemia, elevated lactate, and RV failure — sometimes referred to as “normotensive shock.”

3. How should intermediate-risk PE be conceptualized clinically?

• Intermediate-risk PE is heterogeneous, ranging from patients who do well on anticoagulation to those who deteriorate rapidly.
• Intermediate-high risk PE is defined by RV dysfunction on imaging and positive cardiac biomarkers.
• Clinical features such as tachycardia, increasing oxygen requirement, and elevated lactate identify patients at highest risk within this group.

4. What are the strengths and limitations of commonly used PE risk scores?

• Legacy scores are useful for initial risk categorization but are static and limited in predicting short-term deterioration.
• Most scores were developed to predict mortality or complications at fixed time points rather than dynamic clinical trajectory.

5. What are the commonly used risk scores and clinical tools in PE, and what is each designed to predict?

• ESC Risk Stratification Algorithm: Identifies high-risk PE by hemodynamics. Uses PESI or sPESI in normotensive patients to distinguish low-risk from non–low-risk PE. Uses RV dysfunction and biomarkers to differentiate intermediate-low from intermediate-high risk. Forms the basis of many institutional PE pathways.
• PESI and sPESI: Validated to predict 30-day mortality. Widely used to identify low-risk patients appropriate for outpatient management. Heavily influenced by age and comorbidities.
• Bova Score: Predicts 30-day PE-related complications in normotensive patients.
• Composite PE Shock Score (CPES): Predicts normotensive shock in hemodynamically stable PE patients.
• Pulmonary Embolism Progression (PEP) Score: Predicts progression from intermediate-risk to high-risk PE within 72 hours of diagnosis.
• PE Short-term Clinical Outcomes Risk Estimation (PE-SCORE): Predicts clinical deterioration or death within 5 days of PE diagnosis.
• Hestia Criteria: Identifies low-risk PE patients safe for outpatient treatment.
• Wells’ Criteria and Revised Geneva Score: Determine pretest probability for diagnostic triage.
• PERC Score: Rules out PE in very low-risk patients.

6. What is the role of biomarkers in PE risk stratification?

• Troponin and natriuretic peptides reflect RV myocardial injury and strain.
• Current guidelines treat biomarkers as binary (positive vs negative), despite risk being continuous.
• Biomarkers are most helpful for: Initial risk classification.
• They are less useful for: Short-interval monitoring and Detecting rapid clinical deterioration.

7. Why is lactate an important physiologic marker in PE?

• Lactate reflects global tissue hypoxia and impaired perfusion.
• Elevated lactate may identify patients with: Early circulatory failure and Increased risk of imminent hemodynamic collapse.
• Lactate is not currently included in ESC risk algorithms but may add important prognostic information in intermediate-risk patients.

8. How does trajectory influence decision-making in PE management?

• Risk stratification should be viewed as a dynamic process, not a one-time label.
• Worsening clinical trajectory may include: Rising heart rate, Increasing oxygen needs, Rising lactate, and Progressive RV dysfunction.
• Serial reassessment is essential for timely escalation of care.

9. What role do Pulmonary Embolism Response Teams (PERT) play in risk stratification?

• PERT facilitates: Multidisciplinary decision-making and Integration of imaging, biomarkers, and clinical physiology.
• PERT is most valuable for: Intermediate-risk and high-risk PE and Patients with complex comorbidities or uncertain trajectory.
• PERT enables a shift from category-based to physiology-driven PE care.

References1. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54(3):1901647. Published 2019 Oct 9. doi:10.1183/13993003.01647-2019

1. Leidi A, Bex S, Righini M, Berner A, Grosgurin O, Marti C. Risk Stratification in Patients with Acute Pulmonary Embolism: Current Evidence and Perspectives. J Clin Med. 2022;11(9):2533. Published 2022 Apr 30. doi:10.3390/jcm11092533

2. Choi WH, Kwon SU, Jwa YJ, et al. The pulmonary embolism severity index in predicting the prognosis of patients with pulmonary embolism. Korean J Intern Med. 2009;24(2):123-127. doi:10.3904/kjim.2009.24.2.123

3. Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383-1389. doi:10.1001/archinternmed.2010.199

4. Chen X, Shao X, Zhang Y, et al. Assessment of the Bova score for risk stratification of acute normotensive pulmonary embolism: A systematic review and meta-analysis. Thromb Res. 2020;193:99-106. doi:10.1016/j.thromres.2020.05.047

5. Zhang RS, Yuriditsky E, Zhang P, et al. Composite Pulmonary Embolism Shock Score and Risk of Adverse Outcomes in Patients With Pulmonary Embolism. Circ Cardiovasc Interv. 2024;17(8):e014088. doi:10.1161/CIRCINTERVENTIONS.124.014088

6. Zhang RS, Alam U, Sharp ASP, et al. Validating the Composite Pulmonary Embolism Shock Score for Predicting Normotensive Shock in Intermediate-Risk Pulmonary Embolism. Circ Cardiovasc Interv. 2024;17(2):e013399. doi:10.1161/CIRCINTERVENTIONS.123.013399

7. Ehret J, Wakefield D, Badlam J, Antkowiak M, Erdreich B. Development of the Pulmonary Embolism Progression (PEP) score for predicting short-term clinical deterioration in intermediate-risk pulmonary embolism: a single-center retrospective study. J Thromb Thrombolysis. 2025;58(2):243-253. doi:10.1007/s11239-024-03051-5

8. Weekes AJ, Raper JD, Lupez K, et al. Development and validation of a prognostic tool: Pulmonary embolism short-term clinical outcomes risk estimation (PE-SCORE). PLoS One. 2021;16(11):e0260036. Published 2021 Nov 18. doi:10.1371/journal.pone.0260036

9. Zondag W, Hiddinga BI, Crobach MJ, et al. Hestia criteria can discriminate high- from low-risk patients with pulmonary embolism. Eur Respir J. 2013;41(3):588-592. doi:10.1183/09031936.00030412

10. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med. 2001;135(2):98-107. doi:10.7326/0003-4819-135-2-200107170-00010

11. Wolf SJ, McCubbin TR, Feldhaus KM, Faragher JP, Adcock DM. Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. Ann Emerg Med. 2004;44(5):503-510. doi:10.1016/j.annemergmed.2004.04.002

12. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med. 2006;144(3):165-171. doi:10.7326/0003-4819-144-3-200602070-00004

13. Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost. 2004;2(8):1247-1255. doi:10.1111/j.1538-7836.2004.00790.x

14. Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost. 2008;6(5):772-780. doi:10.1111/j.1538-7836.2008.02944.x

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CardioNerds Dr. Joseph Kassab, Dr. Mariana Garcia-Arango, and Dr. Christopher Mason explore the technological revolution of Coronary CT Angiography (CCTA) with expert faculty Dr. Michael Gallagher. The discussion details how CCTA has evolved into a frontline diagnostic and preventive tool, moving beyond simple anatomy to incorporate physiology via CT-FFR and biology through AI-driven plaque quantification. The episode reviews landmark evidence like the SCOT-HEART and PROMISE trials, the nuances of CAD-RADS 2.0 reporting, and the emerging role of AI in monitoring treatment response and personalizing cardiovascular care. Critically, they also discuss some of the assumptions and limitations of these techniques.

Stay tuned for a matching review article to be submitted to US Cardiology Review, the official Journal of CardioNerds.

This episode was supported by an independent medical education grant from HeartFlow. All CardioNerds education is planned, produced, and reviewed solely by CardioNerds.

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here.

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Pearls1. Shift in Paradigm: CCTA is no longer just an anatomic test; with some key limitations, it can provide anatomy, physiology (CT-FFR), and plaque biology (AI-CPA) in a single non-invasive scan. 2. The “Power of Zero” vs. Plaque: While a normal CCTA has a >95% negative predictive value, future MIs often arise from non-obstructive plaque that traditional stress tests might miss. 3. CAD-RADS 2.0 Utility: The addition of plaque burden modifiers (P1–P4) is a “game changer,” allowing clinicians to identify high-risk patients who need aggressive lipid-lowering despite having only mild stenosis. 4. CT-FFR as a Virtual Stress Test: CT-FFR uses computational fluid dynamics to simulate blood flow, potentially reducing unnecessary invasive catheterizations by approximately 61% without sacrificing safety. 5. Seeing the Invisible: AI-based quantitative plaque analysis (QCPA) can identify “subvisual” plaque and low-attenuation (lipid-rich) components that are the primary drivers of acute coronary syndromes.

Show Notes1. How has the role of CCTA changed compared to traditional functional testing? * Historically, stress testing answered “is there ischemia today?”, which often reflects late-stage disease. * CCTA identifies disease across the entire spectrum, asking “is there atherosclerosis and how much plaque is present?”. * Landmark evidence: SCOT-HEART showed a 41% relative risk reduction in MI at 5 years attributed to intensified preventive therapies, and PROMISE showed CCTA was better at selecting patients who truly needed invasive angiography. * Diagnostic CCTA imaging depends on the protocol, contrast timing, heart rate, heart rhythm, breathholding, scanner quality, and several patient factors (obesity, prior stents, heavy calcification, complex bypass anatomy, and motion artifact all may limit imaging). “CCTA is exceptional for the right patient, with the right scanner, and the right team.” 2. What are the key modifiers introduced in CAD-RADS 2.0, and why do they matter? * CAD-RADS 2.0 moved beyond stenosis severity to include plaque burden (P0 to P4), high-risk plaque (HRP) features, and the presence of ischemia based on CT-FFR. * It serves as a clinical decision support tool: a patient with mild (25-49%) stenosis but “extensive” (P4) plaque burden is considered high risk and warrants aggressive risk factor modification. 3. How is CT-FFR calculated, and when is it most useful in clinical practice? * CT-FFR uses resting CCTA data and computational fluid dynamics to create a 3D model of coronary flow during simulated maximal hyperemia. * It is often used for intermediate lesions (40–90% stenosis) to predict if they are ischemia-producing, guiding the decision whether to proceed with invasive angiography. * The assumptions necessary for this computational modeling may not apply well to patients with microvascular dysfunction, significant myocardial scar or prior infarction, or ventricular hypertrophy. Still, data indicate that CT-FFR performs similarly to PET in predicting hemodynamically significant lesions. * CT-FFR performs well at the extremes (either clearly normal or clearly abnormal). Accuracy dips, however, in the intermediate range (~0.75-0.80), where decision-making is most critical. In this grey zone, additional factors can help guide the approach, including the amount of myocardium supplied, translesional gradient, and plaque features. * CT-FFR has not been validated in distal segments, stented segments, heavily calcified coronary arteries, or in patients with severe aortic stenosis. Caution with CT-FFR should be utilized in very calcified coronary segments. 4. What is AI-based quantitative plaque analysis (QCPA), and what metrics are ready for clinical use? * This is potentially a paradigm shift, moving away from stenosis-centric thinking to a more disease burden and plaque biology focus. * QCPA uses deep learning algorithms to automatically segment the vessel wall and quantify plaque volume in mm³. * Ready for “prime time” metrics include: Total Plaque Volume (TPV), non-calcified plaque volume, and Low-Attenuation Plaque (LAP) burden. 5. Can serial CCTA be used to monitor the effectiveness of medical therapies like statins? * While not yet a routine guideline-driven practice, trials like PARADIGM and EVAPORATE show that therapies can stabilize plaque; notably, CCTA is better for monitoring than CAC scores, which can be misleading as statins often increase plaque calcification as part of the stabilization process. * There are no randomized trials that serial CCTAs improve outcomes. Cost and radiation exposure will be notable limitations. Serial scan timing, scan acquisition and interpretation standardization would be key. * Dr. Gallagher notes that we are moving toward a world in which plaque burden may become a “treatment biomarker,” similar to tumor burden in oncology.

References 1. Coronary Computed Tomography Angiography From Clinical Uses to Emerging Technologies: JACC State-of-the-Art Review. Abdelrahman KM, Chen MY, Dey AK, et al. Journal of the American College of Cardiology. 2020;76(10):1226-1243. doi:10.1016/j.jacc.2020.06.076.

1. Non-Invasive Imaging in Coronary Syndromes: Recommendations of the European Association of Cardiovascular Imaging and the American Society of Echocardiography, in Collaboration With the American Society of Nuclear Cardiology, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. Edvardsen T, Asch FM, Davidson B, et al. Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2022;35(4):329-354. doi:10.1016/j.echo.2021.12.012.

2. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Gulati M, Levy PD, Mukherjee D, et al. Journal of the American College of Cardiology. 2021;78(22):e187-e285. doi:10.1016/j.jacc.2021.07.053.

3. Contemporary, Non-Invasive Imaging Diagnosis of Chronic Coronary Artery Disease. van der Bijl P, Gulati M, Saraste A, et al. Lancet (London, England). 2025;406(10519):2577-2587. doi:10.1016/S0140-6736(25)01586-7.

4. State of the Art: Evaluation and Medical Management of Nonobstructive Coronary Artery Disease in Patients With Chest Pain: A Scientific Statement From the American Heart Association. Slipczuk L, Blankstein R, Bucciarelli-Ducci C, et al. Circulation. 2025;152(23):e443-e466. doi:10.1161/CIR.0000000000001394.

5. Diagnostic Performance of Fractional Flow Reserve Derived From Coronary CT Angiography: The ACCURATE-CT Study. Li C, Hu Y, Jiang J, et al. JACC. Cardiovascular Interventions. 2024;17(17):1980-1992. doi:10.1016/j.jcin.2024.06.027.

6. Clinical Outcomes Based on Coronary Computed Tomography-Derived Fractional Flow Reserve and Plaque Characterization. Sato Y, Motoyama S, Miyajima K, et al. JACC. Cardiovascular Imaging. 2024;17(3):284-297. doi:10.1016/j.jcmg.2023.07.013.

7. Clinical Use of Coronary Computed Tomography Angiography-Derived Fractional Flow Reserve: Expert Consensus by an International Working Group. Tang CX, Leipsic JA, Nørgaard BL, et al. European Radiology. 2026;:10.1007/s00330-025-12313-6. doi:10.1007/s00330-025-12313-6.

8. Diagnostic accuracy of computed tomography–derived fractional flow reserve: a systematic review. Cook CM, Petraco R, Shun-Shin MJ, et al. JAMA Cardiol. 2017;2(7):803-810. Doi:10.1001/jamacardio.2017.1314

9. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). Nørgaard BL, Leipsic J, Gaur S, et al. J Am Coll Cardiol. 2014;63(12):1145-1155. Doi:10.1016/j.jacc.2013.11.043

10. Comparison of coronary computed tomography angiography, fractional flow reserve, and perfusion imaging for ischemia diagnosis. Driessen RS, Danad I, Stuijfzand WJ, et al. J Am Coll Cardiol. 2019;73(2):161-173. Doi:10.1016/j.jacc.2018.10.056.

11. 1-year outcomes of FFRCT-guided care in patients with suspected coronary disease: the PLATFORM study. Douglas PS, De Bruyne B, Pontone G, et al. J Am Coll Cardiol. 2016;68(5):435-445. Doi:10.1016/j.jacc.2016.05.057.

12. Comparison of an initial risk-based testing strategy vs usual testing in stable symptomatic patients with suspected coronary artery disease: the PRECISE randomized clinical trial. Douglas PS, Nanna MG, Kelsey MD, et al; PRECISE Investigators. JAMA Cardiol. 2023;8(10):904-914. Doi:10.1001/jamacardio.2023.2595.

13. Diagnostic and clinical value of FFRCT in stable chest pain patients with extensive coronary calcification: the FACC study. Mickley H, Veien KT, Gerke O, et al. JACC Cardiovasc Imaging. 2022;15(6):1046-1058. doi:10.1016/j.jcmg.2021.12.010.

14. Low-Attenuation Noncalcified Plaque on Coronary Computed Tomography Angiography Predicts Myocardial Infarction: Results From the Multicenter SCOT-HEART Trial (Scottish Computed Tomography of the HEART). Williams MC, Kwiecinski J, Doris M, et al. Circulation. 2020;141(18):1452-1462. doi:10.1161/CIRCULATIONAHA.119.044720.

15. AI-Guided Quantitative Plaque Staging Predicts Long-Term Cardiovascular Outcomes in Patients at Risk for Atherosclerotic CVD. Nurmohamed NS, Bom MJ, Jukema RA, et al. JACC. Cardiovascular Imaging. 2024;17(3):269-280. doi:10.1016/j.jcmg.2023.05.020.

16. Interaction of AI-Enabled Quantitative Coronary Plaque Volumes on Coronary CT Angiography, FFRCT, and Clinical Outcomes: A Retrospective Analysis of the ADVANCE Registry. Dundas J, Leipsic J, Fairbairn T, et al. Circulation. Cardiovascular Imaging. 2024;17(3):e016143. doi:10.1161/CIRCIMAGING.123.016143.

17. Prognostic Value of AI-Based Quantitative Coronary CTA vs Human Reader-Based Visual Assessment: Results From the CONFIRM2 Registry. van Rosendael A, Nakanishi R, Bax JJ, et al. JACC. Cardiovascular Imaging. 2026;19(3):345-359. doi:10.1016/j.jcmg.2025.09.021.

18. Pericoronary Adipose Tissue as a Marker of Cardiovascular Risk: JACC Review Topic of the Week. Tan N, Dey D, Marwick TH, Nerlekar N. Journal of the American College of Cardiology. 2023;81(9):913-923. doi:10.1016/j.jacc.2022.12.021.

19. Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy: Final Results of the EVAPORATE Trial. Budoff MJ, Bhatt DL, Kinninger A, et al. European Heart Journal. 2020;41(40):3925-3932. doi:10.1093/eurheartj/ehaa652.

20. Coronary CT Angiography Evaluation With Artificial Intelligence for Individualized Medical Treatment of Atherosclerosis: A Consensus Statement From the QCI Study Group. Schulze K, Stantien AM, Williams MC, et al. Nature Reviews. Cardiology. 2026;23(2):100-115. doi:10.1038/s41569-025-01191-6.

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Join CardioNerds EP Council Chair Dr. Naima Maqsood and Episode Lead Dr. Sukriti Banthiya as they discuss the results of the International Collaborative LBBAP Study (I-CLAS) with expert faculty Dr. Theofanie Mela and Dr. Pugazhendhi Vijayraman. Audio editing by CardioNerds academy intern, Grace Qiu.

The International Collaborative LBBAP Study (I-CLAS) evaluated clinical outcomes between biventricular pacing (BVP) and left bundle branch area pacing (LBBAP) in patients with left ventricular ejection fraction (LVEF) ≤50% undergoing cardiac resynchronization therapy. Between January 2018 and June 2023, 2,579 patients were enrolled across 18 centers. The primary composite outcome was defined as all-cause mortality or heart failure hospitalization. LBBAP demonstrated a shorter paced QRS duration and was associated with a lower risk of primary composite outcome and heart failure hospitalization. No significant difference was observed in all-cause mortality. Additionally, procedural complications were lower with LBBAP.

This episode was planned in collaboration with  Heart Rhythm TV with mentorship from Dr. Daniel Alyesh and Dr. Mehak Dhande.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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In this episode, CardioNerds Dr. Colin Blumenthal, Dr. Kelly Arps, and Dr. Yong Hao Yeo are joined by electrophysiology expert Dr. Bradley Knight to discuss atrial fibrillation (AF) management in challenging clinical scenarios. We explore arrhythmias in patients with pre-excitation syndromes, particularly Wolff-Parkinson-White (WPW) syndrome, and strategies for rhythm control. We also discuss AF management in pregnancy, adult congenital heart disease, and patients with tachycardia-bradycardia (tach-brady) syndrome. This episode provides essential insights into nuanced decision-making for the care of patients with complex arrhythmia profiles. Audio editing by CardioNerds academy intern, Grace Qiu.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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PEARLS1. AF in WPW is a true emergency—AV nodal blocking agents can be deadly. In patients with WPW syndrome, AF can rapidly conduct through the accessory pathway, risking ventricular fibrillation and sudden death. Avoid AV nodal blockers like beta-blockers and calcium channel blockers. 2. Catheter ablation is the first-line rhythm control strategy in WPW. Catheter ablation carries a Class I recommendation and offers >90% success. If antiarrhythmic drugs are needed, sodium channel blockers like flecainide or propafenone are preferred in patients without structural heart disease. 3. In pregnancy, protecting the mother is protecting the fetus. An unstable mother means an unstable fetus. Rate control is the first step in AF with rapid ventricular responses and electrical cardioversion is safe when needed. Multidisciplinary care is essential. 4. AF in congenital heart disease is often outside the pulmonary veins. Surgical scars and chamber remodeling in ACHD patients often lead to AF from non-pulmonary vein foci. Electrogram-based mapping and targeted ablation strategies are essential to increase success rate of durable rhythm control. 5. Tachy-brady syndrome may require pacing to unlock therapy. AF may cause atrial myopathy and sinus node dysfunction. These patients often require permanent pacing to allow safe use of rate-controlling medications like beta-blockers and to prevent syncope or chronotropic incompetence.

Notes: Notes drafted by Dr. Yong Hao YeoWhy is atrial tachycardia in patients with WPW syndrome dangerous?* Patients with WPW commonly present with supraventricular tachycardia (SVT) due to atrioventricular reentrant circuits, either orthodromic or antidromic. This SVT can degenerate into AF. * In the absence of AV nodal as the governor between the atrium and ventricles, the accessory pathway may conduct impulses rapidly and frequently. This can lead to dangerously high ventricular rates, predisposing patients to ventricular fibrillation and sudden cardiac arrest.

What are some strategies for rhythm control in patients with WPW and atrial tachycardia?* Catheter ablation is the first-line therapy (Class I recommendation), with a success rate of over 90%. * Ablation reduces the risk of sudden cardiac arrest, though some patients may remain prone to AF. * If ablation is not feasible/ contraindicated, sodium channel blockers such as flecainide and propafenone are good options in patients without ischemia or structural heart disease (Class IIa recommendation). * Amiodarone should be avoided because it has a long half-life, can accumulate in the system, and may delay definitive treatment with catheter ablation. * AV nodal blocking agents like beta blockers and calcium channel blockers should be avoided, as they are less effective at controlling ventricular rate in WPW and can increase conduction over the accessory pathway. These agents can also exacerbate the risk of rapid ventricular rates during AF and worsen left ventricular function.

What are some special considerations in managing AF in pregnant patients?* The primary goal in managing cardiovascular disease during pregnancy is to protect the mother, as fetal outcomes depend on maternal well-being. Therefore, while caution is necessary, we should avoid undertreating pregnant patients with AF. * In cases of AF with rapid ventricular response (RVR), rate control is usually the first-line strategy, with beta blockers preferred over digoxin or non-dihydropyridine calcium channel blockers. It is then reasonable to initially observe for spontaneous conversion in stable patients. * Antiarrhythmic drugs (AADs) are generally avoided during the first trimester, but clinical judgment on a case-by-case basis is essential. * Evidence for the safety of AADs in pregnancy is limited, often derived from their use in other conditions such as fetal SVT. Flecainide and sotalol are reasonable options for rhythm control (Class IIa recommendation). * Electrical cardioversion is considered safe in pregnancy and should be utilized when indicated (Do not forget!). * There is no pregnancy-specific thromboembolic risk stratification tool. CHA₂DS₂-VASc scoring and the presence of risk factors like mitral stenosis can help guide anticoagulation decisions, though the magnitude of thromboembolic risk during pregnancy remains unclear. * Rate control agents are typically continued during delivery due to the increased physiologic stress of labor and delivery. * Multidisciplinary care is crucial and should involve obstetrics, maternal-fetal medicine, cardiology, and electrophysiology specialists.

What are some key considerations for AF management in patients with adult congenital heart disease (ACHD)?* Patients with repaired congenital heart disease are at increased risk for arrhythmias due to two main factors: surgical scars that create arrhythmogenic foci and mechanical remodeling of the atria or ventricles resulting from the underlying disease. + In these patients with structural heart disease, sodium channel blockers may not be ideal antiarrhythmic options. * When selecting an antiarrhythmic drug, clinicians must consider the nature of structural or surgical impairments, such as right bundle branch block or prolonged QT interval. * It is also essential to assess renal and hepatic function (often impaired in patients with ACHD) to ensure appropriate metabolism and clearance of antiarrhythmic medications. * Electrogram-based ablation strategies (those leveraging artificial intelligence are developing!) may help identify effective ablation targets, which are often outside the pulmonary veins in patients with ACHD. These individualized approaches can improve ablation success rates in this complex patient population.

What makes tachycardia-bradycardia (tach-brady) syndrome a unique challenge in arrhythmia management?* Patients who present with both AF and bradycardia, especially with syncope, require a thoughtful diagnostic approach to identify the underlying rhythm disturbance. * Extended cardiac monitoring, including event monitors or implantable loop recorders, can help capture intermittent arrhythmias and correlate them with symptoms. * AF may lead to atrial myopathy, and since the sinus node resides within the atrium, this can result in sinus node dysfunction—a hallmark of tachy-brady syndrome. * Following spontaneous conversion from AF to sinus rhythm, sinus node dysfunction may persist, leading to prolonged pauses or chronotropic incompetence. * Management becomes more complex when beta-blockers are needed for AF with RVR, as they can exacerbate bradycardia. Permanent pacemaker implantation is often the next step to consider. * Permanent pacemaker implantation is often considered to facilitate safe rate control in these cases. * In younger patients, aggressive AF burden reduction may prevent atrial remodeling and the development of true atrial myopathy, potentially avoiding pacemaker implantation.

References1. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2023;149(1). doi:https://doi.org/10.1161/CIR.0000000000001193 ‌ 2. Van IC, Rienstra M, Bunting KV, et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal. 2024;45(36). doi:https://doi.org/10.1093/eurheartj/ehae176 ‌ 3. Joglar JA, Kapa S, Saarel EV, et al. 2023 HRS expert consensus statement on the management of arrhythmias during pregnancy. Heart Rhythm. Published online May 1, 2023. doi:https://doi.org/10.1016/j.hrthm.2023.05.017 ‌ 4. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary. Journal of the American College of Cardiology. 2019;73(12):1494-1563. doi:https://doi.org/10.1016/j.jacc.2018.08.1028 ‌

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CardioNerds (Amit Goyal, Daniel Ambinder, Carine Hamo, and Karan Desai) are honored to bring you The Braunwald Chronicles — a special tribute to the life and legacy of Dr. Eugene Braunwald.

Originally released as a 6-part series, we are now bringing these chapters together as one complete experience. These are stories of discovery, innovation, accidents, perseverance, and more… truly, these are the stories of cardiology itself — told firsthand by the father of modern cardiology. Dr. Braunwald’s life and work form the very foundation of contemporary cardiovascular medicine, and his story is, in many ways, the story of our field. Join us as we journey through the history of cardiology across six extraordinary chapters — from the early days of physiologic discovery, to the development of transseptal access, to defining the natural history of valvular disease, to shaping modern therapies for myocardial infarction, and beyond. Through it all, Dr. Braunwald reflects on the principles that guided his career — curiosity, perseverance, mentorship, and the importance of being in the right place, at the right time, with the right people.We hope this collection serves not only as an educational experience, but as a tribute to one of the greatest minds in the history of medicine.

We thank Dr. Karan Desai, Editorial APD with the CardioNerds Academy and fellow at the University of Maryland, for all the work he put into designing The Braunwald Chronicles. Audio editing by Pace Wetstein.

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CardioNerds Drs. Dinu Balanescu, Billy-Joe Mullinax, and Mariana Garcia discuss systemic thrombolysis in pulmonary embolism with expert Dr. Allison Burnett. Audio editing by CardioNerds Academy intern, student doctor, Pace Wetstein.

Pulmonary embolism is the third leading cause of cardiovascular death in the US, and high-risk PE carries a 30-day mortality risk as high as 30-50%. In this episode, we discuss the indications for systemic thrombolysis, including high-risk PE and cardiac arrest. We addressed how to appropriately select candidates for systemic thrombolysis, balancing the high risk of bleeding. Additionally, we discussed anticoagulation management and timing concurrent with lytic therapy, as well as the importance of multidisciplinary PERT teams.

The 2026 American multi-society PE guidelines were published after this episode was recorded.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. Risk stratification is crucial in acute pulmonary embolism care. Based on the ESC 2019 guidelines, low-risk PE patients are those who are normotensive with no evidence of right ventricular dysfunction. Intermediate risk includes two categories: intermediate-low, with normotensive patients who have a high PE score with negative biomarkers, and intermediate-high risk, which has elevated biomarkers or signs of RV strain. High-risk PE includes hemodynamically unstable patients (SBP<90) who have end-organ dysfunction, shock, or cardiac arrest. * The 2026 American multi-society PE guidelines presented a new clinical classification scheme is presented, entitled “Acute Pulmonary Embolism Clinical Categories,” with 5 categories (A-E) and subcategories, ranging from low to high risk for adverse outcomes. 2. Systemic lysis has been studied in patients at high and intermediate risk. Overall, the reduction in mortality has been seen in patients with high-risk PE. 3. Systemic thrombolysis is associated with high rates of bleeding, 2% fatal or high-risk intracranial hemorrhage per the PEITHO trial; therefore, selecting the appropriate population is critical to improve outcomes and balance the risks and benefits. 4. Multidisciplinary PERT teams are crucial for making high-quality decisions, and stewardship is necessary to optimize the care of patients with PE.

NotesNotes: Notes drafted by Dr. Mariana Garcia-Arango

1. What is the role of systemic thrombolysis in the current era of available catheter-directed therapies?
   • Thrombolytic therapy reduces mortality, PE recurrence, and PE-related mortality in patients with acute PE.
   • The evidence supports use during high-risk PE and cardiac arrest.
   • The clinical presentation is often severe, with high stakes and limited time to mobilize to the cath lab on time for catheter therapies, especially in rural populations.
2. How to approach the use of systemic thrombolysis during CPR?
   • Cardiac arrest from PE carries a very poor outlook, with survival rates under 10%. Rapid, targeted interventions to restore circulation are critical.
   • Systemic thrombolysis may be considered for patients in cardiac arrest due to confirmed or strongly suspected pulmonary embolism, especially when standard ACLS interventions have not been successful.
3. What is the best anticoagulation approach while using lytics?
   • Most of the time, we should opt for low-molecular-weight heparin over unfractionated heparin, which has been shown to lead to less major bleeding and reduction of recurrent PE.
   • Exceptions to the rule include renal dysfunction or if there is consideration of cannulation for ECMO or other invasive procedures.
   • There is variation in practice regarding timing and initiation of anticoagulation while using lytics. There are different protocols given the variety of how studies were conducted.
   • If they are going to get mechanical catheter-based therapy, the trend is to prefer LMWH.
   • When lytics are included, either systemic or catheter-directed lytics, there is flexibility and room to discuss with the multidisciplinary PERT team which strategy to use.
   • Future studies and trials are needed to standardize the best therapies.
4. What are the pharmacologic properties of available thrombolytics?
   • Thrombolytics catalyze the conversion of plasminogen to plasmin, leading to fibrin degradation and thrombus dissolution.
   • Alteplase is a recombinant tissue plasminogen activator, administered intravenously at a dose of IV 100 mg infusion over 2 hours. In cardiac arrest, the initial: 50 mg bolus over 2 minutes and continue CPR; after 15 minutes, if return of spontaneous circulation is not achieved and the medical team decides to continue CPR, repeat 50 mg bolus.
   • Tenecteplase is a modified variant of alteplase with increased fibrin specificity. The usual dose is weight-based and delivered via IV bolus, which facilitates rapid delivery in emergency settings. Dose per weight: ≥60 to <70 kg: 35 mg, ≥70 to <80 kg: 40 mg, ≥80 to <90 kg: 45 mg, ≥90 kg: 50 mg
5. Are there any ongoing clinical trials and emerging therapies investigating novel thrombolytics and strategies to optimize efficacy while minimizing bleeding risk?
   • PEITHO-3 is a large, randomized, double-blind, multinational study comparing reduced-dose intravenous alteplase with standard heparin in patients with intermediate-high-risk PE.

References1. Sedhom R, Megaly M, Elbadawi A, et al. Contemporary national trends and outcomes of pulmonary embolism in the United States. Am J Cardiol. 2022;176:132-138. doi:10.1016/j.amjcard.2022.03.060 2. Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14. Epub 2014 Jun 10. 3. Zuo Z, Yue J, Dong BR, Wu T, Liu GJ, Hao Q. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2021;CD004437. 4. Feltes J, Popova M, Hussein Y, Pierce A, Yamane D. Thrombolytics in cardiac arrest from pulmonary embolism: a systematic review and meta-analysis. J Intensive Care Med. 2023;39(5):477-483. 5. Javaudin F, Lascarrou JB, Le Bastard Q, Bourry Q, Latour C, De Carvalho H, Le Conte P, Escutnaire J, Hubert H, Montassier E, Leclère B; Research Group of the French National Out-of-Hospital Cardiac Arrest Registry (GR-RéAC). Thrombolysis during resuscitation for out-of-hospital cardiac arrest caused by pulmonary embolism increases 30-day survival: findings from the French National Cardiac Arrest Registry. Chest. 2019 Dec;156(6):1167-1175. Epub 2019 Aug 2. 6. Bonnard T, Tennant Z, Niego B, Kanojia R, Alt K, Jagdale S, Law LS, Rigby S, Medcalf RL, Peter K, Hagemeyer CE. Novel thrombolytic drug based on thrombin cleavable microplasminogen coupled to a single-chain antibody specific for activated GPIIb/IIIa. J Am Heart Assoc. 2017 Feb 3;6(2):e004535. 7. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S-e496S. Erratum in: Chest. 2012 Dec;142(6):1698-1704. 8. Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AG, Gent M. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990 Dec;98(6):1473-1479. 9. Rivera-Lebron B, Weinberg AS. Acute pulmonary embolism in adults: Reperfusion therapy in intermediate- and high-risk patients. In: Connor RF, ed. UpToDate. Waltham, MA: UpToDate Inc. Accessed August 28, 2025.

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CardioNerds (Drs. Natalie Marrero, Shivani Reddy, and Rebecca S. Steinberg), discuss the role of SGLT2i in cancer therapy-related cardiac dysfunction (CTRCD) with Dr. Manu Murali Mysore.

This episode was produced as part of the CardioNerds Academy curriculum by House Taussig under the guidance of House Chief, Dr. Natalie Marrero, and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

Summary: Cancer therapy-related cardiac dysfunction (CTRCD) spans a spectrum from subclinical biomarker elevation to overt heart failure, with risk amplified by preexisting cardiovascular disease, diabetes, hypertension, obesity, and exposure to therapies, such as anthracyclines, HER2-targeted therapies, or radiation. This episode explores the emerging and promising role of SGLT2 inhibitors as a cardioprotective adjunct in cardio-oncology — examining mechanisms, clinical evidence, ongoing trials, and critical knowledge gaps — while affirming that guideline-directed medical therapy remains the cornerstone of prevention and treatment.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. CTRCD is a spectrum — catch it early. CTRCD ranges from subclinical injury detected by imaging and biomarkers to overt heart failure. Early identification in high-risk patients (preexisting CVD, diabetes, HTN, obesity, anthracycline/HER2/radiation exposure) is essential, and early initiation of guideline-directed medical therapy — including ACE inhibitors/ARBs/ARNIs, mineralocorticoid receptor antagonists, and beta-blockers — remains the backbone of prevention and treatment to preserve LVEF and allow safe continuation of cancer therapy. 2. SGLT2 inhibitors are a promising new pillar of cardioprotection in cardio-oncology. They act through a unique combination of mechanisms: renal effects, metabolic reprogramming of the myocardium, anti-inflammatory and antioxidant pathways, and vascular fibrosis modulation — making them a compelling complement to standard therapies rather than a replacement. 3. Early clinical data is encouraging but not yet definitive. The 2024 EMPACARD-PILOT trial demonstrated preserved LVEF and reduced CTRCD in higher-risk patients with diabetes or kidney disease. Ongoing trials — EMPACT and PROTECT — are actively exploring SGLT2 inhibitors for primary prevention during anthracycline and HER2-targeted therapy. 4. SGLT2 inhibitors are NOT yet indicated for ICI-related myocarditis. Immune checkpoint inhibitor (ICI)-related myocarditis is mechanistically immune-driven. While SGLT2 inhibitors have theoretically anti-inflammatory benefits, there is currently no clinical evidence to support their use in this specific setting. 5. The use of SGLT2 inhibitors should be guided by patient risk, existing indications, and ongoing research. Large prospective trials, clarity on timing and patient selection, long-term safety data, and deeper mechanistic understanding in humans remain the most urgent gaps in the field before broader adoption can be recommended.

References1. Theofilis P, Vlachakis PK, Oikonomou E, et al. Cancer therapy-related cardiac dysfunction: A review of current trends in epidemiology, diagnosis, and treatment. Biomedicines. 2024;12(12):2914. doi:10.3390/biomedicines12122914. https://pubmed.ncbi.nlm.nih.gov/39767820/ 2. Lyon AR, Dent S, Stanway S, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. Eur J Heart Fail. 2020;22(11):1945-1960. doi:10.1002/ejhf.1920. https://pmc.ncbi.nlm.nih.gov/articles/PMC8019326/ 3. Li X, Li Y, Zhang T, et al. Role of cardioprotective agents on chemotherapy-induced heart failure: A systematic review and network meta-analysis of randomized controlled trials. Pharmacol Res. 2020;151(104577):104577. doi:10.1016/j.phrs.2019.104577. https://pubmed.ncbi.nlm.nih.gov/31790821/ 4. Lee YH, Lim S, Davies MJ. Cardiometabolic and renal benefits of sodium-glucose cotransporter 2 inhibitors. Nat Rev Endocrinol. 2025;21(12):783-798. doi:10.1038/s41574-025-01170-4. https://pubmed.ncbi.nlm.nih.gov/40935880/ 5. Dabour MS, George MY, Daniel MR, Blaes AH, Zordoky BN. The cardioprotective and anticancer effects of SGLT2 inhibitors: JACC: CardioOncology state-of-the-art review. JACC CardioOncol. 2024;6(2):159-182. doi:10.1016/j.jaccao.2024.01.007. https://pubmed.ncbi.nlm.nih.gov/38774006/ 6. Armillotta M, Angeli F, Paolisso P, et al. Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure. Pharmacol Ther. 2025;270(108861):108861. doi:10.1016/j.pharmthera.2025.10886. https://pubmed.ncbi.nlm.nih.gov/40245989/ 7. Góes-Santos BR, Castro PC, Girardi ACC, Antunes-Correa LM, Davel AP. Vascular effects of SGLT2 inhibitors: evidence and mechanisms. Am J Physiol Cell Physiol. 2025;329(4):C1150-C1160. doi:10.1152/ajpcell.00569.2025. https://pubmed.ncbi.nlm.nih.gov/40908107/ 8. Daniele AJ, Gregorietti V, Costa D, López-Fernández T. Use of EMPAgliflozin in the prevention of CARDiotoxicity: the EMPACARD – PILOT trial. CardioOncology. 2024;10(1):58. doi:10.1186/s40959-024-00260-y. https://pubmed.ncbi.nlm.nih.gov/39237985/ 9. Clinicaltrials.gov. Clinicaltrials.gov. Accessed April 16, 2026. https://clinicaltrials.gov/study/NCT05271162 10. Greco A, Quagliariello V, Rizzo G, et al. SGLT2i Dapagliflozin in primary prevention of chemotherapy induced cardiotoxicity in breast cancer patients treated with neo-adjuvant anthracycline-based chemotherapy +/- trastuzumab: rationale and design of the multicenter PROTECT trial. CardioOncology. 2025;11(1):79. doi:10.1186/s40959-025-00368-9. https://pmc.ncbi.nlm.nih.gov/articles/PMC12400668/

Key Guideline Reference: Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European hematology association (EHA), the European society for therapeutic radiology and oncology (ESTRO) and the international cardio-oncology society (IC-OS). Eur Heart J Cardiovasc Imaging. 2022;23(10):e333-e465. doi:10.1093/ehjci/jeac106. https://pubmed.ncbi.nlm.nih.gov/36017575/

Be sure to check out the corresponding review article on the cardioprotective role of SGLT2 inhibitors in CTRCD that will be published in US Cardiology Review, the official journal of CardioNerds. Additionally, please reference CardioNerds Cardio-Oncology Episodes 261 and 274 for related content.

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Dr. Jenna Skowronski, Dr. Shazli Khan, and Dr. Alix Barnes discuss the involvement of palliative care throughout the heart failure spectrum with Dr. Sarah Chuzi. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

In this episode, we discuss utilizing palliative care principles while caring for patients with heart failure, particularly those being considered for advanced therapies. We emphasize utilization of communication frameworks when discussing prognosis and making decisions on pursuing therapies such as palliative inotropes, left ventricular assist devices (LVADs), and heart transplant. Additionally, we discuss when to involve specialty palliative care services. Finally, we highlight the difference between palliative care and hospice and how to help patients navigate the transition from life-prolonging care to hospice.

Dr. Jenna Skowronski is the Chair for the CardioNerds Heart Failure Council. Dr. Jenna Skowronski and Dr. Shazli Khan are the Co-chairs for the CardioNerds Advanced Heart Failure Therapies Series. Dr. Alix Barnes is the CardioNerds FIT Ambassador at UPMC and member of the CardioNerds Critical Care Cardiology Council.

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey.

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Pearls1. Primary palliative care is care provided by a clinician that is not a palliative care specialist, such as a heart failure clinician having a conversation with a patient about their goals and values in clinic. 2. Taking time to get to know a patient as an individual and learning their goals and values prior to diving into conversations about prognosis and change in treatment plan facilitates more effective goals of care discussions. 3. Utilizing and practicing a communication framework can improve our skills at goals of care discussions. 4. Palliative inotropes should be reserved for patients experiencing symptomatic benefit from the therapy that outweighs the associated risks including arrhythmias and infections. The burden of managing these therapies at home should also be considered. 5. Partnerships between cardiologists and hospice agencies can improve the experience for patients with heart failure who enroll in hospice. Cardiologists can continue to see their patients even after hospice enrollment and help with symptom management.

NotesNotes: Notes drafted by Dr. Barnes.

1. What is the difference between primary palliative care and specialty palliative care?

2. Primary palliative care is the delivery of palliative care services that any clinician can deliver.

3. This includes aligning treatment with a patient’s goals and basic symptom management. For heart failure patients, symptom management can include cardiac symptoms such as dyspnea and chest pain as well as managing comorbid mood disorders such as adjustment disorder, depression, and anxiety.

4. Advanced palliative care skills take additional training and time to develop. These include leading a difficult family meeting, managing symptoms that are not controlled with standard therapies and responding to emotional and spiritual distress. When these situations are encountered, referral to a specialty palliative care service should be considered. 1

5. How is palliative care integrated throughout the disease trajectory of a patient with heart failure?

6. Heart failure clinicians deliver primary palliative care when assessing a patient’s preferences, goals and values or managing symptoms.

7. As a patient’s disease progresses, the heart failure team also engages in primary palliative care when delivering news about prognosis.
8. When advanced therapies are being considered, utilization of shared decision-making (SDM) should be employed (see question 3 for further discussion on SDM).
9. For patients being considered for LVAD, the Centers for Medicare and Medicaid Services (CMS) mandates that patients are seen by a palliative care specialist prior to implantation. 2
10. Despite this, there remains variability in how institutions involve specialty palliative care in this decision-making process. Thoughtful consideration of what palliative care resources are available at your institution should guide how best to integrate specialty palliative care teams into the LVAD decision tree.

11. One example of a model for meeting this mandate is having a small team of heart failure clinicians with additional palliative care training meet all patient’s being evaluate for LVAD.

12. What is shared decision-making (SDM) and how is it utilized when evaluating a patient for advanced therapies?

13. SDM is a collaborative process where patients and clinicians work together to make medical decisions that are aligned with a patient’s goals and values.3

14. There are a variety of communication frameworks that can be used to engage in effective SDM.
15. One framework is the Serious Illness Conversation guide. This is an evidenced based framework that can be used to deliver the news about a patient’s current condition and then assess their goals, values and preferences for next steps in their treatment plan.4 This framework can be helpful when discussing prognosis prior to introducing the idea of an evaluation for advanced therapies.
16. REMAP is a second commonly used framework which stands for Reframe, Expect Emotion, Map What’s Important, Align, and Plan.5 This framework is similarly helpful when starting a discussion about advanced therapies with a patient.
17. Both frameworks prioritize learning about a patient’s goals, values, and preferences prior to making a recommendation for a treatment plan. Listening more than speaking and accepting that a patient and their family may choose a path that is different than what you personally might choose for yourself or your loved ones are vital pillars to engaging in these conversations effectively.
18. When discussing LVAD, it is important to avoid framing the decision as “LVAD or no LVAD,” rather LVAD versus best supportive care.

19. The “Best Case, Worst Case” framework is an effective way to create choice awareness for patients when they are faced with making this decision. This is a way to discuss both the best outcomes after LVAD implantation as well as the potential complications so a patient is better able to understand the full spectrum of possible outcomes. 6

20. How do you select which patients would benefit from home inotrope therapy?

21. There is no data demonstrating a survival benefit with use of palliative inotropes. There may be subsets of patients who derive a survival benefit, such as patients whose renal function worsens when the agent is withdrawn, however there is no concrete data proving this. 7

22. Therefore, the benefit of home inotrope therapy should be based on if the patient derives symptomatic benefit from these agents. Additionally, risks of the therapy such as arrhythmias and infection as well as the burden of managing these therapies at home should also be weighed in the decision.8

23. Life expectancy for patients being initiated on palliative inotropes likely ranges from 6 to 9 months. Given this prognosis, concordant palliative care efforts should be intensified when starting patients on these agents. This can either be through involvement in specialty palliative care or increasing primary palliative care interventions. 9

24. How do you determine if a patient would be a candidate for hospice and how do you discuss hospice with patients and their families?

25. Hospice is a comprehensive program that provides supportive care to patients at end of life. This includes a team of physicians, nurses, aids, social workers and chaplains that can deliver care in the home, at a nursing facility, or in an inpatient hospice facility. 10

26. Patients with a prognosis of 6 months or less can qualify for hospice services.
27. Even if a patient qualifies for hospice based on their prognosis, it is important to assess if a patient’s goals and values align with hospice. Introducing hospice to patients who still desire life prolonging care can cause mistrust between the patient and their health care team.

28. When introducing hospice, it is helpful to describe the services hospice offers in addition to naming the service as some patients may have a negative connotation with the word “hospice.”

29. How can cardiologists partner with hospice agencies to provide better care for these patients?

30. Heart failure specialists can continue to see their patients even after they enroll in hospice. Partnering in hospice agencies in this way can help improve symptom management for patients while also allowing them to continue meaningful relationships with providers with whom they’ve developed a longitudinal relationship with.

31. Guideline directed medical therapy (GDMT) and diuretics can be continued while enrolled in hospice as long as they are offering symptomatic benefit. Heart failure specialists can help with adjusting GDMT to cheaper formulations, such as exchanging angiotensin receptor-neprilysin inhibitors (ANRIs) for angiotensin receptor blockers (ARBs).
32. Many hospice agencies cannot accept patients receiving palliative inotropes due to the resources and training required to safely care for these patients. Understanding what hospice agencies in your area can and cannot support allows heart failure specialists to have informed discussions with patients and make appropriate referrals.

References1. Quill TE, Abernethy AP. Generalist plus Specialist Palliative Care — Creating a More Sustainable Model. N Engl J Med. 2013;368(13):1173-1175. doi:10.1056/NEJMp1215620. https://www.nejm.org/doi/full/10.1056/NEJMp1215620 2. Ventricular Assist Devices for Bridge-to-Transplant and Destination Therapy. Published online August 1, 2013. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=268 3. Godfrey S, Barnes A, Gao J, Katz JN, Chuzi S. Shared Decision-making in Palliative and End‑of‑life Care in the Cardiac Intensive Care Unit. US Cardiol Rev. 2024;18:e13. doi:10.15420/usc.2024.03. https://pubmed.ncbi.nlm.nih.gov/39494405/ 4. Baxter R, Pusa S, Andersson S, Fromme EK, Paladino J, Sandgren A. Core elements of serious illness conversations: an integrative systematic review. BMJ Support Palliat Care. 2024;14(e3):e2268-e2279. doi:10.1136/spcare-2023-004163. https://pmc.ncbi.nlm.nih.gov/articles/PMC11671901/ 5. Childers JW, Back AL, Tulsky JA, Arnold RM. REMAP: A Framework for Goals of Care Conversations. J Oncol Pract. 2017;13(10):e844-e850. doi:10.1200/JOP.2016.018796. https://ascopubs.org/doi/10.1200/JOP.2016.018796 6. Kruser JM, Nabozny MJ, Steffens NM, et al. “Best Case/Worst Case”: Qualitative Evaluation of a Novel Communication Tool for Difficult in-the-Moment Surgical Decisions. J Am Geriatr Soc. 2015;63(9):1805-1811. doi:10.1111/jgs.13615. https://pmc.ncbi.nlm.nih.gov/articles/PMC4747100/ 7. Tolia S, Khan M, Khan S, et al. Mortality and long-term outcomes of palliative inotropes in ischemic and non-ischemic cardiomyopathy. Eur Heart J. 2021;42(Supplement_1):ehab724.0915. doi:10.1093/eurheartj/ehab724.0915. https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.0915/6392681 8. Chuzi S, Allen LA, Dunlay SM, Warraich HJ. Palliative Inotrope Therapy: A Narrative Review. JAMA Cardiol. 2019;4(8):815. doi:10.1001/jamacardio.2019.2081. https://jamanetwork.com/journals/jamacardiology/article-abstract/2737414#google_vignette 9. Chuzi S, Gao J, Thariath J, et al. Characteristics and Outcomes of Palliative Continuous Intravenous Inotrope Support Among Medicare Beneficiaries With Heart Failure. J Am Heart Assoc. 2025;14(14):e039397. doi:10.1161/JAHA.124.039397. https://www.ahajournals.org/doi/10.1161/JAHA.124.039397 10. What is hospice? Published online September 24, 2024. https://hospicefoundation.org/what-is-hospice/

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CardioNerds (Dr. Hamza Patel, Dr. Jenna Skowronski, and Dr. Apoorva Gangavelli) discuss advanced heart failure and LVAD management with Dr. Mark Belkin, Advanced Heart Failure & Transplant Cardiologist, and Dr. Chris Salerno, Cardiothoracic Surgeon. They explore the nuances of right ventricular (RV) physiology, perioperative hemodynamic optimization, long-term complications, sensitization and transplant considerations, and the evolving role of GDMT in LVAD patients. This episode highlights the delicate interplay between surgical and medical management in achieving optimal outcomes for patients living with durable mechanical circulatory support.Audio editing by CardioNerds Academy intern, student doctor, Pace Wetstein.

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Pearls1. “The right ventricle sets the stage.” — LVAD success hinges on RV performance; a struggling RV can turn a perfect LVAD surgery into a perfect storm. 2. “Watch the ratios.” — A PAPi < 2 and RA:PCWP >0.6 signal high risk for RV failure post-implant; trends and response to optimization matter more than static numbers. 3. “From hemocompatibility to hemodynamics.” — The LVAD field has moved from fighting pump thrombosis to mastering long-term RV failure and aortic insufficiency. 4. “Not all antibodies are created equal.” — LVAD-related sensitization often resolves post-transplant, reminding clinicians to interpret PRA trends in context. 5. “Recovery is possible.” — The RESTAGE-HF trial and emerging SGLT2 data hint at a new era: not just sustaining life with LVADs but restoring native heart function.

NotesNotes drafted by Dr. Hamza Patel.

1. Hemodynamic & Vasoactive Management of the RV

2. Use norepinephrine and vasopressin for pressor support; consider dobutamine as inotrope of choice.

3. Consider avoiding early milrinone due to hypotension and reduced coronary perfusion.
4. Use inhaled NO or epoprostenol selectively; institutional variation depends on cost and supply.
5. Key hemodynamic markers:
   • PAPi = (PA systolic – PA diastolic) / RA pressure.
   • PAPi < 2 → increased RV failure risk.
   • RA:PCWP ratio ≈ 0.6 normal; ≈ 1 → severe RV dysfunction.
6. RV reserve—the ability to improve these indices with optimization—is a stronger predictor of outcomes than baseline numbers alone.

7. NOTE: there is no robust data to guide vasoactive medical decision-making and there is substantial institutional variability in practive.

8. Long-Term LVAD Complications

9. MOMENTUM 3 trial: HeartMate 3 reduced pump thrombosis (10 → 1 %), stroke (14 → 5%), and GI bleed (77 → 43 %).

10. Persistent issues: driveline infections, RV failure, and aortic insufficiency.
11. Driveline care: silver sulfadiazine (Silvadene) cream linked to lower infection rates (Cowher & Kenmore 2025).
12. Field now focuses on hemodynamic-related adverse events—the next frontier in LVAD outcomes.

13. Innovation ahead: smaller drivelines and fully implantable LVADs to eliminate infection risk.

14. Sensitization and Transplant Candidacy

15. LVADs may induce de novo HLA antibodies, complicating transplant matching.

16. These antibodies tend to be transient and less cytotoxic, often resolving post-transplant.
17. Sensitization degree varies by device and patient; management strategies are center-dependent.

18. The field is redefining which antibodies are truly LVAD-induced versus incidental.

19. GDMT & Myocardial Recovery

20. GDMT data in LVAD patients limited—excluded from major HFrEF trials.

21. RESTAGE-HF: aggressive GDMT post-LVAD yielded 52% explant rate within 18 months.
22. SGLT2 inhibitors: emerging evidence of reverse remodeling and reduced LV size (Belkin et al., THT 2025).

23. GDMT promotes recovery but requires cautious titration to avoid hypotension and RV strain.

24. Future of LVAD Therapy

25. The fully implantable LVAD remains the goal—wireless energy, no driveline, and fewer infections.

26. Short-term focus: device miniaturization, improved energy efficiency, and better hemocompatibility.
27. HeartMate 3 remains gold standard until next-generation systems mature.

References1. Mehra MR et al. NEJM 2018 — MOMENTUM 3 Final Report. 2. Takeda K et al. JHLT 2020 — Predictors of RV Failure After LVAD. 3. Imamura T et al. Circ Heart Fail 2017 — Hemodynamics and RV Adaptation Post-LVAD. 4. RESTAGE-HF Trial, JHLT 2019. 5. Cowher J, Kenmore C et al. 2025 — Driveline Care & Infection Outcomes. 6. Belkin M et al. THT 2025 — SGLT2 Inhibition and Reverse Remodeling Post-LVAD.

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This inaugural episode of the CardioNerds Pulmonary Embolism (PE) Series explores the evolution of acute PE care. Dr. Ibrahim Zahid, Dr. Dinu Balanescu, and Dr. Billy Joe Mullinax join guest expert Dr. Kenneth Rosenfield to discuss the shifting landscape of PE management.

Pulmonary embolism (PE) remains a leading cause of cardiovascular mortality and a frequent diagnostic challenge, often masquerading as myocardial infarction or a benign illness. Over the past decade, PE care has evolved from anticoagulation-only strategies to nuanced, risk-stratified, multidisciplinary management. Modern approaches integrate hemodynamics, biomarkers, and advanced imaging to guide therapy, including catheter-directed interventions and large-bore thrombectomy. The Pulmonary Embolism Response Team (PERT) model addresses historical gaps by coordinating rapid, multispecialty decision-making and standardizing care pathways. The PERT Consortium further advances PE care through education, research, and the world’s largest PE registry, while fostering leadership and research opportunities for trainees. Despite advances, long-term outcomes and post-PE syndromes remain important areas for future investigation. Audio editing by CardioNerds Academy intern, student doctor, Pace Wetstein.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. PE is a “master masquerader”—maintain suspicion for atypical presentations like myocardial infarction, heart failure, flu, or anxiety. 2. Multidisciplinary management mediated through pulmonary embolism response teams improves outcomes and standardizes care. 3. Risk stratification integrates hemodynamics, biomarkers, and imaging. 4. Advanced therapies have expanded beyond anticoagulation. 5. Long‑term follow‑up and post‑PE syndrome need more research.

NotesNotes: Notes drafted by Dr. Ibrahim Zahid.

1. How has the clinical approach to PE changed over the past decade?

2. PE is the third leading cause of cardiovascular death and historically under‑recognized.

3. Symptoms mimic MI, HF, asthma, syncope, and more.PE is a silent killer, and it should be recognized more as a cause of spontaneous cardiac arrest.

4. Where life threatening disease like stroke which is owned by neurological specialists and MI is primarily managed by cardiac specialists, PE is an entity without a professional home. The PERT Consortium brings the specialties together for PE care.

5. Ten years ago, a 58-year-old patient with a large bilateral PE, RV dilation, and positive biomarkers might have been managed with anticoagulation and close observation alone. Today, with evolving—but still uneven—data on advanced therapies, PE care feels far more nuanced and highly dependent on where you practice. What are the major gaps in traditional PE management that clinicians should recognize, and what care pathways should they be aware of across different hospital systems?

6. Care has shifted from anticoagulation‑only to multidisciplinary approaches like catheter directed thrombectomy.

7. Risk‑based pathways and the use of CT angiogram has improved early recognition. Risk stratification tools must be used as tools for early recognition of intermediate risk PE.

8. Untreated PE leads to chronic complications like chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension, which requires long term clinic follow up.

9. What is the role of risk stratification tools such as PeSI, sPeSI scores, cardiac biomarkers, and imaging findings in PE, and how do they guide treatment decisions in real world practice?

10. Integrate vitals (blood pressure and heart rate), biomarkers (troponin, pro-BNP), RV/LV ratio assessment, acid‑base status, and scores.

11. Tools include PESI, sPESI, BOVA, HESTIA, FAST, Geneva, NEWS, shock index.
12. Vitals, lactate, acid-base status, and tools like NEWS or shock index track clinical evolution.
13. PESI/sPESI estimate 30-day mortality and help identify low-risk patients who may be candidates for early discharge or outpatient therapy.

14. Clinical judgment matters—scores don’t fully capture clot burden, trajectory, or bleeding risk.

15. How was the pulmonary embolism response team created, and since its creation, what evidence or outcome data became available to support the PERT model?

16. Originated after a sentinel case at MGH: A young, pregnant woman in her 30s, who collapsed at home, underwent thrombectomy, and had to be on ECMO for a few days. The case brought cardiology, cardiac surgeons and critical care physicians together for planning and improvement in her health, which was rewarding.

17. Thereby, it was decided to bring specialties involved in PE care together to create a response team.
18. The name of the team, Pulmonary Embolism Response Team (PERT), was coined by Richard Channick in the first meeting.
19. Posters were set up all over the hospital to call a centralized line when an acute PE is recognized
20. A meeting was held to present the concept of putting together a consortium, with development of action items and a PERT database.

21. Enabled rapid multidisciplinary input using early teleconferencing tools.

22. Given concerns about having too many ‘cooks in the kitchen’ during the initial PE call—especially with rotating teams—how can institutions reconcile workflow complexity with standardized pathways in a way that meaningfully supports and justifies the added burden on frontline clinicians?

23. Every hospital’s PERT is different, catering to their needs and workflow

24. At least two disciplines are needed to make a PERTData is currently being collected to guide further on how the workflow can be standardized

25. Most importantly, the team brings in resources that were not available prior to PERT formation.

26. What are the main goals of the PERT consortium, and how does it support clinicians and institutions involved?

27. To improve care and improve outcomes for patients with PE

28. Expand education, refine algorithms, standardize care with Centers of Excellence.

29. Maintain the largest PE registry for research and outcomes improvement.

30. Beyond global networking, shared learning from successful systems, and the pathway toward Center of Excellence designation, what additional benefits can clinicians and health systems gain by participating in the PERT Consortium?

31. The ability to learn from other systems, the ability to share experiences.

32. Allow people to develop their professional careers like leadership experience, becoming a member of the trainee council

33. Initiate projects and receive funding for your ideas

34. For trainees interested in pulmonary embolism care, how can a trainee be a champion at their institution? Does PERT provide assistance and how can they really contribute meaningfully even before becoming a fellow/attending?

35. Medical students and residents interested in PE should reach out to the consortium and the consortium will hook you up with the correct mentors who can nurture you along.

36. Listen to the podcasts.
37. Participate with your local PERT team
38. PERT wants involvement of people who are social media savvy to help spread the word on PE.

Top three take-away points from this episode

1. Acute PE care has advanced and multiple treatment modalities for acute PE including catheter directed therapy, large bore thrombectomy, are becoming standard of care.
2. Multidisciplinary models like PERT improve coordination and outcomes.
3. Trainees play a vital role in advancing PE care through involvement, research, and education

References1. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jiménez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ní Áinle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020 Jan 21;41(4):543-603. doi: 10.1093/eurheartj/ehz405. PMID: 31504429. https://pubmed.ncbi.nlm.nih.gov/31504429/ 2. Rosovsky R, Zhao K, Sista A, Rivera-Lebron B, Kabrhel C. Pulmonary embolism response teams: Purpose, evidence for efficacy, and future research directions. Res Pract Thromb Haemost. 2019 Jun 9;3(3):315-330. doi: 10.1002/rth2.12216. PMID: 31294318; PMCID: PMC6611377. https://pmc.ncbi.nlm.nih.gov/articles/PMC6611377/ 3. Rosenfield K, Bowers TR, Barnett CF, Davis GA, Giri J, Horowitz JM, Huisman MV, Hunt BJ, Keeling B, Kline JA, Klok FA, Konstantinides SV, Lanno MT, Lookstein R, Moriarty JM, Ní Áinle F, Reed JL, Rosovsky RP, Royce SM, Secemsky EA, Sharp ASP, Sista AK, Smith RE, Wells P, Yang J, Whatley EM; Pulmonary Embolism Research Collaborative (PERC) Attendees. Standardized Data Elements for Patients With Acute Pulmonary Embolism: A Consensus Report From the Pulmonary Embolism Research Collaborative. Circulation. 2024 Oct;150(14):1140-1150. doi: 10.1161/CIRCULATIONAHA.124.067482. Epub 2024 Sep 12. PMID: 39263752; PMCID: PMC11698503. https://pubmed.ncbi.nlm.nih.gov/39263752/ 4. Sharifi M, Awdisho A, Schroeder B, Jiménez J, Iyer P, Bay C. Retrospective comparison of ultrasound facilitated catheter-directed thrombolysis and systemically administered half-dose thrombolysis in treatment of pulmonary embolism. Vasc Med. 2019 Apr;24(2):103-109. doi: 10.1177/1358863X18824159. Epub 2019 Mar 5. PMID: 30834822. https://pubmed.ncbi.nlm.nih.gov/30834822/ 5. Pandya V, Chandra AA, Scotti A, Assafin M, Schenone AL, Latib A, Slipczuk L, Khaliq A. Evolution of Pulmonary Embolism Response Teams in the United States: A Review of the Literature. J Clin Med. 2024 Jul 8;13(13):3984. doi: 10.3390/jcm13133984. PMID: 38999548; PMCID: PMC11242386. https://pubmed.ncbi.nlm.nih.gov/38999548/ 6. Rivera-Lebron B., McDaniel M., Ahrar K., Alrifai A., Dudzinski D.M., Fanola C., Blais D., Janicke D., Melamed R., Mohrien K., et al. Diagnosis, Treatment and Follow Up of Acute Pulmonary Embolism: Consensus Practice from the PERT Consortium. Clin. Appl. Thromb. Hemost. 2019;25:1076029619853037. doi: 10.1177/1076029619853037.
https://pubmed.ncbi.nlm.nih.gov/31185730/

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CardioNerds (Dr. Jenna Skowronski [Heart Failure Council Chair], Dr. Shazli Khan, and Dr. Josh Longinow) are joined by renowned leaders in the field of AHFTC (Advanced Heart Failure and Transplant Cardiology) and mechanical circulatory support, Dr. Jeff Teuteberg and Dr. Mani Daneshmand to continue the discussion of advanced heart failure therapies by taking a deep dive into the world of durable LVADs (Left Ventricular Assist Devices). In this episode, we will review the history of ventricular assist devices, the basics of LVAD function, selection criteria for LVAD therapy, and surgical nuances of LVAD implantation. Audio Editing by CardioNerds intern, Joshua Khorsandi.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. There have been significant advances in the field of MCS/LVAD therapy since the first implanted LVAD in the 1960s, to the first FDA approved device in the early 2000’s, to now the HM3 LVAD, with the most important change being a centrifugal flow/magnetically levitated design that led to minimized hemocompatibility-related adverse events (HRAE’s) (MOMENTUM 3 trial comparing HM2 and HM3). 2. The REMATCH trial in 2001 was a pivotal trial for LVAD therapy, demonstrating that in a population of patients with advanced HF (70% IV inotrope dependent), LVAD therapy significantly improved survival at both 1 and 2 years as compared to medical therapy alone. 3. MOMENTUM 3 trial was a landmark trial for the HM3 device, showing that in a population of end stage HF patients (86% inotrope dependent, 32% INTERMACS 1-2, and 60% DT strategy), 5-year survival with HM3 was 58% and HM3 had lower HRAE’s compared with HM2. 4. There are both patient-specific factors and surgical considerations when it comes to candidacy for LVAD therapy. 5. RV function prior to LVAD is a key determinant for success post-LVAD * Many patients being considered for LVAD may not have robust RV function, however, predicting RV failure after LVAD is exceedingly difficult. * In general, it doesn’t matter how bad the RV may look on imaging; we care more about the pre-LVAD hemodynamics (look at the PAPi and RA/wedge ratio). * What happens in the OR may be the most important determinant of how the RV will do with the LVAD!

NotesNotes drafted by Dr. Josh Longinow.

1. Historical background of heart pumps and LVADs

| LVAD Evolution | | FDA approval year | 2001 | 2008 | 2012 | 2017 | | Pump | HeartMate XVE | HeartMate II | Heartware HVAD | HeartMate III | | Flow/Design Features | Pulsatile Technology | Continuous flow Axial design | Continuous flow Centrifugal design | Continuous flow Full MagLev + Centrifugal design |

The 1960’s ushered in the first ‘LVADs’, when the first air-powered ‘LVAD’ was implanted. It kept the patient alive for four days before the patient expired.

• The first generation of LVADs were pulsatile pumps
• The first nationally recognized, FDA approved LVAD was the HeartMate XVE (late 1990s to early 2000s, REMATCH trial). The XVE pump used compressed air (pneumatically driven) to power the pump.
  • Prior to the XVE, OHT was the standard of care for patients with advanced, end-stage heart failure.
• The second and third generations of LVADs were non-pulsatile, continuous flow devices and included the HVAD, HM2, and HM3 devices.
• MOMENTUM 3 was a landmark trial for the HM3 device, showing that in a population of sick patients with end stage HF (86% inotrope dependent, 32% INTERMACS 1-2, and 60% DT strategy), 5-year survival with HM3 was 58% and HM3 had lower HRAE’s compared with HM2.

• The only pump that is currently FDA approved for implant is the HM3, although other pumps are in clinical trials (BrioVAD system, INNOVATE Trial).

• What are LVADs, and how do they work?

In simplest terms, the LVAD is a heart pump comprised of several key mechanistic components:

1. Inflow cannula
2. Mechanical pump
3. Outflow cannula
4. Driveline
5. Controller/Power source

The HM3 differs from its predecessors (HM2 and HVAD) in several key ways;

1. HM3 is placed intrapericardial whereas the HM2 was placed pre-peritoneal.
2. Perhaps most importantly, the HM3 is a fully magnetically levitated, centrifugal flow pump, whereas the HM2 is an axial flow device.

Axial flow pumps are not magnetically levitated, leading to more friction produced between the ruby bearing’s contact with the pump rotors, and higher rates of hemocompatibility related adverse events (HRAEs, i.e. pump thrombosis) and the HM2 was ultimately discontinued in favor of the HM3 (MOMENTUM 3 trial).

1. What do the terms ‘Destination Therapy’ (DT) or ‘Bridge to Transplant’ (BTT) mean when it comes to LVADs?

2. When LVADs first came on the stage, EVERYONE was a BTT; these early pumps weren’t designed for long term use (I.e. REMATCH Trial, Heartmate XVE)

3. Destination therapymeans the LVAD was placed in leu of transplant because there are contraindications to transplant
   • REMATCH trial brought about the concept of “Destination therapy”, comparing outcomes in patients (with contraindications for transplant) who received an LVAD vs optimal medical therapy
4. Bridge to transplantmeans we are placing the LVAD in a patient who may not be a transplant candidate at this moment in time (is too sick, or conversely, not sick enough), but may be down the line

5. Bridge to recoveryis another term used when the LVAD is being placed for a patient we think may have a recoverable cardiomyopathy

6. What are some factors we should consider when assessing a patient’s candidacy for LVAD, in general, and from a surgical perspective?

Patient factors

1. Older age might push us towards thinking LVAD rather than transplant
   • In general, age > 70 is the cutoff for transplant, but this is not a hard cut off and varies institution to institution
2. In general, think about things that help predict recovery after a major surgery; Frailty and Nutritional status are important, we try to optimize these prior to LVAD implant
3. Right ventricular function remains the Achilles heel of LV support
   • We know that needing temporary RV support post LVAD puts you on a different survival curve than patients who don’t need RVAD support
   • Studies have not been able to successfully predict who will develop RV failure after LVAD implantation
   • What happens in the time between when the patient goes to the OR and when they get back to the ICU is an important determinant who might develop RV failure post LVAD
   • Surgical techniques such as implanting the HM3 in the intra-thoracic cavity, rather than intra-pericardial may help maintain LV/RV geometry to help optimize the RV post LVAD

Surgical considerations for LVAD candidacy

• Small, hypertrophied LV: HM3 inflow cannula is small, but small hypertrophied ventricles tend towards chamber collapse during systole causing suction, needing to run slower with lower flow rates
• Chest size/diameter: pumps have gotten so small now, that for adults, these have become less of a consideration
• BMI: low BMI used to be more of a concern with the older pumps due to where they were placed, and the relative size of the pump itself, not so much now with the smaller HM 3 pumps
• Calcified LV apex: would increase risk of stroke, bleeding

• Driveline tunneling becomes a concern in the super obese population, higher risk for driveline infections (might tunnel these driveline’s shorter, and to a less fatty region of the abdomen, could even tunnel out the thoracic cavity in the super obese to limit skin motion)

• Is there a role for MCS (i.e. temporary LVAD such as Impella) in pre-habilitation of patients prior to LVAD surgery?

• The theory of being able to improve systemic perfusion, decongest the organs, and make the patient feel better prior to surgery makes sense, but becomes problematic due to the lack of a hard end point/time for prehabilitation which might risk delays in surgery

• More likely that it can lead to delay in the surgery, with less-than-optimal benefit; you don’t want to prolong the wait for surgery and increase the risk for complications prior to surgery
• An Impella 5.5 is currently FDA approved for 2 weeks of support, not 2 months so timing is important to keep in mind

• It’s unlikely that you will take a patient and convert them from a malnourished, cachectic person in 2 weeks’ time

• Is there a role for LVAD therapy in the younger patient population? Should we be thinking of LVAD up front for these patients, with the goal of transplanting down the line?

• Recovery may be more likely in certain populations, particularly younger females with smaller LV’s; in those populations, perhaps bridge to recovery should be the focus, optimizing them on GDMT etc.

• The replacement of transplant, with MCS (LVAD) in young patients has become a topic of discussion, because these pumps have become better and better, with the thinking that an LVAD could bridge a patient for 10 years or so, and they could get a transplant later
• It is still a big unknown, but several concerns exist
  • Patients who get LVADs might end up with complications that become contraindication to transplant down the line (stroke, sensitization etc)
  • Patients and providers are more hesitant because of the more recent iteration for the UNOS criteria for OHT listing which no longer gives patients with an uncomplicated LVAD higher priority, and therefore they could end up waiting a longer time for a heart after undergoing LVAD

References1. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):1435-1443. doi:10.1056/NEJMoa012175 2. Mehra MR, Uriel N, Naka Y, et al. A Fully Magnetically Levitated Left Ventricular Assist Device – Final Report. N Engl J Med. 2019;380(17):1618-1627. doi:10.1056/NEJMoa1900486 3. Mancini D, Colombo PC. Left Ventricular Assist Devices: A Rapidly Evolving Alternative to Transplant. J Am Coll Cardiol. 2015;65(23):2542-2555. doi:10.1016/j.jacc.2015.04.039 4. Mehra MR, Goldstein DJ, Cleveland JC, et al. Five-Year Outcomes in Patients With Fully Magnetically Levitated vs Axial-Flow Left Ventricular Assist Devices in the MOMENTUM 3 Randomized Trial. JAMA. 2022;328(12):1233-1242. doi:10.1001/jama.2022.16197 5. Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg. 1999;67(3):723-730. doi:10.1016/s0003-4975(99)00042-9 6. Kittleson MM, Shah P, Lala A, et al. INTERMACS profiles and outcomes of ambulatory advanced heart failure patients: A report from the REVIVAL Registry. J Heart Lung Transplant. 2020;39(1):16-26. doi:10.1016/j.healun.2019.08.017 7. Mehra MR, Netuka I, Uriel N, et al. Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial. JAMA. 2023;330(22):2171-2181. doi:10.1001/jama.2023.23204 8. Mehra MR, Nayak A, Morris AA, et al. Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device. JACC Heart Fail. 2022;10(12):948-959. doi:10.1016/j.jchf.2022.08.002 9. Bhardwaj A, Salas de Armas IA, Bergeron A, et al. Prehabilitation Maximizing Functional Mobility in Patients With Cardiogenic Shock Supported on Axillary Impella. ASAIO J. 2024;70(8):661-666. doi:10.1097/MAT.0000000000002170

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CardioNerds (Dr. Ramy Doss, Dr. Kelly Arps, and Dr. Naima Maqsood) dive into the nuances of atrial fibrillation (AF) ablation with Dr. Jon Piccini. They provide a high-yield overview of AF ablation, guiding listeners from patient selection through post-procedural management. We review appropriate candidacy for catheter ablation across AF phenotypes, key elements of pre-procedural evaluation including imaging and anticoagulation strategy, and the fundamental procedural steps with pulmonary vein isolation as the cornerstone. The discussion compares lesion set strategies in de novo ablation and reviews currently used energy sources—including radiofrequency, cryoablation, and pulsed-field ablation—highlighting differences in safety and efficacy. They also examine surgical and hybrid approaches for selected patients and outline essential components of post-ablation care, including rhythm monitoring, anticoagulation decisions, and management of complications. This episode integrates contemporary evidence with practical insights to support clinicians delivering comprehensive AF ablation care. Audio editing for this episode was performed by CardioNerds intern Dr. Bhavya Shah.

NOTE: This episode was recorded in March 2025. Since then, the OCEAN trial showed that among patients who had had successful catheter ablation for atrial fibrillation at least 1 year earlier and had risk factors for stroke, treatment with rivaroxaban did not result in a significantly lower incidence of a composite of stroke, systemic embolism, or new covert embolic stroke than treatment with aspirin.

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PEARLS * Pulmonary veins (PVs) are the dominant triggers in early AF due to their unique myocardial sleeve electrophysiology. * Pulmonary vein isolation (PVI) remains the cornerstone of AF ablation by blocking PV triggers from reaching the left atrium. Posterior wall isolation is sometimes performed in persistent AFib, but large RCTs found no significant benefit over PVI alone. * Paroxysmal AF has the highest ablation success rates. Left atrial health remains the major determinant of outcome. * Ablation modalities include pulsed field ablation, radiofrequency ablation, and cryo-balloon ablation. PFA offers advantage of relative myocardial selectivity with near zero risk of atrio-esophageal fistula. * Long-term anticoagulation decisions after ablation currently depend on CHA₂DS₂-VASc score. Recent evidence suggests the safety of stopping anticoagulation in low-risk patients after ablation. * Early atrial arrhythmia recurrence during a blanking period after ablation (≤3 months) often reflects inflammation — not procedural failure. Late recurrence suggests PV reconnection or residual substrate and often requires repeat ablation. * Hybrid surgical and catheter Afib ablation represent an aggressive strategy for rhythm control in patients with persistent or long-standing persistent AF with extensive substrate and/or patients who have had multiple failed catheter ablations.

Notes1. What is the mechanism behind AF initiation?* Atrial fibrillation (AF) is a progressive condition. * Early AF is primarily trigger-driven, most commonly from the pulmonary veins. * Pulmonary vein myocardial sleeves have unique electrophysiologic properties that promote premature beats and afterdepolarizations. * As AF progresses, atrial remodeling (fibrosis and scar) leads to a more substrate-driven arrhythmia.

1. How does early catheter ablation for atrial fibrillation work?* Electrical Isolation of pulmonary veins, blocking PV triggers from reaching the left atrium.
2. By reducing burden of atrial fibrillation, this may slow adverse atrial remodeling.

1. Which patients are good candidates for Afib ablation?* Functional Status: ambulatory, active patients derive the greatest benefit. Advanced frailty or severe end-stage cardiovascular disease reduces expected benefit.
2. Comorbidity Burden: CHA₂DS₂-VASc score helps risk-stratify not only stroke risk but also rhythm-control outcomes.
3. Type and Duration of AF
   • Paroxysmal AF → highest likelihood of success (burden reduction often 95–99%).
   • Long-standing persistent AF → lower suppression rates (often 50–80%).
4. Left Atrial Health: a major determinant of outcomes.
   • LA diameter >5.5 cm associated with significantly worse outcomes.
   • LA volume index (normal ≤34 mL/m²) is preferred over diameter for assessment.

1. What are the predictors of complications from AFib ablation procedures?* Low and high body mass index (BMI)
2. Chronic corticosteroid use
3. Severe enlargement of other cardiac chambers
4. Female gender is associated with a numerically higher risk of complications.

1. Role of preprocedural imaging with cardiac CT or MRI* Cardiac CT
   • Faster and convenient
   • Help define LA geometry and Pulmonary vein anatomy
   • Anatomic Variants as Right middle pulmonary vein, accessory pulmonary veins common pulmonary vein ostium, Atrial diverticula or Accessory left atrial appendage
2. Consider Cardiac MRI when:
   • Strong family history of atrial fibrillation or cardiomyopathy
   • Suspicion of occult structural heart disease

1. Key Procedural Steps in AF Ablation* There is significant variation across centers in anesthesia, mapping, and ablation strategies.
2. The following outline reflects a common contemporary approach.

Anesthesia & Monitoring

• Most commonly performed under general anesthesia.
• Benefits include improved catheter stability, enhanced patient comfort, and controlled ventilation (e.g., low-volume, high-frequency).
• Invasive arterial line (A-line) is preferred for rapid detection of hypotension.

Vascular Access

• Ultrasound-guided femoral venous access with multiple sheaths.
• Micropuncture technique is ideal to minimize complications.

Intracardiac Echocardiography (ICE)

• ICE catheter insertion.
• Reduces complications, guides transseptal puncture, assesses catheter contact, and monitors for pericardial effusion.

Anticoagulation

• Systemic heparin initiated before or immediately after transseptal access.
• Activated clotting time (ACT) maintained in therapeutic range (typically >300 seconds).

Transseptal Puncture

• Access to the left atrium via transseptal sheath.
• Often uses electrocautery-assisted wire, with ICE guidance to improve safety.

Left Atrial Mapping

• Creation of electroanatomic map (common in many centers).
• Ideally performed in sinus rhythm.
• Assesses left atrial geometry, voltage (for scar/substrate), and activation timing.

Ablation Strategy

• Core component is pulmonary vein isolation (PVI).
• Technology options include pulse field ablation (PFA), radiofrequency ablation, and cryoballoon ablation.
• Additional ablation (case-dependent):
  • Posterior wall isolation
  • Targeting non-pulmonary vein triggers
  • Linear lesions
  • Ablation of organized atrial tachycardias/flutters
• Emerging approaches include AI-guided strategies.

Post-Ablation Assessment

• Confirm pulmonary vein entrance and exit block.
• Remap left atrium (in many practices) to evaluate lesion completeness.
• Check for complications (e.g., ICE assessment for pericardial effusion).

1. What is Electroanatomic Mapping?* Combines 3D geometry (anatomic reconstruction of cardiac chamber) with electrophysiology (electrical signals from tissue).
2. How it works:
   • Mapping catheter is moved along the atrial wall
   • Records electrograms
   • System generates:
     • 3D chamber model
     • Voltage map (tissue health/scar)
     • Activation map (depolarization timing)

Key information provided

• Voltage map (substrate assessment):
  • High voltage = healthy tissue
  • Low voltage = scar/fibrosis
  • Identifies areas needing additional ablation (e.g., posterior wall scar)
• Activation map:
  • Visualizes wavefront propagation
  • Essential for diagnosing and ablating macroreentrant atrial flutters and organized atrial tachycardias

1. What is the current role of Afib ablaton outside pulmonary vein isolation?* While Pulmonary Vein Isolation (PVI) remains the cornerstone of atrial fibrillation (AF) ablation, adjunctive strategies are increasingly used for persistent AF, with varying levels of supporting data.
2. Non-PVI Triggers:
   • Arrhythmogenic foci found outside the pulmonary veins in 10% to 20% of patients.
   • Common sites include SVC, LAA, CS, and Crista Terminalis.
   • Identifying and ablating these inducible triggers—often provoked by isoproterenol—can reduce recurrence in persistent AF.
3. Posterior Wall Isolation (PWI):
   • The posterior wall is a driver for persistent AF.
   • Randomized evidence for routine PWI is conflicting.
   • Large RCTs found no significant benefit over PVI alone for first-time ablations.
   • Remains a primary adjunctive target for redo procedures.
4. AI-Guided Ablation:
   • Uses AI to identify “spatio-temporal dispersion” areas.
   • Recent TAILORED-AF trial demonstrate increased freedom from AF at 12 months compared to conventional PVI.

1. Comparison of ablation techniquesPulsed Field Ablation (PFA) – Non-Thermal

2. Mechanism: irreversible electroporation

3. Key advantages:
   • Shorter procedural time
   • Comparable efficacy to thermal ablation
   • Higher myocardial tissue selectivity
   • No known risk of esophageal fistula or pulmonary vein stenosis
   • Low risk of phrenic nerve (usually transient)
4. Disadvantages:
   • Less flexibility for complex substrate
   • Hemolysis with possible AKI
   • Early and delayed coronary spasms
   • Skeletal muscle stimulation during energy delivery
   • Loss of all electrograms even with reversible injury can be misleading
   • Limited long term data

Radiofrequency Ablation (RFA) – Thermal (Heat)

• Mechanism: resistive heating
• Key advantages:
  • Highly versatile
  • Can tailor lesions
  • Long term experience
• Disadvantages:
  • More procedural time (less with ultrahigh power RFA)
  • Very small risk of esophageal fistula (1/2000 but 50% mortality!)
  • Pulmonary vein stenosis
  • Rare Phrenic nerve palsy
  • Stem pops

Cryoballoon Ablation (CBA) – Thermal (Cold)

• Mechanism: Uses extreme cold
• Key Advantages:
  • Short learning curve
  • Single shot balloon
  • Highly reproducible
  • Good catheter stability (adhesion during freeze)
  • Low risk of thrombus
• Disadvantages:
  • Similar to RFA
  • More phrenic nerve palsy
  • Less esophageal fistula and pulmonary vein stenosis

1. Other Complications of AF Catheter Ablation common to all modalities* Pericardial effusion/tamponade: 0.4–2.2%
2. Stroke/TIA: ~0.2–1.8%
3. In-hospital mortality: Very low (0.05–0.46%)
4. Often overstated in studies based on National Inpatient Sample (NIS) due to selection bias
5. Vascular access complications: Hematoma

1. Expert approach to Antiarrhythmic Drug (AAD) Therapy After AF Ablation* Continue AAD for the 3-month blanking period after catheter ablation.
2. Supported by multiple trials to reduce early AF recurrences.
3. Decreases hospitalizations during the healing phase by suppressing inflammation-related arrhythmias.
4. AADs do not clearly improve long-term freedom from AF.
5. At the 3-month follow-up:
   • If the patient is asymptomatic with no documented recurrence → discontinue AAD.
   • If recurrent AF occurs or high substrate burden persists → consider continuing AAD.

1. Expert approach to Anticoagulation After AF Ablation* All patients require anticoagulation for at least 3 months post–ablation.
2. Current guidelines recommend long-term anticoagulation decisions guided solely by CHA₂DS₂-VASc score.
3. Decisions should not be based on ablation success or arrhythmia burden.
4. New data support discontinuation in low-risk patients after careful shared decision-making.
5. In high-risk patients:
   • Observational data indicate ~2.5-fold increased stroke risk when anticoagulation is stopped.
6. OCEAN trial:
   • Generally low risk patients (mean CHA2DS2-VASc score 2.2).
   • Rivaroxaban did not significantly reduce composite stroke outcomes compared with aspirin.

1. Approach to recurrent Atrial Arrhythmias After AF Ablation* Early (≤3 months – blanking period):
   • True blanking probably less (6 weeks to 2 months)
   • Likely less with PFA
   • Often due to inflammation or lesion maturation
   • Should not be considered procedural failure
2. Management:
   • Continue or restart AAD
   • Electrical cardioversion for persistent symptomatic episodes
   • Avoid early repeat ablation
3. Late (>3 months) recurrences:
   • More likely due to pulmonary vein reconnection or residual atrial substrate
4. Arrhythmias include:
   • Recurrent atrial fibrillation
   • Atypical (macroreentrant) atrial flutter
   • Typical atrial flutter (cavotricuspid isthmus–dependent)
   • Focal atrial tachycardia
5. Management is often challenging and may include AAD, cardioversion, or repeat ablation.

1. When to Consider Hybrid Surgical and Catheter Ablation for Atrial Fibrillation?* Aggressive rhythm control strategy when standard endocardial approaches are insufficient.
2. Typically for persistent or long-standing persistent AF (>12 months).
3. Often used in patients with extensive substrate or multiple failed catheter ablations.
4. Can be performed during concomitant cardiac surgery or as a stand-alone hybrid procedure.
5. Benefits of surgical approach:
   • Epicardial posterior wall/dome ablation
   • PVI
   • Ligation of the ligament of Marshall
   • Left atrial appendage closure (e.g., AtriClip)
6. Approach:
   • Subxiphoid/minimally invasive surgical access
   • Endocardial EP confirmation
   • Additional PVI ablation and gap closure
7. Evidence suggests increased freedom from atrial arrhythmias at the expense of higher major adverse event risk.

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CardioNerds (Dr. Shazli Khan, Dr. Jenna Skowronski, and Dr. Shiva Patlolla) discuss the management of patients post‑heart transplantation with Dr. Shelley Hall from Baylor University Medical Center and Dr. MaryJane Farr from UTSW. In this comprehensive review, we cover the physiology of the transplanted heart, immunosuppression strategies, rejection surveillance, and long-term complications including cardiac allograft vasculopathy (CAV) and malignancy. Audio editing for this episode was performed by CardioNerds intern Dr. Bhavya Shah.

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Pearls1. The Denervated Heart: The donor heart is surgically severed from the autonomic nervous system, leading to a higher resting heart rate (90-110 bpm) due to loss of vagal tone. Because the heart relies on circulating catecholamines rather than neural input to increase heart rate, patients experience a delayed chronotropic response to exercise and stress. Importantly, because afferent pain fibers are severed, ischemia is often painless. 2. Rejection Surveillance: Rejection is classified into Acute Cellular Rejection (ACR), which is T-cell mediated, and Antibody-Mediated Rejection (AMR), which is B-cell mediated. While endomyocardial biopsy remains the gold standard for diagnosis, non-invasive surveillance using gene-expression profiling (e.g., AlloMap) and donor-derived cell-free DNA (dd-cfDNA) is increasingly utilized to reduce the burden of invasive procedures. 3. The Infection Timeline: The risk of infection follows a predictable timeline based on the intensity of immunosuppression. The first month is dominated by nosocomial infections. Months one through six are the peak for opportunistic infections (Cytomegalovirus, Pneumocystis, Toxoplasmosis) requiring prophylaxis. After six months, patients are primarily at risk for community-acquired pathogens, though late viral reactivation can occur. 4. Cardiac Allograft Vasculopathy (CAV): Unlike native coronary artery disease, CAV presents as diffuse, concentric intimal thickening that affects the entire length of the vessel, including the microvasculature. Due to denervation, patients rarely present with angina; instead, CAV manifests as unexplained heart failure, fatigue, or sudden cardiac death. 5. Malignancy Risk: Long-term immunosuppression significantly increases the risk of malignancy. Skin cancers (squamous and basal cell) are the most common, followed by Post-Transplant Lymphoproliferative Disorder (PTLD), which is often driven by Epstein-Barr Virus (EBV) reactivation.

NotesNotes: Notes drafted by Dr. Patlolla

1. What are the unique physiological features of the transplanted heart?

The hallmark of the transplanted heart is denervation. Because the autonomic nerve fibers are severed during harvest, the heart loses parasympathetic or vagal tone, resulting in a resting tachycardia (typically 90-110 bpm). The heart also loses the ability to mount a reflex tachycardia; thus, the heart rate response to exercise or hypovolemia relies on circulating catecholamines, which results in a slower “warm-up” and “cool-down” period during exertion.

2. What are the pillars of maintenance immunosuppression regimen?

The triple drug maintenance regimen typically consists of:

1. Calcineurin Inhibitor (CNI): Tacrolimus is preferred over cyclosporine. Key side effects include nephrotoxicity, hypertension, tremor, hyperkalemia, and hypomagnesemia.
2. Antimetabolite: Mycophenolate mofetil (MMF) inhibits lymphocyte proliferation. Key side effects include leukopenia and GI distress.
3. Corticosteroids: Prednisone is used for maintenance but is often weaned to low doses or discontinued after the first year to mitigate metabolic side effects (diabetes, osteoporosis, weight gain).

3. How is rejection classified and diagnosed?

Rejection is the immune system’s response to the foreign graft and is categorized by the arm of the immune system involved:

• Acute Cellular Rejection (ACR): Mediated by T-lymphocytes infiltrating the myocardium. It is graded from 1R (mild) to 3R (severe) based on the extent of infiltration and myocyte damage.
• Antibody-Mediated Rejection (AMR): Mediated by B-cells producing donor-specific antibodies (DSAs) that attack the graft endothelium. It is diagnosed via histology (capillary swelling) and immunofluorescence (C4d staining).

Diagnosis has historically relied on endomyocardial biopsy. However, non-invasive tools are gaining traction. Gene Expression Profiling (GEP) assesses the expression of genes associated with immune activation to rule out rejection in low-risk patients. Donor-Derived Cell-Free DNA (dd-cfDNA) measures the fraction of donor DNA in the recipient’s blood. Elevated levels suggest graft injury which can occur in both ACR and AMR.

4. What is the timeline of infectious risk and how does it guide prophylaxis?

Infectious risk correlates with the net state of immunosuppression.

• < 1 Month (Nosocomial): Risks include surgical site infections, catheter-associated infections, and aspiration pneumonia.
• 1 – 6 Months (Opportunistic): This is the period of peak immunosuppression. Patients are at risk for PJP, CMV, Toxoplasma, and fungal infections. Prophylaxis typically includes Trimethoprim-Sulfamethoxazole (for PJP/Toxo) and Valganciclovir (for CMV, dependent on donor/recipient serostatus).

• 6 Months (Community-Acquired): As immunosuppression is weaned, the risk profile shifts toward community-acquired respiratory viruses (Influenza, RSV) and pneumonias. However, patients with recurrent rejection requiring boosted immunosuppression remain at risk for opportunistic pathogens.

5. How does Cardiac Allograft Vasculopathy (CAV) differ from native CAD?

CAV is the leading cause of late graft failure. Unlike the focal, eccentric plaques seen in native atherosclerosis, CAV is an immunologically driven process causing diffuse, concentric intimal hyperplasia. It affects both epicardial vessels and the microvasculature. Because of this diffuse nature, percutaneous coronary intervention (PCI) is often technically difficult and provides only temporary palliation. The only definitive treatment for severe CAV is re-transplantation. Surveillance is critical and is typically performed via annual coronary angiography, often using intravascular ultrasound (IVUS) to detect early intimal thickening before it is visible on the angiogram.

References1. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914-956. doi:10.1016/j.healun.2010.05.034. https://www.jhltonline.org/article/S1053-2498(10)00358-X/fulltext 2. Kittleson MM, Kobashigawa JA. Cardiac Allograft Vasculopathy: Current Understanding and Treatment. JACC Heart Fail. 2017;5(12):857-868. doi:10.1016/j.jchf.2017.07.003. https://www.jacc.org/doi/10.1016/j.jchf.2017.07.003 3. Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023;42(5):e1-e141. doi:10.1016/j.healun.2022.10.015. https://www.jhltonline.org/article/S1053-2498(22)02187-5/fulltext

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CardioNerds (Dr. Colin Blumenthal, Dr. Kelly Arps, and Dr. Natalie Marrero) discuss anti-arrhythmic drugs in the management of atrial fibrillation and atrial flutter with electrophysiologist Dr. Andrew Epstein. We discuss two major classes of anti-arrhythmic drugs, class IC and class III, as well as digoxin. Dr. Epstein explains their mechanisms of action, indications and specific patient populations in which they would be particularly helpful, efficacy, adverse side effects, contraindications, and key drug-drug interactions. We also elaborate on defining clinical trials and their clinical implications. Given the large burden of atrial fibrillation and atrial flutter in our patient population and the high prevalence of anti-arrhythmic drug use, this episode is sure to be applicable to many practicing physicians and trainees. Audio editing by CardioNerds academy intern, Grace Qiu.

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Pearls1. Anti-arrhythmic drugs should not be thought of as an alternative to ablation but, instead, should be considered an adjunct to catheter ablation. 2. Class IC anti-arrhythmic drugs, flecainide and propafenone, are highly efficacious for acute cardioversion and a great option for patients with infrequent episodes of AF who do not have a history of ischemic heart disease. 3. Class III anti-arrhythmic drugs like ibutilide, sotalol, and dofetilide, are highly effective for acute conversion; however, they require hospitalization for close monitoring during initiation and dose titration given the risk of prolonged QT. 4. Amiodarone should not be used as a first line agent given its toxicities, prolonged half-life, large volume of distribution, and drug-drug interactions. 5. Dr. Epstein notes that, “All drugs are poisons with a few beneficial side effects,” when highlighting the many adverse side effects of anti-arrhythmic drugs, particularly amiodarone, and the importance of balancing their benefit in rhythm control with their side effect profile.

NotesNotes: Notes drafted by Dr. Natalie Marrero.

1. What are the Class IC anti-arrhythmic drugs and what indications exist for their use?
2. Class IC anti-arrhythmic drugs are anti-arrhythmic drugs that work by blocking sodium channels and, thereby, prolonging depolarizing.
3. Class IC anti-arrhythmic drugs include flecainide and propafenone.
4. Class IC anti-arrhythmic drugs are good agents to use in patients that have infrequent episodes of AF and do not want daily dosing as these agents can be used by patients when they feel palpitations and desire acute conversion back to sinus rhythm (“pill in the pocket” approach).
5. What are the adverse consequences and/or contraindications to using a class IC agent?
6. Class IC anti-arrhythmic agents are contraindicated in patients with a history of ischemic heart disease based on increased mortality associated with their use in these patients in the CAST trial.
7. Given the results of the CAST trial, providers should screen annually for ischemia via a functional stress test in patients on these drugs at risk for coronary disease.
8. These drugs can increase 1:1 conduction of atrial flutter and, therefore, require concomitant use of a beta blocker.
9. These agents are generally well-tolerated without any organ toxicities; however, they can precipitate heart failure in patients with cardiomyopathies, cause sinus node depression, and unmask genetic arrythmias such as a Brugada pattern.
10. What are the class III agents and what are indications for their use?
11. Class III agents are drugs that block the potassium channel, prolonging the QT, and include Ibutilide, Sotalol, and Dofetilide.
12. Class III agents can be considered in patients with or without a history of ischemic heart disease that desire effective acute chemical cardioversion and are willing to go to the hospital for close monitoring during dose initiation and titration.
13. Other specific circumstances in which one can use these agents, specifically Ibutilide, are in patients with recurrent atrial fibrillation and Wolf Parkinson White (due to slowed conduction via the accessory pathway).
14. What are the adverse consequences and/or contraindications to using a class III agent?
15. Ibutilide, Sotalol, and Dofetilide prolong the QT and increase the risk of torsade de pointes, which is why they require ECG monitoring in-patient during drug initiation and dose titration.
16. These agents are generally well-tolerated.
17. Sotalol should be avoided or used cautiously in patients with left ventricular dysfunction, while dofetilide can be used and has dose-response beneficial effects in patients with left ventricular dysfunction.
18. Both sotalol and dofetilide are renally cleared with specific creatinine clearance cutoffs (CrCl < 20 for dofetilide and CrCl <40 for sotalol) and their dose should be adjusted based on the patient’s creatinine clearance (not eGFR).
19. What is the mechanism of action and indications for using amiodarone?
20. Amiodarone is a class III anti-arrhythmic agent, so it blocks the potassium channel prolonging the QT. Amiodarone is a “dirty drug” as it also has Class I (sodium channel blockade), Class II (antisympathetic action), and Class IV (calcium channel blockade) actions.
21. Amiodarone should be used as a second line agent.
22. Amiodarone can be considered in young, stable outpatients who are already in sinus rhythm especially greater than 60 beats per minute for outpatient loading.
23. What are the drawbacks of amiodarone?
24. Amiodarone, given its large volume of distribution and need to reach ~10 g for efficacy in conversion, takes a longer time to load and, therefore, a longer time to cardiovert.
25. Amiodarone is associated with multiple organ toxicities including pulmonary fibrosis, thyroid toxicity (both hypothyroidism and hyperthyroidism), peripheral neuropathy, sinus bradycardia, QT prolongation, corneal deposits, retinitis and vision loss.
26. Given the organ toxicities, patients on amiodarone should have their LFTs and TSH, a chest X-ray, and electrocardiogram checked at least every 6 months.
27. Amiodarone sensitizes patients to warfarin and increases digoxin levels, so if patients are on amiodarone with warfarin or digoxin, lower levels of warfarin or digoxin should be used.
28. What is dronedarone? How does it differ from amiodarone?
29. Dronedarone is a class III antiarrhythmic, which means it works by blocking the potassium channel and prolonging the QT.
30. Dronedarone differs from amiodarone in that it lacks iodine moiety and, therefore, does not have the associated thyroid toxicities. It also has a shorter half-life and smaller volume of distribution.
31. What are the contraindications to using dronedarone?
32. In the PALACE trial, dronedarone was associated with increased mortality in patients with heart failure, so it should be avoided in patients with clinical heart failure within the last six months.
33. What is the mechanism of action and indication for using digoxin?
34. Digoxin has several mechanisms of action including increasing vagal tone, inhibiting the sodium potassium ATPase, and acting as a positive inotrope.
35. Digoxin is indicated as a second line drug when better rate control is needed.
36. Digoxin improves rate control by increasing vagal tone and so may have an impact on resting rates. However, exertional rates may remain unctonrolled since these are mediated by sympathetic tone.
37. Digoxin is a good option in patients that are not particularly active given that it decreases ventricular rate at rest, but not with exercise.
38. Digoxin may be particularly beneficial in patients with heart failure given its positive ionotropic effects.
39. What are the adverse side effects of digoxin and special monitoring required for patients on digoxin?
40. Typically, digoxin levels are monitored, however they are usually not helpful as the levels are often drawn randomly. To be informative, the levels need to be a trough levels drawn right before the drug is given.
41. The literature contains conflicting results on the mortality associated with digoxin levels.
42. In general, the consensus in the field is that lower levels are better.
43. Digoxin is renally cleared, so levels should be closely monitored in patients with renal failure.

References1. Mar PL, Horbal P, Chung MK, et al. Drug interactions affecting antiarrhythmic drug use. Circulation: Arrhythmia and Electrophysiology. 2022;15(5):e007955. https://doi.org/10.1161/CIRCEP.121.007955. doi: 10.1161/CIRCEP.121.007955.

1. Gianfranchi L, Luzi M, Solano A, et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med. 2004;351(23):2384–2391. https://doi.org/10.1056/NEJMoa041233. doi: 10.1056/NEJMoa041233.

2. Barker AH, Echt DS, Arensberg D, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. N Engl J Med. 1991;324(12):781–788. https://doi.org/10.1056/NEJM199103213241201. doi: 10.1056/NEJM199103213241201.

3. Markman Timothy M., Jarrah Andrew A., Ye T, et al. Safety of pill-in-the-pocket class 1C antiarrhythmic drugs for atrial fibrillation. JACC: Clinical Electrophysiology. 2022;8(12):1515–1520. https://doi.org/10.1016/j.jacep.2022.07.010. doi: 10.1016/j.jacep.2022.07.010.

4. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: A report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2024;149(1):e1–e156. https://doi.org/10.1161/CIR.0000000000001193. doi: 10.1161/CIR.0000000000001193.

5. Ferrari F, Santander IRMF, Stein R. Digoxin in Atrial Fibrillation: An Old Topic Revisited. Curr Cardiol Rev. 2020;16(2):141-146. doi:10.2174/1573403X15666190618110941

6. Van Gelder I,C., Rienstra M, Bunting KV, et al. 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the european association for cardio-thoracic surgery (EACTS): Developed by the task force for the management of atrial fibrillation of the european society of cardiology (ESC), with the special contribution of the european heart rhythm association (EHRA) of the ESC. endorsed by the european stroke organisation (ESO). Eur Heart J. 2024;45(36):3314–3414. https://doi.org/10.1093/eurheartj/ehae176. doi: 10.1093/eurheartj/ehae176.

7. Copaescu AM, Vogrin S, James F, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023;183(9):944-952. doi:10.1001/jamainternmed.2023.2986

8. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383(14):1305-1316. doi:10.1056/NEJMoa2019422

9. Anderson JL, Platia EV, Hallstrom A, et al. Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST). Circulation. 1994;90(6):2843-2852. doi:10.1161/01.cir.90.6.2843

11.Akiyama T, Pawitan Y, Greenberg H, Kuo C, Reynolds-Haertle R, The CI. Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the cardiac arrhythmia suppression trial. Am J Cardiol. 1991;68(17):1551–1555. https://doi.org/10.1016/0002-9149(91)90308-8. doi: 10.1016/0002-9149(91)90308-8.

1. Parkash R, Wells GA, Rouleau J, et al. Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial. Circulation. 2022;145(23):1693-1704. doi:10.1161/CIRCULATIONAHA.121.057095

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In this episode, the CardioNerds (Dr. Natalie Tapaskar, Dr. Jenna Skowronski, and Dr. Shazli Khan) discuss the process of heart transplantation from the initial donor selection to the time a patient is discharged with Dr. Dave Kaczorowski and Dr. Jason Katz. We dissect a case where we understand criteria for donor selection, the differences between DBD and DCD organ donors, the choice of vasoactive agents in the post-operative period, complications such as cardiac tamponade, and the choice of immunosuppression in the immediate post-operative period. Most importantly, we highlight the importance of multi-disciplinary teams in the care of transplant patients. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

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Pearls1. When thinking about donor selection, you need to consider how much physiologic stress your recipient can tolerate, and this may guide your selection of “higher risk” or “lower risk” donors. 2. The use of DCD donors has increased the potential donor pool and shortened waitlist times with very similar perioperative outcomes to DBD transplantation. 3. Post-operative critical care management rests on a fundamental principle to apply as much inotropic/vasoactive therapy as needed to achieve some reasonable physiologic hemostasis, and then getting “the heck out of the way!” There are no standard regimens as practices vary across centers, but rest on providing adequate RV support, maintaining AV synchrony, and early resuscitation. 4. The RV is fickle and doesn’t take a joke too well. RV dysfunction post-transplant is important to watch for, and it can be transient or require aggressive support. Don’t miss assessing for cardiac tamponade which can require surgical evacuation- “where there’s space, that space can be filled with fluid.” 5. Induction immunosuppression post-transplant varies across centers, but some considerations for use may include (1) high sensitization of the patient, (2) high risk immunologic donor-recipient matching, and (3) recipient renal dysfunction to provide a calcineurin inhibitor (CNI) sparing regimen long term. 6. Management of heart transplant patients is a multi-disciplinary effort that requires coordination amongst heart failure/transplant cardiologists, cardiac surgeons, anesthesiologists, pathology/immunologists and a slew of ancillary services. Without a dynamic and collaborative team, successful cardiac transplantation could not be possible.

NotesNotes: Notes drafted by Dr. Natalie Tapaskar

What are the basic components of donor heart selection?In practicality, it can be a very inexact science, but we use some basic selection criteria such as:

• (1) size matching
• (2) ischemic time
• (3) donor graft function
• (4) immunologic compatibility
• (5) age of the potential donor and recipient
• (6) severity of illness of the recipient
• (7) regional variation in donor availability

When thinking about accepting older donors (>50 years old), we ideally would screen for donor coronary disease and try to keep ischemic times as short as possible.

We may accept an older donor for a recipient who is highly sensitized, which leaves a smaller potential donor pool.

There is no clear consensus on size matching, but the predicted heart mass is most used. We are generally more comfortable oversizing than under-sizing donor hearts.

Serial echocardiography is important in potential donors as initially reduced ejection fractions can improve on repeat testing, and these organs should not be disregarded automatically.

For recipients who are more surgically complex, (i.e. multiple prior sternotomies or complex anatomy), it’s probably preferable to avoid older donors with some graft dysfunction and favor donors with shorter ischemic times.

What is the difference between DBD and DCD?DBD is donation after brain death- these donors meet criteria for brain death.

Uniform Determination of Death Act 1980: the death of an individual is

• The irreversible cessation of circulatory and respiratory functions or
• The irreversible cessation of all functions of the entire brain, including those of the brain stem

DCD is donation after circulatory death- donation of the heart after confirming that circulatory function has irreversibly ceased.

Only donors in category 3 of the Maastricht Classification of DCD donors are considered for DCD donations: anticipated circulatory arrest (planned withdrawal of life-support treatment).

DCD hearts can be procured via direct procurement or normothermic regional perfusion (NRP). The basic difference is the way the hearts are assessed, either on an external circuit or in the donor body.

For the most complex recipient, DCD may not be utilized at some centers due to concern for higher rates of delayed graft function, but this is center specific and data is still evolving.

What are some features surgeons consider when procuring the donor heart?Visual assessment of the donor heart is key in DBD or NRP cases. LV function may be hard to assess, but visually the RV can be inspected.

Palpation of the coronary arteries is important to assess any calcifications or abnormalities.

Ventricular arrhythmias at the time of procurement may be concerning.

Key considerations in the procurement process:

• (1) Ensuring the heart remains decompressed at all times and doesn’t become distended
• (2) adequate cardioplegia delivery
• (3) aorta is cross-clamped properly all the way across the vessel
• (4) avoiding injury to adjacent structures during procurement

What hemodynamic parameters should we monitor and what vasoactive agents are used peri-heart transplant?There is no consensus regarding vasoactive agent use post-transplant and practice varies across institutions. Some commonly seen regimens may include:

• (1) AAI pacing around 110 bpm to support RV function and preserve AV synchrony
• (2) inotropic agents such as epinephrine and dobutamine to support RV function
• (3) pulmonary vasodilators such as inhaled nitric oxide to optimize RV afterload

Early post-transplant patients tend to have low cardiac filling pressures and require preload monitoring and resuscitation initially.

Slow weaning of inotropes as the patient shows signs of stable graft function and hemodynamics.

RV dysfunction may manifest as elevated central venous pressure with low cardiac index or hypotension with reducing urine output.

Optimize inotropic support, volume status, metabolic status (acidosis and hypoxia), afterload (pulmonary hypertension), and assess for cardiac tamponade.

Tamponade requires urgent take-back to the operating room to evacuate material.

Refractory RV failure requires mechanical circulatory support, with early consideration of VA-ECMO. Isolated RV MCS may be used in the right clinical context.

Why do pericardial effusions/cardiac tamponade happen after transplant?They are not uncommon after transplant and can be due to:

• Inherent size differences between the donor and recipient (i.e. if the donor heart is much smaller than the recipient’s original heart)
• Bleeding from suture lines and anastomoses, pacing wires, and cannulation sites

Depending on the hemodynamic stability of the patient and the location of the effusion, these effusions may require urgent return to the OR for drainage/clot evacuation via reopening the sternotomy, mini thoracotomy, and possible pericardial windows.

What are the basics of immunosuppression post-transplant?Induction immunosuppression is variably used and is center-specific.

Considerations for using induction therapy may include:

• (1) high sensitization of the patient
• (2) younger patients or multiparous women with theoretically more robust immune systems
• (3) crossing of recipient antibodies with donor antigens
• (3) renal function to provide a CNI sparing regimen long term

Some considerations for avoiding induction may include:

• (1) older age of the recipient
• (2) underlying comorbid conditions such as infections or frailty of the recipient

What are expected activity restrictions post-transplant?Sternal precautions are important to maintain sternal wire integrity. Generally avoiding lifting >10 pounds in the first 4-12 weeks, no driving usually in the first 4 weeks, monitoring for signs and symptoms of wound infections, and optimizing nutrition and physical activity.

Cardiac rehabilitation is incredibly important as soon as feasible.

References1. Kharawala A , Nagraj S , Seo J , et al. Donation after circulatory death heart transplant: current state and future directions. Circ: Heart Failure. 2024;17(7). doi: 10.1161/circheartfailure.124.011678 2. Copeland H, Knezevic I, Baran DA, et al. Donor heart selection: Evidence-based guidelines for providers. The Journal of Heart and Lung Transplantation. 2023;42(1):7-29. doi:10.1016/j.healun.2022.08.030 3. Moayedifar R, Shudo Y, Kawabori M, et al. Recipient Outcomes With Extended Criteria Donors Using Advanced Heart Preservation: An Analysis of the GUARDIAN-Heart Registry. J Heart Lung Transplant. 2024;43(4):673-680. doi:10.1016/j.healun.2023.12.013 4. Kharawala A, Nagraj S, Seo J, et al. Donation After Circulatory Death Heart Transplant: Current State and Future Directions. Circ Heart Fail. 2024;17(7):e011678. doi:10.1161/CIRCHEARTFAILURE.124.011678 5. Copeland H, Hayanga JWA, Neyrinck A, et al. Donor heart and lung procurement: A consensus statement. J Heart Lung Transplant. 2020;39(6):501-517. doi:10.1016/j.healun.2020.03.020 6. Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023;42(5):e1-e141. doi:10.1016/j.healun.2022.10.015 7. Sicim H, Tam WSV, Tang PC. Primary graft dysfunction in heart transplantation: the challenge to survival. J Cardiothorac Surg. 2024;19(1):313. doi:10.1186/s13019-024-02816-6

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In this episode, the CardioNerds (Dr. Naima Maqsood, Dr. Akiva Rosenzveig, and Dr. Colin Blumenthal) are joined by renowned educator in electrophysiology, Dr. Joshua Cooper, to discuss everything atrial flutter; from anatomy and pathophysiology to diagnosis and management. Dr. Cooper’s expert teaching comes through as Dr. Cooper vividly describes atrial anatomy to provide the foundational understanding to be able to understand why management of atrial flutter is unique from atrial fibrillation despite their every intertwined relationship. A foundational episode for learners to understand atrial flutter as well as numerous concepts in electrophysiology. Audio editing for this episode was performed by CardioNerds intern Dr. Bhavya Shah.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. “The biggest mistake is failure to diagnose”. Atrial flutter, especially with 2:1 conduction, is commonly missed in both inpatient and outpatient settings so look carefully at that 12-lead EKG so you can mitigate the stroke and tachycardia induced cardiomyopathy risk 2. Decremental conduction of the AV node makes it more challenging to rate control atrial flutter than atrial fibrillation 3. Catheter Ablation is the first line treatment for atrial flutter and is highly successful, but cardioversion can be utilized as well prior to pursuing ablation in some cases. 4. Class I AADs like propafenone and flecainide may stability the atrial flutter circuit by slowing conduction and thus may worsen the arrhythmia. Therefore, the preferred anti-arrhythmic medication in atrial flutter are class III agents. 5. Atrial flutter can be triggered by firing from the left side of the heart, so in patients with both atrial fibrillation and flutter, ablating atrial fibrillation makes atrial flutter less likely to recur. 6. BONUS PEARL: Dr. Cooper’s youtube video on atrial flutter is a MUST SEE!

NotesNotes: Notes drafted by Dr. Akiva Rosenzveig

1. What are the distinguishing features of atrial fibrillation and flutter?
2. Atrial flutter is an organized rhythm characterized by a wavefront that continuously travels around the same circuit leading to reproducible P-waves on surface EKG as well as a very mathematical and predictable relationship between atrial and ventricular activity
3. Atrial fibrillation is an ever changing, chaotic rhythm that consists of small local circuits that interplay off each other. Consequently, no two beats are the same and the relationship between the atrial activity and ventricular activity is unpredictable leading to an irregularly irregular rhythm
4. What are common atrial flutter circuits?
5. Cavo-tricuspid isthmus (CTI)-dependent atrial flutter is the most common type of flutter. It is characterized by a circuit that circumnavigates the tricuspid valve.
6. Typical atrial flutter is characterized by the circuit running in a counterclockwise pattern up the septum, from medial to lateral across the right atrial roof, down the lateral wall, and back towards the septum across the floor of the right atrium between the IVC and the inferior margin of the tricuspid valve i.e. the cavo-tricuspid isthmus. Surface EKG will show a gradual downslope in leads II, III, and AvF and a rapid rise at end of each flutter wave.
7. Atypical CTI-dependent flutter follows the same route but in the opposite direction (clockwise). Therefore, we will see positive flutter waves in the inferior leads
8. Mitral annular flutter is more commonly seen in atrial fibrillation patients who’ve been treated with ablation leading to scarring in the left atrium.
9. Roof-dependent flutter is characterized by a circuit that travels around left atrium circumnavigating a lesion (often from prior ablation), traveling through the left atrial roof, down the posterior wall, and around the pulmonary veins
10. Surgical/scar/incisional flutter is seen in people with a history of prior cardiac surgery and have iatrogenic scars in right atrium due to cannulation sites or incisions
11. How does atrial flutter pharmacologic management differ from other atrial arrhythmias?
12. The atrioventricular (AV) node is unique in that the faster it is stimulated, the longer the refractory period and the slower it conducts. This characteristic is called decremental conduction. In atrial fibrillation, the atrial rate is so fast that the AV node becomes overwhelmed and only lets some of those signals through to the ventricles creating an irregular tachycardia but at lower rates. In atrial flutter, the atrial rate is slower, therefore the AV node has more capability to conduct allowing for higher ventricular rates. Therefore, to achieve rate control one will need a higher dose of AV blocking medications. Atrial tachycardia may require even higher doses due to the increased ability of the AV node to conduct, as the atrial rates are slower than in atrial flutter.
13. Sodium channel blockers (Class I) such as flecainide and propafenone slow wavefront propagation, making it easier for the AV node to handle the atrial rates. This will end up leading to increased ventricular rates which can be dangerously fast. That is why AV nodal blockers should be used in conjunction with flecainide and propafenone.
14. What is the role of cardioversion in atrial flutter management?
15. Due to high success rate with atrial flutter ablation, ablation is the first line treatment. However, sometimes cardioversion may be utilized in patients depending on how symptomatic they are and how long it will take to get an ablation. Cardioversion may also be utilized preferentially when the atrial flutter was triggered by infection or cardiac surgery to see if it will come back.
16. If cardioversion is pursued, the patient will need to be anticoagulated due to the stroke risk after the procedure due to post-conversion stunning.
17. How effective is atrial flutter ablation?
18. The landmark Natale et al study in 2000 demonstrated 80% success rate after radiofrequency ablation as compared to 36% in patients on anti-arrhythmic therapy. The LADIP study in 2006 further corroborated these findings. Contemporary data shows above 90% success rate of atrial flutter ablation.
19. In patients who have had both atrial fibrillation and atrial flutter, most electrophysiologists would ablate both. However, in patients with atrial fibrillation, the atrial flutter usually is initiated by trigger spots firing in the left atrium. Once the atrial fibrillation is ablated, the flutter will become less likely. Therefore, there are those who say there’s no need to ablate the flutter circuit as well. Alternatively, if a patient has severe comorbidities and/or is high risk for ablation, one may consider performing the atrial flutter ablation only since atrial flutter is harder to manage medically compared with atrial fibrillation.
20. How do you manage atrial flutter in the acute inpatient setting?
21. In the inpatient setting, electrical cardioversion is often limited by blood pressure and the hypotensive effects of the sedatives required. If one is awake and too hypotensive, chemical cardioversion can be pursued. The most effective anti-arrhythmic for this is ibutilide. Amiodarone is not effective for acute cardioversion. Since ibutilide prolongs refractoriness in atrial and ventricular tissue, there’s a risk of long QT induced torsades de pointes. Pretreating with magneisum reduces the risk to 1-2%.

References1. Jolly WA, Ritchie WT. Auricular flutter and fibrillation. 1911. Ann Noninvasive Electrocardiol. 2003;8(1):92-96. doi:10.1046/j.1542-474x.2003.08114.x 2. McMichael J. History of atrial fibrillation 1628-1819 Harvey – de Senac – Laënnec. Br Heart J. 1982;48(3):193-197. doi:10.1136/hrt.48.3.193 3. Lee KW, Yang Y, Scheinman MM; University of Califoirnia-San Francisco, San Francisco, CA, USA. Atrial flutter: a review of its history, mechanisms, clinical features, and current therapy. Curr Probl Cardiol. 2005;30(3):121-167. doi:10.1016/j.cpcardiol.200 4. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e167. doi:10.1161/ 5. Cosío F. G. (2017). Atrial Flutter, Typical and Atypical: A Review. Arrhythmia & electrophysiology review, 6(2), 55–62. https://doi.org/10.15420/aer.2017.5.2 6. https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-11/Atrial-flutter-common-and-main-atypical-forms 7. Natale A, Newby KH, Pisanó E, et al. Prospective randomized comparison of antiarrhythmic therapy versus first-line radiofrequency ablation in patients with atrial flutter. J Am Coll Cardiol. 2000;35(7):1898-1904. doi:10.1016/s0735-1097(00)00635-5 8. Da Costa A, Thévenin J, Roche F, et al. Results from the Loire-Ardèche-Drôme-Isère-Puy-de-Dôme (LADIP) trial on atrial flutter, a multicentric prospective randomized study comparing amiodarone and radiofrequency ablation after the first episode of symptomatic atrial flutter. Circulation. 2006;114(16):1676-1681. doi:10.1161/CIRCULATIONAHA.106.638395 9. https://www.acc.org/Membership/Sections-and-Councils/Fellows-in-Training-Section/Section-Updates/2015/12/15/16/58/Atrial-Fibrillation#:~:text=The%20first%20’modern%20day’%20account,in%20open%20chest%20animal%20models.&text=In%201775%2C%20William%20Withering%20first,(purple%20foxglove)%20in%20AFib.

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In this episode, the CardioNerds (Dr. Rachel Goodman, Dr. Shazli Khan, and Dr. Jenna Skowronski) discuss a case of AMI-shock with a focus on listing for heart transplant with faculty expert Dr. Kelly Schlendorf. We dive into the world of pre-transplant management, discuss the current allocation system, and additional factors that impact transplant timing, such as sensitization. We conclude by discussing efforts to increase the donor pool. Audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. The current iteration of heart allocation listing is based on priority, with status 1 being the highest priority. 2. The are multiple donor and recipient characteristics to consider when listing a patient for heart transplantation and accepting a heart offer. 3. Desensitization is an option for patients who need heart transplantation but are highly sensitized. Protocols vary by center. 4. Acceptance of DCD hearts is one of many efforts to expand the donor pool

NotesNotes: Notes drafted by Dr. Rachel Goodman

Once a patient is determined to be a candidate for heart transplantation, how is priority determined?

The current iteration of heart listing statuses was implemented in 2018. Priority is determined by acuity, with higher statuses indicating higher acuity and given higher priority. Status 1 is the highest priority status, and Status 7 is inactive patients. (1,2)

What criteria should be considered in organ selection when listing a patient for heart transplant?

Once it is determined that a patient will be listed for heart transplantation, there are certain criteria that should be assessed. These factors may impact pre-transplant care and/or donor matching (3).

(1) PVR

(2) Height/weight

(3) Milage listing criteria

(4) Blood typing/cPRA/HLA typing

What is desensitization and why would it be considered?

Desensitization is an attempt to reduce or remove anti-HLA antibodies in the recipient. It is done to increase the donor pool. In general, desensitization is reserved for patients who are highly sensitized. Desensitization protocols vary by transplant center, and some may opt against it. When considering desensitization, it is important to note two key things: first, there is no promise that it will work, and second desensitization involves the use of immunosuppressive agents, thereby putting patients at increased risk of infection and cytopenia. (4)

Can you explain DCD and DBD transplant?

DBD: donor that have met the requirements for legal definition of brain death.

DCD: donors that have not met the legal definition of brain death but have been determined to have circulatory death. Because the brain death criteria have not been met, organ recovery can only take place once death is confirmed based on cessation of circulatory and respiratory function. Life support is only withdrawn following declaration of circulatory death—once the heart has stopped beating and spontaneous respirations have stopped. (5,6)

References1: Maitra NS, Dugger SJ, Balachandran IC, Civitello AB, Khazanie P, Rogers JG. Impact of the 2018 UNOS Heart Transplant Policy Changes on Patient Outcomes. JACC Heart Fail. 2023;11(5):491-503. doi:10.1016/j.jchf.2023.01.009

2: Shore S, Golbus JR, Aaronson KD, Nallamothu BK. Changes in the United States Adult Heart Allocation Policy: Challenges and Opportunities. Circ Cardiovasc Qual Outcomes. 2020;13(10):e005795. doi:10.1161/CIRCOUTCOMES.119.005795

3: Copeland H, Knezevic I, Baran DA, et al. Donor heart selection: Evidence-based guidelines for providers. J Heart Lung Transplant. 2023;42(1):7-29. doi:10.1016/j.healun.2022.08.030

4: Kittleson MM. Management of the sensitized heart transplant candidate. Curr Opin Organ Transplant. 2023;28(5):362-369. doi:10.1097/MOT.0000000000001096

5: Kharawala A, Nagraj S, Seo J, et al. Donation After Circulatory Death Heart Transplant: Current State and Future Directions. Circ Heart Fail. 2024;17(7):e011678. doi:10.1161/CIRCHEARTFAILURE.124.011678

6: Siddiqi HK, Trahanas J, Xu M, et al. Outcomes of Heart Transplant Donation After Circulatory Death. J Am Coll Cardiol. 2023;82(15):1512-1520. doi:10.1016/j.jacc.2023.08.006

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CardioNerds (Dr. Kelly Arps, Dr. Naima Maqsood, and Dr. Elizabeth Davis) discuss chronic AF management with Dr. Edmond Cronin. This episode seeks to explore the chronic management of atrial fibrillation (AF) as described by the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. The discussion covers the different AF classifications, symptomatology, and management including medications and invasive therapies. Importantly, the episode explores current gaps in knowledge and where there is indecision regarding proper treatment course, as in those with heart failure and AF. Our expert, Dr. Cronin, helps elucidate these gaps and apply guideline knowledge to patient scenarios. Audio editing for this episode was performed by CardioNerds intern Dr. Bhavya Shah.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. Review the guidelines- Catheter ablation is a Class I recommendation for select patient groups 2. Appropriately recognize AF stages- preAF conditions, symptomatology, classification system (paroxysmal, persistent, long-standing persistent, permanent) 3. Be familiar with the EAST-AFNET4 trial, as it changed the approach of rate vs rhythm control 4. Understand treatment approaches- lifestyle modifications, management of comorbidities, rate vs rhythm control medications, cardioversion, ablation, pulmonary vein isolation, surgical MAZE 5. Sympathize with patients- understand their treatment goals

NotesNotes: Notes drafted by Dr. Davis.  

What are the stages of atrial fibrillation?

• The stages of AF were redefined in the 2023 guidelines to better recognize AF as a progressive disease that requires different strategies at the different therapies
• Stage 1 At Risk for AF: presence of modifiable (obesity, lack of fitness, HTN, sleep apnea, alcohol, diabetes) and nonmodifiable (genetics, male sex, age) risk factors associated with AF
• Stage 2 Pre-AF: presence of structural (atrial enlargement) or electrical (frequent atrial ectopy, short bursts of atrial tachycardia, atrial flutter) findings further pre-disposing a patient to AF
• Stage 3 AF: patient may transition between these stages
  • Paroxysmal AF (3A): intermittent and terminates within ≤ 7 days of onset
  • Persistent AF (3B): continuous and sustained for > 7 days and requires intervention
  • Long-standing persistent AF (3C): continuous for > 12 months
  • Successful AF ablation (3D): freedom from AF after percutaneous or surgical intervention
• Stage 4 Permanent AF: no further attempts at rhythm control after discussion between patient and clinician
• The term chronic AF is considered obsolete and such terminology should be abandoned

What are common symptoms of AF?

• Symptoms vary with ventricular rate, functional status, duration, and patient perception
• May present as an embolic complication or heart failure exacerbation
• Most commonly patients report palpitations, chest pain, dyspnea, fatigue, or lightheadedness. Vague exertional intolerance is common
• Some patients also have polyuria due to increased production of atrial natriuretic peptide
• Less commonly can present as tachycardia-associated cardiomyopathy or syncope
• Cardioversion into sinus rhythm may be diagnostic to help determine if a given set of symptoms are from atrial fibrillation to help guide the expected utility of more aggressive rhythm control strategies.

What are the current guidelines regarding rhythm control and available options?

• COR-LOE 1B: In patients with reduced LV function and persistent (or high burden) AF, a trial of rhythm control should be recommended to evaluate whether AF is contributing to the reduced LV function
• COR-LOE 2a-B: In patients with reduced LV function and persistent (or high burden) AF, a trial of rhythm control should be recommended to evaluate whether AF is contributing to the reduced LV function. In patients with a recent diagnosis of AF (<1 year), rhythm control can be useful to reduce hospitalizations, stroke, and mortality. In patients with AF and HF, rhythm control can be useful for improving symptoms and improving outcomes, such as mortality and hospitalizations for HF and ischemia. In patients with AF, rhythm-control strategies can be useful to reduce the likelihood of AF progression.
• COR-LOE 2b-C: In patients with AF where symptoms associated with AF are uncertain, a trial of rhythm control (eg, cardioversion or pharmacological therapy) may be useful to determine what if any symptoms are attributable to AF.
• COR-LOE 2b-B: In patients with AF, rhythm-control strategies may be useful to reduce the likelihood of development of dementia or worsening cardiac structural abnormalities.
• While both rate and rhythm control can improve AF symptoms, several studies (such as AF-CHF) show improved quality of life with rhythm control
• EAST-AFNET 4 was significant in that it showed rhythm control was associated with a 25% reduction in the combined endpoint of mortality rate, stroke, and hospitalizations due to HF or ACS
• Acute rhythm control can be achieved with electrical or pharmacological cardioversion. Electrical is more effective and faster than pharmacological and is preferred for patients with hemodynamic instability attributable to AF. However, both approaches involved considerations for anticoagulation and thromboembolic risk. Pharmacologic options for cardioversion include ibutilide, amiodarone, flecainide, propafenone, procainamide, dofetilide, and sotalol.
• COR-LOE 1-A: In patients with symptomatic AF in whom antiarrhythmic drugs have been ineffective, contraindicated, not tolerated or not preferred, and continued rhythm control is desired, catheter ablation is useful to improve symptoms.
• AF ablation is also a suitable first-line option in some patients with paroxysmal AF to reduce recurrence and burden. Patient selection is important. Younger patients, those with minimal atrial enlargement, less myocardial fibrosis, and less persistent forms are more likely to have successful ablations, meaning less likely to have recurrence of AF after ablation.
• HFrEF patients derive greater benefit than others from AF ablation in terms of improved functional status, LV function, and cardiovascular outcomes
• Surgical ablation can be considered in those undergoing cardiac surgery for some other etiology such as valve surgery or CABG and is associated with increased survival, but some risk of pacemaker placement and renal dysfunction

How would you monitor for AF recurrence in post-ablation or cardioversion? Is there a role for monitoring in every patient?

• Cardiac monitoring may be advised to AF patients for various reasons, such as for detecting recurrences, screening, or response to therapy
• Long-term surveillance to detect recurrent AF can be beneficial and can be accomplished by various modalities, including wearable devices, smart watches, random monitoring (Holter, event, mobile telemetry), and implantable loop recorders. This is especially helpful in those who had AF-induced cardiomyopathy, especially if their LVEF recovered after rate/rhythm control. This is a population in whom recurrence of AF would want to be promptly noted and addressed.
• Loop recorders can also be helpful in detecting subclinical AF or in patients with stroke or TIA of undetermined cause (COR-LOE 2a-B)

What AF burden warrants intervention?

• It is important to recognize that AF is a chronic condition and tends to recur, so treatment often is focused on reducing risk of recurrence
• Patient-clinician shared decision making is important when deciding when/how to intervene, as there is no cut-off for “significant” burden (COR-LOE 1-B)

What are some options for antiarrhythmic drugs and their characteristics?

• Antiarrhythmic drugs are reasonable for long-term maintenance of sinus rhythm for patients with AF who are not candidates for, or decline, catheter ablation, or who prefer antiarrhythmic therapy
• Amiodarone can be used in patients with or without HFrEF, as opposed to many other anti-arrhythmics that are (relatively) contraindicated in HFrEF or should be used with caution in such patients, such as flecainide, propafenone, dronedarone, and sotalol. However, due to its adverse effects and multiple drug interactions, is should be used only in patients in which other antiarrhythmic drugs are contraindications, ineffective, or not preferred. Dofetilide can also be used in patients with HFrEF.
• In patients on amiodarone, labs should be checked regularly for thyroid, liver and kidney functions. There is also a role for pulmonary function testing and chest x-rays to monitor for pulmonary fibrosis, but frequency is not clearly established. It should be noted that amiodarone-induced lung toxicity occurs between 6 months and 2 years of use.
• Flecainide is well tolerated, but is contraindicated in patients with significant coronary artery disease and possibly structural heart disease in general. It can also lead to the development of atrial flutter.
• Dofetilide and sotalol require regular renal function monitoring and QTC monitoring

When should AV node ablation (AVNA) be considered?

• In patients with AF and uncontrolled rapid ventricular response refractory to rate-control medications (who are not candidates for or in whom rhythm control has been unsuccessful), AVNA can be useful to improve symptoms and QOL (COR-LOE 2a-B)
• AVNA is effective for rate control and does not require continuation of medications; however, patients become dependent on pacing and lifelong pacemaker implantation, and the potential for device complications
• AVNA does not prevent progression or recurrence of AF
• The type of device is dependent on patient comorbidities but the advent of conduction system pacing may improve outcomes in these patients compared with RV pacing.

What are some recommendations for managing atrial fibrillation in the perioperative period?

• In patients with AF (excluding those with recent stroke or TIA, or a mechanical valve) and on oral anticoagulation with either warfarin or DOAC who are scheduled to undergo an invasive procedure or surgery, temporary cessation of oral anticoagulation without bridging anticoagulation is recommended (COR-LOE 1-B)
• In patients with AF on DOAC that has been interrupted for an invasive procedure or surgery, in general, resumption of anticoagulation the day after low bleeding risk surgery and between the evening of the second day and the evening of the third day after high bleeding risk surgery is reasonable, as long as hemostasis has been achieved and further bleeding is not anticipated (COR-LOE 2a-B)
• Preop prophylaxis to prevent AF after cardiac surgery with either beta blocker or amiodarone shows mixed benefit and carries a 2a-B recommendation; however, beta blocker is a class 1-A recommendation in patients who do develop AF in the postop period
• It should be noted that patients who develop AF in the setting of an acute illness or surgery are at risk of recurrence

References1. Joglar, J, Chung, M. et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. JACC.2024 Jan, 83 (1) 109–279. https://doi.org/10.1016/j.jacc.2023.08.017 2. Fuster F, Rydén L, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation. 2001 Oct, 104 (17). https://doi.org/10.1161/circ.104.17.2118 3. Kirchhof P, Camm A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020 Aug, 383 (14) 1305-1416. DOI: 10.1056/NEJMoa2019422 4. Olshansky, B, Rosenfeld, L, Warner, A. et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: Approaches to control rate in atrial fibrillation. JACC.2004 Apr, 43 (7) 1201–1208.https://doi.org/10.1016/j.jacc.2003.11.032 5. Whitlock R, Belley-Cote E, et al. Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke. N Engl J Med. 2021 May, 384 (22) 2081-2091. DOI: 10.1056/NEJMoa2101897 6. Kirchhof P, Toennis T, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. N Engl J Med. 2023 Aug, 389 (13) 1167-1179. DOI: 10.1056/NEJMoa2303062 7. Healey J, Lopes R, et al. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. N Engl J Med. 2023 Nov, 390 (2) 107-117. DOI: 10.1056/NEJMoa2310234 8. Roy D, Talajic M, et al. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure. N Engl J Med. 2008 Jun, 358 (25) 2667-2677. DOI: 10.1056/NEJMoa0708789 9. Gillinov A, Bagiella E, et al. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. N Engl J Med. 2016 Mar, 374 (20) 1911-1921. DOI: 10.1056/NEJMoa1602002

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CardioNerds kicks off its advanced therapies series with Chair of the CardioNerds Heart Failure Council, Dr. Jenna Skowronski, co-chair of the series, Dr. Shazli Khan, and Episode FIT lead, Dr. Jason Feinman. In this first episode, they discuss the process of advanced therapies evaluation with Dr. Michelle Kittleson, Professor of Medicine and Director of Education in Heart Failure and Transplantation at Cedars-Sinai. In this case-based discussion, they cover the signs and symptoms of end-stage heart failure, the initial management strategies, and the diagnostic workup required when considering advanced therapies. Importantly, they discuss the special considerations for pursuing left-ventricular assist device (LVAD) versus heart transplantation as well as the multidisciplinary, team-based approach needed when advanced therapies are indicated.

Notes were drafted by Dr. Shazli Khan. Audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

We Were Thrilled to Join the American Heart Association’s Scientific Sessions 2025!AHA Scientific Sessions 2025 took place November 7–10 in New Orleans, LA — one of the premier annual gatherings in cardiovascular science and education.

It was an incredible opportunity to connect with colleagues, hear cutting-edge research, and contribute to the ongoing conversations shaping the future of cardiovascular care.

We’re grateful to everyone who joined us in New Orleans and made this year’s meeting so impactful.

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Pearls1. Guideline-directed medical therapy (GDMT) is indicated in all heart failure patients and improves survival, but progressive symptoms and intolerance to GDMT can be warning signs of disease progression. The I-NEED-HELP mnemonic is an excellent reference when considering referral for advanced therapies (Figure). 2. Management of acute decompensation includes diuretics and possible inotropic support. The inotropic agent used should be whichever best suits your specific patient. Milrinone may result in more hypotension, whereas dobutamine may result in more tachycardia. Tachycardic and normotensive patients may do better with milrinone, while hypotensive patients with normal heart rates may do better with dobutamine. Notably, DoReMi found no difference between milrinone and dobutamine for patients with cardiogenic shock. 3. The initial diagnostic evaluation includes an echocardiogram, right heart catheterization (RHC), and often cardiopulmonary exercise testing (CPET) to objectively assess the status of the heart. Comprehensive labs, imaging and cancer screening are also needed to assess all other organs. 4. When making the decision to pursue advanced therapies, always ask: 1. Is the heart sick enough? 2. Is the rest of the body well enough?

These two questions provide a framework to guide if patients are optimal candidates for transplant versus LVAD.

1. The advanced therapies evaluation is a team sport! Patients will meet not only with advanced heart failure cardiologists, but also cardiac surgeons, psychiatrists, social workers, nutritionists and pharmacists. All team members are of critical value in the process.

Notes1.) What are the key features of advanced cardiomyopathy, and when should providers consider referral for advanced therapies?

• Advanced cardiomyopathy may present as recurrent hospitalizations for decompensated heart failure, intolerance to GDMT with symptomatic orthostasis and hypotension, and progressive symptoms of heart failure despite medical therapy.
• The I-NEED-HELP mnemonic is a helpful tool to identify patients at risk of heart failure and is defined as follows: Need for Inotropic support, New York Heart Association (NYHA) Class IV symptoms, End-Organ Dysfunction, Ejection fraction <20%, Defibrillator shocks for ventricular arrhythmias, Recurrent HF hospitalizations, Escalating diuretic dose, Low blood pressure and Progressive intolerance of GDMT. See the Figure designed by Dr. Gurleen Kaur.
• When patients demonstrate any of the above warning signs, they should be referred to advanced heart failure specialists for consideration of advanced therapies.

2.) What diagnostic testing is pursued when working up patients for advanced therapies? How does this workup differ whether you are in the inpatient or outpatient setting?

• Work-up generally answers two key questions: is the heart sick enough and is the rest of the body well enough?
• Workup includes an echocardiogram that may show specific features concerning for end-stage heart failure (EF <20%, dilated and remodeled left ventricle, reduced right ventricular function, etc.).
• A RHC provides information on the filling pressures of the heart for management in the acute setting, but also helps give an objective measure of the cardiac output to assess how sick the heart is. Importantly the RHC also provides key information on the presence of pulmonary hypertension.
• Obtaining a comprehensive metabolic panel provides valuable information on end-organ dysfunction, as kidney or liver abnormalities are suggestive of worsening disease.
• Outpatients presenting for referral may also undergo CPET as an objective confirmation of decreased functional capacity. Typically, a peak VO2 max of <14 mL/kg/min is indicative of advanced disease.
• CT imaging, as well as other cancer screening tools, may be employed to ensure there is no systemic disease that would prohibit advanced therapies.

3.) Who makes up the multidisciplinary advanced therapies team?

• The ACC/AHA/HFSA 2022 guidelines for heart failure support using a multidisciplinary team approach in managing HF. This collaborative care model has been shown to reduce hospital admissions and healthcare expenses while enhancing patient adherence to self-care practices and recommended medical treatments.
• The multidisciplinary team consists of cardiologists, cardiac surgeons, advanced practice providers, psychiatrists, pharmacists, social workers, nutritionists, and other specialists.

4.) What are the medical factors to consider when deciding between transplant versus LVAD, and what social determinants of health play a role?

• The medical evaluation and workup done during the advanced therapies evaluation help answer two crucial questions: Is the heart sick enough? Is the rest of the body well enough? All patients should be assessed for extracardiac disease that may impact survival after advanced therapies.
• While selection between transplant versus LVAD varies by program and institution, general principles considered include the allocation system and regional wait times, patient’s age, and extracardiac comorbidities.
• Generally, patients being considered for heart transplantation should be devoid of conditions that have a five-year survival of <70% or a ten-year survival of <50%. This is also because patients undergoing organ transplantation require immunosuppressive medications, which may further exacerbate their other systemic conditions.
• Social support and internal motivation also play a role, as it is important for patients to attend multiple follow-up appointments and maintain strict adherence to their immunosuppressive medications.

Graphic – Stage D (Advanced) Heart Failure

Designedby Dr. Gurleen Kaur

References1. Morris AA, Khazanie P, Drazner MH, et al; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Hypertension. Guidance for timely and appropriate referral of patients with advanced heart failure: a scientific statement from the American Heart Association. Circulation. 2021;144(15):e238-e250. doi:10.1161/CIR.0000000000001016 https://www.ahajournals.org/doi/10.1161/CIR.0000000000001016 2. Truby LK, Rogers JG. Advanced heart failure: epidemiology, diagnosis, and therapeutic approaches. JACC Heart Fail. 2020;8(7):523-536. doi:10.1016/j.jchf.2020.01.014 https://www.sciencedirect.com/science/article/pii/S2213177920302080?via%3Dihub 3. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, et al; ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063 https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063 4. Guglin M, Zucker MJ, Borlaug BA, Breen E, Cleveland J, Johnson MR, Panjrath GS, et al; ACC Heart Failure and Transplant Member Section and Leadership Council. Evaluation for heart transplantation and LVAD implantation: JACC Council perspectives. J Am Coll Cardiol. 2020;75(12):1471-1487. doi:10.1016/j.jacc.2020.01.034 https://www.sciencedirect.com/science/article/pii/S0735109720304150?via%3Dihub

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In this second episode of a collaborative series with the AHA Women in Cardiology (WIC) Committee, CardioNerds (Dr. Gurleen Kaur and Dr. Anna Radhakrishnan) are joined by four leading experts in Cardio-Obstetrics to explore this rapidly evolving field. Dr. Rina Mauricio (Director of Women’s Cardiovascular Health and Cardio-Obstetrics at UT Southwestern Medical Center), Dr. Afshan Hameed (Director of Maternal Fetal Medicine and Cardio-Obstetrics at UC Irvine), Dr. Doreen DeFaria Yeh (Co-director of the MGH Cardiovascular Disease and Pregnancy Program), and Dr. Garima Sharma (Director of Women’s Cardiovascular Health and Cardio-Obstetrics at Inova) define Cardio-Ob as encompassing not only care of women during pregnancy, but also the complex decision-making that extends through the preconception and postpartum periods. From counseling patients with pre-existing or congenital heart disease before pregnancy to managing cardiovascular health during pregnancy and after delivery, they trace how the field has developed in response to the urgent need to address maternal mortality. Listeners will gain valuable insight into the multidisciplinary teamwork, patient-centered decision-making, and advocacy that drive this field – along with the importance of expanding Cardio-Ob education for clinicians and trainees, and innovations and system-level changes shaping its future. Audio editing by CardioNerds academy intern, Grace Qiu.

This episode was planned in collaboration with the AHA CLCD Women in Cardiology Committee with mentorship from Dr. Monika Sanghavi.

We Were Thrilled to Join the American Heart Association’s Scientific Sessions 2025!AHA Scientific Sessions 2025 took place November 7–10 in New Orleans, LA — one of the premier annual gatherings in cardiovascular science and education.

It was an incredible opportunity to connect with colleagues, hear cutting-edge research, and contribute to the ongoing conversations shaping the future of cardiovascular care.

We’re grateful to everyone who joined us in New Orleans and made this year’s meeting so impactful.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Dr. Jeanne De Lavallaz and Dr. Ramy Doss discuss the results of the  TRANSFORM-AF Trial with expert faculty Dr. Sanjeev Saksena and Dr. Varun Sundaram.

The TRANSFORM-AF trial enrolled 2,510 patients with atrial fibrillation (AF), type 2 diabetes, and obesity across 170 Veterans Affairs hospitals to evaluate the impact of diabetes-dose GLP-1 receptor agonists on AF-related outcomes. Participants were assigned to receive either a GLP-1 receptor agonist, a DPP-IV inhibitor, or a sulfonylurea. The primary composite outcome included AF-related hospitalizations, cardioversions, ablation procedures, and all-cause mortality. Over a median follow-up of 3.2 years, GLP-1 use was associated with a 13% reduction in major AF-related events compared to other therapies. The study population was predominantly male, with a high prevalence of severe obesity (BMI >40 kg/m²) in whom the benefit appeared most pronounced. Notably, the observed benefit occurred despite only modest additional weight loss, suggesting potential non-weight-mediated effects of GLP-1 therapy

This episode was planned in collaboration with  Heart Rhythm TV with mentorship from Dr. Daniel Alyesh and Dr. Mehak Dhande.

We Were Thrilled to Join the American Heart Association’s Scientific Sessions 2025!AHA Scientific Sessions 2025 took place November 7–10 in New Orleans, LA — one of the premier annual gatherings in cardiovascular science and education.

It was an incredible opportunity to connect with colleagues, hear cutting-edge research, and contribute to the ongoing conversations shaping the future of cardiovascular care.

We’re grateful to everyone who joined us in New Orleans and made this year’s meeting so impactful.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Dr. Naima Maqsood, Dr. Kelly Arps, and Dr. Jake Roberts discuss the acute management of atrial fibrillation with guest expert Dr. Jonathan Chrispin. Episode audio was edited by CardioNerds Intern Dr. Bhavya Shah.

This episode reviews acute management strategies for atrial fibrillation. Atrial fibrillation is the most common chronic arrhythmia worldwide and is associated with increasingly prevalent comorbidities, including advanced age, obesity, and hypertension. Atrial fibrillation is a frequent indication for hospitalization and a complicating factor during hospital stays for other conditions. Here, we discuss considerations for the acute management of atrial fibrillation, including indications for rate versus rhythm control strategies, treatment targets for these approaches, considerations including pharmacologic versus electrical cardioversion, and management in the post-operative setting.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

We Were Thrilled to Join the American Heart Association’s Scientific Sessions 2025!AHA Scientific Sessions 2025 took place November 7–10 in New Orleans, LA — one of the premier annual gatherings in cardiovascular science and education.

It was an incredible opportunity to connect with colleagues, hear cutting-edge research, and contribute to the ongoing conversations shaping the future of cardiovascular care.

We’re grateful to everyone who joined us in New Orleans and made this year’s meeting so impactful.

CardioNerds Atrial Fibrillation Page
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Pearls1. A key component to the management of acute atrial fibrillation involves addressing the underlying cause of the acute presentation. For example, if a patient presents with rapid atrial fibrillation and signs of infection, treatment of the underlying infection will help improve the elevated heart rate. 2. Selecting a rate control versus rhythm control strategy in the acute setting involves considerations of comorbid conditions such as heart failure and competing risk factors such as critical illness that may favor one strategy over another. Recent data strongly supports the use of rhythm control in heart failure patients. Patients should be initiated on anticoagulation prior to pursuing a rhythm control strategy. 3. There are several strategies for rate control medications with therapies including beta-blockers, non-dihydropyridine calcium channel blockers, and digoxin. The selection of which agent to use depends on additional comorbidities and the overall clinical assessment. For example, a patient with severely decompensated low-output heart failure may not tolerate a beta-blocker or calcium channel blocker in the acute phase due to hypotension risks but may benefit from the use of digoxin to provide rate control and some inotropic support. 4. Thromboembolic prevention remains a cornerstone of atrial fibrillation management, and considerations must always be made in terms of the duration of atrial fibrillation, thromboembolic risk, and risks of anticoagulation. 5. While postoperative atrial fibrillation is more common after cardiac surgeries, there is no major difference in management between patients who undergo cardiac versus non-cardiac procedures. Considerations involve whether the patient has a prior history of atrial fibrillation, surgery-specific bleeding risks related to anticoagulation, and monitoring in the post-operative period to assess for recurrence.

Notes1. Our first patient is a 65-year-old man with obesity, hypertension, obstructive sleep apnea, and pre-diabetes presenting for evaluation of worsening shortness of breath and palpitations. The patient has no known history of heart disease. Telemetry shows atrial fibrillation with ventricular rates elevated to 130-140 bpm. What would be the initial approach to addressing the acute management of atrial fibrillation in this patient? What are some of the primary considerations in the initial history and chart review?

• An important first step involves taking a careful history to understand the timing of symptom onset and potential underlying causes contributing to a patient’s acute presentation with rapid atrial fibrillation.
• Understanding the episode trigger determines management by targeting reversible causes of the acute presentation and elucidating whether the episode is triggered by a cardiac or non-cardiac condition. For example, if a patient presents with a few days of infectious symptoms, treating the infection is likely to lead to improvements in heart rate.
• Determining the tempo of symptoms has further importance for assessing the risk of thromboembolism and anticoagulation consideration.

2. How would the initial evaluation be different for patients who have a new diagnosis of atrial fibrillation compared to those who have a known prior history of this arrhythmia?

• The acuity of symptom onset plays an essential role in these considerations. For example, a patient may describe symptoms that have been ongoing for several months, which indicate a diagnosis beyond the acute phase of their presentation and would involve different considerations than for a patient who first noticed symptoms within the past few hours.
• One way to view RVR rates in a patient with longstanding or permanent atrial fibrillation is to consider this vital sign as that patient’s version of sinus tachycardia in response to another physiologic process. In that setting, you would not try an approach to directly lower their heart rate but would instead attempt to determine and address the underlying cause of their presentation.
• An additional consideration for patients without known prior atrial fibrillation is that they have likely never been on any rate-controlling agents and may have variable initial responses to these interventions.

3. In cases for which acute rate control of atrial fibrillation is indicated, what is the recommended heart rate target and how quickly should we aim to reach that target?

• The initial first step in management should focus on addressing the underlying cause of the patient’s elevated heart rate while in atrial fibrillation. Once those factors are addressed and elevated heart rates persist, a rate-controlling agent can be considered.
• Often, a primary reason for rate control is for symptom relief since patients can be very symptomatic from an elevated heart rate alone.
• A reasonable goal for the intermediate setting is to achieve a heart rate of less than 100-110 bpm. One study compared lenient (resting heart rate <110 bpm) versus strict (resting heart rate <80 bpm and heart rate during moderate exercise <110 bpm) rate control in patients with atrial fibrillation and found no difference in outcomes related to mortality, hospitalization for heart failure, stroke, embolism, bleeding, or life-threatening arrhythmic events but that lenient control was easier to achieve.1 For this reason, aggressive rate control in the acute setting may not have a significant impact apart from symptom relief. There are not often clear indications to rapidly lower a patient’s heart rate, for example, from 140 to 90 bpm. Conversely, lowering a patient’s heart rate too rapidly can be detrimental by causing bradycardia or hypotension with excessive use of nodal blocking agents.

4. What are some of the considerations for the selection of rate-controlling agents?

• Beta-blockers and non-dihydropyridine calcium channel blockers remain the mainstay of therapies used for rate control. The choice between these agents often depends on the comorbidities present. For example, if a patient has a known reduced LVEF, you may often avoid calcium channel blockers and opt for careful titration of beta-blockers. Often, the use of beta-blockers also allows for the management of additional comorbidities, including heart failure and coronary disease.
• Digoxin is another agent to consider when a patient presents with acutely decompensated heart failure with a low LVEF and may not tolerate a beta-blocker or calcium channel blocker due to the risk of hypotension or worsening cardiogenic shock. Digoxin provides rate control while adding some positive inotropy. In terms of chronic management, digoxin use can be more challenging with close follow-up required to monitor levels. In some cases, amiodarone can be used as an acute rate-control agent, but there is a risk of conversion to sinus rhythm and thromboembolism if not on anticoagulation.

5. In what clinical scenarios might it be more optimal to consider an upfront rhythm control strategy?

• Recent data support the benefit of an upfront rhythm control approach in heart failure patients, with complications including cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome, reduced in heart failure patients managed with any early rhythm control strategy.2,3
• In certain patients with known atrial fibrillation and heart failure, cardioversion can be considered as a strategy to help improve their heart failure symptoms. In these patients, initiating an anti-arrhythmic drug (AAD) prior to cardioversion can improve the likelihood of remaining in sinus rhythm after cardioversion.

6. Our second patient is a 58-year-old woman with a history of heart failure with reduced EF presenting to the ED with progressive lower extremity swelling and shortness of breath. She has a prior diagnosis of paroxysmal atrial fibrillation, and her most recent echo demonstrated an LVEF of 35%. She is found to have bilateral lower extremity pitting edema to her knees and elevated jugular venous pressure while requiring 2L of oxygen by nasal cannula. She is in rapid atrial fibrillation on presentation. Interrogation of her primary prevention ICD shows that she has been in atrial fibrillation for the past 3 weeks. In this scenario involving a patient with an acute heart failure exacerbation, are there considerations for a more upfront rhythm control strategy and perhaps electrical cardioversion?

• In this scenario, there is an indication for utilizing an early rhythm control strategy. Even if an initial trial of diuresis and beta-blockers is used initially, the fact that this patient has been in atrial fibrillation for several weeks with only prior paroxysmal episodes indicates that her arrhythmia is likely contributing to her decompensation and therefore should be addressed during hospitalization. This patient should be considered for AAD initiation and careful considerations should be made to ensure that this patient is appropriately anticoagulated. Once anticoagulation has been established, interventions including electrical cardioversion can be considered.
• For this patient with a reduced LVEF, AAD initiation should be considered prior to cardioversion with options limited to amiodarone or dofetilide. For patients with renal disease and concerns for QT prolongation, amiodarone can be used as a reasonable short-term solution to bridge the patient to more definitive long-term strategies for rhythm control. This patient can be initiated on AAD and, if she does not convert on medication, can be considered for electrical cardioversion. The timing of cardioversion would depend on when the patient is optimized from a heart failure standpoint, including when the patient has become more euvolemic. With dofetilide, electrical cardioversion is typically attempted after the fourth dose is given to ensure that the patient can stay in sinus rhythm after cardioversion.

7. A common scenario in which we often find ourselves managing atrial fibrillation is in the postoperative setting. What are some of the management strategies for postoperative atrial fibrillation and how does this vary between patients who underwent cardiac versus non-cardiac procedures?

• Compared to non-cardiac surgery, in cardiac surgery there is an increased risk for developing postoperative atrial fibrillation, with rates of occurrence ranging from 30-60%.4,5 While there are higher rates of post-operative atrial fibrillation in patients undergoing cardiac surgeries, there is no significant difference in the strategies used to treat patients who underwent cardiac versus non-cardiac surgeries.
• For patients who have no prior history of atrial fibrillation prior to developing post-operatively, historical teaching endorsed the idea that this arrhythmia developed in response to inflammation occurring during acute recovery and should not have long-term consequences; however, more recent data suggests that if a patient develops atrial fibrillation post-operatively, they are more likely to have recurrence of this arrhythmia in the future.6
• Current guidelines support anticoagulation based on the CHADSVASc score for at least 60 days post-operatively while monitoring for persistence of the arrhythmia.7 Further, data suggest that rhythm approaches post-operatively lead to better long-term outcomes in terms of re-hospitalizations and mortality.
• In patients who underwent surgeries with high bleeding risk during recovery and have contraindications to anticoagulation, rate-control strategies are most appropriate initially.
• If a patient has new atrial fibrillation without a prior diagnosis, they will need monitoring for recurrence for 30-60 days post-operatively.

8. What are some of the considerations for a pill-in-the-pocket strategy for those patients who experience infrequent episodes of symptomatic atrial fibrillation?

• In this strategy, the patient takes medication when they are having symptoms with the intention of terminating the atrial fibrillation episode acutely.
• When initiating this approach, it is essential to do so in a monitoring setting because of the effects that can result from giving high doses of these medications to treat acute episodes. For example, with flecainide, a dose of 300 mg may be given at one time compared to a dose of 50-150 mg twice daily to reach the maintenance dose. When medications such as flecainide are given in these loading doses, it is important to monitor for any acute toxicity.
• Given the potential toxicities and challenges inherent to a pill-in-the-pocket approach, the desire to prevent rather than reactively treat episodes of atrial fibrillation, and improvements in catheter ablation techniques, this strategy is now rarely used in practice, with patients managed either with a maintenance medication or ablation.

References1. Van Gelder IC, Groenveld HF, Crijns HJGM, et al. Lenient versus Strict Rate Control in Patients with Atrial Fibrillation. New England Journal of Medicine. 2010;362(15). doi:10.1056/nejmoa1001337

1. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. New England Journal of Medicine. 2020;383(14). doi:10.1056/nejmoa2019422

2. Rillig A, Magnussen C, Ozga AK, et al. Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure. Circulation. 2021;144(11). doi:10.1161/CIRCULATIONAHA.121.056323

3. Gaudino M, Di Franco A, Rong LQ, Piccini J, Mack M. Postoperative atrial fibrillation: From mechanisms to treatment. Eur Heart J. 2023;44(12). doi:10.1093/eurheartj/ehad019

4. Perezgrovas-Olaria R, Alzghari T, Rahouma M, et al. Differences in Postoperative Atrial Fibrillation Incidence and Outcomes After Cardiac Surgery According to Assessment Method and Definition: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2023;12(19). doi:10.1161/JAHA.123.030907

5. Gilbers MD, Kawczynski MJ, Bidar E, et al. Determinants and impact of postoperative atrial fibrillation burden during 2.5 years of continuous rhythm monitoring after cardiac surgery: Results from the RACE V prospective cohort study. Heart Rhythm. 2024;22(3):647-660. doi:10.1016/j.hrthm.2024.08.014

6. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1). doi:10.1161/CIR.0000000000001193

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In this powerful kickoff to a collaborative series with the AHA Women in Cardiology (WIC) Committee, CardioNerds (Dr. Apoorva Gangavelli, Dr. Gurleen Kaur, and Dr. Jenna Skowronski) explore the evolving landscape of women in advanced heart failure and transplant cardiology, featuring insights from two inspiring leaders in the field. Dr. Mariell Jessup, Chief Science and Medical Officer of the American Heart Association, reflects on her decades-long journey in heart failure cardiology, from navigating early career barriers to becoming a trailblazer in clinical leadership and research. Dr. Nosheen Reza, an advanced heart failure and transplant cardiologist at the University of Pennsylvania, shares how Dr. Jessup’s pioneering work has inspired her own career and shaped her approach to mentorship, advocacy, and academic development. Together, they discuss the systemic challenges women continue to face, the importance of sponsorship, and the evolving culture within cardiology. Listeners will gain a multigenerational perspective on how far the field has come and what is still needed to ensure equity, excellence, and innovation in advanced heart failure care.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Join Us at American Heart Association’s Scientific Sessions 2025!Don’t miss one of the biggest cardiovascular meetings of the year — AHA Scientific Sessions 2025!
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This is your chance to connect with colleagues, hear the latest cutting-edge science, and be part of the conversation shaping the future of cardiovascular care.

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ReferencesDeFilippis EM, Moayedi Y, Reza N. Representation of Women Physicians in Heart Failure Clinical Practice. Card Fail Rev. 2021;7:e05. Published 2021 Mar 31. doi:10.15420/cfr.2020.31

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CardioNerds (Dr. Abby Frederickson, Dr. Claire Cambron, and Dr. Rawan Amir) are joined by Dr. Leigh Reardon for a powerful conversation on navigating adult congenital heart disease as both a patient and provider. Dr. Reardon shares his personal journey with congenital heart disease and how it shaped his path to becoming an expert in the field himself. The discussion highlights patient-centered perspectives, barriers to care within the healthcare system, and the importance of advocacy and empathy.

This episode was planned by the CardioNerds ACHD Council.

Join Us at American Heart Association’s Scientific Sessions 2025!Don’t miss one of the biggest cardiovascular meetings of the year — AHA Scientific Sessions 2025!
📅 November 7–10, 2025
📍 New Orleans, LA

This is your chance to connect with colleagues, hear the latest cutting-edge science, and be part of the conversation shaping the future of cardiovascular care.

👉 Register now and join us in New Orleans!

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Dr. Kelly Arps, Dr. Naima Maqsood, and Dr. Sahi Allam discuss modifiable risk factors and lifestyle management of atrial fibrillation with Dr. Prash Sanders. Atrial fibrillation is becoming more prevalent across the world as people are living longer with cardiovascular disease. While much of our current focus lies on the pharmacological and procedural management of atrial fibrillation, several studies have shown that targeted reduction of risk factors, such as obesity, sleep apnea, hypertension, and alcohol use, can also significantly reduce atrial fibrillation burden and symptoms. Today, we discuss the data behind lifestyle management and why it is considered the “4th pillar” of atrial fibrillation treatment. We also explore ways to incorporate prevention strategies into our general cardiology and electrophysiology clinics to better serve the growing atrial fibrillation population. Audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. More people have atrial fibrillation because it is being detected earlier using wearable technology, and patients are living longer with subclinical or clinical cardiovascular disease 2. There are 3 components of atrial fibrillation: an electrical “trigger” + a susceptible substrate (due to age, sex, genetics) + “perpetuators” that cause the trigger to continue stimulating the substrate (lifestyle risk factors such as obesity, smoking, diabetes, etc.) 3. Obesity is the highest attributable risk factor for atrial fibrillation. Treating obesity often helps to treat other risk factors, such as hypertension and sleep apnea. 4. Counseling is patient-dependent. Most patients are unable to make major behavioral changes cold-turkey and will need to make small, incremental changes. 5. Dr. Sanders’ tip: He tells his own patients that “atrial fibrillation is the body’s response to stress.” The key to treating atrial fibrillation is to control your underlying stressors – procedures and medications are simply band-aids that do not fix the root of the problem.

NotesNotes drafted by Dr. Allam.

1. How common is atrial fibrillation?

2. Atrial fibrillation is the most common sustained arrhythmia. Currently, an estimated 50-60 million individuals worldwide are estimated to have atrial fibrillation, or roughly 1 in 4 individuals over the age of 45.1

3. The rising global prevalence of atrial fibrillation can be attributed to the aging of the population, increased rates of obesity, and greater accumulation of cardiovascular risk factors and survival with clinical cardiovascular disease.2 Atrial fibrillation is also being detected earlier through digital and wearable devices.2

4. Annually, we spend approximately $5,312 per adult on the management of atrial fibrillation in the United States.3

5. What is the underlying pathophysiology of atrial fibrillation? How do risk factors like sleep apnea or obesity “trigger” atrial fibrillation?

6. For atrial fibrillation to occur, there is an electrical “trigger”, a susceptible substrate (due to age, sex, genetics), and “perpetuators” that allow the trigger to continue stimulating the substrate.2

7. 90% of electrical “triggers” come from the pulmonary veins
8. “Perpetuators” influence how the autonomic nervous system interacts with the triggers and substrate to perpetuate atrial fibrillation. Sleep apnea, obesity, and other risk factors are the “perpetuators”

9. Over time, as atrial fibrillation recurs, the substrate remodels to result in persistent atrial fibrillation.

10. What are some of the risk factors for atrial fibrillation and what are the possible benefits of controlling them?

11. Reference 4 provides an excellent review of the individual risk factors

12. Tobacco use
13. Nicotine patches/gums and counseling are associated with successful nicotine cessation in RCTs.
14. In the long term, nicotine itself can cause atrial fibrosis. However, it is safe to use patches and gums in the short term to abet cessation.
15. Obesity
16. The highest attributable risk factor for atrial fibrillation. Treating obesity often helps to treat other risk factors, such as hypertension and sleep apnea
17. In addition to regular exercise, reducing caloric intake can help combat obesity. Eating more fiber-laden food such as vegetables instead of carbohydrates, limiting portions, sugary drinks, and alcohol, and increasing fasting periods can all help decrease weight.
18. GLP-1 agonists can significantly reduce obesity and improve both symptoms and mortality for patients with comorbid conditions, such as HFpEF.
19. Obstructive sleep apnea
20. This is an evolving area of research with upcoming randomized trial data
21. Sleep apnea is probably not a static condition. Our likelihood of having sleep apnea changes with how rested we are, how much we’ve exercised, or whether we’ve consumed alcohol, etc. The testing and treatment of the future will reflect the changeable nature of sleep apnea.
22. Current data:
23. In the atrial fibrillation ablation population, treatment of sleep apnea was associated with an improvement in time to arrhythmia recurrence.
24. Another observational study from Norway, which included various patients who used dental sleep appliances, found no significant difference in atrial fibrillation between those who were treated for sleep apnea and those who were not. It was severely underpowered to detect a difference.
25. Caffeine
26. There is no evidence to support cessation of caffeine in patients with atrial fibrillation
27. For patients with bothersome palpitations, caffeine cessation can be tried if it improves their symptoms
28. Alcohol use
29. Per data from the UK Biobank, a single drink of alcohol daily does not increase your risk for developing atrial fibrillation. However, multiple drinks per day will increase your risk.
30. A proof-of-concept study showed that patients who abstained from alcohol for at least 6 months had complete resolution of atrial fibrillation. However, the dropout rate was very high as most patients could not completely abstain from alcohol
31. Dr. Sanders recommends alcohol consumption of ≤ 3 drinks/week, which is the cutoff used in lifestyle management studies.
32. Heart Failure
33. For patients with heart failure, the 4 pillars of heart failure management are also crucial to treating atrial fibrillation. SGLT2 inhibitors in particular are likely to confer benefits. 40-50% of patients in the SGLT2 inhibitor clinical trials had co-morbid atrial fibrillation.

34. About half of patients undergoing atrial fibrillation ablation appear to have HFpEF based on their hemodynamics.

35. Can atrial fibrillation be treated with only lifestyle modifications?

36. Potentially. This is an evolving area of research without much published data. Empirically, Dr. Sanders has noticed that in patients referred for atrial fibrillation ablation, aggressive lifestyle modifications result in 40% of them no longer requiring ablation. After a 10-year follow-up, 20% still do not require ablation.

37. However, ablation is still an effective modality to achieve rhythm control. It is also becoming a safer procedure owing to novel techniques, such as pulse field ablation.

38. In the future, we foresee most patients utilizing a combination of lifestyle modification and rhythm control strategies (ablation and/or medications) to control their atrial fibrillation.

39. What are the benefits of exercise in patients with atrial fibrillation? How much exercise do you recommend to your patients? Also, on the other end of the spectrum, does participation in endurance sports paradoxically promote atrial fibrillation?

40. The ACTIVE-AF study tested whether an intensive aerobic exercise regimen, up to 210 minutes per day, is safe and effective in controlling atrial fibrillation. Intensive exercise was associated with a significant reduction in atrial fibrillation burden and symptoms as well as an increase in quality of life and maintenance of sinus rhythm.5

41. Endurance athletes do have an approximately 5-fold higher risk of atrial fibrillation compared to sedentary people.6 However, this occurs at very high levels of exercise, exceeding 4 hours per day. Low to moderate levels of exercise have been shown to reduce rates of atrial fibrillation.4,5

42. How should we counsel patients about lifestyle management? Are there any good resources to use?

43. Dr. Sanders’ tip: Counseling is patient-dependent. For the majority of patients, the key to behavioral change is to make incremental adjustments over time, accompanied by encouragement. Some patients respond well to continuous feedback from digital devices. We can also supplement pharmacological therapies, such as medications to assist with weight loss or tobacco/alcohol cessation, to behavioral counseling.

44. Risk factor modification should be the central pillar of atrial fibrillation management and reviewed early on with patients in their atrial fibrillation course. It may be beneficial to have clinic sessions specifically dedicated to lifestyle counseling, which can be run by a multidisciplinary team of electrophysiologists, general cardiologists, and nurse educators.

45. How should we explain what atrial fibrillation is to our patients?

46. Dr. Sanders’ tip: He tells his own patients that “atrial fibrillation is the body’s response to stress. It occurs because the heart is not coping well with increased stress. Procedures and medications for atrial fibrillation are simply band-aids that do not fix the root of the problem, but controlling the risk factors contributing to increased stress will.”

47. He also emphasizes the increased stroke risk of atrial fibrillation.

References1. Linz D, Gawalko M, Betz K, Hendriks J, Lip G, Vinter N. Atrial fibrillation: epidemiology, screening and digital health. The Lancet Regional Health – Europe. 2024;37(100786).

1. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Jan 02 2024;149(1):e1-e156.

2. Serpa F, Tale A, Zimetbaum P, Kramer D. Trends in health care expenditures and incremental health care cost in adults with atrial fibrillation in the United States. Heart Rhythm O2. 2025;6(1).

3. Chung MK, Eckhardt LL, Chen LY, et al. Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association. Circulation. Apr 21 2020;141(16):e750-e772. doi:10.1161/CIR.0000000000000748

4. Elliott AD, Verdicchio CV, Mahajan R, et al. An exercise and physical activity program in patients with atrial fibrillation. JACC: Clinical Electrophysiology. 2023;9(4):455-465. doi:10.1016/j.jacep.2022.12.002

5. Atrial fibrillation in competitive athletes. American College of Cardiology. Accessed February 22, 2025. https://www.acc.org/Latest-in-Cardiology/Articles/2019/08/16/08/20/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fArticles%2f2019%2f08%2f16%2f08%2f20%2fAtrial-Fibrillation-in-Competitive-Athletes

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CardioNerds join Dr. Neel Patel, Dr. Victoria Odeleye, and Dr. Jay Ramsay from the University of Tennessee, Nashville, for a deep dive into cardiovascular medicine in the vibrant city of Nashville. They discuss the following case: A 57-year-old male with a history of prior cardiac surgery, hypertension, and polysubstance use presented with syncope and chest pain. Initial workup revealed a large saccular ascending aortic aneurysm. While under conservative management, he experienced acute hemodynamic collapse, leading to the discovery of an unprecedented aorto-right ventricular fistula. This episode examines the clinical presentation, diagnostic journey, and management challenges of this rare and complex aortic pathology, highlighting the role of multimodal imaging and the interplay of multifactorial risk factors. Expert commentary is provided by Dr. Andrew Zurick III. Episode audio was edited by CardioNerds Intern student Dr. Pacey Wetstein.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls1. Saccular Aneurysm Risk: Saccular aortic aneurysms, though less common than fusiform, carry a higher inherent rupture risk due to concentrated wall shear stress, often exacerbated by prior cardiac surgery, chronic hypertension, and polysubstance use. 2. Unprecedented Rupture: The direct rupture of an aortic aneurysm into a cardiac chamber, specifically the right ventricle, is an exceedingly rare event, with no prior reported cases in the literature, highlighting the unpredictable nature of complex aortic pathology. 3. Hemodynamic Catastrophe: A large aorto-right ventricular fistula creates a massive left-to-right shunt, leading to acute right ventricular pressure and volume overload, culminating in rapid cardiogenic shock and refractory right ventricular failure. 4. Multimodal Imaging Imperative: Multimodal imaging (CT angiography for anatomy, TTE/TEE for real-time hemodynamics and fistula detection, CMR for tissue characterization) is indispensable for rapid diagnosis and comprehensive characterization of life-threatening cardiovascular emergencies. 5. High-Risk Intervention: Emergent surgical repair of a ruptured aortic aneurysm with an aorto-right ventricular fistula is a high-risk procedure associated with significant mortality, underscoring the need for prompt multidisciplinary care and realistic outcome expectations.

Notes – Notes (drafted by Dr Neel Patel):

What are the unique characteristics and rupture risk of saccular aortic aneurysms?

• Saccular aortic aneurysms are less common than fusiform aneurysms.
• They are generally considered more prone to rupture due to higher wall shear stress concentrated at the neck of the aneurysm, acting as a focal point of weakness.
• Contributing Factors to Aneurysm Formation and Rupture in this Case:
• Prior Cardiac Surgery: Aortic cannulation during the VSD/ASD repair decades ago likely created a localized structural weakness or predisposition.
• Chronic, Poorly Controlled Hypertension: Imposed relentless systemic stress on the arterial walls, accelerating dilation and weakening.
• Polysubstance Use: Particularly stimulants like cocaine and methamphetamines, which directly contribute to vascular damage by inducing severe, uncontrolled hypertension and direct arterial wall injury. This significantly increases the risk of aneurysm formation and rupture, especially with pre-existing conditions.
• The direct rupture of an aortic aneurysm into a cardiac chamber, specifically the right ventricle, is an exceedingly rare event, with no prior reported cases in the literature, making this a “first of its kind” report.

What are the hemodynamic consequences and management challenges associated with aorto-right ventricular fistulas?

• Hemodynamic Impact: A large aorto-right ventricular fistula results in a significant anatomic left-to-right shunt, where blood from the high-pressure aorta is shunted directly into the lower-pressure right ventricle.
• This leads to acute right ventricular pressure and volume overload, causing rapid right ventricular dilation, increased right ventricular wall stress, and ultimately, acute right ventricular failure.
• This directly explained the sudden onset of cardiogenic shock, as the right ventricle was unable to maintain forward flow, leading to systemic hypoperfusion and shock.
• Management Challenges:
• The patient required emergent, extremely high-risk salvage aortic aneurysm repair surgery.
• Marked hemodynamic instability occurred immediately after anesthesia induction (systolic blood pressure dropped to 50 mmHg), necessitating immediate initiation of external cardiopulmonary bypass.
• Intra-operatively, a large (2 cm diameter) hole in the ascending aorta communicating with the saccular aneurysm was found, along with a massive (4-5 cm) fistula into the right ventricular outflow tract (RVOT) area, just proximal to the pulmonic valve, with several smaller holes.
• Surgical repair involved a 5×10 cm bovine pericardial patch for the right ventricular wall and replacement of a 5 cm segment of the ascending aorta with a 34 mm gelweave straight graft.
• Post-operative Course: Severely complicated by severe coagulopathy and extensive bleeding (requiring multiple blood products and a Cabral fistula).
• Continued severe right ventricular dysfunction necessitated the placement of a Right Ventricular Assist Device (RVAD).
• Despite support, hemodynamic function continued to decline, with severely depressed Left Ventricular (LV) function observed.
• The patient ultimately passed away due to refractory right heart failure and hemodynamic collapse, highlighting the extremely high mortality risk associated with such complex, emergent cardiac surgical interventions.

What is the role of multimodal imaging in diagnosing this complex and rare cardiovascular emergency?

• CT Angiography: Crucial for initial identification and comprehensive characterization of the large saccular ascending aortic aneurysm, providing precise dimensions, revealing layered thrombus, and understanding anatomical relationships. Its high spatial resolution and wide field of view are excellent for aortic assessment.
• Transthoracic and Transesophageal Echocardiography (TTE/TEE): Absolutely critical for real-time diagnosis of the fistula during acute deterioration. Bedside echocardiography, particularly TEE, allowed for visualization of the new continuous, turbulent flow from the aorta directly into the right ventricle, quantification of acute right ventricular dilation, and estimation of significantly increased RVSP. Its accessibility and real-time capabilities are unmatched for acute hemodynamic assessment and shunt detection.
• Cardiac MRI (CMR): Provided additional tissue characterization of the aneurysm, confirming partial thrombosis and, importantly, showing no significant late gadolinium enhancement (LGE) in the myocardium, which was reassuring regarding the absence of significant myocardial scar related to the aneurysm itself. CMR offers superior soft tissue characterization compared to CT.
• Complementary Nature: This case demonstrated the complementary nature of these modalities: CT provided the initial anatomical roadmap, echocardiography offered real-time hemodynamic assessment and immediate diagnosis of the acute rupture and shunt, and CMR contributed valuable tissue characterization. Imaging choices are guided by clinical questions, urgency, and specific information needed for critical management decisions.

What are the multi-factorial risk factors contributing to complex aortic disease, including the often-overlooked impact of polysubstance use?

• Prior Cardiac Surgery: The patient’s history of open-heart surgery decades prior, involving aortic cannulation for cardiopulmonary bypass, is a recognized risk factor for the subsequent development of iatrogenic aneurysms, creating a localized structural weakness or predisposition.
• Chronic, Poorly Controlled Hypertension: Imposes relentless systemic stress on the arterial walls, accelerating dilation and weakening, significantly contributing to aneurysm progression.
• Polysubstance Use:
• The patient’s long-standing history of polysubstance use, particularly stimulants like cocaine and methamphetamines, represents a significant contributing factor to his vascular pathology.
• These substances are not merely comorbidities; they directly contribute to vascular damage.
• Chronic stimulant use can induce severe, uncontrolled hypertension and direct arterial wall injury.
• This significantly increases the risk of aneurysm formation and rupture, especially when combined with pre-existing conditions like essential hypertension and prior cardiac surgery.
• Multi-hit Phenomenon: This case illustrates a multi-factorial pathology where various insults on vascular integrity over time converge to create a highly complex and catastrophic cardiovascular event. The presence of these factors emphasizes the critical importance of a thorough social history in cardiovascular risk assessment, moving beyond a superficial listing to understanding the profound pathophysiological impact on vascular health.

References – 1. Lavall D, Schäfers HJ, Böhm M, Laufs U. Aneurysms of the ascending aorta. Dtsch Arztebl Int. 2012 Mar;109(13):227-33. doi: 10.3238/arztebl.2012.0227. Epub 2012 Mar 30. PMID: 22532815; PMCID: PMC3334714. 2. Shang EK, Nathan DP, Boonn WW, Lys-Dobradin IA, Fairman RM, Woo EY, Wang GJ, Jackson BM. A modern experience with saccular aortic aneurysms. J Vasc Surg. 2013 Jan;57(1):84-8. doi: 10.1016/j.jvs.2012.07.002. Epub 2012 Nov 3. PMID: 23127980. 3. Brown PM, Zelt DT, Sobolev B. The risk of rupture in untreated aneurysms: the impact of size, gender, and expansion rate. J Vasc Surg. 2003 Feb;37(2):280-4. doi: 10.1067/mva.2003.119. PMID: 12563196. 4. Natsume K, Shiiya N, Takehara Y, Sugiyama M, Satoh H, Yamashita K, Washiyama N. Characterizing saccular aortic arch aneurysms from the geometry-flow dynamics relationship. J Thorac Cardiovasc Surg. 2017 Jun;153(6):1413-1420.e1. doi: 10.1016/j.jtcvs.2016.11.032. Epub 2016 Nov 22. PMID: 28027791. 5. Jeroen Walpot, Cees Klazen, Raymond Hokken, Jetze Sorgedrager, Martha Hoevenaar, Judith den Braber, Aorto-right ventricular fistula as an occasional finding, European Journal of Echocardiography, Volume 6, Issue 1, January 2005, Pages 65–66, https://doi.org/10.1016/j.euje.2004.08.009 6. De Viti D, Santoro F, Raimondo P, Brunetti ND, Memmola C. Congenital Aorto-Right Ventricular Fistula Associated with Pulmonary Hypertension in an Old Female Patient. J Cardiovasc Echogr. 2018 Apr-Jun;28(2):141-142. doi: 10.4103/jcecho.jcecho_58_17. PMID: 29911015; PMCID: PMC5989549. 7. Konda MK, Kalavakunta JK, Pratt JW, Martin D, Gupta V. Aorto-right Ventricular Fistula Following Percutaneous Transcatheter Aortic Valve Replacement: Case Report and Literature Review. Heart Views. 2017 Oct-Dec;18(4):133-136. doi: 10.4103/HEARTVIEWS.HEARTVIEWS_115_16. PMID: 29326776; PMCID: PMC5755194. 8. Vainrib AF, Ibrahim H, Hisamoto K, Staniloae CS, Jilaihawi H, Benenstein RJ, Latson L, Williams MR, Saric M. Aorto-Right Ventricular Fistula Post-Transcatheter Aortic Valve Replacement: Multimodality Imaging of Successful Percutaneous Closure. CASE (Phila). 2017 Apr 24;1(2):70-74. doi: 10.1016/j.case.2017.02.002. PMID: 30062248; PMCID: PMC6034486. 9. Walpot J, Klazen C, Hokken R, Sorgedrager J, Hoevenaar M, den Braber J. Aorto-right ventricular fistula as an occasional finding. Eur J Echocardiogr. 2005 Jan;6(1):65-6. doi: 10.1016/j.euje.2004.08.009. PMID: 15664555. 10. Ghuran A, Nolan J. The cardiac complications of recreational drug use. West J Med. 2000 Dec;173(6):412-5. doi: 10.1136/ewjm.173.6.412. PMID: 11112762; PMCID: PMC1071198. 11. Gagnon LR, Sadasivan C, Perera K, Oudit GY. Cardiac Complications of Common Drugs of Abuse: Pharmacology, Toxicology, and Management. Can J Cardiol. 2022 Sep;38(9):1331-1341. doi: 10.1016/j.cjca.2021.10.008. Epub 2021 Nov 1. PMID: 34737034. 12. Alabbady AM, Sattur S, Bauch TD, Harjai KJ. Aorto-Right Ventricular Fistula and Paravalvular Leak After Transcatheter Aortic Valve Implantation. JACC Case Rep. 2019 Dec 18;1(5):859-864. doi: 10.1016/j.jaccas.2019.11.025. PMID: 34316946; PMCID: PMC8288756. 13. Chia R, Kalutota C, Cao K, Douedi S, Chang W, Pinciotti D, Beizaeipour M, Joiner J, Ice D, Ross R, Kovach R, Chen C, Raza M. Management of Aorto-Right Ventricular Fistulas After TAVR. JACC Case Rep. 2024 Nov 6;29(21):102655. doi: 10.1016/j.jaccas.2024.102655. PMID: 39619019; PMCID: PMC11602638. 14. Samuels LE, Kaufman MS, Rodriguez-Vega J, Morris RJ, Brockman SK. Diagnosis and management of traumatic aorto-right ventricular fistulas. Ann Thorac Surg. 1998 Jan;65(1):288-92. doi: 10.1016/s0003-4975(97)01084-9. PMID: 9456147.

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CardioNerds guest host Dr. Colin Blumenthal joins Dr. Juma Bin Firos and Dr. Aishwarya Verma from the Trinity Health Livonia Hospital to discuss a fascinating case involving malignant ventricular arrhythmias. Expert commentary is provided by Dr. Mohammad-Ali Jazayeri. Audio editing for this episode was performed by CardioNerds Intern,Julia Marques Fernandes.

This case explores the puzzling presentation of exercise-induced ventricular tachycardia in a young, otherwise healthy male who suffered recurrent out-of-hospital cardiac arrests. With no traditional risk factors and an unremarkable ischemic workup, the challenge lay in uncovering the underlying cause of his malignant arrhythmias. Electrophysiology studies and advanced imaging played a pivotal role in systematically narrowing the differentials, revealing an unexpected arrhythmogenic substrate. This episode delves into the diagnostic dilemma, the role of EP testing, and the critical decision-making surrounding ICD placement in a patient with a concealed but life-threatening condition.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Pearls- Malignant Ventricular ArrhythmiasThis case highlights the challenges and importance of diagnosing and managing ventricular arrhythmias in young, seemingly healthy individuals. Here are five key takeaways from the episode:

1. Electrophysiology (EP) studies play a crucial role in identifying arrhythmogenic substrates in patients with exercise-induced ventricular tachycardia (VT) without obvious structural heart disease. In this case, substrate mapping revealed late abnormal ventricular afterdepolarizations in the basal inferior left ventricle, providing valuable insights into the underlying mechanism.
2. Cardiac MRI can be a powerful tool for detecting subtle myocardial abnormalities. The subepicardial late gadolinium enhancement (LGE) in the lateral and inferior LV walls suggested an underlying myocardial process, even when other imaging modalities appeared normal.
3. The VT morphology can provide clues about the underlying mechanism. In this case, the right bundle branch block pattern with a northwest axis and shifting exit sites pointed towards a scar-mediated mechanism rather than a channelopathy or idiopathic VT.
4. Implantable cardioverter-defibrillator (ICD) placement is crucial for secondary prevention of sudden cardiac death (SCD) in patients with malignant ventricular arrhythmias, even in young individuals. The patient’s initial deferral of ICD implantation highlights the importance of shared decision-making and patient education in these complex cases.
5. “Scar-mediated VT introduces the risk of new arrhythmogenic substrates over time, reinforcing the need for ICD therapy even when catheter ablation is considered.” This pearl emphasizes the dynamic nature of the arrhythmogenic substrate and the importance of long-term risk mitigation strategies.

Notes – Malignant Ventricular ArrhythmiasNotes were drafted by Juma Bin Firos.

1. What underlying pathologies cause ventricular arrhythmias in young patients without overt structural heart disease?Myocardial fibrosis:

2. Detected via late gadolinium enhancement (LGE) on cardiac MRI

3. Present in 38% of nonischemic cardiomyopathy cases
4. Increases sudden cardiac death (SCD) risk 5-fold
5. Often localized to subepicardial regions, particularly in the inferolateral left ventricle (LV)
6. May precede overt systolic dysfunction by years

Subclinical cardiomyopathy:

• 67% of young VT patients show subtle cardiac dysfunction
• Suggests VT may be the first manifestation of cardiomyopathy
• Can include early-stage genetic cardiomyopathies (e.g., ARVC, LMNA mutations)
• Often associated with preserved ejection fraction (EF >50%)

Arrhythmogenic substrate:

• EP studies localize re-entry circuits to specific regions:
  • Basal inferior LV near the mitral annulus (as in this case)
  • Right ventricular outflow tract (RVOT) in idiopathic VT
  • Papillary muscles or fascicular regions
• Substrate can exist even with normal EF and no visible structural abnormalities on echocardiography

Channelopathies:

• Long QT syndrome (LQTS): QTc >460ms in males, >470ms in females
• Brugada syndrome: Coved ST elevation in V1-V3
• Catecholaminergic polymorphic VT (CPVT): Normal resting ECG, bidirectional VT with exercise
• Short QT syndrome: QTc <330ms

Inflammatory conditions:

• Myocarditis: Can cause transient or persistent arrhythmogenic substrate
• Cardiac sarcoidosis: Patchy inflammation and fibrosis, often affecting the septum

1. How do electrophysiology studies differentiate scar-mediated VT from channelopathies?Substrate mapping:

2. Identifies late abnormal potentials (LAPs) with 92% specificity for re-entry circuits

3. Utilizes multi-electrode catheters (e.g., Penta Ray) for high-density mapping
4. LAPs indicate slow conduction through fibrotic tissue, key for re-entry
5. Absent in purely electrical disorders like channelopathies

Inducibility:

• Programmed electrical stimulation (PES) protocols:
• Up to triple extra stimuli at multiple sites (RV apex, RVOT, LV)
• Burst pacing at cycle lengths down to 200-250ms
• Scar-mediated VT is often inducible with aggressive stimulation
• Polymorphic VT/VF induction suggests a structural substrate
• Channelopathies like Catecholaminergic polymorphic ventricular tachycardia CPVT) typically requires isoproterenol or exercise for induction

VT morphology analysis:

• Right bundle branch block (RBBB) + northwest axis localizes to LV basal inferior wall
• Left bundle branch block (LBBB) + inferior axis suggests RVOT origin
• Fascicular VT: RBBB + left anterior or posterior fascicular block pattern
• Papillary muscle VT: RBBB or LBBB with variable axis

Entrainment mapping:

• Performed during sustained monomorphic VT
• Post-pacing interval minus tachycardia cycle length (PPI-TCL) <30ms indicates critical isthmus
• Not applicable to polymorphic VT or channelopathies

Electroanatomic voltage mapping:

• Low voltage areas (<1.5mV bipolar) indicate scar tissue
• Normal voltage throughout suggests functional (non-scar) VT mechanism

1. What are key management considerations for recurrent VT/VF in young patients? ICD for secondary prevention:*
   • Class I indication after cardiac arrest or sustained VT without a reversible cause
   • Reduces mortality from 13% (8-year untreated) to <5%, especially with LGE present
2. Device selection:
   • Single-chamber ICD if no pacing indication
   • Subcutaneous ICD (S-ICD) in young patients to avoid transvenous lead complications
   • Consider cardiac resynchronization therapy defibrillator (CRT-D) if LBBB or wide QRS
3. LifeVest limitations:
   • Bridges ≤3 months; not a long-term solution
   • Recurrent arrests double mortality vs. prompt ICD implantation
   • Compliance issues: must be worn consistently to be effective
4. Oral antiarrhythmic medications:
   • Amiodarone:
     • Effective for acute VT suppression
     • Long-term use limited by side effects (thyroid, liver, pulmonary toxicity)
   • Beta-blockers: First line for most VT/VF, especially exercise-induced
   • Sotalol: Alternative for those with preserved LV function
   • Mexiletine: Adjunct for frequent ICD shocks, especially with LQT3
5. Catheter ablation:
   • Consider early in the course for recurrent ICD shocks
   • Success rates 60-80% for scar-related VT
   • May reduce ICD shocks and improve quality of life
   • Limitations: deep intramural or epicardial substrates may require specialized approaches
6. Lifestyle modifications:
   • Exercise restrictions: Avoid high-intensity activities that trigger arrhythmias
   • Stress management: Consider cognitive behavioral therapy or mindfulness training
   • Avoidance of QT-prolonging medications in LQTS patients
7. Genetic testing and family screening:
   • Recommended for suspected inherited arrhythmia syndromes
   • Can guide management and risk stratification for family members

1. Why does exercise exacerbate arrhythmia risk in these patients? Sympathetic surge:*
   • Increases myocardial oxygen demand
   • Enhances automaticity and triggered activity
   • Can unmask concealed conduction abnormalities
2. Hemodynamic changes:
   • Increased preload and afterload stress fibrotic regions
   • Volume shifts may alter electrolyte concentrations locally
3. Metabolic factors:
   • Lactic acid accumulation can promote ectopic beats
   • Catecholamine release exacerbates ion channel dysfunction in channelopathies
4. Exercise-induced VT/VF correlates with 8× higher SCD risk vs. rest-onset arrhythmias:
   • Warrants activity restrictions tailored to individual risk profile
   • May indicate more malignant substrate or advanced disease process
5. Treadmill testing:
   • Should guide therapy in asymptomatic patients with exercise-related VT
     • Protocols:
     • Bruce protocol for general assessment
     • Modified protocols (e.g., longer stages) for specific arrhythmia provocation
   • Endpoints:
     • Induction of sustained VT/VF
     • Achieving target heart rate (85% of age-predicted maximum)
     • Development of concerning symptoms (pre-syncope, chest pain)
6. Cardiac rehabilitation:
7. Supervised exercise programs can improve outcomes
8. Gradual increase in intensity with continuous monitoring
9. Helps define safe exercise thresholds for patients

1. How does LGE on cardiac MRI refine risk stratification?Late gadolinium enhancement (LGE) on cardiac MRI acts like a “scar map” of the heart, revealing areas of damaged or fibrotic tissue. These scars create electrical instability, increasing the risk of dangerous heart rhythms and sudden cardiac death (SCD). Here’s how LGE refines risk assessment:

1. Predicting Sudden Cardiac Death (SCD)

• Major risk multiplier:
  • Patients with LGE have 4.3× higher odds of life-threatening arrhythmia, regardless of their heart’s pumping ability (ejection fraction, EF).
  • For every 1% increase in scar size (as % of heart muscle), SCD risk rises by 15%.
• Thresholds matter:
  • In hypertrophic cardiomyopathy (HCM), LGE covering ≥5% of the heart muscle adds critical risk stratification, even in patients not initially flagged as high-risk by guidelines.
  • Larger scars (≥10-15%) correlate with dramatically higher SCD risk, especially in HCM.

2. Mortality Signals

• Annual death rates:
  • LGE+ patients: 4.7% annual mortality (similar to ischemic heart disease).
  • LGE− patients: 1.7% annual mortality.
• Patterns and locations:
  • Midwall scars (e.g., in dilated cardiomyopathy): 4.6× higher risk of SCD.
  • Inferolateral scars (common in cardiac sarcoidosis): Linked to frequent ventricular tachycardia (VT).

3. Quantifying Scars: Methods Matter

• Full Width at Half Maximum (FWHM):
  • Most reproducible method for measuring scar size.
  • Reduces overestimation compared to other techniques.
• Standard Deviation (SD) thresholds:
  • 5-SD method: Widely used but may overestimate scar size.
  • 6-SD method: Best studied; 10% LGE is the optimal cutoff for predicting SCD in HCM.
• Dark-blood vs. bright-blood imaging:
  • Dark-blood LGE improves scar visualization in ischemic heart disease but performs similarly to bright-blood LGE in non-ischemic conditions.

4. Guideline Gaps and Solutions

• Current ICD criteria fall short:
  • Guidelines focus on EF ≤35%, missing high-risk patients with EF >35% but significant LGE.
  • Example: A patient with EF 45% and 12% LGE has higher SCD risk than many with EF ≤35%.
• Emerging recommendations:
  • Use LGE to guide ICD decisions in the “grey zone” (EF 36-50%).
  • The 2022 ESC HCM model now integrates LGE for better risk prediction.

5. Tracking Changes Over Time

• Serial imaging:
  • Repeat MRIs every 1-2 years monitor scar progression.
  • Example: If LGE grows from 8% to 14%, ICD may be warranted even if EF remains normal.

6. Limitations

• Not all scars are equal:
  • Ischemic scars (from blocked arteries) vs. non-ischemic scars (e.g., HCM) carry different risks.
• Technical challenges:
  • Labs use different methods (e.g., FWHM vs. SD), causing variability in measurements.
• Contraindications:
  • Severe kidney disease (risk of gadolinium toxicity) or implanted devices (e.g., older pacemakers) may limit MRI use.

References – Malignant Ventricular ArrhythmiasAl-Khatib, S. M., Stevenson, W. G., Ackerman, M. J., Bryant, W. J., Callans, D. J., Curtis, A. B., … & Page, R. L. (2018). 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology, 72(14), e91-e220. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000549

Di Marco, A., Anguera, I., Schmitt, M., Klem, I., Neilan, T. G., White, J. A., … & Cequier, A. (2017). Late gadolinium enhancement and the risk for ventricular arrhythmias or sudden death in dilated cardiomyopathy: systematic review and meta-analysis. JACC: Heart Failure, 5(1), 28-38. https://www.sciencedirect.com/science/article/pii/S2213177916305698?via%3Dihub

Kuruvilla, S., Adenaw, N., Katwal, A. B., Lipinski, M. J., Kramer, C. M., & Salerno, M. (2014). Late gadolinium enhancement on cardiac magnetic resonance predicts adverse cardiovascular outcomes in nonischemic cardiomyopathy: a systematic review and meta-analysis. Circulation: Cardiovascular Imaging, 7(2), 250-258.

https://pubmed.ncbi.nlm.nih.gov/24363358

Gulati, A., Jabbour, A., Ismail, T. F., Guha, K., Khwaja, J., Raza, S., … & Prasad, S. K. (2013). Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. Jama, 309(9), 896-908. https://jamanetwork.com/journals/jama/fullarticle/1660382

Piers, S. R., Tao, Q., van Huls van Taxis, C. F., Schalij, M. J., van der Geest, R. J., & Zeppenfeld, K. (2013). Contrast-enhanced MRI–derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy. Circulation: Arrhythmia and Electrophysiology, 6(5), 875-883. https://pubmed.ncbi.nlm.nih.gov/24036134/

Priori, S. G., Blomström-Lundqvist, C., Mazzanti, A., Blom, N., Borggrefe, M., Camm, J., … & Van Veldhuisen, D. J. (2015). ESC Scientific Document Group. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J, 36(41), 2793-2867. https://pubmed.ncbi.nlm.nih.gov/26320108/

Wang, J., Yang, S., Ma, X., Zhao, K., Yang, K., Yu, S., … & Zhao, S. (2023). Assessment of late gadolinium enhancement in hypertrophic cardiomyopathy improves risk stratification based on current guidelines. European heart journal, 44(45), 4781-4792. https://pubmed.ncbi.nlm.nih.gov/37795986/

Kiaos, A., Daskalopoulos, G. N., Kamperidis, V., Ziakas, A., Efthimiadis, G., & Karamitsos, T. D. (2024). Quantitative late gadolinium enhancement cardiac magnetic resonance and sudden death in hypertrophic cardiomyopathy: a meta-analysis. Cardiovascular Imaging, 17(5), 489-497. https://pubmed.ncbi.nlm.nih.gov/37795986/

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CardioNerds (Drs. Rick Ferraro and Georgia Vasilakis Tsatiris) discuss ATTR cardiac amyloidosis with expert Dr. Justin Grodin. This episode is a must-listen for all who want to know how to diagnose and treat ATTR with current available therapies, as well as management of concomitant diseases through a multidisciplinary approach. We take a deep dive into the importance of genetic testing, not only for patients and families, but also for gene-specific therapies on the horizon. Dr. Grodin draws us a roadmap, guiding us through new experimental therapies that may reverse the amyloidosis disease process once and for all. Audio editing by CardioNerds academy intern, Christiana Dangas.

This episode was developed in collaboration with the American Society of Preventive Cardiology and supported by an educational grant from BridgeBio.

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here.

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Pearls:1. You must THINK about your patient having amyloid to recognize the pattern and make the diagnosis. Start with a routine ECG and TTE, and look for a disproportionately large heart muscle with relatively low voltages on the ECG. 2. Before you diagnose ATTR amyloidosis, AL amyloidosis must be ruled out (or ruled in) with serum light chains, serum/urine immunofixation, and/or tissue biopsy. 3. Genetic testing is standard of care for all patients and families with ATTR amyloidosis, and the future is promising for gene-specific treatments. Current FDA-approved treatments for TTR amyloidosis are TTR stabilizers and TTR silencers, but TTR fibril-depleting agents are on their way. 4. Early diagnosis of ATTR affords patients maximal benefit from current amyloidosis therapies. 5. TTR amyloidosis patients require a multidisciplinary approach for success, given the high number of concomitant diseases with cardiomyopathy.

Notes:Notes: Notes drafted by Dr. Georgia Vasilakis Tsatiris.

1. What makes you most suspicious of a diagnosis of cardiac amyloidosis from the typical heart failure patient?

You must have a strong index of suspicion, meaning you THINK that the patient could have cardiac amyloidosis, to consider it diagnostically. Some characteristics or “red flags” to not miss:

• Disproportionately thick heart muscle with a relatively low voltages on EKG
• Bilateral carpal tunnel syndrome – estimated that 1 in 10 people >65 years old will have amyloidosis
• Previously tolerated antihypertensive medications
• Atraumatic biceps tendon rupture
• Bilateral carpal tunnel syndrome
• Spinal stenosis
• Concomitant with other diseases: HFpEF, low-flow low-gradient aortic stenosis
• How would you work up a patient for cardiac amyloidosis?
• Start with a routine ECG (looking for disproportionally low voltage) and routine TTE (looking for thick heart muscle)
• CBC, serum chemistries, hepatic function panel, NT proBNP, and troponin levels

NOTE: It is critical to differentiate between amyloid light chain (AL amyloidosis) and transthyretin ATTR amyloidosis, as both make up 95-99% of amyloidosis cases.

• Obtain serum free light chains, serum & urine electrophoresis, and serum & urine immunofixation to rule out AL amyloidosis. (See table below)

| AL Amyloidosis | ATTR Amyloidosis | | --- | --- | | → Positive serum free light chains and immunofixation (Abnormal M protein) → Tissue biopsy (endomyocardial, fat pad) to confirm diagnosis | → Negative serum free light chains and immunofixation (ruled out AL amyloidosis) → Cardiac scintigraphy (Technetium pyrophosphate with SPECT imaging) |

1. What treatment options do we have to offer now for ATTR CM, and how has this compared to prior years?
2. Before 2019, treatment options were limited outside of cardiac transplantation and prophylactic liver transplants for hereditary ATTR amyloidosis.

Treatments since 2019 have utilized the amyloidogenic cascade:

• TTR protein is formed in the liver and circulates in the bloodstream.
• Current treatments aim to either slow ATTR progression by stopping deposition or clearing amyloid deposits
• Only FDA-approved treatments are for stopping deposition, while agents that clear amyloid deposits remain investigational. Two classes of agents that stop amyloid deposition are TTR stabilizers and TTR Silencers. (See table below)

| TTR Stabilizers | TTR Silencers | | --- | --- | | Tafamidis (ATTR-ACT, 2018) Acoramidis (ATTRibute-CM, 2024) | Inotersen (Clinical Trial, 2018) Eplontersen (Clinical Trial, 2023) Patisiran (Clinical Trial, 2018) Vutrisiran (Clinical Trial, 2022) | | Mechanism: prevents dissociation of, or stabilizes, the TTR tetramer to halt disease progression | Mechanism: inhibit the liver’s production of TTR in the bloodstream via small interfering RNAs (siRNAs)/antisense oligonucleotides | | Route of administration: PO (pills) | Route of Administration: IV infusions Vutrisiran is a subQ injection q3months | | Outcomes: improve morbidity and mortality in both wildtype (wtATTR) and hereditary ATTR (hATTR) amyloidosis | Outcomes: only approved for treatment of hATTR with polyneuropathy |

• Agents that clear amyloid deposits are still in clinical trials (ALXN2200, Coramitug PRX004).
• Liver transplantation is the only method of clearing amyloid fibril deposits until the FDA approves a fibril-depleting agent, as perhaps one of the aforementioned agents.
• How do you use genetic testing in your practice? How does the role of genetic testing impact treatment options for patients and their families?
• Genetic testing = standard of care; everyone with ATTR-CM should get genetic sequencing!
• Family screening is also important, as hATTR is an autosomal dominant disease. Patients and families can be referred to genetic counseling, become educated on the GINA Act, and choose to start cascade screening for family members.
• Family members can be affected in different ways, as penetrance can occur at different ages
• Due to current FDA labeling patients must have hereditary ATTR with polyneuropathy and a pathologic variant to qualify for TTR silencer treatment. Patients can have concomitant cardiomyopathy but must also have polyneuropathy and pathologic variant.
• TTR stabilizers are approved for ATTR cardiomyopathy regardless of the presence of the pathogenic TTR variant.
• Are there differences in treatment response between wtATTR or hATTR? What about differences in men and women?
• Epidemiological studies suggest variant (hereditary) ATTR patients have more aggressive disease than wildtype ATTR patients.
• Since current treatments do not cure the disease and work to slow progression, patients with advanced stages of disease do not show much benefit from current therapies.
• Whether it is wild type or hereditary, diagnosing ATTR as early as possible will afford patients the greatest therapeutic impact of current treatments.
• The current data does not suggest a therapeutic difference in response between men and women with ATTR cardiac amyloidosis
• What is the role of CRISPR/Cas9 in the treatment of cardiac amyloidosis?
• ATTR amyloidosis is an elegant disease model because it is one gene responsible for one protein and ultimately one disease process.
• NTLA 2001 (currently in a phase-three clinical trial, link to phase one) is an agent administered in a single infusion to silence hepatic production of TTR indefinitely.
• We are awaiting promising results from this trial at the time of this recording.
• How can we best call on our friends in other subspecialities to take care of the concomitant diseases – peripheral neuropathy, symptomatic atrial fibrillation, aortic stenosis? Do any ATTR specific treatments show improvement in these manifestations?
• TTR amyloidosis patients need a multidisciplinary care model for success.
• Carpal tunnel syndrome is common in ATTR amyloidosis, so referrals to neurology and hand surgery are common
• Patients with autonomic dysfunction secondary to autonomic neuropathy could benefit from neurology referral for blood pressure strategies and gastroenterology due to gut dysmotility and constipation.
• Electrophysiology (EP) referral is common for atrial fibrillation and atrial flutter
• ATTR is a disease of aging, so collaborating with geriatricians is important to help coordinate care and establish the patient’s individualized goals.
• What is your management of subclinical ATTR and strategies for early detection?
• Again, having a strong index of suspicion for cardiac amyloidosis is prudent.
• The most common TTR variant that causes hATTR on earth is the V122I mutation (PV142I), which is very common in Western African ancestry. We suspect 1.5 million carriers of this variant in the USA alone, which puts individuals at 2-3x higher risk for heart failure than their age, sex, and race-matched non-carrier controls.
• Expert consensus suggests monitoring individuals with this variant about 10 years before when the proband (i.e. if patient was diagnosed at 70, family members start screening at 60).
• Initial work-up should include standard tests: ECG, echocardiogram, blood work.
• Upcoming clinical trial will enroll patients in this critical 10-year window and randomize them into acoramadis vs placebo to see if treatment before symptom/disease onset can prevent amyloid disease.

References 1. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC). Eur Heart J. 2023;44(37):3503-3626. doi:10.1093/eurheartj/ehad194 2. Maron MS, Masri A, Nassif ME, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy. N Engl J Med. 2024;390(20):1849-1861. DOI: 10.1056/NEJMoa2401424 3. Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, Grogan M, Cheng RK. ATTR amyloidosis: current and emerging management strategies: JACC: CardioOncology state-of-the-art review. JACC CardioOncol. 2021;3(4):488-505. doi:10.1016/j.jaccao.2021.06.006 4. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689 5. Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2024;390(2):132-142. doi:10.1056/NEJMoa2305434 6. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):22-31. doi:10.1056/NEJMoa1716793 7. Benson MD, Waddington-Cruz M, Berk JL, et al. Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy. JAMA. 2023;330(1):37-46. doi:10.1001/jama.2023.10025. 8. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153 9. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023;30(1):1-9. doi:10.1080/13506129.2022.2091985 10. Redman M, King A, Watson C, King D. What is CRISPR/Cas9? Arch Dis Child Educ Pract Ed. 2016 Aug;101(4):213-5. doi: 10.1136/archdischild-2016-310459. Epub 2016 Apr 8. PMID: 27059283; PMCID: PMC4975809. 11. Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021;385(6):493-502. doi:10.1056/NEJMoa2107454

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CardioNerds (Dr. Rick Ferraro and Dr. Dan Ambinder) join Dr. Sahar Samimi and Dr. Lorraine Mascarenhas from Baylor College of Medicine, Houston, Texas, at the Houston Rodeo for some tasty Texas BBQ and a tour of the lively rodeo grounds to discuss an interesting case full of clinical pearls involving a patient with nonbacterial thrombotic endocarditis (NBTE). Expert commentary is provided by Dr. Basant Arya. Episode audio was edited by CardioNerds Intern Dr. Bhavya Shah.

(Photo by Xu Jianmei/Xinhua via Getty Images)Xinhua News Agency via Getty ImagesWe discuss a case of a 38-year-old woman with advanced endometrial cancer who presents with acute abdominal pain, found to have splenic and renal infarcts, severe aortic regurgitation, and persistently negative blood cultures, ultimately diagnosed with nonbacterial thrombotic endocarditis (NBTE). We review the definition and pathophysiology of NBTE in the context of malignancy and hypercoagulability, discuss initial evaluation and echocardiographic findings, and highlight important management considerations. Emphasis is placed on the complexities of anticoagulation choice, the role of valvular surveillance, and the need for coordinated, multidisciplinary care.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
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Check out CardioNerds SWAG!
Become a CardioNerds Patron!

Pearls- Nonbacterial Thrombotic Endocarditis1. Eliminate the Usual Suspects. NBTE is a diagnosis of exclusion! Always rule out infective endocarditis (IE) first with serial blood cultures and serologic tests. 2. More than Meets the Echo. Distinguishing NBTE from culture-negative endocarditis can be tricky. Look beyond the echo—focus on clinical context (underlying malignancy, autoimmune issues) and lab findings to clinch the diagnosis. 3. TEE for the Win… Mostly. While TEE is more sensitive than TTE, NBTE vegetations can be sneaky and may embolize quickly. Don’t hesitate to use advanced imaging (i.e., cardiac MRI, CTA) or repeat imaging if you still suspect NBTE. 4. Choose your champion. In cancer-associated NBTE, guideline recommendations for anticoagulation choice are lacking. Consider DOACs and LMWH as agents of choice, but ultimately use shared decision-making to guide management. 5. No obvious trigger? Go hunting for hidden malignancies or autoimmune disorders. A thorough workup is essential to uncover the driving force behind NBTE.

Check out this state-of-the-art review for a comprehensive, one-stop summary of NBTE: European Heart Journal, 46(3), 236–245. Please note that the figures and tables referenced in the following notes are adapted from this review.

notes- Nonbacterial Thrombotic EndocarditisNotes were drafted by Dr. Sahar Samimi.

1. What is nonbacterial thrombotic endocarditis (NBTE)?
2. NBTE, previously known as marantic endocarditis, is a rare condition in which sterile vegetations form on heart valves.1
3. It occurs most commonly in association with malignancies and autoimmune conditions (i.e, antiphospholipid antibody syndrome or systemic lupus erythematosus).1 In addition, NBTE has been reported in association with COVID-19 infection, burns, sepsis, and indwelling catheters.2
4. Precise mechanisms remain unclear, but an interplay of endothelial injury, hypercoagulability, hypoxia, and immune complex deposition contributes to the formation of these sterile vegetations. 1
5. How do we diagnose NBTE?
6. Physicians should have a high level of suspicion for NBTE in at-risk patients (e.g., with active malignancy) who present with recent or recurrent embolic events (i.e., stroke, splenic, renal, or mesenteric infarct, and acute coronary syndrome).1
7. Once vegetations are observed, the diagnosis of NBTE is focused on ruling out IE, followed by looking for the underlying etiology, if not already evident.1 A focused clinical assessment, including a thorough history, physical exam, and relevant microbiological and serological tests, should aim to rule out IE using the modified Duke criteria.3
8. Persistently negative blood cultures after adequate sampling increase the likelihood of NBTE but do not exclude culture-negative endocarditis. Vegetations found in patients with risk factors raise the suspicion for NBTE, whereas signs of systemic infection—such as ongoing fever, recent antibiotic exposure, or potential zoonotic sources—may point instead toward CNE.1

9. New diagnostic techniques, including specialized serology and metagenomic sequencing, have significantly enhanced our ability to detect elusive pathogens in CNE.1

10. How should imaging be approached in suspected NBTE?

11. In cases of suspected endocarditis, guidelines from the American College of Cardiology, the American Heart Association, and the European Society of Cardiology recommend starting the assessment with a TTE to visualize potential valvular vegetations. 4,5
12. TTE is less sensitive than TEE, particularly for detecting smaller vegetations < 5 mm that are often associated with NBTE. Therefore, a subsequent TEE is recommended due to its superior ability to detect subtle valvular abnormalities. 4,5
13. Echocardiographic features of vegetations alone do not reliably distinguish NBTE from IE; hence, clinical context, along with laboratory and microbiological findings, is crucial for accurate diagnosis. 1

14. Uncertainty may remain following a TEE or in cases where TEE is not feasible. In such situations, advanced imaging techniques like cardiac MRI and CT scanning are emerging tools for more detailed cardiac tissue characterization. 1

15. What are the management strategies for NBTE?

16. NBTE’s complexity necessitates a multidisciplinary treatment strategy, with each patient’s prognosis shaped by individual clinical factors. 1
17. Primary therapy involves anticoagulation, alongside targeted management of malignancy or autoimmune disorder driving the hypercoagulable state. 1
18. While the criteria for surgical intervention are similar to those used in IE, surgery generally has a more limited role in NBTE. 1
19. What factors into choosing the anticoagulation agent?
20. Anticoagulation outcomes in NBTE can vary greatly: some patients have vegetations resolve, while others experience disease progression to new valves despite therapy.1
21. Because NBTE-specific evidence remains sparse, the underlying clinical context primarily guides the choice of anticoagulant:
22. Multiple case reports describe DOAC failure with recurrent embolization in patients with cancer and NBTE. 6-8
23. LMWH remains a mainstay for patients with cancer or when patients experience thrombotic complications on DOACs. 1
24. Warfarin is the preferred anticoagulant among patients with thrombotic antiphospholipid syndrome. 9
25. The duration of anticoagulation should take into consideration the status of the underlying disease, the presence of valvular lesions on follow-up imaging, and an individualized assessment of risks and benefits. 1

References – Nonbacterial Thrombotic Endocarditis1. Ahmed O, King NE, Qureshi MA, et al. Non-bacterial thrombotic endocarditis: a clinical and pathophysiological reappraisal. European Heart Journal. 2025;46(3):236-49. 2. Balata D, Mellergård J, Ekqvist D, et al. Non-bacterial thrombotic endocarditis: a presentation of COVID-19. European journal of case reports in internal medicine. 2020;7(8). 3. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30: 633–8. 4. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:e25–197. 5. Vahanian A, Beyersdorf F, Praz F, et al.; ESC/EACTS Scientific Document Group. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022 Feb 12;43(7):561-632. 6. Mantovani F, Navazio A, Barbieri A, Boriani G. A first described case of cancer- associated non-bacterial thrombotic endocarditis in the era of direct oral anticoagulants. Thromb Res 2017;149:45–7. 7. Panicucci E, Bruno C, Ferrari V, Suissa L. Recurrence of ischemic stroke on direct oral anticoagulant therapy in a patient with marantic endocarditis related to lung cancer. J Cardiol Cases 2021;23:242–5. 8. Shoji MK, Kim JH, Bakshi S, et al. Nonbacterial thrombotic endocarditis due to primary gallbladder malignancy with recurrent stroke despite anticoagulation: case report and literature review. J Gen Intern Med 2019;34:1934–40. 9. Khairani CD, Bejjani A, Piazza G, et al. Direct oral anticoagulants vs vitamin K antagonists in patients with antiphospholipid syndromes: meta-analysis of randomized trials. J Am Coll Cardiol 2023;81:16–30.

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Drs. Rick Ferraro and Sneha Nandy discuss ‘Diagnosis of ATTR Cardiac Amyloidosis’ with Dr. Venkatesh Murthy. In this episode, we explore the diagnosis of ATTR cardiac amyloidosis, a condition once considered rare but now increasingly recognized due to advances in imaging and the availability of effective therapies. Dr. Venkatesh Murthy, a leader in multimodality imaging, discusses key clinical and laboratory features that should raise suspicion for the disease. We also examine the role of nuclear imaging and genetic testing in confirming the diagnosis, as well as the importance of early detection. Tune in for expert insights on navigating this challenging diagnosis and look out for our next episode on treatment approaches for cardiac amyloidosis! Audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

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Pearls: – Diagnosis of Transthyretin amyloid cardiomyopathy1. Recognizing the Red Flags – ATTR cardiac amyloidosis often presents with subtle but telling signs, such as bilateral carpal tunnel syndrome, low-voltage ECG, and a history of lumbar spinal stenosis or biceps tendon rupture. If you see these features in a patient with heart failure symptoms, think amyloidosis!

1. “Vanilla Ice Cream with a Cherry on Top” – On strain echocardiography, apical sparing is a classic pattern for cardiac amyloidosis. While helpful, it’s not foolproof—multimodal imaging and clinical suspicion are key!

2. Nuclear Imaging is a Game-Changer – When suspicion for cardiac amyloidosis is high à a positive PYP scan with SPECT imaging (grade 2 or 3 myocardial uptake) in the absence of monoclonal protein (ruled out by SPEP, UPEP, and free light chains) is diagnostic for ATTR amyloidosis—no biopsy needed!

3. Wild-Type vs. Hereditary? Know the Clues – Older patients (70+) are more likely to have wild-type ATTR, while younger patients (40s-60s), especially those with neuropathy and a family history of heart failure, should raise suspicion for hereditary ATTR. Genetic testing is crucial for distinguishing between the two. Note that some ATTR variants may predispose to a false negative PYP scan!

4. Missing Amyloidosis = Missed Opportunity – With multiple disease-modifying therapies now available, early diagnosis is critical. If you suspect cardiac amyloidosis, don’t delay the workup—early treatment improves outcomes!

Notes – Diagnosis of Transthyretin amyloid cardiomyopathyWhat clinical features should raise suspicion for ATTR cardiac amyloidosis?

• ATTR cardiac amyloidosis is underdiagnosed because symptoms overlap with other forms of heart failure.
• Red flags include bilateral carpal tunnel syndrome (often years before cardiac symptoms), low-voltage ECG despite increased LV wall thickness, heart failure with preserved ejection fraction (HFpEF) with a restrictive pattern, and history of lumbar spinal stenosis, biceps tendon rupture, and/or peripheral neuropathy, including possible autonomic dysfunction (e.g., orthostatic hypotension).
• Remember: If an older patient presents with heart failure and unexplained symptoms like neuropathy or musculoskeletal issues, think amyloidosis!

What is the differential diagnosis for a thick left ventricle (LVH) and how does ATTR amyloidosis fit into it?

• Hypertension: Most common cause of LVH, typically with a history of uncontrolled high blood pressure.
• Aortic stenosis: May present with concentric LVH.
• Hypertrophic cardiomyopathy (HCM): Genetic disorder typically presenting with asymmetric LVH, especially in younger patients.
• Infiltrative cardiomyopathy: Often due to amyloidosis, sarcoidosis, or hemochromatosis.
• Storage disorder: Fabry’s, Danon, Pompe, etc.

What are the key imaging modalities used to diagnose ATTR cardiac amyloidosis?

• Echocardiography: Thickened LV walls (>12 mm) with a restrictive filling pattern, Speckled appearance on 2D echo (not specific), apical sparing on strain imaging (“Vanilla ice cream with a cherry on top”).
• Cardiac MRI (CMR): Late gadolinium enhancement (LGE) in a global subendocardial pattern, T1 mapping & extracellular volume (ECV) expansion are supportive findings.
• Nuclear Scintigraphy (99mTc-PYP scan): Gold standard noninvasive test for ATTR. Grade 2 or 3 uptake (equal to or greater than bone uptake) is diagnostic if monoclonal protein is absent in the right clinical scenario.

What lab tests are used to diagnose ATTR cardiac amyloidosis?

• Check troponin and NTproBNP (useful for staging)
• Rule out AL amyloidosis with monoclonal protein studies like serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) with immunofixation and serum free light chain (FLC) assay (to detect clonal plasma cell disorders)

Why is ruling out AL amyloidosis critical before diagnosing ATTR?

• They are treated very differently- AL amyloidosis is an oncologic emergency requiring chemotherapy, while ATTR is treated with medications.
• If workup for AL amyloidosis, such as SPEP/UPEP or serum free light chains ratio, comes back positive, you do not need to pursue further testing for ATTR amyloidosis.

When should genetic testing be performed in suspected ATTR amyloidosis?

• All patients diagnosed with ATTR amyloidosis should undergo genetic testing to distinguish wild-type from hereditary forms.
• Wild-type ATTR: More common in older men (≥70 years), no known mutation, sporadic occurrence, often presents with predominantly cardiac involvement
• Familial ATTR: Autosomal dominant inheritance, more common in Black patients (V122I mutation), more likely to have neuropathy and earlier onset of heart failure (4th or 5th decade). Specific variants have typical geographic distribution and predilection to causing neuropathy and/or cardiomyopathy.

When is a biopsy necessary to confirm ATTR amyloidosis?

• Biopsy is not needed if PYP scan is positive (Grade 2-3) and AL amyloidosis is ruled out.
• If the diagnosis remains uncertain, a biopsy can be performed of either a fat pad or salivary gland biopsy (easier, lower sensitivity) or an endomyocardial biopsy (gold standard but invasive).

References – Diagnosis of Transthyretin amyloid cardiomyopathy1. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 1 of 2-evidence base and standardized methods of imaging [published correction appears in J Nucl Cardiol. 2021 Aug;28(4):1761-1762. doi: 10.1007/s12350-021-02711-w.]. J Nucl Cardiol. 2019;26(6):2065-2123. doi:10.1007/s12350-019-01760-6

https://pubmed.ncbi.nlm.nih.gov/31468376

1. Writing Committee, Kittleson MM, Ruberg FL, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis: A Report of the American College of Cardiology Solution Set Oversight Committee [published correction appears in J Am Coll Cardiol. 2023 Mar 21;81(11):1135. doi: 10.1016/j.jacc.2023.02.013.]. J Am Coll Cardiol. 2023;81(11):1076-1126. doi:10.1016/j.jacc.2022.11.022

https://pubmed.ncbi.nlm.nih.gov/36697326

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CardioNerds (Dr. Claire Cambron and Dr. Rawan Amir) join Dr. Ayan Purkayastha, Dr. David Song, and Dr. Justin Wang from NewYork-Presbyterian Queens for an afternoon of hot pot in downtown Flushing. They discuss a case of congenital heart disease presenting in adulthood. Expert commentary is provided by Dr. Su Yuan, and audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

A 53-year-old woman with a past medical history of hypertension visiting from Guyana presented with 2 days of chest pain. EKG showed dominant R wave in V1 with precordial T wave inversions. Troponin levels were normal, however she was started on therapeutic heparin with plan for left heart catheterization. Her chest X-ray revealed dextrocardia and echocardiogram was suspicious for the systemic ventricle being the morphologic right ventricle with reduced systolic function and the pulmonic ventricle being the morphologic left ventricle. Patient underwent coronary CT angiography which confirmed diagnosis of congenitally corrected transposition of the great arteries (CCTGA) as well as minimal non-obstructive coronary artery disease. Her chest pain spontaneously improved and catheterization was deferred. Patient opted to follow with a congenital specialist back in her home country upon discharge.

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Pearls- A Case of Congenital Heart Disease Presenting in Adulthood1. Congenitally Corrected Transposition of the Great Arteries (CCTGA) is a rare and unique structural heart disease which presents as an isolated combination of atrioventricular and ventriculoarterial discordance resulting in physiologically corrected blood flow. 2. CCTGA occurs due to L looping of the embryologic heart tube. As a result, the morphologic right ventricle outflows into the systemic circulation, and the morphologic left ventricle outflows into the pulmonary circulation. 3. CCTGA is frequently associated with ventricular septal defects, pulmonic stenosis, tricuspid valve abnormalities and dextrocardia. 4. CCTGA is often asymptomatic in childhood and can present later in adulthood with symptoms of morphologic right ventricular failure, tricuspid regurgitation, or cardiac arrhythmias. 5. Systemic atrioventricular valve (SAVV) intervention can be a valuable option for treating right ventricular failure and degeneration of the morphologic tricuspid valve.

notes- A Case of Congenital Heart Disease Presenting in AdulthoodNotes were drafted by Ayan Purkayastha.

What is the pathogenesis of Congenitally Corrected Transposition of the Great Arteries?

• Occurs due to disorders in the development of the primary cardiac tube
• Bulboventricular part of the primary heart forms a left-sided loop instead of right-sided loop, leading to the normally located atria being connected to morphologically incompatible ventricles
• This is accompanied by abnormal torsion of the aortopulmonary septum (transposition of the great vessels)
• As a result, there is ‘physiologic correction’ of blood flow. Non-oxygenated blood flows into the right atrium and through the mitral valve into the morphologic left ventricle, which pumps blood into the pulmonary artery. Oxygenated blood from the pulmonary veins flows into the left atrium and through the tricuspid valve to the morphologic right ventricle, which pumps blood to the aorta. Compared with standard anatomy, the flow of blood is appropriate, but it is going through the incorrect ventricle on both sides.
• Frequent conditions associated with CCTGA include VSD, pulmonic stenosis and dextrocardia

What is the presentation of Congenitally Corrected Transposition of the Great Arteries?

In cases without concomitant deficits CCTA is asymptomatic early in life and often for several decades. Cyanosis and dyspnea are common presenting symptoms.

1. Systemic right ventricular dysfunction due to high systemic pressures over time
2. Arrythmias, commonly AV block, due to abnormal structure of the conduction system
3. Tricuspid valve regurgitation resulting from dilation of the right ventricle and tricuspid valve annulus

What is Dextrocardia and how is it associated with CCTGA?

• Dextrocardia is a cardiac positional anomaly where the heart is located in the right hemithorax with base to apex axis directed to the right and caudad
• Dextrocardia can occur in up to 20% cases of CCTGA
• Can be associated with both situs solitus (normal anatomic arrangement of chest and abdominal organs) or situs inversus (chest and abdominal organs are mirrored from their normal positions)

How is CCTGA Diagnosed?

• Transthoracic echocardiography is the primary diagnostic tool in CCTGA
• Assessment of the systemic RV function is crucial but can be challenging. Techniques such as speckle tracking echocardiography and global longitudinal strain can help with assessment of systemic RV function
• Cardiac MRI can also provide accurate measurements of ventricular volumes as well as quantification of valvular regurgitation

What is the long-term management of CCTGA in adults?

• Many patients with CCTGA and no associated lesions have long life expectancies with minimal or non-specific symptoms
• Symptoms of circulatory failure occur mainly in 5th and 6th decades of life

The 2018 AHA/ACC Guidelines for the Management of Adults with Congenital Heart Disease recommends the following routine follow-up and testing intervals for CCTGA

• Physiologic stage A: Outpatient ACHD follow up every 12 months with ECG(12 months), TTE(12-24 months), Holter monitor(12-60 months), CMR/CCT and exercise test(36-60 months)
• Physiologic stage B: outpatient ACHD follow up every 12 months with ECG and TTE(12 months), Holter monitor(12-60 months), CMR/CCT and exercise test(36-60 months)
• Physiologic stage C: outpatient ACHD follow up every 6-12 months with ECG and TTE(12 months), pulse oximetry at each visit, Holter monitor(12-36 months), CMR/CCT and exercise test(12-24 months)
• Physiologic stage D: outpatient ACHD follow up every 3-6 months, ECG and TTE every 12 months, pulse oximetry at each visit, Holter monitor, CMR/CCT and exercise test every 12 months

What is the role of Systemic Atrioventricular Valve Surgery (SAVV) for treatment of CCTGA as an adult?

• In CCTGA the morphologic tricuspid valve acts as the SAVV and is subject to functional deterioration from high systemic pressures
• Tricuspid valve regurgitation is a key prognostic overall survival determinant in CCTGA patients
• Studies have shown that 94% of patients with CCTGA suffered from intrinsic tricuspid valve abnormalities
• SAV surgery remains a valuable option with low early mortality and good long-term outcomes, especially with ejection fraction > 40%.
• The 2018 AHA/ACC Guidelines for the Management of Adults with Congenital Heart Disease recommends tricuspid valve replacement for symptomatic adults with CCTGA and severe TR and preserved or mildly depressed systemic ventricular function (class IB recommendation).

References – A Case of Congenital Heart Disease Presenting in Adulthood1. Baruteau AE, Abrams DJ, Ho SY, Thambo JB, McLeod CJ, Shah MJ. Cardiac Conduction System in Congenitally Corrected Transposition of the Great Arteries and Its Clinical Relevance. J Am Heart Assoc. 2017;6(12). doi:10.1161/JAHA.117.007759

1. Susheel Kumar TK. Congenitally corrected transposition of the great arteries. J Thorac Dis. 2020;12(3):1213-1218. doi:10.21037/jtd.2019.10.15

2. Osakada K, Ohya M, Waki K, Nasu H, Kadota K. Congenitally Corrected Transposition of the Great Arteries at Age 88 Years. CJC Open. 2020;2(6):726-728. doi:10.1016/j.cjco.2020.08.003

3. Munaf M, Farooqui S, Kazmi SK, Ul-Haque I. Congenitally Corrected Transposition of Great Arteries with Dextrocardia, Patent Ductus Arteriosus, Atrial Septal Defects and Ventricular Septal Defects in a 15-Year-Old Marfanoid Habitus Patient: A Case Study. Cureus. Published online July 1, 2020. doi:10.7759/cureus.8937

4. Abdelrehim AA, Stephens EH, Miranda WR, et al. Systemic Atrioventricular Valve Surgery in Patients With Congenitally Corrected Transposition of the Great Vessels. J Am Coll Cardiol. 2023;82(23):2197-2208. doi:10.1016/j.jacc.2023.09.822

5. Lippmann MR, Maron BA. The Right Ventricle: From Embryologic Development to RV Failure. Curr Heart Fail Rep. 2022;19(5):325-333. doi:10.1007/s11897-022-00572-z

6. Brida M, Diller GP, Gatzoulis MA. Systemic Right Ventricle in Adults with Congenital Heart Disease. Circulation. 2018;137(5):508-518. doi:10.1161/CIRCULATIONAHA.117.031544

7. Bevilacqua F, Pasqualin G, Ferrero P, et al. Overview of Long-Term Outcome in Adults with Systemic Right Ventricle and Transposition of the Great Arteries: A Review. Diagnostics. 2023;13(13). doi:10.3390/diagnostics13132205

8. Maldjian PD, Saric M. Approach to dextrocardia in adults: Review. American Journal of Roentgenology. 2007;188(6 SUPPL.). doi:10.2214/AJR.06.1179

9. Kandakure PR, Katta Y, Batra MJ, Timmanwar A, Lakka VK, Reddy B. Dextrocardia and corrected transposition of the great arteries with rheumatic tricuspid stenosis: a unique association. Indian J Thorac Cardiovasc Surg. 2019;35(2):230-232. doi:10.1007/s12055-018-0778-0

10. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(14):e698-e800. doi:10.1161/CIR.0000000000000603

11. Zubrzycki M, Schramm R, Costard-Jäckle A, et al. Pathogenesis and Surgical Treatment of Congenitally Corrected Transposition of the Great Arteries (ccTGA): Part III. J Clin Med. 2024;13(18). doi:10.3390/jcm13185461

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In this episode, CardioNerds Dr. Gurleen Kaur, Dr. Richard Ferraro, and Dr. Jake Roberts are joined by Cardio-Rheumatology expert, Dr. Monica Mukherjee, to discuss the role of utilizing multimodal imaging for cardiovascular disease risk stratification, monitoring, and management in patients with chronic systemic inflammation. The team delves into the contexts for utilizing advanced imaging to assess systemic inflammation with cardiac involvement, as well as the role of imaging in monitoring various specific cardiovascular complications that may develop due to inflammatory diseases. Audio editing by CardioNerds academy intern, Christiana Dangas.

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Pearls – Cardiovascular Multimodality Imaging & Systemic Inflammation1. Systemic inflammatory diseases are associated with an elevated CVD risk that has significant implications for early detection, risk stratification, and implementation of therapeutic strategies to address these risks and disease-specific complications. As an example, patients with SLE have a 48-fold increased risk for developing ASCVD compared to the general population. They may also develop disease-specific complications, such as pericarditis, that require focused imaging approaches to detect. 2. In addition to increasing the risk for CAD, systemic inflammatory diseases can also result in cardiac complications, including myocardial, pericardial, and valvular involvement. Assessment of these complications requires the use of different imaging techniques, with the modality and serial studies selected based on the suspected disease process involved. 3. In most contexts, echocardiography remains the starting point for evaluating cardiac involvement in systemic inflammatory diseases and can inform the next steps in terms of diagnostic study selection for the assessment of specific cardiac processes. For example, if echocardiography is completed in an SLE patient and demonstrates potential myocardial or pericardial inflammation, the next steps in evaluation may include completing a cardiac MRI for better characterization. 4. While no current guidelines or standards of care directly guide our selection of advanced imaging studies for screening and management of CVD in patients with systemic inflammatory diseases, our understanding of cardiac involvement in these patients continues to improve and will likely lead to future guideline development. 5. Due to the vast heterogeneity of cardiac involvement both across and within different systemic inflammatory diseases, a personalized approach to caring for each individual patient remains central to CVD evaluation and management in these patients. For example, patients with systemic sclerosis and symptoms of shortness of breath may experience these symptoms due to a range of causes. Echocardiography can be a central guiding tool in assessing these patients for potential concerns related to pulmonary hypertension or diastolic dysfunction. Based on the initial echocardiogram, the next steps in evaluation may involve further ischemic evaluation or right heart catheterization, depending on the pathology of concern.

Show notes – Cardiovascular Multimodality Imaging & Systemic InflammationEpisode notes drafted by Dr. Jake Roberts.

What are the contexts in which we should consider pursuing multimodal cardiac imaging, and are there certain inflammatory disorders associated with systemic inflammation and higher associated CVD risk for which advanced imaging can help guide early intervention?

• Systemic inflammatory diseases are associated with elevated CVD risk, which has significant implications for early detection, risk stratification, prognostication, and implementation of therapeutic strategies to address CVD risk and complications in these patient populations.
  • The most well-characterized autoimmune diseases with an association between systemic inflammation and CVD risk are inflammatory arthritic conditions such as rheumatoid arthritis. Additional inflammatory diseases with elevated CVD risk include spondyloarthropathies and psoriatic arthritis.
  • Patients with rheumatoid arthritis have a 1.5- 2x risk of developing coronary artery disease compared to the general population.
  • The mechanism of elevated CVD risk in inflammatory disease patients is likely related to a combination of abnormalities in lipid metabolism, endothelial dysfunction, and vascular inflammation.
  • Conditions including systemic lupus erythematosus (SLE), myositis, vasculitis disorders, and systemic sclerosis may have additional cardiovascular complications beyond CAD, including pericarditis, myocarditis, electrical, and valvular complications.

Are there any established or emerging technologies to help with improving early detection or characterization of cardiac involvement in systemic inflammatory diseases?

• Echocardiography remains the most common and useful starting point for screening and early detection of cardiac involvement in systemic inflammatory diseases due to its widespread availability, real-time interpretation, low cost, and noninvasive nature. Furthermore, echocardiography remains a crucial tool in serial monitoring for disease progression and the detection of therapeutic effects. This modality additionally provides significant utility for early detection and screening of pericardial and valvular involvement.
  • Given that patients with inflammatory disorders have an elevated risk for developing CAD, utilizing CAC scores and CCTA are often additionally helpful for CAD detection in these patient populations.

Are there different imaging techniques that should be used to assess complications specific to different systemic inflammatory diseases?

• Based on the specific disease involved, the choice of imaging technique may vary depending on the clinical context and the cardiovascular complication requiring further investigation.
• As an example, in systemic sclerosis, there can be a wide range of variable cardiac manifestations that emerge depending on the subtype of the disease, with the cardiac complications developing either because of the fibrotic disease process or from other secondary effects of the disease. Specifically, if the patient’s phenotype involves interstitial lung disease, the right ventricle of the heart will encounter chronic increased afterload, which can lead to adverse adaptive responses and remodeling over time. As a result, screening tools such as echocardiography can be very useful in this patient population, with these patients often requiring regular annual screening echocardiograms coupled with pulmonary function testing to screen for coupled changes in individual patients’ physiology. When these patients develop complications of their disease, including pulmonary hypertension, echocardiography can help evaluate the underlying cause of this complication and inform subsequent diagnostic steps.
• In terms of assessing myocardial disease and inflammation in myocardial tissue, cardiac MRI remains a valuable tool in detecting subclinical myocardial disease and can identify areas of low-grade myocardial inflammation. One of the advantages of cardiac MRI over other imaging techniques involves its ability to allow for noninvasive tissue characterization.
• For disease complications such as pericarditis, which can commonly develop in SLE, 2D echocardiography remains the first-line imaging modality of choice to detect pericardial disease involvement. In SLE patients who have long-standing pericardial disease with progression, they can also develop constrictive symptoms resulting from this process. In those cases, either CT or cardiac MRI can assist in defining the pericardial or myocardial anatomy.

As an example, what would be the approach to utilizing advanced imaging to assess for CVD detection and monitoring in a patient with SLE with relatively well-controlled symptoms on chronic immunosuppressive agents and no prior history of heart failure or CVD?

• As a starting point, all patients with systemic inflammatory diseases should undergo comprehensive ASCVD risk assessment. Initial stratification involves completing a laboratory assessment with a standard lipid panel and diabetes screening studies. Further evaluation of any symptoms that a patient may describe, which could indicate potential early cardiovascular disease processes, should also be thoroughly assessed and may influence the next steps in screening.
• In the context of SLE, pericardial disease is common, and therefore, obtaining a baseline echocardiogram to assess for any early pericardial involvement should be the initial step in evaluation. If the patient also has an elevated ASCVD risk, they should also undergo assessment for coronary artery disease.

What should be the approach to the sequence of imaging technique selection, serial imaging, monitoring, and follow-up in patients with systemic inflammatory disorders undergoing evaluation of CVD screening and monitoring?

• The initial selection of imaging modality should be based on what is suspected to be the primary driver of the patient’s symptoms or as the primary underlying process of concern that requires further evaluation.
• As an important consideration in the context of systemic inflammatory diseases such as SLE, ischemic disease may involve atypical presentations due to underlying myocardial dysfunction and microvascular disease. Therefore, imaging and other diagnostic studies may be warranted to assess for reversible ischemia. There is emerging evidence that cardiac PET perfusion and cardiac MRI may be particularly useful in this patient population to assess coronary flow reserve to evaluate for coronary microvascular disease.

What evidence currently exists to demonstrate the impact on cardiovascular outcomes resulting from the utilization of advanced multimodality imaging for CVD detection and monitoring in patients with systemic inflammatory disorders?

• While there is limited evidence that has directly measured the impact of advanced imaging utilization on CVD outcomes in this patient population, there is growing recognition of the increased risk of cardiac complications in patients with systemic inflammatory diseases. With increasing recognition of the commonality of cardiac involvement in these diseases, we are now more often utilizing appropriate testing in these patients.
• Directly measuring outcomes in these patient populations is somewhat challenging in large part due to the wide heterogeneity of phenotypes both across and within specific inflammatory diseases. Much of the approach in cardio-rheumatology should emphasize personalized medicine specific to each patient, given the wide range of cardiovascular complications and unique presentations of cardiac involvement in individual patients. Providing care for patients with systemic inflammatory diseases further requires a collaborative approach across disciplines and subspecialties within medicine to provide appropriate comprehensive care.

Is there a need for more standardized approaches for utilizing imaging in patients with systemic inflammatory diseases?

• Currently, there are no formal guidelines or standards of care to direct the use of multimodality imaging to assess CVD risk and direct management in patients with systemic inflammatory diseases.
• Many of the current standardized approaches are institution-dependent and often informed by clinical observations at individual medical centers.
• As we work to better understand the role of cardiac involvement in systemic inflammatory diseases and gain more experience in the evaluation of CVD and specific cardiovascular complications in these disorders, we will likely have ongoing development of standards of care and guidelines for management of CVD in these patients.

References – Cardiovascular Multimodality Imaging & Systemic Inflammation1. Weber BN, Paik JJ, Ayaz Aghayev, et al. Novel Imaging Approaches to Cardiac Manifestations of Systemic Inflammatory Diseases. Journal of the American College of Cardiology. 2023;82(22):2128-2151. doi:https://doi.org/10.1016/j.jacc.2023.09.819 2. Mortensen MB, Jensen JM, Sand NP, et al. Association of Autoimmune Diseases with Coronary Atherosclerosis Severity and Ischemic Events. Journal of the American College of Cardiology. 2024;83(25):2643-2654. doi:https://doi.org/10.1016/j.jacc.2024.04.030 3. Thackeray JT, Lavine KJ, Liu Y. Imaging Inflammation Past, Present, and Future: Focus on Cardioimmunology. The Journal of Nuclear Medicine. 2023;64(Supplement 2):39S48S. doi:https://doi.org/10.2967/jnumed.122.264865 4. West HW, Katerina Dangas, Antoniades C. Advances in Clinical Imaging of Vascular Inflammation. JACC Basic to Translational Science. 2023;9(5):710-732. doi:https://doi.org/10.1016/j.jacbts.2023.10.007 5. Milner JJ, Kim AHJ. Cardiac Manifestations of Systemic Lupus Erythematosus. Rheumatic Disease Clinics of North America. 2024;40(1):51-60. https://doi.org/10.1016/j.rdc.2013.10.003 6. Lu J, Jani V, Mercurio V, et al. Stress Echocardiographic Prediction of Emerging Pulmonary Vascular Disease in Systemic Sclerosis. Journal of the American Society of Echocardiography. 2023;36(2):259-261. https://doi.org/10.1016/j.echo.2022.10.006 7. Gilotra NA, Griffin JM, Pavlovic N, et al. Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review. Journal of Cardiac Failure. 2022;28(1):113-132. https://doi.org/10.1016/j.cardfail.2021.06.016 8. Trivieri MG, Spagnolo P, Birnie P, et al. Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review. 2020;76(16):1878-1901. https://doi.org/10.1016/j.jacc.2020.08.042

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In this episode, CardioNerds Dr. Anna Radakrishnan and Dr. Apoorva Gangavelli are joined by prevention expert Dr. Martha Gulati and heart failure expert Dr. Anu Lala to discuss heart failure with preserved ejection fraction (HFpEF), a multifactorial, evolving challenge, particularly in women. In this episode, we delve into the distinctive clinical presentation and pathophysiology of HFpEF among women, exploring both traditional and gender-specific risk factors, from metabolic and inflammatory processes to the impact of obesity, sleep apnea, and gender-specific conditions. We also discussed the latest evidence on prevention strategies and emerging therapies that not only target HFpEF symptoms but also address underlying risk factors. This conversation highlights the importance of multidisciplinary, holistic care to advance diagnosis, management, and ultimately, patient outcomes for women with HFpEF. Audio editing by CardioNerds academy intern, Christiana Dangas.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls – HFpEF in Women1. HFpEF Is a Multisystem Syndrome:
HFpEF in women involves more than just diastolic dysfunction—it represents a convergence of metabolic, inflammatory, and hormonal factors that make its diagnosis and management uniquely challenging. 2. Visceral Adiposity Drives Risk:
Obesity isn’t just excess weight; central or visceral adiposity actively promotes inflammation, insulin resistance, and microvascular dysfunction, which are crucial in triggering HFpEF in women. 3. Early Identification Is Key:
Recognizing—and treating—subtle risk factors such as sleep-disordered breathing, hypertension, and subtle metabolic dysfunction early, especially in women who may underreport symptoms, can prevent progression to HFpEF. 4. Holistic, Lifespan Approach Matters:
Effective HFpEF care involves managing the whole cardiometabolic profile with tailored lifestyle interventions, advanced medications (e.g., SGLT2 inhibitors, GLP-1 agonists), and even cardiac rehabilitation, which remain critical at every stage, even after diagnosis. 5. Tailoring Prevention to Unique Risks in Women:
Gender-specific factors such as postmenopausal hormonal changes, pregnancy-related complications, and autoimmune conditions demand a customized prevention strategy, reminding us that prevention isn’t one-size-fits-all.

Show notes – HFpEF in WomenNotes drafted by Dr. Apoorva Gangavelli

1. What are the gender-based differences in HFpEF presentation?

2. HFpEF in women often presents with more subtle symptoms such as exertional dyspnea and fatigue, which may be mistakenly attributed to aging or obesity.

3. Women tend to have a higher prevalence of preserved ejection fraction despite a similar heart failure symptom burden to men.

4. The diagnostic challenge is compounded by lower natriuretic peptide levels influenced by hormonal factors, particularly postmenopausal estrogen deficiency, leading to false negatives and underdiagnosis.

5. How do traditional and gender-specific risk factors contribute to the development of HFpEF in women?

6. Traditional risk factors include obesity, hypertension, diabetes, and metabolic syndrome.

7. Gender-specific risk factors encompass pregnancy-related complications, menopause, and autoimmune diseases, which may uniquely affect cardiovascular structure and function in women.

8. The interaction between visceral adiposity and systemic inflammation is central in predisposing women to HFpEF.

9. What underlying pathophysiological mechanisms make women more susceptible to HFpEF?

10. Chronic inflammation and endothelial dysfunction contribute to myocardial stiffness and diastolic dysfunction.

11. Insulin resistance results in impaired myocardial metabolism and lipotoxicity.

12. Microvascular dysfunction, with reduced nitric oxide bioavailability, is more pronounced in women, exacerbating cardiac remodeling and fibrosis.

13. What prevention strategies can be tailored across different life stages to reduce HFpEF risk in women?

14. Early detection and aggressive management of traditional risk factors (e.g., blood pressure control, weight management) during perimenopause and early adulthood.

15. Incorporating lifestyle modifications such as structured exercise programs, improved dietary habits, and sleep optimization.

16. Preventive interventions might also include screening for gender-specific risk factors like pregnancy complications and autoimmune conditions early in life.

17. What current and emerging therapeutic approaches are used in the management of HFpEF in women?

18. Use of mineralocorticoid receptor antagonists and nonsteroidal alternatives shows promise, particularly in reducing hospitalizations.

19. Novel pharmacologic agents such as SGLT2 inhibitors and GLP-1 receptor agonists address both heart failure symptoms and metabolic dysfunction.
20. Cardiac rehabilitation is advocated to improve functional capacity and quality of life despite challenges with insurance coverage.

References – HFpEF in Women1. Borlaug BA, Sharma K, Shah SJ, Ho J. Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology. 2023;81(18). doi:https://doi.org/10.1016/j.jacc.2023.01.049 2. ‌Kittleson MM, Gurusher Panjrath, Kaushik Amancherla, et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology. 2023;81(18). doi:https://doi.org/10.1016/j.jacc.2023.03.393 3. Radakrishnan A, Agrawal S, Singh N, et al. Underpinnings of Heart Failure With Preserved Ejection Fraction in Women – From Prevention to Improving Function. A Co-publication With the American Journal of Preventive Cardiology and the Journal of Cardiac Failure. Journal of Cardiac Failure. Published online February 2025. doi:https://doi.org/10.1016/j.cardfail.2025.01.008

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In this webinar, the CardioNerds collaborated with the Cardiogenic Shock Working Group (CSWG) to discuss LV unloading and the updated AMI guidelines, which upgraded transvalvular flow pumps to a Class 2A recommendation in AMI shock.

Dr. Rachel Goodman and Dr. Gurleen Kaur from CardioNerds were joined by Dr. Navin Kapur (Tufts Medical Center), Dr. Shashank Sinha (INOVA Fairfax Hospital), and Dr. Rachna Kataria (Brown University) from the CSWG.

Together, they explore a case of an older woman who presented with inferior STEMI and was found to have complete occlusion of an anomalous single coronary artery originating from the right coronary cusp and supplying the entire left ventricle. She was treated with DES to the anomalous RCA. Her course was complicated by AMI shock with re-occlusion of the DES, which was treated with thrombectomy and balloon angioplasty. An IABP was placed. After transfer to a tertiary care center, a pulmonary artery catheter revealed a CI of 0.96. With worsening shock, rising lactate, and end organ dysfunction, the team proceeded with VA-ECMO and Impella CP for LV unloading. Her lactate subsequently normalized.

Produced by CardioNerds in collaboration with the Cardiogenic Shock Working Group.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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CardioNerds Critical Care Cardiology Council members Dr. Gurleen Kaur and Dr. Katie Vanchiere meet with Dr. Yash Patel, Dr. Akanksha, and Dr. Mohammed El Nayir from Trinity Health Ann Arbor. They discuss a case of pulmonary air embolism, RV failure, and cardiac arrest secondary to an ocular venous air embolism. Expert insights provided by Dr. Tanmay Swadia. Audio editing by CardioNerds Academy intern, Grace Qiu.

A 36-year-old man with a history of multiple ocular surgeries, including a complex retinal detachment repair, suffered a post-vitrectomy collapse at home. He was found hypoxic, tachycardic, and hypotensive, later diagnosed with a pulmonary embolism from ocular venous air embolism leading to severe right heart failure. Despite a mild embolic burden, the cardiovascular response was profound, requiring advanced hemodynamic support, including an Impella RP device (Abiomed, Inc.). Multidisciplinary management, including fluid optimization, vasopressors and mechanical support to facilitate recovery. This case underscores the need for early recognition and individualized intervention in cases of ocular venous air embolism.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls- Clear Vision, Clouded Heart: Ocular Venous Air Embolism with Pulmonary Air Embolism, RV Failure, and Cardiac Arrest 1. Hypoxia, hypotension and tachycardia in a patient following ocular instrumentation are classic findings suggestive of pulmonary embolism from possible air embolism. 2. The diagnosis of RV failure is based on clinical presentation, echocardiographic findings (such as McConnell’s sign), and invasive hemodynamic assessment via right heart catheterization. 3. Mechanical circulatory support can be considered as a temporary measure for patients with refractory RV failure.

Central Figure: Approach to Pulmonary Embolism with Acute RV FailureNotes – Clear Vision, Clouded Heart: Ocular Venous Air Embolism with Pulmonary Air Embolism, RV Failure, and Cardiac Arrest 1. What is an Ocular Venous Air Embolism (VAE), and how can it be managed in critically ill patients?

• An Ocular Venous Air Embolism is defined as the entry of air into the systemic venous circulation through the ocular venous circulation, often during vitrectomy procedures. Early diagnosis is key to preventing cardiovascular collapse in cases of Ocular Venous Air Embolism (VAE).
• The goal is to stop further air entry. This can be done by covering the surgical site with saline-soaked dressings and checking for air entry points.
• Adjusting the operating table can help, especially with a reverse Trendelenburg position for lower-body procedures.
• The moment VAE is suspected, discontinue nitrous oxide and switch to 100% oxygen. This helps with oxygenation, speeds up nitrogen elimination, and shrinks air bubbles.
• Hyperbaric Oxygen Therapy can reduce bubble size and improve oxygenation, especially in cases of cerebral air embolism, when administered within 6 hours of the incident.
• Though delayed hyperbaric oxygen therapy can still offer benefits, the evidence is mixed.
• VAE increases right heart strain, so inotropic agents like dobutamine can help boost cardiac output, while norepinephrine supports ventricular function and systemic vascular resistance, but this may also worsen pulmonary resistance.

• Aspiration of air via multi-orifice or Swan-Ganz catheters has limited success, with success rates ranging from 6% to 16%. In contrast, the Bunegin-Albin catheter has shown more promise, with a 30-60% success rate. Catheterization for acute VAE-induced hemodynamic compromise is controversial, and there’s insufficient evidence to support its widespread emergency use.

• What are the key hemodynamic parameters used to assess RV function?

• On echocardiogram, there are a number of parameters that can assess RV function:

  • Tricuspid Annular Plane Systolic Excursion (TAPSE): Measures the lateral tricuspid annulus’ movement during systole. A TAPSE value below 1.6 cm is associated with poor prognosis.
  • RV Outflow Tract (RVOT) Acceleration Time: Measured via pulsed wave Doppler, an acceleration time of <100 ms is abnormal, with values ≤60 ms indicating a worse prognosis.
  • Global RV Longitudinal Strain: Assessed via speckle tracking, with a strain value of −20% being highly predictive of RV dysfunction (normal values typically range -24.5 to -28.5%).
  • Tricuspid Regurgitation (TR) Jet Velocity: Helps estimate pulmonary systolic pressure and provides prognostic information.
  • Inferior Vena Cava (IVC) Collapsibility: Useful in estimating right atrial pressure and guiding volume resuscitation, though it lacks prognostic significance.
  • The RV:LV diameter ratio offers prognostic value, with a ratio greater than 0.9 linked to worse outcomes.

• Invasive Hemodynamic Monitoring (Right heart catheterization, PA Catheter)

  • The Pulmonary Artery Pulsatility Index (PAPI) is an invasive hemodynamic parameter used to assess right ventricular (RV) function, particularly in cases of RV failure and cardiogenic shock. PAPi is the pulmonary arterial pulse pressure divided by the RA pressure. A PAPi of <0.9 is a poor indicator, especially in the acute myocardial infarction population.

• What are the core principles in managing a patient with RV failure?

• The management to optimize RV function is centered around optimizing preload, afterload, and contractility.

  • Optimizing preload – Optimizing preload is one of the most important aspects in the management of acute decompensated RV failure. The majority of us are taught that the RV is “preload dependent” and patients should be fluid resuscitated. However, many patients are actually volume overloaded and may benefit from diuresis. Overall, this is a patient-to-patient decision, depending on the clinical picture, to optimize preload; though the use of pulmonary artery (PA) catheters in this setting is not well supported.
  • Reducing afterload – Avoid intubation if clinically feasible, as they may increase PVR; however, if essential, ideally, oxygen saturation (SaO₂) should be maintained above 92%, and ventilator settings should be adjusted to optimize lung volume and maintain a normal pH and PCO₂. Nitric oxide has also been beneficial in improving oxygenation and reducing PVR with its vasodilatory effects.
  • Support cardiac output
    • May support with the use of inotropes as well as mechanical circulatory support.
      • Pressors: The ideal vasopressor increases systemic arterial pressure and RV contractility without raising pulmonary vascular resistance.
        • Norepinephrine: Primarily an α1 agonist, it improves systemic blood pressure with some β1 stimulation. It has shown benefits in maintaining RV-PA coupling.
        • Dobutamine: A β1 agonist that improves myocardial contractility and RV-PA coupling, though it can cause vasodilation at higher doses.
        • In general, dobutamine is considered the best for acute RVF with PH, unless hypotension is a significant concern, in which case norepinephrine might be preferred. Milrinone is another option.
      • MCS: short-term MCS should be considered in patients with cardiogenic shock as a bridge to recovery, a bridge to decision, or a bridge to bridge whilst the underlying causes for cardiogenic shock are addressed further described below
        • Options include:
          • Venous-arterial extracorporeal membranous oxygenation (V-A ECMO)
          • RA to PA extracorporeal pump. (surgical RVAD)
          • Flow device with an intake in the RA and an output in the PA. (Impella RP, Protek Duo)

• When should we consider mechanical circulatory support for right ventricular (RV) failure?

• Short-term MCS should be considered in patients with cardiogenic shock as a bridge to recovery, a bridge to decision, or a bridge to bridge whilst the underlying causes for cardiogenic shock are addressed.

• Clinical parameters that suggest acute MCS use include signs of relative hypoperfusion plus hemodynamic features suggestive of RV failure, which were present in our patient. A specific additional consideration relates to where acute left-sided MCS reveals acute RV failure. Discerning whether this is intrinsic RV failure or due to persistently elevated RV afterload from inadequate LV support is also essential, as it will define management.
• The goal of percutaneous mechanical support is to bypass the right ventricle and improve hemodynamics, while allowing time for optimization of the patient and recovery of the RV.

ReferencesArrigo, Mattia, et al. “Diagnosis and Treatment of Right Ventricular Failure Secondary to Acutely Increased Right Ventricular Afterload (Acute Cor Pulmonale). A Clinical Consensus Statement of the Association for Acute CardioVascular Care (ACVC) of the ESC.” European Heart Journal. Acute Cardiovascular Care, vol. 13, no. 3, 22 Dec. 2023, pp. 304–312, https://doi.org/10.1093/ehjacc/zuad157. Accessed 17 May 2024.

Chen, Guohai, et al. “INCIDENCE of ENDOPHTHALMITIS after VITRECTOMY: A Systematic Review and Meta-Analysis.” Retina (Philadelphia, Pa.), vol. 39, no. 5, May 2019, pp. 844–852, pubmed.ncbi.nlm.nih.gov/29370034/, https://doi.org/10.1097/IAE.0000000000002055.

Fakkert, Raoul A, et al. “Early Hyperbaric Oxygen Therapy Is Associated with Favorable Outcome in Patients with Iatrogenic Cerebral Arterial Gas Embolism: Systematic Review and Individual Patient Data Meta-Analysis of Observational Studies.” Critical Care, vol. 27, no. 1, 12 July 2023, https://doi.org/10.1186/s13054-023-04563-x. Accessed 7 June 2024.

Flaxel, Christina J., et al. “Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern®.” Ophthalmology, vol. 127, no. 2, Feb. 2020, pp. P145–P183, https://doi.org/10.1016/j.ophtha.2019.09.022. Accessed 16 July 2020.

Frémont, Benoît, et al. “Prognostic Value of Echocardiographic Right/Left Ventricular End-Diastolic Diameter Ratio in Patients with Acute Pulmonary Embolism.” Chest, vol. 133, no. 2, Feb. 2008, pp. 358–362, https://doi.org/10.1378/chest.07-1231.

Huang, Ryan S, et al. “Pars Plana Vitrectomy with Silicone Oil or Gas Tamponade for Uncomplicated Retinal Detachment: A Systematic Review and Meta-Analysis.” American Journal of Ophthalmology, vol. 266, Oct. 2024, pp. 144–155, pubmed.ncbi.nlm.nih.gov/38815844/, https://doi.org/10.1016/j.ajo.2024.05.008.

Kanwar, Manreet K, et al. “Epidemiology and Management of Right Ventricular-Predominant Heart Failure and Shock in the Cardiac Intensive Care Unit.” European Heart Journal. Acute Cardiovascular Care, vol. 11, no. 7, 29 June 2022, pp. 584–594, https://doi.org/10.1093/ehjacc/zuac063. Accessed 5 Mar. 2023.

Lahm, Tim, et al. “Medical and Surgical Treatment of Acute Right Ventricular Failure.” Journal of the American College of Cardiology, vol. 56, no. 18, Oct. 2010, pp. 1435–1446, www.onlinejacc.org/content/56/18/1435, https://doi.org/10.1016/j.jacc.2010.05.046. Accessed 30 Nov. 2019.

Mirski, Marek A., et al. “Diagnosis and Treatment of Vascular Air Embolism.” Anesthesiology, vol. 106, no. 1, 1 Jan. 2007, pp. 164–177, pubs.asahq.org/anesthesiology/article/106/1/164/8884/Diagnosis-and-Treatment-of-Vascular-Air-Embolism, https://doi.org/10.1097/00000542-200701000-00026. Accessed 13 Apr. 2021.

Moon, Young Eun. “Venous Air Embolism during Vitrectomy: A Rare but Potentially Fatal Complication.” Korean Journal of Anesthesiology, vol. 67, no. 5, 1 Jan. 2014, pp. 297–297, pmc.ncbi.nlm.nih.gov/articles/PMC4252339/, https://doi.org/10.4097/kjae.2014.67.5.297. Accessed 10 Mar. 2025.

“Right Ventricular Failure.” Escardio.org, 2016, www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-14/Right-ventricular-failure.

Stickel, Simone, et al. “The Practical Management of Fluid Retention in Adults with Right Heart Failure due to Pulmonary Arterial Hypertension.” European Heart Journal Supplements, vol. 21, 1 Dec. 2019, pp. 46–53, academic.oup.com/eurheartjsupp/article/21/Supplement_K/K46/5678698, https://doi.org/10.1093/eurheartj/suz207.

Ventetuolo, Corey E., and James R. Klinger. “Management of Acute Right Ventricular Failure in the Intensive Care Unit.” Annals of the American Thoracic Society, vol. 11, no. 5, 1 June 2014, pp. 811–822, www.ncbi.nlm.nih.gov/pmc/articles/PMC4225807/#:~:text=Abstract, https://doi.org/10.1513/AnnalsATS.201312-446FR. Accessed 10 Aug. 2020.

What Is Vitrectomy. “What Is Vitrectomy?” American Academy of Ophthalmology, 15 May 2019, www.aao.org/eye-health/treatments/what-is-vitrectomy.

Zhao, Steven, and Oren Friedman. “Management of Right Ventricular Failure in Pulmonary Embolism.” Critical Care Clinics, vol. 36, no. 3, July 2020, pp. 505–515, https://doi.org/10.1016/j.ccc.2020.02.006. Accessed 29 Nov. 2020.

1. CCC: Approach to RV Predominant Cardiogenic Shock with Dr. Ryan Tedford

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CardioNerdsACHD Council members Dr. Rawan Amir and Dr. Claire Cambron lead a profound conversation with ACHD faculty Dr. Allison Tsao, Dr. Jill Steiner, and Dr. Katherine Salciccioli. Together, they explore the emotional and professional challenges that ACHD providers face across the lifespan of congenital heart disease. Topics discussed include navigating challenging case scenarios, empowering patients through tough decisions, leveraging multi-subspecialty expertise, celebrating the successes, preparing for and grieving loss, and more.

This episode was planned by the CardioNerds ACHD Council.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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CardioNerds (Drs. Daniel Ambinder and Eunice Dugan) are joined by Namrita Ashokprabhu, incoming medical student, along with Drs. Yulith Roca Alvarez and Mehmet Yildiz from The Christ Hospital. Expert insights provided by Dr. Odayme Quesada. Audio editing by CardioNerds intern Christiana Dangas. This episode explores how cardiac MRI and coronary function testing revealed coronary vasospasm in a case of MINOCA.

Cardiac MRI is crucial in evaluating myocardial infarction with nonobstructive coronary arteries (MINOCA) and diagnosing myocarditis, but findings must be interpreted within clinical context. A 58-year-old man with hypertension, hyperlipidemia, diabetes, a family history of cardiovascular disease, and smoking history presented with sudden chest pain, non-ST-elevation on EKG, and elevated troponin I (0.64 µg/L). Cardiac angiography revealed nonobstructive coronary disease, including a 40% stenosis in the LAD, consistent with MINOCA. Eight weeks later, another event (troponin I 1.18 µg/L) led to cardiac MRI findings suggesting myocarditis. Further history revealed episodic chest pain and coronary vasospasm, confirmed by coronary functional angiography showing severe vasoconstriction, resolved with nitroglycerin. Management included calcium channel blockers and long-acting nitrates, reducing symptoms. Coronary vasospasm is a frequent MINOCA cause and can mimic myocarditis on CMRI. Invasive coronary functional testing, including acetylcholine provocation testing, is indicated in suspicious cases.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Notes – Coronary Vasospasm1. What are the potential underlying causes of MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries)? * Plaque Rupture: Plaque disruption, which includes plaque rupture, erosion, and calcified nodules, occurs as lipids accumulate in coronary arteries, leading to inflammation, necrosis, fibrosis, and calcification. Plaque rupture exposes the plaque to the lumen, causing thrombosis and thromboembolism, while plaque erosion results from thrombus formation without rupture and is more common in women and smokers. Intravascular imaging, such as IVUS and OCT, can detect plaque rupture and erosion, with studies showing plaque disruption as a frequent cause of MINOCA, particularly in women, though the true prevalence may be underestimated due to limited imaging coverage. * Coronary Vasospasm: Coronary vasospasm is characterized by nitrate-responsive chest pain, transient ischemic EKG changes, and >90% vasoconstriction during provocative testing with acetylcholine or ergonovine, due to hyper-reactivity in vascular smooth muscle. It is a common cause of MINOCA, with approximately half of MINOCA patients testing positive in provocative tests, and Asians are at a significantly higher risk than Whites. Smoking is a known risk factor for vasospasm. In contrast, traditional risk factors like sex, hypertension, and diabetes do not increase the risk, and vasospasm is associated with a 2.5–13% long-term risk of major adverse cardiovascular events (MACE). * Spontaneous Coronary Artery Dissection: Spontaneous coronary artery dissection (SCAD) involves the formation of a false lumen in epicardial coronary arteries without atherosclerosis, caused by either an inside-out tear or outside-in intramural hemorrhage. SCAD is classified into four types based on angiographic features, with coronary angiography being the primary diagnostic tool. However, in uncertain cases, advanced imaging like IVUS or OCT may be used cautiously. While the true prevalence is unclear due to missed diagnoses, SCAD is more common in women and is considered a cause of MINOCA when it results in non-obstructive lesions, with various predisposing factors including genetics, fibromuscular dysplasia, and emotional stress. * Coronary Embolism/Thrombosis: Coronary embolism, often underdiagnosed, can be classified based on thrombus origin as direct, paradoxical, or iatrogenic, with atrial fibrillation being the most common cause. A Japanese study found that only 2.9% of AMI patients were related to coronary embolism, and 73% of these cases were due to atrial fibrillation, with recurrent thromboembolic events occurring in 10% of patients during follow-up. Risk factors for coronary thromboembolism include hereditary thrombophilia, with 14% of MINOCA patients having hereditary thrombophilia, and an extensive evaluation, including a hypercoagulable workup and screening for atrial fibrillation or patent foramen ovale, is crucial to determine the underlying cause. * Coronary Microvascular Dysfunction: The role of microvascular dysfunction in MINOCA remains uncertain due to limited data, though it is characterized by impaired vasodilation, increased vasoconstriction, and abnormal microcirculation remodeling, which affects coronary flow reserve without epicardial disease. Microvascular dysfunction is often underdiagnosed because it requires invasive functional testing, and studies in patients with ischemia but no obstructive coronary disease (INOCA) show a prevalence of up to 41%. A small study of MINOCA patients found that 25% had low myocardial perfusion reserve, suggesting potential involvement, but further research is needed to establish its role as a cause of MINOCA. * MINOCA mimickers: * Myocarditis: Myocarditis, often caused by viral infections, can also result from bacterial infections, toxic substances, or autoimmune disorders, and is more common in younger patients, though it can affect all ages. Fulminant myocarditis, though rare, can lead to life-threatening cardiogenic shock, and is diagnosed through CMR showing diffuse myocardial edema on T2 and myocardial biopsy. A meta-analysis found that one-third of MINOCA patients had myocarditis, particularly younger patients and those with elevated C-reactive protein levels. * Non-ischemic Cardiomyopathy: Non-ischemic cardiomyopathy encompasses conditions like dilated, hypertrophic, restrictive, and arrhythmogenic cardiomyopathy, with dilated cardiomyopathy being the most common. A longitudinal study found that 25% of MINOCA patients had non-ischemic cardiomyopathy, which was associated with the highest mortality compared to other MINOCA mechanisms. Stress CMR has also identified underlying microvascular dysfunction in patients with dilated cardiomyopathy. * Takotsubo Cardiomyopathy: Takotsubo cardiomyopathy, or stress-induced cardiomyopathy, is characterized by reversible wall motion abnormalities without obstructive CAD. It is often triggered by emotional or physical stress and is associated with a catecholamine surge. The condition is more common in postmenopausal women and has four main anatomical variants, with apical ballooning being the most common. Diagnosis typically involves coronary angiography, ventriculography, and CMRI to rule out other causes of AMI, with risks of cardiogenic shock and death comparable to those of AMI patients with CAD. 2. What are the key diagnostic tests to evaluate MINOCA, and how are they applied in this case? * Coronary Intravascular Imaging: Coronary intravascular imaging with IVUS and OCT is essential for diagnosing plaque disruption in MINOCA and should be performed during coronary angiography of all three major epicardial arteries. IVUS identifies plaque disruption in up to 40% of MINOCA cases, while OCT detects the culprit lesion in about 50%. These imaging techniques are also valuable for evaluating SCAD in cases of diagnostic uncertainty. * Cardiac Imaging: Transthoracic echocardiography is valuable for assessing cardiac function after MINOCA, diagnosing Takotsubo and non-ischemic cardiomyopathy, and monitoring recovery of left ventricular function. Transesophageal echocardiography may be considered when coronary embolism is suspected. CMR is recommended for uncertain MINOCA diagnoses, providing accurate results in 74–87% of cases. It can differentiate between ischemic and non-ischemic MI, diagnose myocarditis, and detect coronary microvascular dysfunction through perfusion imaging. CMR’s diagnostic accuracy improves when performed closer to the event and also serves as a prognostic tool for long-term cardiovascular outcomes. * Invasive Coronary Functional Testing: Provocative spasm testing with intracoronary acetylcholine helps diagnose coronary vasospasm (epicardial or microvascular) and endothelial-dependent microvascular dysfunction, with a low complication rate (0.5%). In MINOCA patients, spasm testing is positive in about half, with epicardial spasm in 65% and microvascular spasm in 35%. CFR assessed by doppler flow velocity or thermodilution (with values <2.0) and IMR (>25) are used to assess microvascular dysfunction, though CFR is more sensitive. While coronary microvascular dysfunction is linked to worse outcomes in INOCA, its prognostic impact in MINOCA is less clear. However, low CFR has been associated with increased mortality across various patient populations. 3. How is MINOCA treated based on its underlying etiology? * Plaque Rupture: Patients with plaque disruption should be treated with aspirin and high-intensity statin therapy. Additionally, for those with plaque disruption who do not require stenting, dual antiplatelet therapy with ticagrelor for up to 1 month may be considered, given the low revascularization rates at 1 year (5.7%) and 4 years (21.1%) follow-up. * Coronary Vasospasm: Long-acting calcium channel blockers (both dihydropyridine and non-dihydropyridine) are commonly used in MINOCA patients with epicardial coronary vasospasm. They relax vascular smooth muscle by inhibiting calcium ion influx. For patients with refractory angina, nitrates may be added to calcium channel blockers to enhance smooth muscle relaxation through increased nitric oxide availability. * SCAD: Conservative management is preferred over PCI in SCAD patients, as most dissections heal without intervention and PCI carries higher complication risks. PCI is reserved for STEMI, cardiogenic shock, or persistent ischemia. The use of antithrombotic agents during acute SCAD is debated, and secondary prevention (aspirin, beta-blockers, statins, and ACE inhibitors) should be tailored to individual risk factors. * CMD: Treatment options for coronary microvascular dysfunction are limited and mainly based on data from INOCA patients. Statins and renin-angiotensin system inhibitors have been shown to improve coronary flow reserve (CFR). Antianginal therapies such as beta-blockers, calcium channel blockers, and ranolazine are commonly used for patients with chest pain. * MINOCA Mimickers: * Takotsubo Cardiomyopathy: Management of MINOCA mimickers mainly involves supportive care and guideline-directed medical therapy for heart failure, though evidence is limited. Most patients with Takotsubo cardiomyopathy recover normal cardiac function spontaneously, while those with left ventricular dysfunction are treated with beta-blockers and renin-angiotensin system inhibitors. In cases of progressive circulatory failure, mechanical circulatory support may be needed. * Myocarditis: Myocarditis typically resolves within 2–4 weeks, but patients with arrhythmias or persistent cardiac dysfunction should receive guideline-directed therapy. Physical activity should be avoided in the acute phase for up to 6 months. Ongoing trials on antiviral and immunosuppressive treatments may offer targeted therapies in the future.

References – Coronary Vasospasm1. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation. 2019;139:e891–908. doi:10.1161/CIR.0000000000000670 2. Reynolds HR, Maehara A, Kwong RY, et al. Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women. Circulation. 2021;143:624–40. doi:10.1161/CIRCULATIONAHA.120.052008 3. di Fusco SA, Rossini R, Zilio F, et al. Spontaneous coronary artery dissection: overview of pathophysiology. Trends Cardiovasc Med. 2022;32:92–100. doi:10.1016/j.tcm.2021.01.002 4. Zilio F, Muraglia S, Morat F, et al. Sex differences in clinical and angiographic characteristics in spontaneous coronary artery dissection. Future Cardiol. 2021;17:669–75. doi:10.2217/fca-2020-0124 5. Omerovic E, Citro R, Bossone E, et al. Pathophysiology of takotsubo syndrome – a joint scientific statement from the heart failure association takotsubo syndrome study group and myocardial function working group of the European society of cardiology – part 2: vascular pathophysiology, gender and sex hormones, genetics, chronic cardiovascular problems and clinical implications. Eur J Heart Fail. 2022;24:274–86. doi:10.1002/ejhf.2368 6. Agdamag AC, Patel H, Chandra S, et al. Sex differences in takotsubo syndrome: a narrative review. J Womens Health. 2020;29:1122–30. doi:10.1089/jwh.2019.7741 7. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114:1852–66. doi:10.1161/CIRCRESAHA.114.302721 8. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13–8. doi:10.1016/j.jacc.2005.10.065 9. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J. 2017;39:91–8. doi:10.1093/eurheartj/ehx667 10. Raphael CE, Heit JA, Reeder GS, et al. Coronary embolus: an underappreciated cause of acute coronary syndromes. JACC Cardiovasc Interv. 2018;11:172–80. doi:10.1016/j.jcin.2017.08.057 11. Tschöpe C, Ammirati E, Bozkurt B, et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol. 2021;18:169–93. doi:10.1038/s41569-020-00435-x 12. Tornvall P, Gerbaud E, Behaghel A, et al. Myocarditis or “true” infarction by cardiac magnetic resonance in patients with a clinical diagnosis of myocardial infarction without obstructive coronary disease: a meta-analysis of individual patient data. Atherosclerosis. 2015;241:87–91. doi:10.1016/j.atherosclerosis.2015.04.816 13. Lintingre P-F, Nivet H, Clément-Guinaudeau S, et al. High-resolution late gadolinium enhancement magnetic resonance for the diagnosis of myocardial infarction with nonobstructed coronary arteries. JACC Cardiovasc Imaging. 2020;13:1135–48. doi:10.1016/j.jcmg.2019.11.020 14. AlBadri A, Bairey Merz CN, Johnson BD, et al. Impact of abnormal coronary reactivity on long-term clinical outcomes in women. J Am Coll Cardiol. 2019;73:684–93. doi:10.1016/j.jacc.2018.11.040 15. Kelshiker MA, Seligman H, Howard JP, et al. Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis. Eur Heart J. 2022;43:1582–93. doi:10.1093/EURHEARTJ/EHAB775 16. Slavich M, Patel RS. Coronary artery spasm: current knowledge and residual uncertainties. IJC Heart Vasculat. 2016;10:47–53. doi:10.1016/j.ijcha.2016.01.003 17. Samuels B, Shah S, Widmer R, et al. Comprehensive management of ANOCA, Part 1—definition, patient population, and diagnosis: JACC state-of-the-art review. JACC. 2023;82(12):1245–63. doi:10.1016/j.jacc.2023.06.043 18. Smilowitz N, Prasad M, Widmer R, et al. Comprehensive management of ANOCA, Part 2—program development, treatment, and research initiatives: JACC state-of-the-art review. JACC. 2023;82(12):1264–79. doi:10.1016/j.jacc.2023.06.044 19. Quesada O, Ashokprabhu ND, Tapp DN, et al. Utilizing invasive coronary functional testing in a coronary microvascular and vasomotor dysfunction program: methods and considerations. Catheter Cardiovasc Interv. 2024;104(7):1327–36. doi:10.1002/ccd.31282 20. Yildiz M, Ashokprabhu N, Shewale A, et al. Myocardial infarction with non-obstructive coronary arteries (MINOCA). Front Cardiovasc Med. 2022;9:1032436. doi:10.3389/fcvm.2022.1032436

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CardioNerds co-founders Dr. Daniel Ambinder and Dr. Amit Goyal are joined by Dr. Spencer Weintraub, Chief Resident of Internal Medicine at Northwell Health, Dr. Michael Albosta, third-year Internal Medicine resident at the University of Miami, and Anna Biggins, Registered Dietitian Nutritionist at the Georgia Heart Institute. Expert commentary is provided by Dr. Zahid Ahmad, Associate Professor in the Division of Endocrinology at the University of Texas Southwestern. Together, they discuss a fascinating case involving a patient with a new diagnosis of hypertriglyceridemia. Episode audio was edited by CardioNerds Intern Student Dr. Pacey Wetstein.

A woman in her 30s with type 2 diabetes, HIV, and polycystic ovarian syndrome presented with one day of sharp epigastric pain, non-bloody vomiting, and a new lower extremity rash. She was diagnosed with hypertriglyceridemia-induced pancreatitis, necessitating insulin infusion and plasmapheresis.

The CardioNerds discuss the pathophysiology of hypertriglyceridemia-induced pancreatitis, potential organic and iatrogenic causes, and the cardiovascular implications of triglyceride disorders. We explore differential diagnoses for cardiac and non-cardiac causes of epigastric pain, review acute and long-term management of hypertriglyceridemia, and discuss strategies for the management of the chylomicronemia syndrome, focusing on lifestyle changes and pharmacotherapy.

This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos.

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Pearls – Hypertriglyceridemia1. Cardiac sarcoidosis can present with a variety of symptoms, including arrhythmias, heart block, heart failure, or sudden cardiac death. The acute management of hypertriglyceridemia-induced pancreatitis involves prompt recognition and initiation of therapy to lower triglyceride levels using either plasmapheresis or intravenous insulin infusion +/- heparin infusion. Insulin infusion is used more commonly, while plasmapheresis is preferred in pregnancy. 2. Medications such as fibrates and omega-3 fatty acids can be used to maintain long-term triglyceride reduction to prevent the recurrence of pancreatitis, especially in patients with persistent triglyceride elevation despite lifestyle modifications. Statins can be used in patients for ASCVD reduction in patients with a 10-year ASCVD risk > 5%, age > 40 years old, and diabetes or diabetes with end-organ damage or known atherosclerosis. Consider preferential use of icosapent ethyl as an omega-3 fatty acid for triglyceride lowering if the patients fit the populations that appeared to benefit in the REDUCE IT trial. 3. Apply targeted dietary interventions within the context of an overall healthy dietary pattern, such as a Mediterranean or DASH diet. Limit full-fat dairy, fatty meats, refined starches, added sugars, and alcohol. Encourage high-fiber vegetables, whole fruits, low-fat or fat-free dairy, plant proteins, lean poultry, and fish. Pay special attention to the cooking oils to ensure the patient is not using palm oil, coconut oil, or butter when cooking. Instead, use liquid non-tropical plant oils. Initiate a very low-fat diet (< 5% of total daily calories from fat) for 1-4 weeks when TG levels are > 750 mg/dL. 4. Recommend and encourage patients to exercise regularly, with a minimum goal of 150 minutes/week of moderate-intensity aerobic activity. If weight loss is required, aim for more than >225 – 250 minutes/week. 5. Develop patient-centered and multidisciplinary strategies for preventing hypertriglyceridemia-induced pancreatitis by incorporating patient education on the importance of medication adherence, specialist follow-up, regular monitoring of triglyceride levels, and lifestyle modifications to maintain optimal lipid profiles and reduce the future risk of pancreatitis.

Notes – Hypertriglyceridemia1. Who is at risk for hypertriglyceridemia and what are the key pathophysiological mechanisms by which elevated triglycerides may lead to pancreatitis? * The exact mechanism is not clear. The proposed mechanism is that when serum triglycerides exceed 1000 mg/dL, blood flow is impaired through the capillary beds supplying the pancreas, resulting in ischemia. The ischemic injury resulting from this disruption of microcirculation disrupts the acinar structure of pancreatic cells and exposes pancreatic enzymes to triglyceride-rich particles. This results in activation of enzymatic activity with degradation of the chylomicron-triglycerides particles, which causes inflammation, subsequently leading to hemorrhage, edema, and necrosis of the pancreatic tissue. * Chylomicronemia syndrome can be multifactorial or familial. Familial chylomicronemia syndrome (FCS) is often discovered very early in life, and patients have a loss of function in one of the several genes involved in regulating triglyceride metabolism. These genes include LPL, APOC2, APOA5, LMF1, and GPIHBP1. * Multifactorial chylomicronemia syndrome is the most common cause of chylomicronemia syndrome. It is usually the result of a clustering of genetic variants, including heterozygosity of one of the five genes previously mentioned, as well as more frequent variants with small effects in more than 40 additional genes that have been implicated. Having a genetic variant plus an aggravating factor will often exacerbate the metabolic defect and lead to chylomicronemia syndrome. There are many potential aggravating factors, but some of the more common ones include a diet high in refined sugars, heavy alcohol consumption, obesity with or without metabolic syndrome, medications, renal disease, HIV, and pregnancy. 2. What are the acute treatment strategies for hypertriglyceridemia-induced pancreatitis, and how are they similar and different to treating pancreatitis from other etiologies? * All patients should be assessed for hemodynamic compromise, the severity of illness with or without scoring systems, and end-organ damage to determine the need for intensive care resources. Initially, patients usually require aggressive fluid resuscitation and pain management, which are standard across all types of acute pancreatitis. Delayed fluid resuscitation has been associated with worse outcomes. Multiple trials have been performed evaluating the best amount of fluid. Although there is not an exact answer to this, as all patients are different, all patients should be resuscitated until euvolemic. The WATERFALL trial showed that administration of 10 mL/kg bolus followed by 1.5 mL/kg maintenance until the patient reaches euvolemia was a superior approach to more aggressive fluid resuscitation. A patient’s volume status should be reassessed every 6 hours for 24 – 48 hours, and fluids should be discontinued once euvolemia has been achieved. There is no guideline consensus on the preferred analgesic management, but it is generally recommended to administer medication to mitigate symptoms of pain and nausea for all patients. * For hypertriglyceridemia-induced pancreatitis, it is key to initiate fasting to decrease chylomicron production and further increasing triglyceride levels. Although historically, this was the same approach for other causes of pancreatitis, more recent data shows that early enteral feeding reduces the risk of complications such as pancreatic necrosis. However, these studies were not performed in patients with pancreatitis from hypertriglyceridemia and should not be extrapolated to this distinct population. Currently, it is recommended that patients be kept NPO until triglycerides are below 500 mg/dL, which is the point at which LPL activity becomes saturated. When feeding is initiated, it should be with a very low-fat diet with no refined carbohydrates. * Hypertriglyceridemia differs from other causes of pancreatitis as the management is centered around the rapid reduction of triglyceride content in the blood. Generally, these patients are admitted to the intensive care unit to undergo either insulin infusion +/- heparin drip or plasmapheresis. Although there has never been a clinical trial comparing these two approaches, a recent comprehensive meta-analysis showed no significant difference in mortality or clinical outcomes. Insulin infusion had a lower number of deaths, but a higher rate of acute renal failure, hypoglycemia, and hypotension, neither of which reached statistical significance. Insulin is more commonly used and generally preferred given that it is more cost-effective, less invasive, and can have utility in treating underlying diabetes exacerbation, which is common amongst these patients. Insulin infusion works by increasing the activity of lipoprotein lipase (LPL), resulting in increased clearance of chylomicron particles. Although in some countries, insulin is combined with heparin, given heparin’s ability to increase LPL release, this is rarely done as heparin can deplete endothelial LPL, increase bleeding events, and potentially cause heparin-induced thrombocytopenia. Plasmapheresis, on the other hand, works by removing the triglycerides directly from the bloodstream, which can rapidly reduce levels. It does require central venous access, which is more invasive. Plasmapheresis is preferred in pregnancy as data in case series supports it reduces the risk of a systemic inflammatory response. 3. What are the proposed mechanisms by which high triglycerides may contribute to atherosclerosis? * There are several proposed mechanisms for the association between elevated triglyceride levels and ASCVD. First, elevated triglyceride levels correspond with high circulating triglyceride-rich lipoprotein particles, also known as remnant cholesterol. This includes VLDL, IDL, and chylomicron remnants. These particles are thought to be at least as, if not more, atherogenic than LDL-C. Remnant particles readily penetrate the arterial wall, similar to LDL, but do not require oxidative modification for macrophage uptake and can be taken up unregulated, leading to foam cells and atherosclerosis. * Second, having elevated levels of triglyceride-rich lipoproteins is pro-inflammatory. When triglyceride-rich lipoproteins are hydrolyzed by lipoprotein and endothelial lipases, the release of oxidized free fatty acids along the endothelial wall leads to the activation of pro-inflammatory signaling pathways that can increase vascular permeability and promote the migration of leukocytes and atherogenic lipoprotein particles into the arterial wall. This is mediated by cytokines and chemoattractant proteins. 4. What long-term pharmacologic management strategies should be considered in patients with hypertriglyceridemia-induced pancreatitis? * Fibrates are the first line pharmacotherapy when the goal of treatment is to prevent acute pancreatitis, especially when triglyceride levels are >1000. The ability of lipoprotein lipase to clear triglyceride-rich lipoproteins becomes saturated at TG levels of approximately 500-700 mg/dL. When the ability to clear TRL is impaired, dietary fat intake can lead to large increases in blood TG levels. Those with TG >1000 are at particularly high risk of acute pancreatitis. Fibrates stimulate PPAR alpha and primarily decrease TGs via the upregulation of LPL. The reduction of TGs from fibrates ranges from 25-50%. Some data suggests fenofibrate may be more effective at lowering TG then gemfibrozil. Gemfibrozil is the only Fibrate therapy that has shown a reduction in cardiovascular events in the VA-HIT and HHS trials. However, it is worth noting these trials were not performed on background statin therapy, which is now contraindicated in patients taking Gemfibrozil due to the increased risk of rhabdomyolysis. * Prescription Omega-3 fatty acids lower TGs, possibly via decreased activity of SREBP1c. These are less potent reducers of triglycerides with reductions between 10-50%. While Icosapent Ethyl, a purified form of EPA, does have TG-lowering effects, it is primarily used for ASCVD risk reduction in individuals >age 50 with TG >150 and a history of ASCVD or those without ASCVD but with diabetes mellitus and multiple risk factors. This is based on the aforementioned REDUCE-IT trial. Briefly, REDUCE-IT randomized patients having moderate hypertriglyceridemia and a history of ASCVD or diabetes and other risk factors on background statin therapy to receive icosapent ethyl (pure EPA) or placebo. Patients in the icosapent ethyl group experienced an 18.3% reduction in triglyceride level compared to a 2.2% increase in the placebo group, as well as a 4.8% absolute risk reduction and 25% relative risk reduction in the primary endpoint, a composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina with an NNT of 21. The therapy was associated with a slight, although significant, increase in risk of atrial fibrillation, which occurred in 5.3% of patients receiving IPE compared to 3.9% in the placebo group. There was also an increased risk of bleeding, which approached statistical significance. The use of biologically active mineral oil as the placebo has led to some controversy regarding the validity of REDUCE-IT results. In this case, our patient does not exactly fit this study population investigated in that clinical trial. Other Omega-3 fatty acids include mixtures of EPA/DHA such as Omega-3-acid ethyl esters and Omega-3-carboxylic acids, which are often used to reduce the risk of pancreatitis in those with triglyceride levels >500 mg/dL. Combined EPA/DHA products have been investigated in several trials, including but not limited to STRENGTH, VITAL, ASCEND, and OMEMI. However, none of these trials have shown any significant reduction in cardiovascular endpoints. * Statins are primarily used for reducing ASCVD risk, although they do lower triglycerides primarily through increased clearance of VLDL via upregulation of the remnant receptor. The 2021 ACC Expert Consensus Decision Pathway for hypertriglyceridemia recommends initiating or intensifying statin therapy for patients aged 40-75 years, with triglycerides of 500-999 mg/dL and with either a 10-year ASCVD risk of ≥5% or diabetes mellitus. The 2018 ACC/AHA multisociety Guideline on the Management of Blood Cholesterol provides key groups that qualify for primary prevention of statin therapy, including those with ASCVD risk >7.5%, age between 40-75 with diabetes mellitus type 1 or 2, and low-density lipoprotein cholesterol (LDL-c) >190 mg/dL. These guidelines further elaborate that in adults 20 to 39 years of age with diabetes mellitus type 2, statin therapy can be considered if they have type 2 diabetes mellitus ≥10 years, albuminuria (≥30 mcg of albumin/mg creatinine), eGFR < 60 mL/min/1.73 m2, retinopathy, neuropathy, or ABI <0.9. 5. What dietary management approaches are effective in preventing recurrent episodes of hypertriglyceridemia-induced pancreatitis, and how do they impact triglyceride levels? * There are many ways to approach dietary interventions in the clinic. The National Lipid Association created a 2023 guideline called “Nutrition interventions for adults with dyslipidemia: A Clinical Perspective from the National Lipid Association,” which can be helpful in guiding clinical care. Always use a patient-centered approach and incorporate patients’ preferences, cultural backgrounds, financial resources, and food availability when applying the dietary guidelines. * Start by identifying the food sources in a patient’s diet that can dramatically raise triglycerides: foods rich in added sugars, refined starches, saturated fats, and alcohol. Identifying and minimizing or eliminating these foods upfront (depending on the severity of the hypertriglyceridemia) will lead to substantial improvements in a patient’s lipid profile. * The NLA guidelines created four categories based on the severity of hypertriglyceridemia and whether patients have FCS. These categories include patients with triglycerides >= 750 mg/dL with FCS, >= 750mg/dL with suspected MCS, >= 500 mg/dL and < 500 mg/dL. * All patients with elevated triglycerides should be advised to strive for an overall healthy dietary pattern such as a Mediterranean or DASH Diet, maximize plant sources of protein, limit or eliminate beverages and foods with added sugars, limit full-fat dairy products, maximize intake of fibrous vegetables, and are encouraged to perform at least 150 minutes/week of moderate-intensity exercise or 75 minutes/week of vigorous exercise but increasing the exercise past this threshold will continue to have added benefits as recommended by the American College of Sports Medicine. * The NLA recommends completely abstaining from alcohol for patients with triglycerides >500 mg/dL. For those below 500 mg/dL the recommendation is that men do not exceed two drinks/day and women do not exceed one drink/day. However, in general, it’s best to advise all patients to limit their alcohol as much as possible because it increases the secretion of VLDL, impairs lipolysis, and increases free fatty acid fluxes from adipose tissue to the liver. * Dietary saturated fats can also raise both triglycerides and LDL-C and should be replaced with unsaturated fatty acids. Foods rich in saturated fats include those such as butter, beef, and tropical oils such as coconut oil, palm, and palm kernel oil. A thorough review of how patients prepare their food should be performed because making simple changes, such as cooking with olive oil rather than butter or tropical oils, can improve triglycerides and LDL-C. * For those with TG levels > 750mg/dL: the goal should be initially to maintain a very low-fat diet with <5%, but after 4 weeks and improvement of triglyceride elevations, there can be liberalization of the patient’s diet. Depending on the patient’s risk profile, including whether they have FCS and current triglyceride levels, cautious relaxation of dietary restrictions can be allowed to improve quality of life and allow for more flexibility in food intake. Patients with FCS must maintain a very low-fat diet for life and should be referred to a registered dietitian specializing in lipid management.

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A Comprehensive Update on the Chylomicronemia Syndrome. Front Endocrinol (Lausanne). 2020;11:593931. doi:10.3389/fendo.2020.593931. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2020.593931/full 5. Kaur G, Gulati M. Considerations for treatment of lipid disorders during pregnancy and breastfeeding. Prog Cardiovasc Dis. 2022 Nov-Dec;75:33-39. doi:10.1016/j.pcad.2022.11.001. https://www.sciencedirect.com/science/article/abs/pii/S003306202200113X?via%3Dihub 6. Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK. American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc. 2009 Feb;41(2):459-471. doi:10.1249/MSS.0b013e3181949333. https://journals.lww.com/acsm-msse/fulltext/2001/12000/appropriate_intervention_strategies_for_weight.26.aspx 7. 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Updates in Drug Treatment of Severe Hypertriglyceridemia. Curr Atheroscler Rep. 2023 Oct;25(10):701-709. doi: 10.1007/s11883-023-01140-z. PMID: 37642858; PMCID: PMC10564803. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10564803/ 10. Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N, Pordy R, Weinreich DM, Yancopoulos GD, Zhang Y, Gaudet D; ELIPSE HoFH Investigators. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215. PMID: 32813947. https://www.nejm.org/doi/full/10.1056/NEJMoa2004215 11. Rosenson RS, Gaudet D, Ballantyne CM, Baum SJ, Bergeron J, Kershaw EE, Moriarty PM, Rubba P, Whitcomb DC, Banerjee P, Gewitz A, Gonzaga-Jauregui C, McGinniss J, Ponda MP, Pordy R, Zhao J, Rader DJ. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial. Nat Med. 2023 Mar;29(3):729-737. doi: 10.1038/s41591-023-02222-w. PMID: 36879129; PMCID: PMC10033404. https://www.nature.com/articles/s41591-023-02222-w 12. Witztum JL, Gaudet D, Arca M, Jones A, Soran H, Gouni-Berthold I, Stroes ESG, Alexander VJ, Jones R, Watts L, Xia S, Tsimikas S. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome: Long-term efficacy and safety data from patients in an open-label extension trial. J Clin Lipidol. 2023 May-Jun;17(3):342-355. doi: 10.1016/j.jacl.2023.03.007. PMID: 37100699. Erratum in: J Clin Lipidol. 2023 Oct 13;: PMID: 37100699. https://www.lipidjournal.com/article/S1933-2874(23)00065-X/fulltext 13. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, Yang Q, Hughes SG, Geary RS, Arca M, Stroes ESG, Bergeron J, Soran H, Civeira F, Hemphill L, Tsimikas S, Blom DJ, O’Dea L, Bruckert E. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 2019 Aug 8;381(6):531-542. doi: 10.1056/NEJMoa1715944. PMID: 31390500. https://www.nejm.org/doi/10.1056/NEJMoa1715944?url_ver=Z39.88-2003𝔯_id=ori:rid:crossref.org𝔯_dat=cr_pub%20%200pubmed 14. Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O’Dea LSL, Tsimikas S, Gaudet D. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820. PMID: 35025993; PMCID: PMC8986458. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986458/ 15. Kirkpatrick CF, Sikand G, Petersen KS, Anderson CAM, Aspry KE, Bolick JP, Kris-Etherton PM, Maki KC. Nutrition interventions for adults with dyslipidemia: A Clinical Perspective from the National Lipid Association. J Clin Lipidol. 2023 Jul-Aug;17(4):428-451. doi: 10.1016/j.jacl.2023.05.099. PMID: 37271600. https://www.lipidjournal.com/article/S1933-2874(23)00185-X/fulltext 16. Fialkow J. Omega-3 Fatty Acid Formulations in Cardiovascular Disease: Dietary Supplements are Not Substitutes for Prescription Products. Am J Cardiovasc Drugs. 2016 Aug;16(4):229-239. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947114/ 17. Skulas-Ray AC, Wilson PWF, Harris WS, Brinton EA, Kris-Etherton PM, Richter CK, Jacobson TA, Engler MB, Miller M, Robinson JG, Blum CB, Rodriguez-Leyva D, de Ferranti SD, Welty FK., American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019 Sep 17;140(12) https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000709?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003𝔯_id=ori%3Arid%3Acrossref.org 18. Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P T. 2015 Dec;40(12):826-857. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671468/ 19. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J. 2020 Jan 1;41(1):99-109c. doi: 10.1093/eurheartj/ehz785. PMID: 31764986; PMCID: PMC6938588. https://academic.oup.com/eurheartj/article/41/1/99/5640489 20. Virani SS, Morris PB, Agarwala A, Ballantyne CM, Birtcher KK, Kris-Etherton PM, Ladden-Stirling AB, Miller M, Orringer CE, Stone NJ. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021 Aug 31;78(9):960-993. doi: 10.1016/j.jacc.2021.06.011. PMID: 34332805. https://www.jacc.org/doi/10.1016/j.jacc.2021.06.011 21. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25). doi: 10.1161/CIR.0000000000000625. Epub 2018 Nov 10. Erratum in: Circulation. 2019 Jun 18;139(25). doi: 10.1161/CIR.0000000000000698. Erratum in: Circulation. 2023 Aug 15;148(7). doi: 10.1161/CIR.0000000000001172. PMID: 30586774; PMCID: PMC7403606.\ https://www.ahajournals.org/doi/10.1161/CIR.0000000000000625 22. Writing Committee; Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr, Waring AA, Wilkins JT. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022 Oct 4;80(14):1366-1418. doi: 10.1016/j.jacc.2022.07.006. Epub 2022 Aug 25. Erratum in: J Am Coll Cardiol. 2023 Jan 3;81(1):104. doi: 10.1016/j.jacc.2022.11.016. PMID: 36031461. https://www.jacc.org/doi/10.1016/j.jacc.2022.07.006

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CardioNerds (Dr. Rick Ferraro and Dr. Dan Ambinder) join Dr. Sri Mandava, Dr. David Meister, and Dr. Marissa Donatelle from the Columbia University Division of Cardiology at Mount Sinai Medical Center in Miami. Expert commentary is provided by Dr. Pranav Venkataraman. They discuss the following case involving a patient with cardiac sarcoidosis presenting as STEMI.

A 57-year-old man with a history of hyperlipidemia presented with sudden onset chest pain. On admission, he was vitally stable with a normal cardiorespiratory exam but appeared in acute distress and was diffusely diaphoretic. His ECG revealed sinus rhythm, a right bundle branch block (RBBB), and ST elevation in the inferior-posterior leads. He was promptly taken for emergent cardiac catheterization, which identified a complete thrombotic occlusion of the mid-left circumflex artery (LCX) and large obtuse marginal (OM) branch, with no underlying coronary atherosclerotic disease. Aspiration thrombectomy and percutaneous coronary intervention (PCI) were performed, with one drug-eluting stent placed. An echocardiogram showed a left ventricular ejection fraction (EF) of 31%, hypokinesis of the inferior, lateral, and apical regions, and an apical left ventricular thrombus. The patient was started on triple therapy. A hypercoagulable workup was negative. A cardiac MRI was obtained to further evaluate non-ischemic cardiomyopathy. In conjunction with a subsequent CT chest, the results raised suspicion for cardiac sarcoidosis with systemic involvement. In view of a reduced EF and significant late-gadolinium enhancement, electrophysiology was consulted to evaluate for ICD candidacy. A decision was made to delay ICD implantation until a definitive diagnosis of cardiac sarcoidosis could be established by tissue biopsy. The patient was started on HF-GDMT and discharged with a LifeVest. Close outpatient follow-up with cardiology and electrophysiology was arranged.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Pearls – Cardiac Sarcoidosis Presenting as STEMI1. Cardiac sarcoidosis can present with a variety of symptoms, including arrhythmias, heart block, heart failure, or sudden cardiac death. Symptoms can be subtle or mimic other cardiac conditions. 2. Conduction abnormalities, particularly AV block or ventricular arrhythmias, are common and may be the initial indication of cardiac involvement with sarcoidosis. 3. The additive value of Echocardiography, FDG-PET, and cardiac MR is indispensable in the diagnostic workup of suspected cardiac sarcoidosis. 4. Specific role of MRI/PET: Both cardiac MRI and FDG-PET provide a complementary role in the diagnosis of cardiac sarcoidosis. Cardiac MRI is an effective diagnostic screening tool with fairly high sensitivity but is limited by its inability to decipher inflammatory (“active” disease) versus fibrotic myocardium. FDG-PT helps to make this discrimination, refine the diagnosis, and guide clinical management. Ultimately, these studies are most useful when interpreted in the context of other clinical information. 5. Primary prevention of sudden cardiac death in cardiac sarcoidosis focuses on risk stratification, with ICD placement for high-risk patients. For patients awaiting definitive diagnosis, a LifeVest may be used as a temporary measure to protect from sudden arrhythmic events until an ICD is placed.

Notes – Cardiac Sarcoidosis Presenting as STEMI1. Is STEMI always a result of coronary artery disease?

By definition, a STEMI is an acute S-T segment elevation myocardial infarction. This occurs when there is occlusion of a major coronary artery, which results in transmural ischemia and damage, resulting in electrical changes seen on the ECG. The most common cause of coronary artery occlusion is coronary artery disease (CAD) from plaque rupture and thrombus formation; however, many other causes of coronary artery occlusion are not related to CAD. These include vasospasm (isolated and recurrent), in-situ thrombotic occlusion, spontaneous coronary artery dissection, and supply-demand mismatch, such as in the setting of severe anemia. DDx includes other causes of injury current, such as myocarditis. It is important to keep these other differentials in mind while preparing for coronary angiography, as it may help guide intra-catheterization and post-catheterization management.

2. What are the most common causes of LV thrombus?

When considering the causes of thrombus formation, think of Virchow’s triad. As with any other location, thrombus formation in the LV may be caused by injury/inflammation, systemic thrombophilia, and stasis.

1. Acute myocardial infarction (especially anterior MI) – damaged myocardium and impaired LV function lead to blood stasis and thrombus formation.
2. Heart failure with reduced ejection fraction (HFrEF) – severely impaired contractility increases the risk of thrombus development
3. Non-Ischemic cardiomyopathies – dilated or hypertrophic cardiomyopathies may cause abnormal blood flow, promoting thrombus formation.
4. Arrhythmias – although more associated with atrial thrombus, atrial fibrillation can also contribute to LVT in cases of significant LV dysfunction. Ventricular arrhythmias can also cause LV thrombus.
5. Hypercoagulable conditions – Conditions such as antiphospholipid antibody syndrome, inherited thrombophilias, malignancy-associated hypercoagulability, polycythemia vera, hyperhomocysteinemia, nephrotic syndrome or systemic lupus erythematous may predispose to LV thrombus formation
6. Inflammatory conditions – conditions like myocarditis or cardiac sarcoidosis can lead to inflammation along with focal stasis from aneurysmal changes, contributing to thrombus formation

3. What is the clinical presentation of cardiac sarcoidosis?

1. Chest pain: can arise from several mechanisms such as myocardial inflammation, pericarditis, coronary artery involvement, or arrhythmias.
2. Heart Failure: symptoms such as dyspnea, fatigue, and peripheral edema may result from left ventricular dysfunction or restrictive cardiomyopathy.
3. Arrhythmias: palpitations, dizziness or syncope may occur due to ventricular tachycardia or ventricular fibrillation.
4. Conduction abnormalities: Heart block, especially complete AV block, is a common early manifestation. Some studies have found that AV block is the presenting symptom in more than 40% of patients with cardiac sarcoidosis.
5. Sudden cardiac death (SCD): sudden death can occur due to ventricular arrhythmias or severe heart block.
6. Asymptomatic: in some cases, cardiac sarcoidosis is discovered incidentally during imaging or evaluation for systemic sarcoidosis.

4. What are the key imaging modalities used in the diagnosis of cardiac sarcoidosis?

Echocardiography, FDG-PET, and cardiac MRI are the key imaging modalities used to diagnose cardiac sarcoidosis. The echocardiogram is often normal in clinically silent disease, but several key features may be seen in clinically active disease. The most specific findings are basal interventricular thinning and LV aneurysm. Other less specific findings include increased LV wall thickness, LV/RV diastolic and/or systolic dysfunction, and wall motion abnormalities (non-coronary distribution). Strain imaging is promising for use in earlier stages of disease, but this is not well established yet. FDG-PET is crucial in the initial diagnosis of cardiac sarcoidosis, allowing active inflammatory disease to be detected. There is no pathognomonic PET finding; however, focal or focal-on-diffuse FDG uptake patterns are highly suggestive of active disease. It should be noted that FDG-PET is also useful in guiding treatment or response to immunosuppressive therapy, as it can track the degree of inflammation over time. The role of cardiac MRI is discussed below.

5. What is the specific role of cardiac MRI in the diagnosis of cardiac sarcoidosis?

This depends on the specific clinical setting. A patient with established extra-cardiac sarcoidosis but asymptomatic from a cardiac standpoint should be appropriately screened for cardiac involvement by clinical history, ECG, echocardiography, and cardiac monitoring (e.g. Holter monitor, etc). If any of the aforementioned “screening” tests are abnormal, a cardiac MRI is then indicated to assess for evidence of cardiac sarcoidosis. More specifically, cardiac MRI detects inflammation and edema at earlier stages of disease and scar tissue at later stages. The classical finding specific for cardiac sarcoidosis is patchy late gadolinium enhancement, with a predilection for the basal septum and basal inferolateral wall. The enhancement is either subepicardial or mid-wall and rarely transmural. It should be noted that once cardiac sarcoidosis is diagnosed, FDG-PET imaging should be utilized in conjunction with, or complementary to MRI, to assess for “active sarcoid” (i.e. myocardial inflammation).

On the other hand, a patient with no known extracardiac sarcoidosis but with suggestive cardiac findings should have a cardiac MRI to assess for typical features as mentioned above, in addition to assessment for non-cardiac involvement.

It should be noted that cardiac MRI can also provide significant prognostic information. The presence of LGE portends a worse prognosis due to increased CV death and ventricular arrhythmias. It should also be noted that LGE does not discriminate between active inflammation and fibrosis. Tissue characterization with T1 and T2 mapping techniques or PET imaging, as described above, can be more useful in this sense.

References1.) Cheng RK, Kittleson MM, Beavers CJ, et al. Diagnosis and management of cardiac sarcoidosis: a scientific statement from the American Heart Association. Circulation. 2024;149.

2.) Lehtonen J, Uusitalo V, Pöyhönen P, Mäyränpää MI, Kupari M. Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis. European Heart Journal. 2023;44:1495–1510.

3.) Kouranos V, Sharma R. Cardiac sarcoidosis: state-of-the-art review. Heart. 2021;107:1591–1599.

4.) Birnie DH, Nery PB, Ha AC, Beanlands RSB. Cardiac sarcoidosis. Journal of the American College of Cardiology. 2016;68:411–421.

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CardioNerds Cardiac Amyloidosis Series Chair Dr. Rick Ferraro and Episode Lead Dr. Anna Radakrishnan discuss the biology of transthyretin amyloid cardiomyopathy (ATTR-CM ) with Dr. Daniel Judge. Notes were drafted by Dr. Anna Radakrishnan. The audio was engineered by student Dr. Julia Marques.

This episode provides a comprehensive overview of transthyretin (ATTR) cardiac amyloidosis, a complex and rapidly evolving disease process. The discussion covers the key red flags for cardiac amyloidosis, the diagnostic pathway, and the implications of hereditary versus wild-type ATTR. Importantly, the episode delves into the current and emerging therapies for ATTR, including stabilizers, gene silencers, and promising treatments like CRISPR-Cas9 and antibody-based approaches. Dr. Judge shares his insights and excitement about the rapidly advancing field, highlighting the need for early diagnosis and the potential to improve long-term outcomes for patients with this condition.

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Pearls: – Biology of Transthyretin amyloid cardiomyopathy1. Maintain a high index of suspicion! Look for subtle (yet telling) signs like ventricular hypertrophy, discordant EKG findings, bilateral carpal tunnel syndrome, and spontaneous biceps tendon rupture. 2. Utilize the right diagnostic tests. Endomyocardial biopsy remains the gold standard, but non-invasive tools like PYP scan with SPECT imaging and genetic testing are essential for accurate diagnosis. 3. Differentiating hereditary from wild-type ATTR is critical, as genetic forms may have a more aggressive course and familial implications. 4. Early diagnosis and intervention significantly improve prognosis, making vigilance in screening and prompt treatment initiation essential. 5. The future is now! Cutting-edge therapies are transforming the treatment landscape, including TTR stabilizers, gene silencers, and emerging technologies like CRISPR-Cas9 and antibody-based treatments.

Notes – Biology of Transthyretin amyloid cardiomyopathy1. What is transthyretin amyloid (aTTR) and how is it derived? * Transthyretin (TTR) is a transport protein primarily synthesized by the liver, responsible for carrying thyroid hormones (thyroxine) and retinol (vitamin A) in the blood. It circulates as a tetramer, composed of four identical monomers, which is essential for its stability and function. * In transthyretin amyloid (ATTR) amyloidosis, the TTR protein becomes unstable, leading to its dissociation into monomers. These monomers misfold and aggregate into insoluble amyloid fibrils, which deposit extracellularly in tissues such as the heart, nerves, and gastrointestinal tract. This progressive amyloid deposition leads to organ dysfunction, including restrictive cardiomyopathy and neuropathy. * There are two main forms of ATTR amyloidosis: hereditary (variant) and wild-type (senile) ATTR. * Hereditary ATTR (ATTRv) is caused by mutations in the TTR gene. These mutations destabilize the TTR tetramer, making it more prone to dissociation. This increases misfolding and amyloid fibril formation, resulting in systemic amyloid deposition. * Wild-type ATTR (ATTRwt) occurs without genetic mutations and is primarily age-related. Over time, even normal TTR tetramers can become unstable, leading to gradual misfolding and amyloid deposition, particularly in the heart. ATTRwt is a common but often underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF) in elderly individuals. 2. How does aTTR lead to deleterious effects in the heart and other organ systems? * Transthyretin amyloidosisleads to organ dysfunction through the deposition of misfolded TTR protein as amyloid fibrils, which accumulate extracellularly and disrupt normal tissue architecture and function. These deposits cause progressive damage by increasing stiffness, inducing oxidative stress, and impairing normal cellular function. * Cardiac manifestations include amyloid deposition in the myocardial interstitium, leading to increased stiffness, diastolic dysfunction, and restrictive cardiomyopathy. As the disease progresses, systolic dysfunction may develop. Amyloid infiltration can also cause arrhythmia, conduction abnormalities such as atrioventricular block and atrial fibrillation, valvular thickening, coronary ischemia, and pericardial effusion. Disruption of transverse tubules in cardiomyocytes contributes to heart failure and arrhythmia. * Systemic involvement depends on the culprit amylodogenic protein. AL amyloidosis caused by deposition of immunoglobulin light chains may deposit in and disrupt the function of any tissue/organ except for the central nevous system. ATTR amyloidosis primarily affects the heart, peripheral nerves, and the musculoskeletal system. * Peripheral neuropathy can cause sensory loss, pain, and motor weakness, while autonomic dysfunction may lead to orthostatic hypotension, gastroparesis, and urinary retention. Carpal tunnel syndrome is a common early sign. Gastrointestinal amyloid deposits (specifically for AL but not ATTR) can cause gastroparesis, diarrhea, constipation, and malabsorption, leading to weight loss and malnutrition. Renal involvement (specifically for AL but not ATTR), though less common, can present as proteinuria and renal dysfunction. Amyloid deposition in soft tissues and the lungs may lead to hoarseness and musculoskeletal stiffness. * As the disease progresses, continued amyloid accumulation leads to worsening organ dysfunction and failure. Early diagnosis and intervention are essential to slowing disease progression and managing symptoms effectively. 3. When and why is aTTR cardiac amyloidosis hereditary versus obtained sporadically? * Hereditary aTTR is caused by genetic mutations in the TTR gene, which are often autosomal dominant. * Common mutations include V122I (more common in African Americans) and V30M (more common in certain regions like Portugal). * Hereditary aTTR typically presents at an earlier age and may have a more aggressive course, with a higher likelihood of neuropathic involvement. * Wild-type aTTR, or senile systemic amyloidosis, occurs sporadically and is more common in older individuals, typically without a family history. * The exact reasons for the development of wild-type aTTR are not fully understood, but factors like chronic inflammation and exercise may play a role in the misfolding and aggregation of the normal TTR protein.

References: Biology of Transthyretin amyloid cardiomyopathy1. Ruberg FL, Maurer MS. Cardiac Amyloidosis Due to Transthyretin Protein. JAMA. 2024;331(9):778-778. https://doi.org/10.1001/jama.2024.0442 2. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy. Journal of the American College of Cardiology. 2019;73(22):2872-2891. https://doi.org/10.1016/j.jacc.2019.04.003 3. ‌Maurer MS, Bokhari S, Damy T, et al. Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis. Circulation: Heart Failure. 2019;12(9). https://doi.org/10.1161/circheartfailure.119.006075 4. ‌Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, Grogan M, Cheng RK. ATTR Amyloidosis: Current and Emerging Management Strategies. JACC: CardioOncology. 2021;3(4):488-505. https://doi.org/10.1016/j.jaccao.2021.06.006

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Join CardioNerds EP Council Chair Dr. Naima Maqsood and Episode Lead Dr. Jeanne De Lavallaz as they discuss the results of the VANISH2 Trial with expert faculty Dr. Jeff Healey and Dr. Roderick Tung. Audio editing by CardioNerds academy intern, Grace Qiu.

The VANISH2 trial enrolled 416 patients with ischemic cardiomyopathy, an ICD in place, and recurrent episodes of sustained monomorphic ventricular tachycardia (VT) to receive either first-line VT catheter ablation or antiarrhythmic drug therapy with the primary composite outcome of death from any cause, appropriate ICD shock, ventricular tachycardia storm (meaning at least 3 ventricular tachycardia events within 24hrs) or treated ventricular tachycardia below the detection limit of the ICD. The study population had a mean age of 68 years, with 94% being men and predominantly of white ethnicity. On average, 14 years had elapsed since their last myocardial infarction, with approximately 60% having undergone percutaneous coronary intervention at the time. The mean ejection fraction was 34%.

This episode was planned in collaboration with Heart Rhythm TV with mentorship from Dr. Daniel Alyesh and Dr. Mehak Dhande.

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References – VANISH2 TrialSapp, J. L., Tang, A. S. L., Parkash, R., Stevenson, W. G., Healey, J. S., Gula, L. J., Nair, G. M., & the VANISH2 Study Team. (2025). Catheter ablation or antiarrhythmic drugs for ventricular tachycardia. The New England Journal of Medicine, 392, 737–747.

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CardioNerds (Dr. Colin Blumenthal and Dr. Saahil Jumkhawala) join Dr. Rohan Ganti, Dr. Nikita Mishra, and Dr. Jorge Naranjo from the Rutgers – Robert Wood Johnson program for a college basketball game, as the buzz around campus is high. They discuss the following case involving a patient with ventricular tachycardia:

The case involves a 61-year-old man with a medical history of hypothyroidism, hypertension, hyperlipidemia, seizure disorder on anti-epileptic medications, and major depressive disorder, who presented to the ER following an out-of-hospital cardiac arrest. During hospitalization, he experienced refractory polymorphic ventricular tachycardia (VT), requiring 18 defibrillation shocks. Further evaluation revealed non-obstructive hypertrophic cardiomyopathy (HCM). We review the initial management of electrical storm, special ECG considerations, diagnostic approaches once ischemia has been excluded, medications implicated in polymorphic VT, the role of multi-modality imaging in diagnosing hypertrophic cardiomyopathy, and risk stratification for implantable cardioverter-defibrillator (ICD) placement in patients with HCM.

Expert commentary is provided by Dr. Sabahat Bokhari. Episode audio was edited by CardioNerds Intern and student Dr. Pacey Wetstein.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls – A Curious Case of Refractory Ventricular Tachycardia – Rutgers-Robert Wood Johnson1. Diagnostic Uncertainty in VT Storm: In VT storm, ischemia is a primary consideration; when coronary angiography excludes significant epicardial disease, alternative causes such as cardiomyopathies, channelopathies, myocarditis, electrolyte disturbances, or drug-induced arrhythmias must be explored. 2. ST elevations in ECG lead aVR: ST elevations in lead aVR and diffuse ST depressions can sometimes represent post-arrest oxygen demand and myocardial mismatch rather than an acute coronary syndrome. This pattern may occur in the context of polymorphic VT (PMVT), where myocardial oxygen demands outstrip supply, especially after an arrest. While these ECG changes could suggest myocardial ischemia, caution is needed, as they might not always indicate coronary pathology. However, PMVT generally should raise suspicion for underlying coronary disease and may warrant a coronary angiogram for further evaluation. 3. Medication Implications in PMVT and HCM: Certain medications, including psychotropic drugs (e.g., antidepressants, antipsychotics) and anti-epileptic drugs, can prolong the QT interval or interact with other drugs, thereby increasing the risk of polymorphic VT in patients with underlying conditions like HCM. Careful management of these medications is critical to avoid arrhythmic events in predisposed individuals. 4. Multi-Modality Imaging in HCM: Cardiac MRI with late gadolinium enhancement (LGE) is invaluable in assessing myocardial fibrosis, a key predictor of arrhythmic risk, and can guide decisions regarding ICD implantation. Echocardiography and contrast-enhanced CT can provide additional insights into structural abnormalities and risk assessment. 5. Polymorphic VT in Nonobstructive HCM: Polymorphic ventricular tachycardia (PMVT) can occur in nonobstructive hypertrophic cardiomyopathy due to myocardial fibrosis and disarray, even in the absence of significant late gadolinium enhancement and left ventricular outflow tract obstruction. 6. ICD Risk Stratification in HCM: Risk stratification for ICD placement in HCM includes assessment of clinical features such as family history of sudden cardiac death, history of unexplained syncope, presence of nonsustained VT on ambulatory monitoring, massive left ventricular hypertrophy (wall thickness ≥30 mm), and evidence of extensive myocardial fibrosis on cardiac MRI.

Notes – A Curious Case of Refractory Ventricular Tachycardia – Rutgers-Robert Wood Johnson1. Is there a benefit of starting antiarrhythmic medications for patients presenting with an out-of-hospital cardiac arrest with shock-refractory VT or VF? * There is likely no benefit. An RCT published by Kudenchuk et al in 2016 in which patients who had a non-traumatic out-of-hospital cardiac arrest with shock-refractory VF or pulseless VT were randomly assigned to receive lidocaine, amiodarone, or saline placebo, in addition to standard care, showed that neither antiarrhythmic drug had a significantly higher rate of survival or favorable neurologic outcome compared to placebo6. 2. What is the differential diagnosis and empiric management for a patient with polymorphic ventricular tachycardia? * The differential diagnosis for ventricular tachycardia includes myocardial ischemia, electrolyte derangements, medications that may cause QT prolongation, congenital long QT syndrome, Brugada syndrome, myocarditis, dilated cardiomyopathy, arrhythmic cardiomyopathies, and infiltrative or structural heart disease. * Standard BLS and ACLS measures are first-line treatment for pulseless VT. * For stable patients, the 2017 AHA/ACC/HRS0 guidelines list beta-blockers as first-line antiarrhythmic therapy because they have been shown to reduce mortality and suppress ventricular arrhythmias in structurally normal hearts3. Amiodarone is also listed, though its long-term effect on survival is unclear, with most studies showing no clear benefit over placebo 3. Lidocaine and mexiletine are also commonly used, but because they are less efficacious compared to amiodarone, they are usually used as combination therapy for refractory patients4. Multiple trials have demonstrated the efficacy of procainamide as an adjunct medication in patients with ongoing ventricular arrhythmias, despite amiodarone and lidocaine4. Quinidine has also been used for patients as a salvage therapy for patients with structural heart disease for recurrent ventricular arrhythmias despite antiarrhythmic drug treatment 4. 3. What medications can be associated with polymorphic VT? * Medications that are commonly associated with QT prolongation, therefore making patients more susceptible to developing VT, include Class I and Class III antiarrhythmics; fluoroquinolone and macrolide antibiotics, as well as antifungals; tricyclic antidepressants as well as certain SSRI’s and SNRI’s; and antipsychotics, among others5. * In this video, Dr. Nino Isakadze explains the proper way to measure the QT interval. 4. How can multimodal imaging help reach a diagnosis in patients with PMVT with a relatively normal echocardiogram and no coronary artery disease? * Multimodal imaging, specifically cardiac MRI, is useful for reaching a diagnosis in patients with PMVT due to improved myocardial tissue characterization. * Improved definition of the myocardium allows for the detection of structural abnormalities that may not be as easily visualized on TTE, such as LV non-compaction, now called excessive trabeculation of the left ventricle, and to more accurately measure left ventricular wall thickness, which is useful for diagnosing and risk stratifying patients with hypertrophic cardiomyopathy. * Improved tissue characterization by measuring T1 relaxation time, T2 relaxation time, extracellular volume, and late gadolinium enhancement (LGE) pattern is also useful for diagnosing infiltrative disease. Certain LGE patterns are associated with different cardiac conditions and play a role in determining prognosis. For example, the detection of mid-wall LGE in patients with dilated cardiomyopathy portends an increased risk of adverse events. 5. What are the risk factors for sudden cardiac death in patients with HCM? * The updated 2024 HCM guidelines have outlined several risk factors for sudden cardiac death 1 1. Family history of sudden cardiac death 2. Unexplained syncope 3. NSVT episodes on ambulatory monitoring when runs are frequent (≥ 3), longer (≥ 10 beats), and faster (≥ 200 bpm) 4. Increased LV wall thickness, with elevated risk greater than 30 mm * Other risk stratification markers include extensive LGE seen on cardiac MRI, apical aneurysm, and EF < 50% in patients without high-risk features 1 * The AHA HCM SCD Calculator can be used to risk stratify patients to assist with decision-making in ICD implantation in these patients2

References 1. Ommen SR, Ho CY, Asif IM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2024 Aug 20;150(8):e198. doi: 10.1161/CIR.0000000000001277]. Circulation. 2024;149(23):e1239-e1311. doi:10.1161/CIR.0000000000001250 2. AHA HCM SCD Calculator 3. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society [published correction appears in Circulation. 2018 Sep 25;138(13):e419-e420. doi: 10.1161/CIR.0000000000000614]. Circulation. 2018;138(13):e272-e391. doi:10.1161/CIR.0000000000000549 4. Larson J, Rich L, Deshmukh A, Judge EC, Liang JJ. Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs. J Clin Med. 2022;11(11):3233. Published 2022 Jun 6. doi:10.3390/jcm11113233 5. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3(5):241-253. doi:10.1177/2042098612454283 6. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016;374(18):1711-1722. doi:10.1056/NEJMoa1514204

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Join CardioNerds EP Council Chair Dr. Naima Maqsood and Episode Lead Dr. Jeanne De Lavallaz as they discuss the results of the ARREST-AF Trial with expert faculty Dr. Prashanthan Sanders and Dr. Mehak Dhande. Audio editing by CardioNerds intern Bhavya Shah.

The ARREST-AF trial enrolled 122 patients with a BMI of 27 kg/m2 or greater and at least one cardiovascular risk factor with either paroxysmal or persistent AF and were scheduled to undergo de novo AF ablation. They were randomized to an intensive risk factor management (RFM) program versus usual care. The RFM program addressed obesity, sleep apnea, HTN, HLD, tobacco, and alcohol abuse, whereas the usual care arm had a discussion of risk factors but without an extensive risk factor modification or follow-up program. The study population had a mean age of 60 years, a mean BMI of 33 kg/m2, and 56-60% of patients with persistent AF. A third of the study population was female. The trial showed a significant improvement in the primary endpoint of the percentage of patients free from atrial fibrillation after ablation in those receiving the intensive lifestyle RFM program. At the end of the 12.3-month follow-up period, 66% percent of patients in the RFM group were free from AF compared to 42% in the usual care group (HR 0.53, p = 0.03). The RFM group also showed significant improvement in AF symptom severity, decline in body weight, systolic blood pressure, glycemic control, and exercise capacity. On average, patients in the RFM arm lost 9 kg of weight compared to 1 kg in the control group. Similarly, systolic blood pressure decreased by 13.1 mmHg in the RFM group but increased by four mmHg in the control group.

This episode was planned in collaboration with Heart Rhythm TV with mentorship from Dr. Daniel Alyesh and Dr. Mehak Dhande.

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References – The SUMMIT TrialPathak, Rajeev K., et al. “Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation: The ARREST-AF Cohort Study.” Journal of the American College of Cardiology, vol. 64, no. 21, 2014, pp. 2222–2231.

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Join CardioNerds Heart Failure Section Chair Dr. Jenna Skowronski, episode lead Dr. Merna Hussein, and expert faculty Dr. Milton Packer as they discuss the SUMMIT trial.

The SUMMIT trial randomized 731 patients with HFpEF with LVEF ≥ 50% and obesity with BMI ≥ 30 kg/m2 to receive tirzepatide or placebo for at least 52 weeks. The two co-primary endpoints were a composite of time to cardiovascular death or a worsening heart failure event and quality of life measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS). Treatment with tirzepatide led to a lower risk of the composite of cardiovascular death or worsening heart failure as well as improved quality of life.

This episode was planned in collaboration with the American College of Cardiology Section of the Prevention of Cardiovascular Disease with mentorship from Section Chair Dr. Eugenia Gianos.

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References – The SUMMIT TrialPacker, M., Zile, M. R., Kramer, C. M., Baum, S. J., Litwin, S. E., Menon, V., Ge, J., Weerakkody, G. J., Ou, Y., Bunck, M. C., Hurt, K. C., Murakami, M., Borlaug, B. A., & SUMMIT Trial Study Group. (2024). Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2410027

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Join CardioNerds Heart Failure Section Chair Dr. Jenna Skowronski, episode lead Dr. Apoorva Gangavelli, and expert faculty Dr. Ronald Witteles as they discuss the Nex-Z trial.

This was a phase 1, open-label trial investigating nex-z, a CRISPR-Cas9-based treatment, in 36 patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The primary objectives were aimed at studying the safety and pharmacodynamics of this novel gene-based treatment modality. This episode dives into the nuances of the data, future directions for investigation, and future clinical implications.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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References – The Nex-Z Trial Fontana, M., Solomon, S. D., Kachadourian, J., Walsh, L., Rocha, R., Lebwohl, D., Smith, D., Täubel, J., Gane, E. J., Pilebro, B., Adams, D., Razvi, Y., Olbertz, J., Haagensen, A., Zhu, P., Xu, Y., Leung, A., Sonderfan, A., Gutstein, D. E., & Gillmore, J. D. (2024). CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2412309

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Join CardioNerds co-founder Dr. Daniel Ambinder, episode lead Dr. Nidhi Patel, and expert faculty Dr. Keith Ferdinand as they discuss the BP ROAD trial.

The BP ROAD trial randomized 12,821 patients 50 years of age or older with type 2 diabetes, elevated systolic blood pressure, and an increased risk of cardiovascular disease to receive intensive treatment that targeted a systolic blood pressure of less than 120 mm Hg or standard treatment that targeted a systolic blood pressure of less than 140 mm Hg for up to 5 years. Investigators found a significant reduction of major cardiovascular events with intensive blood pressure lowering. This episode dives into the nuances of the data and clinical implications.

This episode was planned in collaboration with the American College of Cardiology Section of the Prevention of Cardiovascular Disease with mentorship from Section Chair Dr. Eugenia Gianos.

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US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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References – BPROAD TrialBi, Y., Li, M., Liu, Y., Li, T., Lu, J., Duan, P., Xu, F., Dong, Q., Wang, A., Wang, T., Zheng, R., Chen, Y., Xu, M., Wang, X., Zhang, X., Niu, Y., Kang, Z., Lu, C., Wang, J., … Wang, W. (2024). Intensive Blood-Pressure Control in Patients with Type 2 Diabetes. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2412006

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CardioNerds (Dr. Dan Ambinder and guest host, Dr. Pooja Prasad) join Dr. Donny Mattia from Phoenix Children’s pediatric cardiology fellowship, Dr. Sri Nayak from the Mayo Clinic – Arizona adult cardiology fellowship, and Dr. Harrison VanDolah from the University of Arizona College of Medicine – Phoenix Med/Peds program for a sunrise hike of Piestewa Peak, followed by some coffee at Berdena’s in Old Town Scottsdale (before the bachelorette parties arrive), then finally a stroll through the Phoenix Desert Botanical Gardens to discuss a thought-provoking case series full of clinical cardiology pearls. Expert commentary is provided by Dr. Tabitha Moe. Episode audio was edited by Dan Ambinder.

They discuss the following case: Cardiology is consulted by the OB team for a 27-year-old female G1, now P1, who has just delivered a healthy baby boy at 34 weeks gestation after going into premature labor. She is experiencing shortness of breath and is found to have a significant past cardiac history, including atrial fibrillation and preexcitation, now with a pacemaker and intracardiac defibrillator. We review the differential diagnosis for peripartum cardiomyopathy (PPCM) and then combine findings from her infant son, who is seen by our pediatric cardiology colleagues and is found to have severe hypertrophic cardiomyopathy (HCM). Genetic testing for both ultimately reveals a LAMP2 mutation consistent with Danon Disease. The case discussion focuses on the differential diagnosis for PPCM, HCM, pearls on Danon Disease and other HCM “phenocopies,” and the importance of good history.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Case MediaPearls1. Peripartum cardiomyopathy is a diagnosis of exclusion – we must exclude other possible etiologies of heart failure! 2. Be on the lookout for features of non-sarcomeric HCM – as Dr. Michelle Kittleson said in Episode 166, “LVH plus” states. HCM with preexcitation, heart block, strong family history, or extracardiac symptoms such as peripheral neuropathy, myopathy, or cognitive impairment should be evaluated for infiltrative/inherited cardiomyopathies! 3. As an X-linked dominant disorder, Danon disease will present differently in males vs females, with males having much more severe and earlier onset disease with extracardiac features. 4. Making the diagnosis for genetic disorders such as Danon disease is important for getting the rest of family members tested as well as the opportunity for specialized treatments such as gene therapy 5. Up to 5% of Danon disease cases may be due to copy number variants, which may be missed in genetic testing that does not do targeted deletion/duplication analysis!).

NotesWhat is the differential diagnosis for peripartum cardiomyopathy? Peripartum cardiomyopathy is a diagnosis of exclusion* – we must exclude other possible etiologies of heart failure! * First, ensure that you are not missing an acute life-threatening etiology of acute decompensated heart failure – pulmonary embolism, amniotic fluid embolism, ACS, and SCAD should all be ruled out. * Second, a careful history can identify underlying heart disease or risk factors for the development of heart failure, such as substance use, high-risk behaviors that put one at risk for HIV infection, and family history that suggests an inheritable cardiomyopathy. * Lastly, a careful review of echocardiographic imaging may also identify underlying etiologies that warrant a change in management. * Diagnosis of peripartum cardiomyopathy is important to consider as within 7 days of onset, patients may be eligible for treatment with bromocriptine – consider referring the patient for enrollment in the ongoing RCT ReBIRTH. * Check out Cardionerds Episode 113 and the great article linked below for more details on heart failure in pregnancy and postpartum!

What is the differential diagnosis for hypertrophic cardiomyopathy? Though by far the most common differential diagnosis for HCM is simple LVH or athlete’s heart, as Dr. Michelle Kittleson taught us in CardioNerds Episode 166, we should “remain alert for “LVH+” states.” * It is helpful to think of them in two buckets – sarcomeric mutations (classic HCM) or non-sarcomeric causes (“phenocopies”). * If you see systemic signs like peripheral neuropathy, renal dysfunction, or skin changes – clues towards a systemic pathology (for adult colleagues, first think amyloidosis; for peds, colleagues, think genetic syndromes such as RASopathies like Noonan syndrome, glycogen, and lysosomal storage diseases like Fabry). * Additionally, certain additional cardiac findings can point towards a non-sarcomeric HCM – recall way back in CardioNerds Episode 68 when our friends at VCU presented a man in his 60s with a history of WPW/preexcitation and HCM and was found to have a PRKAG2* mutation, which is a similar lysosomal vacuolopathy to Danon disease. Another example was seen in Episode 349 when we saw a patient with HCM and heart block who was found to have Fabry disease.

What is Danon disease, and how does it present? Danon disease is a rare X-linked dominant genetic disorder due to deficiency in LAMP2, a glycoprotein involved in protecting the lysosome from its roles in endocytosis and autophagy * When deficiency of LAMP2 occurs, products build up into vacuoles and lead to cardiomyocyte dysfunction and death. * Interestingly, autophagy disruption is the suspected mechanism of cardiomyopathies from anthracyclines and hydroxychloroquine – Danon disease severity underscores the importance of this process! * Estimated prevalence of Danon disease in adult patients with HCM is 1-4%, however when both HCM and pre-excitation are present, this rises to 17%. * It is highly penetrant, meaning most patients with the mutation will show symptoms. * There are several extracardiac features such as skeletal myopathy, retinopathy, and cognitive impairment – these correlated with areas in the body where LAMP2 is expressed more! * Classic presentations – remember that X-linked inheritance results in differential expression between males and females! + Males: young onset with severe LVH/HCM and extracardiac phenotype + Females: isolated cardiomyopathy (can be either dilated or hypertrophic) with preexcitation arrhythmias with a family history suggesting X-linked dominant transmission (i.e., males more severely affected than females). * When taking a family history, note that male-to-male transmission (can’t happen since males don’t pass on an X chromosome to their male children) or female-to-offspring transmission (suggests mitochondrial disease) should prompt alternate diagnosis. However, an estimated 1/3 of Danon disease cases are de novo mutations!* * See Episode 300 for a great in-depth overview of the pathophysiology of Danon disease

How is Danon disease diagnosed? Though there are some proposed characteristic cardiac MRI findings (diffuse LGE sparing the interventricular septum), diagnosis is genetic with a loss-of-function mutation in LAMP2 paired with characteristic cardiac or extracardiac features (see below diagnostic algorithm from Hong et al. JACC 2023) * LAMP2 is now included in most hypertrophic and dilated CM panels – if found, it is crucial to ensure the patient’s family members also undergo testing and potentially cardiac evaluation! (Note: up to 5% of Danon disease cases may be due to copy number variants, which may be missed in genetic testing that does not do targeted deletion/duplication analysis!) * Differential Diagnosis + Sarcomeric HCM – the “classic” HCM, which has numerous genetic causes, all of which affect the sarcomere with age-related penetrance leading to three peaks in age at onset (infancy <1yr, teenage/early adulthood, and mid-adulthood). Progression towards massive LVH and systolic dysfunction is uncommon (<10%) and should raise suspicion of a rare genocopy such as Danon. EKG is usually mostly normal in these patients, unlike in Danon disease, which often has striking abnormalities. + Pompe disease – lysosome storage disease from mutations in acid alpha-glucosidase leading to lysosomal glycogen accumulation. Autosomal recessive. It can be an infantile form with severe LVH/HCM, and the later forms can have classic skeletal myopathy as well, but usually, these patients have less severe cardiac features. + RAS-opathies – genetic diseases due to mutations in the RAS/MAPkinase pathway. Classic examples are Noonan syndrome, LEOPARD syndrome, and Costello syndrome. All have classic extracardiac manifestations as well as oftentimes HCM, as well as congenital heart disease such as pulmonary valve stenosis. + Fabry disease – also an X-linked recessive lysosomal disorder due to alpha-galactosidase A enzyme deficiency; however, it is rarely prominent in childhood and is usually more characterized by extracardiac manifestations. HCM is a cardiac manifestation presenting in the 30s-40s. + Friedrich ataxia – autosomal recessive multisystem disease due to GAA sequence expansion in the FXN gene that encodes frataxin, a mitochondrial protein, which impairs mitochondrial oxidative phosphorylation. “HCM” is a common disease manifestation in addition to the classic severe neurologic presentation. + Mitochondrial diseases – heterogenous conditions affecting mitochondrial DNA, transmitted in matrilinear pattern, with cardiac hypertrophy being a classic disease manifestation in addition to preexcitation. These may present with severe cognitive impairment than Danon disease. + PRKAG2 mutations – cause dysregulation of adenosine monophosphate kinase, culminating in accumulation of vacuoles within glycogen stores. Early-onset cardiac hypertrophy with preexcitation can be similar to Danon disease. There are no extracardiac features and the inheritance pattern is autosomal dominant. + For a great summary, see Table 2 in Hong K et al. International Consensus on Differential Diagnosis and Management of Patients with Danon disease: JACC state-of-the-art Review. JACC 2023 Oct, 82 (16) 1628-1647. * For patients who undergo heart transplantation for a genetic/inherited cause, it is crucial to recall their index diagnosis after transplant – they may have extracardiac disease manifestations!*

References * Davis M et al. Peripartum cardiomyopathy: JACC state-of-the-art review. JACC 2020 Jan, 75 (2) 207-221. https://www.jacc.org/doi/10.1016/j.jacc.2019.11.014 * DeFilippis EM et al. Cardio-obstetrics and heart failure: JACC: Heart Failure state-of-the-art review. JACC: HF 2023 Sep, 11(9) 1165-1180. https://www.jacc.org/doi/10.1016/j.jchf.2023.07.009_ga=2.84541658.274573079.1723517623-224546423.1716483762 * Hong K et al. International consensus on differential diagnosis and management of patients with Danon disease: JACC state-of-the-art review. JACC 2023 Oct, 82 (16) 1628- 1647. https://www.jacc.org/doi/abs/10.1016/j.jacc.2023.08.014 * Miliou A et al. Danon cardiomyopathy: specific imaging signs. JACC: Case Rep 2022 Nov 6;4(22):1496-1500. https://www.sciencedirect.com/science/article/pii/S2666084922006015 * Padkins MR, Bell MR. 33-year-old woman with postpartum acute shortness of breath. Mayo Clinic Proceedings 2020;95(9):2000-2004 https://www.mayoclinicproceedings.org/article/S0025-6196(20)30713-8/fulltext * Rigolli M et al. Cardiac magnetic resonance imaging in Danon disease cardiomyopathy. JACC: Imaging 2021 Feb, 14 (2) 514-516. https://www.jacc.org/doi/10.1016/j.jcmg.2020.08.011

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CardioNerds (Dr. Dan Ambinder and Dr. Yoav Karpenshif – Chair of the CardioNerds Critical Care Cardiology Council) join Dr. Munim Khan, Dr. Shravani Gangidi, and Dr. Rachel Goodman from Tufts Medical Center’s general cardiology fellowship program for hot pot in China Town in Boston. They discuss a case involving a patient who presented with stress cardiomyopathy leading to cardiogenic shock. Expert commentary is provided by Dr. Michael Faulx from the Cleveland Clinic. Notes were drafted by Dr. Rachel Goodman. Audio editing by Dr. Diane Masket.

A young woman presents with de novo heart-failure cardiogenic shock requiring temporary mechanical circulatory support who is found to have basal variant takotsubo cardiomyopathy. We review the definition and natural history of takotsubo cardiomyopathy, discuss initial evaluation and echocardiographic findings, and review theories regarding pathophysiology of the clinical syndrome. We also highlight complications of takotsubo cardiomyopathy, with a focus on left ventricular outflow obstruction, cardiogenic shock, and arrythmias.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Pearls1. Takotsubo cardiomyopathy is defined as a reversible systolic dysfunction with wall motion abnormalities that do not follow a coronary vascular distribution. 2. Takotsubo cardiomyopathy is a diagnosis of exclusion; patients often undergo coronary angiography to rule out epicardial coronary artery disease given an overlap in presentation and symptoms with acute myocardial infarction. 3. There are multiple echocardiographic variants of takotsubo. Apical ballooning is the classic finding, but mid-ventricular, basal, and biventricular variants exist as well. 4. Patients with takotsubo cardiomyopathy generally recover, but there are important complications to be aware of. These include arrhythmia, left ventricular outflow tract (LVOT) obstruction related to a hyperdynamic base in the context of apical ballooning, and cardiogenic shock. 5. Patients with Impella devices are at risk of clot formation and stroke. Assessing the motor current can be a clue to what is happening at the level of the motor or screw.

NotesWhat is Takotsubo Syndrome (TTS)?

• TTS is a syndrome characterized by acute heart failure without epicardial CAD with regional wall motion abnormalities seen on echocardiography that do not correspond to a coronary artery territory (see below).1
• TTS classically develops following an acute stressor—this can be an emotional or physical stressor.1
• An important feature of TTS is that the systolic dysfunction is reversible. The time frame of reversibility is variable, though generally hours to weeks.2
• Epidemiologically, TTS has a predilection for post-menopausal women, however anyone can develop this syndrome.1
• TTS is a diagnosis of exclusion. Coronary artery disease (acute coronary syndrome, spontaneous coronary artery dissection, coronary embolus, etc) should be excluded when considering TTS. Myocarditis is on the differential diagnosis.

What are the echocardiographic findings of takotsubo cardiomyopathy?

• The classic echocardiographic findings of TTS is “apical ballooning,” which is a way of descripting basal hyperkinesis with mid- and apical hypokinesis, akinesis, or dyskinesis.3
• There are multiple variants of TTS. The four most common are listed below:3
  • (1) Apical ballooning (classic TTS)
  • (2) Mid-ventricular variant
  • (3) Basal variant
  • (4) Focal variant
• Less common variants include the biventricular variant and the isolated right ventricular variant.3

Do patients with TTS generally have EKG changes or biomarker elevation?

• Patients often have elevated troponin, though the severity wall motion abnormalities seen on TTE is generally out of proportion to the degree of troponin elevation.4
• BNP/NTproBNP are typically elevated, especially early in the course.4
• During the acute phase (defined as within the first 12 hours), patients may have ST elevation or depression, T wave inversions, new LBBB, or QT prolongation.4

What are complications of takotsubo cardiomyopathy?

• Heart failure2
• LV outflow tract obstruction—if there is an LVOT obstruction, it is important to avoid diuretics, vasodilators such as nitroglycerin, and inotropic agents.2
• Cardiogenic shock.2
• Atrial and ventricular arrhythmias.2
• LV thrombus—this is of particular risk in patients with the classic “apical ballooning” variant of takotsubo due to apical akinesis and therefore stagnant flow.2

References 1. Lyon AR, Citro R, Schneider B, et al. Pathophysiology of Takotsubo Syndrome. J Am Coll Cardiol. 2021;77(7):902-921. doi:10. 1016/j.jacc.2020.10.060 2. Singh T, Khan H, Gamble DT, Scally C, Newby DE, Dawson D. Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications. Circulation. 2022;145(13):1002-1019. doi:10.1161/CIRCULATIONAHA.121.055854 3. Ghadri JR, Wittstein IS, Prasad A, et al. International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology. Eur Heart J. 2018;39(22):2032-2046. doi:10.1093/eurheartj/ehy076 4. Current state of knowledge on Takotsubo syndrome: a Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology – Lyon – 2016 – European Journal of Heart Failure – Wiley Online Library

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In this episode, CardioNerds Dr. Gurleen Kaur and Dr. Akiva Rosenzveig are joined by Cardio-Rheumatology experts, Dr. Brittany Weber and Dr. Michael Garshick to discuss treating inflammation, delving into the pathophysiology behind the inflammatory hypothesis of atherosclerotic cardiovascular disease and the evolving data on anti-inflammatory therapies for reducing ASCVD risk, with insights on real-world implementation.

Show notes were drafted by. Dr. Akiva Rosenzveig.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

American Heart Association’s Scientific Sessions 2024 As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS* and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls – Treating Inflammation1. Our understanding of the pathophysiology of atherosclerosis has undergone a few iterations from the incrustation hypothesis to the lipid hypothesis to the response-to-injury hypothesis and culminating with our current understanding of the inflammation hypothesis. 2. Both the adaptive and innate immune systems play instrumental roles in the pathogenesis of atherosclerosis. 3. After adequately controlling classic modifiable risk factors such as blood pressure, dyslipidemia, glucose intolerance, and obesity, systemic inflammation as assessed by CRP can be ascertained as CRP is associated with ~1.8-fold increased risk of cardiovascular events 4. Although the most common side effect of colchicine is gastrointestinal intolerance, colchicine can induce lactose intolerance, so a lactose free diet may help ameliorate colchicine-induced GI symptoms. 5. Anti-inflammatory therapeutics have shown promise in reducing cardiovascular risk but much more is to be learned with ongoing and future basic, translational, and clinical research.

Show notes – Treating InflammationWhat are the origins of the inflammatory hypothesis?

• The first hypothesis as to the pathogenesis of atherosclerosis was the incrustation hypothesis by Carl Von Rokitansky in 1852. He suggested that atherosclerosis begins in the intima with thrombus deposition.
  • In 1856, Rudolf Virchow suggested the lipid hypothesis whereby high levels of cholesterol in the blood lead to atherosclerosis. He observed inflammatory changes in the arterial walls associated with atherosclerotic plaque growth, called endo-arteritis chronica deformans.
  • In 1977, Russell Ross suggested the response-to-injury hypothesis, that atherosclerosis develops from injury to the arterial wall.
  • In the 1990’s the role of inflammation in ASCVD became more recognized. Both the adaptive and innate immune system are critical in atherosclerosis. Lipids and inflammation are synergistic in that lipid exposure is required but they translocate through damaged endothelium which occurs by way of inflammatory cytokines, namely within the NLRP3 inflammasome (IL-1, IL-6 etc.).
  • Smooth muscle cells are also involved. They migrate to the endothelial region and secrete collagen to create the fibrous cap. They can also transform into macrophage-like cells to take up lipids and become foam cells.
  • T, B, and K cells are also part of this milieu. In fact, neutrophils, macrophages and monocytes make up only a small portion of the cells involved in the atherosclerotic process.

What are ways to individually optimize one’s ASCVD risk?

• Ensure the patient is on appropriate antiplatelet therapy, lipid lowering therapy, blood pressure is well controlled, and the Hemoglobin A1c is well controlled. Smoking cessation is pivotal.
  • If the patient has an elevated Lipoprotein (a), pursue more aggressive lipid lowering therapy. Targeted therapies may become available in the future.
  • Assess the patient’s systemic inflammatory risk as measured by C-Reactive Protein (CRP)

What is the evidence for utilizing CRP in risk stratification?

• CRP, initially termed Fraction C (discovered as a c polysaccharide component of the pneumococcal cell wall), was first discovered at Rockefeller University in the 1930’s. It was discovered to be an acute phase reactant in the 1940’s and noted to be synthesized in the liver in the 1960’s.
  • Although it is not causal in atherosclerosis, elevated CRP is associated with elevated rates of cardiovascular disease. This was first noted in the landmark New England Journal of Medicine study by Ridker et al that showed elevated CRP was associated with elevated cardiovascular risk and treating with anti-inflammatory medication (aspirin) lowered CRP and CV risk.
  • The statin trials also showed reduction in CRP levels was associated with better outcomes.
  • High-sensitivity CRP (hsCRP) >3 mg/L has odds ratio of ~1.8 for risk of CV disease.
  • Recent analyses of the PROMINENT, REDUCE-IT, and STRENGTH trials demonstrated that hsCRP was a more powerful determinant of recurrent CV events, CV death, and all-cause mortality than LDL-C.

After effectively controlling the previously stated modifiable risk factors, what therapeutic options remain in a patient with an elevated CRP?

• CANTOS trial was the first proof of concept trial investigating Canakinumab (an IL-1 inhibitor) which showed a ~15% relative risk reduction in cardiovascular events
  • CIRT trial investigated methotrexate in patients without autoimmune disease. It was stopped early due to it being a negative trial. This emphasized the complex role inflammation plays in ASCVD, and that both patient selection and chosen anti-inflammatory therapy are important to consider for ASCVD risk reduction.
  • Colchicine has seen a lot of focus in this space with trials such as COLCOT, COPS, LODOCO, LODOCO 2, LODOCO MI. Overall, it appears that colchicine may be more effective in chronic stable ischemic heart disease. The CLEAR SYNERGY trial investigated colchicine in the peri-MI period and was a negative trial. However, we do not yet have the published data to further analyze it.
  • A review article by Potere et al (referenced below) provides a useful summary of novel therapies and upcoming trials in the inflammation in ASCVD space.

How do we approach inflammation in women?

• We know that immune response differs between men and women. Women have more robust immune response to vaccines and viruses and greater innate and adaptive immune responses.
  • Women have slightly higher CRP than men. Studies have shown that average high sensitivity hsCRP is 1.7 for women and 1.2 for men. In the JUPITER trial, the subgroup of patients with hsCRP>7 mg/L had the highest proportion of women relative to men.
  • Regardless, hsCRP remains a reliable predictor of CV events in both men and women.

What are some practical considerations when starting colchicine?

• It may help with adherence, if you walk patients through what to expect with the medication.
  • Obtain renal and liver function tests as both organs contribute to colchicine metabolism and clearance.
  • Obtain a thorough medication reconciliation as colchicine has some notable drug-drug interactions.
  • The most common side effects is GI intolerance; cytopenias are rare occurrences.
  • Note that colchicine can induce lactose intolerance, a potential mechanism for causing GI intolerance, so a lactose free diet may help with adherence.

What do we have to look forward to in the anti-inflammation space in CV disease?

• There is still a lot to be learned and discovered in this space. Some clinical trials to look out for are the ZEUS, ARTEMIS, and HERMES trials which look at Ziltivekimab, an IL-6 inhibitor, in chronic kidney disease, acute myocardial infarction, and heart failure, respectively.

References – Treating InflammationNidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61(4):404-410. doi:10.1016/j.jacc.2012.10.027

Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. doi:10.1056/NEJMoa2021372

Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-2505. doi:10.1056/NEJMoa1912388

Hennessy T, Soh L, Bowman M, et al. The Low Dose Colchicine after Myocardial Infarction (LoDoCo-MI) study: A pilot randomized placebo controlled trial of colchicine following acute myocardial infarction. Am Heart J. 2019;215:62-69. doi:10.1016/j.ahj.2019.06.003

Tong DC, Quinn S, Nasis A, et al. Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial. Circulation. 2020;142(20):1890-1900. doi:10.1161/CIRCULATIONAHA.120.050771

Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914

Ridker PM, Everett BM, Pradhan A, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019;380(8):752-762. doi:10.1056/NEJMoa1809798

Potere N, Bonaventura A, Abbate A. Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases. Arterioscler Thromb Vasc Biol. Published online October 10, 2024. doi:10.1161/ATVBAHA.124.319980

Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men [published correction appears in N Engl J Med 1997 Jul 31;337(5):356]. N Engl J Med. 1997;336(14):973-979. doi:10.1056/NEJM199704033361401

Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. doi:10.1056/NEJMoa0807646

Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023;401(10384):1293-1301. doi:10.1016/S0140-6736(23)00215-5

Fernandez DM, Rahman AH, Fernandez NF, et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019;25(10):1576-1588. doi:10.1038/s41591-019-0590-4

Moran CA, Collins LF, Beydoun N, et al. Cardiovascular Implications of Immune Disorders in Women. Circ Res. 2022;130(4):593-610. doi:10.1161/CIRCRESAHA.121.319877

Kushner I. C-reactive protein – My perspective on its first half century, 1930-1982. Front Immunol. 2023;14:1150103. Published 2023 Mar 2. doi:10.3389/fimmu.2023.1150103

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The following question refers to Sections 7.3.3 and 7.3.6 of the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure.

The question is asked by Palisades Medical Center medicine resident & CardioNerds Academy Fellow Dr. Maryam Barkhordarian, answered first by UTSW AHFT Cardiologist & CardioNerds FIT Ambassador Dr. Natalie Tapaskar, and then by expert faculty Dr. Robert Mentz.

Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz has been a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

American Heart Association’s Scientific Sessions 2024* As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Question #39

| Ms. Kay Lotsa is a 48-year-old woman with a history of CKD stage 2 (baseline creatinine ~1.2 mg/dL) & type 2 diabetes mellitus. She has recently noticed progressively reduced exercise tolerance, leg swelling, and trouble lying flat. This prompted a hospital admission with a new diagnosis of decompensated heart failure. A transthoracic echocardiogram reveals LVEF of 35%. Ms. Lotsa is diuresed to euvolemia, and she is started on carvedilol 25mg BID, sacubitril/valsartan 49-51mg BID, and empagliflozin 10mg daily, which she tolerates well. Her eGFR is at her baseline of 55 mL/min/1.73 m2 and serum potassium concentration is 3.9 mEq/L. Your team is anticipating she will be discharged home in the next one to two days and wants to start spironolactone. Which of the following is most important regarding her treatment with mineralocorticoid antagonists? | | A | Spironolactone is contraindicated based on her level of renal impairment and should not be started | | B | Serum potassium levels and kidney function should be assessed within 1-2 weeks of starting spironolactone | | C | Eplerenone confers a higher risk of gynecomastia than does spironolactone | | D | The patient will likely not benefit from initiation of spironolactone if her cardiomyopathy is ischemic in origin |

Answer #39

| Explanation | The correct answer is B – after starting a mineralocorticoid receptor antagonist (MRA), it is important to closely monitor renal function and serum potassium levels.MRA (also known as aldosterone antagonists or anti-mineralocorticoids) show consistent improvements in all-cause mortality, HF hospitalizations, and SCD across a wide range of patients with HFrEF.The RALES trial of spironolactone vs. placebo in highly symptomatic HFrEF (LVEF ≤ 35%, NYHA III-IV), trial of eplerenone vs placebo post-MI in patients with LVEF ≤ 40%, and EMPHASIS-HF trial of eplerenone vs placebo in less symptomatic HFrEF (LVEF ≤ 35%, NYHA II) altogether suggest MRAs confer improvements in all-cause mortality, HF hospitalizations, and sudden cardiac death in patients with HFrEF. Importantly, these benefits have been demonstrated across a wide range of HFrEF severity and etiologies, including ischemic cardiomyopathy (Option D).Therefore, in patients with HFrEF and NYHA class II to IV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if eGFR is >30 mL/min/1.73 m2 and serum potassium is <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency (Class 1, LOE A). MRA therapy in this context provides high economic value.Adverse Effects of MRAsBoth spironolactone and eplerenone are excreted by the kidney and due to their inhibition of aldosterone signaling, reduce potassium excretion in the urine. For these reasons, the initiation of MRAs is contraindicated in patients with eGFR of ≤30 mL/min/1.73m2 or serum potassium levels of ≥5.0 mEq/L. After starting or intensifying MRA therapy, serum potassium levels and renal function should be rechecked at approximately 1 week, at 4 weeks, and every 6 months thereafter, provided clinical stability. Hyperkalemia can increase the risk of ventricular arrhythmias and death. Unfortunately, this often results in de-escalation or discontinuation of RAASi and a subsequent loss of long-term cardiorenal benefits of maximally tolerated GDMT.The utility of prescribing potassium binders (e.g., patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating continuation of Patiromer and sodium zirconium cyclosilicate remove potassium by exchanging cations leading to increased fecal excretion and thereby lowering serum potassium levels. These have been FDA approved for treatment of hyperkalemia for patients receiving RAASi.Therefore, the use of potassium binders (patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating the continuation of RAASi therapy in patients with HF who experience hyperkalemia (serum potassium level ≥5.5 mEq/L) received a Class 2b recommendation (LOE B-R), but overall utility remains uncertain.In the DIAMOND trial, patients with HFrEF and hyperkalemia were randomized to patiromer vs. control. In the run-in phase, all patients were started on patiromer, and subsequently, RAASi therapy was initiated/optimized. After this, patients were randomized to continue vs stop patiromer. Hard clinical primary endpoints of time to CV death or first CV hospitalization were changed to mean change in serum potassium due to challenges with recruitment related to the COVID-19 pandemic. There was a significant reduction in the mean change of potassium (0.03 mEq/L in the patiromer group vs. 0.13 mEq/L in the control). Additionally, 85% of the patiromer arm was able to be optimized on RAASi.Aside from hyperkalemia, troublesome side effects of MRAs include gynecomastia and vaginal bleeding. Eplerenone results in lower rates of these side effects than spironolactone given greater specificity for the aldosterone receptor (Option C). | | Main Takeaway | Mineralocorticoid receptor antagonists, like spironolactone and eplerenone, reduce all-cause mortality, HF hospitalizations, and sudden cardiac death in a wide range of patients with HFrEF. Monitoring renal function and potassium levels while on MRA therapy is imperative. | | Guideline Loc. | Section 7.3.3 Section 7.3.6 |

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The following question refers to Sections 7.4 and 7.5 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by the Director of the CardioNerds Internship Dr. Akiva Rosenzveig, answered first by Vanderbilt AHFT cardiology fellow Dr. Jenna Skowronski, and then by expert faculty Dr. Randall Starling.

Dr. Starling is Professor of Medicine and an advanced heart failure and transplant cardiologist at the Cleveland Clinic where he was formerly the Section Head of Heart Failure, Vice Chairman of Cardiovascular Medicine, and member of the Cleveland Clinic Board of Governors. Dr. Starling is also Past President of the Heart Failure Society of America in 2018-2019. Dr. Staring was among the earliest CardioNerds faculty guests and has since been a valuable source of mentorship and inspiration. Dr. Starling’s sponsorship and support was instrumental in the origins of the CardioNerds Clinical Trials Program.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

American Heart Association’s Scientific Sessions 2024* As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Question #38

| Mrs. M is a 65-year-old woman with non-ischemic dilated cardiomyopathy (LVEF 40%) and moderate to severe mitral regurgitation (MR) presenting for outpatient follow-up. Despite improvement overall, she continues to experience dyspnea on exertion with two flights of stairs and occasional PND. She reports adherence with her medication regimen of sacubitril-valsartan 97-103mg twice daily, metoprolol succinate 200mg daily, spironolactone 25mg daily, empagliflozin 10mg daily, and furosemide 80mg daily. A transthoracic echocardiogram today shows an LVEF of 35%, an LVESD of 60 mm, severe MR with a regurgitant fraction of 60%, and an estimated right ventricular systolic pressure of 40 mmHg. Her EKG shows normal sinus rhythm at 65 bpm and a QRS complex width of 100 ms.What is the most appropriate recommendation for management of her heart failure? | | A | Continue maximally tolerated GDMT; no other changes | | B | Refer for cardiac resynchronization therapy (CRT) | | C | Refer for transcatheter mitral valve intervention |

Answer #38

| Explanation | Choice C is correct. The 2020 ACC/AHA Guidelines for the management of patients with valvular heart disease outline specific recommendations.In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent symptoms (NYHA class II, III, or IV) while on optimal GDMT for HF (Stage D), M-TEER is reasonable in patients with appropriate anatomy as defined on TEE and with LVEF between 20% and 50%, LVESD ≤70 mm, and pulmonary artery systolic pressure ≤70 mmHg (Class 2a, LOE B-R).Conversely, mitral valve surgery may have a role in the following contexts:* Severe secondary MR when CABG is planned (Class 2a, LOE B-NR) * Chronic severe secondary MR related to atrial annular dilation with preserved LV systolic function (LVEF ≥50%) who have severe persistent symptoms (NYHA class III or IV) despite therapy for HF and therapy for associated AF or other comorbidities (Stage D) (Class 2b, LOE B-NR) * Chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent severe symptoms (NYHA class III or IV) while on optimal GDMT for HF (Stage D) (Class 2b, LOE B-NR).

Choice A is incorrect. GDMT has been shown to improve MR and LV dimensions in patients with HFrEF and secondary MR, and it is a Class 1 recommendation (LOE B-R) to optimize GDMT before any intervention for secondary MR related to LV dysfunction. This includes both medical GDMT and cardiac resynchronization therapy (CRT) where appropriate. Our patient is still having symptoms despite being on the maximally tolerated doses of medical GDMT. This highlights the importance of a multidisciplinary approach to the management of valvular heart disease in patients with HF in accordance with clinical practice guidelines to prevent worsening of HF and adverse clinical outcomes (Class 1, LOE B-R). A cardiologist with expertise in the management of HF is integral in the shared decision-making for valve intervention and should guide optimization of GDMT to ensure that medical options for HF and secondary MR have been effectively applied for an appropriate time-period and exhausted before considering intervention.Choice B is incorrect. While CRT has been shown to improve MR, LV dimensions, and outcomes in patients with HFrEF and secondary MR in appropriately selected patients, our patient would not be a candidate given that her QRS duration was < 120ms (Class 3: no benefit, LOE B-R). | | Main Takeaway | In patients with severe secondary MR and reduced ejection fraction with persistent symptoms despite GDMT, M-TEER is reasonable in patients with appropriate anatomy as defined on TEE and with LVEF between 20% and 50%, LVESD ≤70 mm, and pulmonary artery systolic pressure ≤70 mmHg. Conversely, surgery may be appropriate for some patients. HF ad VHD should be managed in a multidisciplinary fashion. | | Guideline Loc. | Sections 7.4-7.5Figure 10Also: Section 7.3 from “Otto, C. M., Nishimura, R. A., Bonow, R. O., Carabello, B. A., rwin, J. P., Gentile, F., Jneid, H., Krieger, ric v., Mack, M., McLeod, C., O’Gara, P. T., Rigolin, V. H., Sundt, T. M., Thompson, A., & Toly, C. (2021). 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. In Circulation (Vol. 143, Issue 5, pp. E72–E227). Lippincott Williams and Wilkins. https://doi.org/10.1161/CIR.0000000000000923” |

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In this episode, Dr. Paul Ridker, a pioneer in the field of cardiovascular inflammation, joins the CardioNerds (Dr. Gurleen Kaur, Dr. Richard Ferraro, and Dr. Nidhi Patel) to discuss the evolving landscape of inflammation as a key factor in cardiovascular risk reduction. The discussion dives into the importance of biomarkers like high-sensitivity C-reactive protein (hs-CRP) in guiding treatment strategies, the insights gleaned from landmark trials like the JUPITER and CANTOS studies, and the future of targeted anti-inflammatory therapies in cardiology.

Show notes were drafted by Dr. Nidhi Patel. Audio editing by CardioNerds academy intern, Grace Qiu.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

American Heart Association’s Scientific Sessions 2024 As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS* and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

CardioNerds Prevention Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

Pearls – Targeting Inflammation for Cardiovascular Risk1. “If you don’t measure it, you can’t treat it”: Incorporate hs-CRP into routine practice for patients at risk of cardiovascular events, as it provides crucial information for risk stratification and management. 2. Recognize the dual benefits of statins in lowering both LDL and inflammation, particularly in patients with elevated hs-CRP. 3. Encourage patients to adopt heart-healthy habits, as lifestyle changes remain foundational in reducing both cholesterol and inflammatory risk. 4. Reminder that most autoimmune or inflammatory diseases, from psoriasis to Addison’s disease to lupus to scleroderma to inflammatory bowel disease, have been shown to have elevated cardiovascular risk 5. Ongoing randomized trials including ZEUS, HERMES, and ARTEMIS will inform whether novel targeting of IL-6 can safely lower cardiovascular event rates or slow renal progression

Show notes – Targeting Inflammation for Cardiovascular RiskWhy is it important to measure both LDL and hs-CRP, and what factors increase hs-CRP?

• Inflammation and hyperlipidemia are synergistic in promoting atherosclerosis. They interact to exacerbate plaque formation and instability, increasing the risk of cardiovascular events.
• Just like we measure blood pressure and LDL to know what to treat, we should measure hs-CRP to guide targeted therapy.
• Clinical Example: in Ms. Flame’s case, despite achieving target LDL levels with statins, her elevated hs-CRP indicates ongoing inflammation and residual cardiovascular risk that should be assessed.
• Residual inflammatory risk should be assessed in both primary and secondary prevention.
• Increased BMI1, smoking2, a sedentary lifestyle3, and genetics4 (such as a higher risk of metabolic disease in South Asians) all raise hs-CRP levels.
• SGLTi5 and GLP-1 agonists6 have also been shown to decrease hs-CRP levels.

What data do we have to support measuring hs-CRP?

• Women’s Health Study7: an early study showing that hs-CRP predicted risk at least as well as LDL cholesterol and that models incorporating hs-CRP in addition to lipids were significantly better at predicting risk than models based on lipids alone.
• JUPITER Trial8 (Primary Prevention): Among patients with normal LDL but elevated hs-CRP there was a 44% reduction in major cardiovascular events (>50% in MI and stroke) and a 20% reduction in all-cause mortality in patients treated with statins. These results led to changes in guidelines in recognizing the need to measure and treat inflammation.
• CANTOS Trial9 (Secondary Prevention): Randomized >10K patients with previous MI and hs-CRP ≥ 2mg/L and found that canakinumab reduced hs-CRP level from baseline in a dose-dependent manner, without reduction in the LDL, ApoB, TG, or blood pressure.

What are the guidelines and supportive data on using Colchicine?

• Colchicine 0.5 mg is the first FDA-approved anti-inflammatory therapy indicated for reducing cardiovascular events among adults who have established ASCVD or are at risk of developing it.
• The use of Colchicine is supported by the LoDoCo, LoDoCo-2, and COLCOT trials, which showed a ~25-30% risk reduction in cardiovascular risk. In comparison, studies using ezetimibe10 have shown a 6-7% relative risk reduction and PCSK9 inhibitors11 ~15% risk reduction for LDL reduction.
  • LoDoCo12– in those with stable CAD, patients who received colchicine in addition to standard of care had a significantly lower composite rate of ACS compared to those who only received standard of care at a median follow-up of 3 years.
  • LoDoCo-213– randomized control, multicentric trial in patients with stable CAD showing group randomized to colchicine + standard of compare had reduced MACE compared to those with placebo + standard of care at a median follow-up of 2.8 years.
  • COLCOT14– Addition of colchicine within 30 days of ACS resulted in a reduction of the primary composite outcome of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina

What are examples of ongoing trials that will shape the future of our anti-inflammatory toolbox?

• ZEUS Trial15– ongoing trial that randomizes patients with ASCVD, hs-CRP ≥ 2 and CKD (eGFR between 15-60 OR EGFR ≥ 60 and urinary albumin-to-creatinine ratio ≥200) to Ziltivekimab or placebo, and assesses time to first occurrence of MACE.
• Hermes HFpEF16– ongoing trial that randomizes patients with HFpEF and HFmrEF to Ziltivekimab or placebo, and assesses time to first occurrence of cardiovascular death, heart failure hospitalization, or urgent heart failure visit
• Artemis Acute Ischemia17– ongoing trial that randomizes patients hospitalized with MI to Ziltivekimab or placebo, and assess time to MACE.
• Clazakizumab in patients receiving maintenance dialysis18– this study randomized adults with known cardiovascular disease and/or DM2 receiving dialysis with hs-CRP ≥ 2 to receive Clazakizumab or placebo. The primary endpoint is a reduction in hs-CRP over 12 weeks.

References – Targeting Inflammation for Cardiovascular Risk1. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-Reactive Protein Levels in Overweight and Obese Adults. JAMA. 1999;282:2131-2135. doi: 10.1001/jama.282.22.2131 2. Tonstad S, Cowan JL. C-reactive protein as a predictor of disease in smokers and former smokers: a review. Int J Clin Pract. 2009;63:1634-1641. doi: 10.1111/j.1742-1241.2009.02179.x 3. Esteghamati A, Morteza A, Khalilzadeh O, Anvari M, Noshad S, Zandieh A, Nakhjavani M. Physical inactivity is correlated with levels of quantitative C-reactive protein in serum, independent of obesity: results of the national surveillance of risk factors of non-communicable diseases in Iran. J Health Popul Nutr. 2012;30:66-72. doi: 10.3329/jhpn.v30i1.11278 4. Anand SS, Razak F, Yi Q, Davis B, Jacobs R, Vuksan V, Lonn E, Teo K, McQueen M, Yusuf S. C-reactive protein as a screening test for cardiovascular risk in a multiethnic population. Arterioscler Thromb Vasc Biol. 2004;24:1509-1515. doi: 10.1161/01.ATV.0000135845.95890.4e 5. La Grotta R, de Candia P, Olivieri F, Matacchione G, Giuliani A, Rippo MR, Tagliabue E, Mancino M, Rispoli F, Ferroni S, et al. Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin. Cell Mol Life Sci. 2022;79:273. doi: 10.1007/s00018-022-04289-z 6. Mazidi M, Karimi E, Rezaie P, Ferns GA. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. J Diabetes Complications. 2017;31:1237-1242. doi: 10.1016/j.jdiacomp.2016.05.022 7. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843. doi: 10.1056/nejm200003233421202 8. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. doi: 10.1056/NEJMoa0807646 9. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017;377:1119-1131. doi: 10.1056/NEJMoa1707914 10. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. New England Journal of Medicine. 2015;372:2387-2397. doi: 10.1056/NEJMoa1410489 11. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine. 2017;376:1713-1722. doi: 10.1056/NEJMoa1615664 12. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404-410. doi: 10.1016/j.jacc.2012.10.027 13. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383:1838-1847. doi: 10.1056/NEJMoa2021372 14. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381:2497-2505. doi: 10.1056/NEJMoa1912388 15. ZEUS – Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Participants With Established Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease and Systemic Inflammation. In; 2021. 16. Effects of Ziltivekimab Versus Placebo on Morbidity and Mortality in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation. In; 2022. 17. ARTEMIS – Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Patients With Acute Myocardial Infarction. In: Duke Clinical Research I, ed.; 2023. 18. Chertow GM, Chang AM, Felker GM, Heise M, Velkoska E, Fellström B, Charytan DM, Clementi R, Gibson CM, Goodman SG, et al. IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. Nature Medicine. 2024. doi: 10.1038/s41591-024-03043-1

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The following question refers to Section 7.4 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by the Director of the CardioNerds Internship Dr. Akiva Rosenzveig, answered first by Vanderbilt AHFT cardiology fellow Dr. Jenna Skowronski, and then by expert faculty Dr. Clyde Yancy.

Dr. Yancy is Professor of Medicine and Medical Social Sciences, Chief of Cardiology, and Vice Dean for Diversity and Inclusion at Northwestern University, and a member of the ACC/AHA Joint Committee on Clinical Practice Guidelines.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

American Heart Association’s Scientific Sessions 2024* As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Question #37

| Mr. S is an 80-year-old man with a history of hypertension, type II diabetes mellitus, and hypothyroidism who had an anterior myocardial infarction (MI) treated with a drug-eluting stent to the left anterior descending artery (LAD) 45 days ago. His course was complicated by a new LVEF reduction to 30%, and left bundle branch block (LBBB) with QRS duration of 152 ms in normal sinus rhythm. He reports he is feeling well and is able to enjoy gardening without symptoms, though he experiences dyspnea while walking to his bedroom on the second floor of his house. Repeat TTE shows persistent LVEF of 30% despite initiation of goal-directed medical therapy (GDMT). What is the best next step in his management? | | A | Monitor for LVEF improvement for a total of 60 days prior to further intervention | | B | Implantation of a dual-chamber ICD | | C | Implantation of a CRT-D | | D | Continue current management as device implantation is contraindicated given his advanced age |

Answer #37

| Explanation | Choice C is correct. Implantation of a CRT-D is the best next step.In patients with nonischemic DCM or ischemic heart disease at least 40 days post-MI with LVEF ≤35% and NYHA class II or III symptoms on chronic GDMT, who have reasonable expectation of meaningful survival for >1 year,ICD therapy is recommended for primary prevention of SCD to reduce total mortality (Class 1, LOE A). A transvenous ICD provides high economic value in this setting, particularly when a patient’s risk of death from ventricular arrhythmia is deemed high and the risk of nonarrhythmic death is deemed low.In addition, for patients who have LVEF ≤35%, sinus rhythm, left bundle branch block (LBBB) with a QRS duration ≥150 ms, and NYHA class II, III, orambulatory IV symptoms on GDMT, cardiac resynchronization therapy (CRT) is indicated to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL. Cardiac resynchronization provides high economic value in this setting.Mr. S therefore meets criteria for both ICD and CRT.Choice A is incorrect. All patients should be on maximally tolerated doses of GDMT prior to consideration of device implantation to allow for assessment of LVEF recovery. Patients who have experienced myocardial infarction should be reassessed 40 days after the event and after achieving maximally tolerated doses of GDMT. Choice B in incorrect. For patients in sinus rhythm with a LBBB morphology and QRS duration >150 ms with an LVEF ≤35%, there were significant improvements in 6-minute walk test performance, quality of life, NYHA classification, and LVEF after implantation of CRT. Mortality and hospitalizations were also found to be decreased in patients with CRT-P & CRT-D. Overall, CRT has been shown to have high economic value in these patients.It should be noted that CRT has the most benefit in patients with a wide QRS (>150 ms), LBBB morphology, and LVEF ≤35%, though trials have shown a modest benefit in special populations. CRT has a Class 2a recommendation (LOE B-NR) in patients with LVEF ≤35%, sinus rhythm, and NYHA Class II, III, or ambulatory IV symptoms on GDMT, with either:a) Non-LBBB pattern with a QRS duration ≥150 msb) LBBB with a QRS duration of 120 to 149 msChoice D is incorrect. If LVEF remains ≤35% in a patient with a life expectancy >1 year, trials have shown that ICD placement for primary prevention reduces sudden cardiac death and also has a high economic value. There is no indication that this patient has a life expectancy < 1 year. | | Main Takeaway | In patients 40 days post-MI on GDMT with an LVEF that remains ≤35%, ICD therapy for primary prevention is appropriate and cost effective. For those additional with a LBBB and QRS >150 ms, CRT-D is also appropriate and cost effective. | | Guideline Loc. | Section 7.4 |

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In this episode, Dr. Gurleen Kaur (Cardiology FIT at Brigham and Women’s Hospital and APD of the CardioNerds Academy) and Dr. Diane Masket (Medicine Resident at the University of Chicago Northshore and CardioNerds Academy Intern) discuss with Dr. Minnow Walsh (Medical Director of the Heart Failure and Cardiovascular programs at Ascension St. Vincent Heart Center in Indianapolis) about her personal and professional journey in Cardiology. They discuss Dr. Walsh’s authorship of the recent ACC statement on career flexibility in Cardiology, her involvement with the ACC at both the local and national levels, and her passion for making cardiology a more inclusive and welcoming field for all.

Notes were drafted by Dr. Diane Masket and episode audio was engineered by student Dr. Grace Qiu.

This episode is supported by the5th Annual Going Back to the Heart of Cardiology (A MedscapeLIVE Conference). Join co-chairs Dr. Robert Harrington and Dr. Fatima Rodriguez January 24-26, 2025 at the Fontainebleau Hotel in Miami Beach, Florida.

The agenda will explore the latest advancements in cardiology including cardiovascular prevention, atherosclerosis and thrombosis, cardiovascular dysfunction, arrhythmias, and valvular heart disease. Network, attend engaging presentations by renowned cardiologists, visit the exhibit and poster hall, participate in an exclusive immersive experience, and earn up to 13 CME/CE credits.

Register today with code CARDIONERDS for 30% OFF your registration. Click here for more information.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

The PA-ACC & CardioNerds Narratives in Cardiology is a multimedia educational series jointly developed by the Pennsylvania Chapter ACC, the ACC Fellows in Training Section, and the CardioNerds Platform with the goal to promote diversity, equity, and inclusion in cardiology. In this series, we host inspiring faculty and fellows from various ACC chapters to discuss their areas of expertise and their individual narratives. Join us for these captivating conversations as we celebrate our differences and share our joy for practicing cardiovascular medicine. We thank our project mentors Dr. Katie Berlacher and Dr. Nosheen Reza.

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Video version – Career Flexibility in CardiologyQuoatables – Career Flexibility in Cardiology* “You have to learn to live with ambivalence. You can’t do everything. You can’t do everything all at one time” * “One of the most important things the College is behind and pushing, is that competency-based evaluation is what should be used in fellowship rather than this sort of cookie cutter approach where you have to do these many months of echo and this much of cath lab. So, I think flexibility moving from volume to competency is one push.” * “Fellowship is daunting, and internal medicine residency is too, but I think culture is how we feel every day. And I think the more we increase flexibility the more that culture is going to shift.

Notes – Career Flexibility in CardiologyProcess of developing ACC Health Policy Statements

• These documents address issues that require ACC influence and usually involve a variety of institutions, governing bodies, and other stakeholders. ACC comes to an agreement on how they will approach this topic and shares it broadly.
• Most of the existing ACC health policy statements are disease-based instead of profession-based. The ACC Career Flexibility statement grew out of the diversity, equity, and inclusion task force, which is a standing committee.
• A variety of authors are included in health policy statements to reflect the perspectives of many different interest groups.
• All policy statements, including the one about career flexibility, are available online on JACC.org 1

Major Components of the ACC Career Flexibility Health Policy Statement

• There are 18 principles that highlight the most important aspects regarding career flexibility in cardiology.2
• Flexibility allows for deceleration (decrease in work hours, responsibilities, etc.) and acceleration based on the needs of the physician. For example, during childbearing and rearing time periods, there could be a deceleration, which could accelerate when parenthood responsibilities have decreased.
• It does not only need to be based around parenting; physicians who are not parents also desire flexibility and enjoy spending time on activities other than their careers. These needs will be unique for each person.
• Individuals seeking flexibility also must understand that there will be an adjustment in their compensation as they are no longer working full-time.
• Career flexibility is beneficial at all stages with a desire for a safe training environment early, ability to decelerate mid-career to focus on other priorities and late career to possibly accelerate and works towards a tenure.
• Allowing flexibility in cardiology is a major pathway to increasing diversity in the workforce which ultimately creates a more inclusive and welcoming environment.
• Both men and women in cardiology are interested in flexibility. For many years there was a belief that only women wanted this flexibility; however, in recent years it has become apparent that all cardiologists seek the opportunity for a better work-life balance.

References:1. https://www.jacc.org/guidelines 2. 2022 ACC Health Policy Statement on Career Flexibility in Cardiology. J Am Coll Cardiol 2022;Oct 13

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The following question refers to Sections 2.1and 4.2 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by CardioNerds Academy Intern Dr. Adriana Mares, answered first by CardioNerds FIT Trialist Dr. Christabel Nyange, and then by expert faculty Dr. Shelley Zieroth.

Dr. Zieroth is an advanced heart failure and transplant cardiologist, Head of the Medical Heart Failure Program, the Winnipeg Regional Health Authority Cardiac Sciences Program, and an Associate Professor in the Section of Cardiology at the University of Manitoba. Dr. Zieroth is a past president of the Canadian Heart Failure Society. She has been a PI Mentor for the CardioNerds Clinical Trials Program.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

American Heart Association’s Scientific Sessions 2024* As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Question #36

| A 50-year-old woman presents to establish care. Her medical history includes COPD, prediabetes, and hypertension. She is being treated with chlorthalidone, amlodipine, lisinopril, and a tiotropium inhaler. She denies chest pain, dyspnea on exertion, or lower extremity edema.On physical exam, blood pressure is 154/88 mmHg, heart rate is 90 beats/min, and respiration rate is 22 breaths/min with an oxygen saturation of 94% breathing ambient room air. BMI is 36 kg/m2. Jugular venous pulsations are difficult to assess due to her body habitus. Breath sounds are distant, with occasional end-expiratory wheezing. Heart sounds are distant, and extra sounds or murmurs are not detected. Extremities are warm and without peripheral edema. B-type natriuretic peptide level is 28 pg/mL (28 ng/L).A chest radiograph shows increased radiolucency of the lungs, flattened diaphragms, and a narrow heart shadow consistent with COPD. An electrocardiogram shows evidence of left ventricular hypertrophy. The echocardiogram showed normal LV and RV function with no significant valvular abnormalities.In which stage of HF would this patient be classified? | | A | Stage A: At Risk for HF | | B | Stage B: Pre-HF | | C | Stage C: Symptomatic HF | | D | Stage D: Advanced HF |

Answer #36

| Explanation | The correct answer is A – Stage A or at risk for HF.This asymptomatic patient with no evidence of structural heart disease or positive cardiac biomarkers for stretch or injury would be classified as Stage A or “at risk” for HF.The ACC/AHA stages of HF emphasize the development and progression of disease with specific therapeutic interventions at each stage. Advanced stages and disease progression are associated with reduced survival. The stages were revised in this edition of guidelines to emphasize new terminologies of “at risk” for Stage A and “pre-HF” for Stage B.At Stage A, emphasis is placed on the prevention of structural heart disease by aggressive risk factor modification. Healthy lifestyle habits, including regular physical activity, maintaining a normal weight, healthy dietary habits, and avoiding smoking, help reduce the future risk of HF.For patients with established hypertension, coronary disease, or diabetes, optimal control of risk factors is crucial.For hypertension, the SPRINT trial and subsequent meta-analysis of 35 BP-lowering trials have demonstrated a substantial reduction in incident HF and mortality with aggressive BP control.For diabetes, SGLT2 inhibitors have demonstrated reductions in HF hospitalizations regardless of baseline HF status.Screening patients “at risk” for HF for disease progression may be beneficial. The STOP-HF study randomized patients with risk factors but without established LV systolic dysfunction or symptomatic HF to screening with BNP testing or usual care. Screening with BNP followed by an echocardiogram and referral to a cardiovascular specialist for those with levels ≥50 pg/mL led to a reduction in the composite endpoint of incident asymptomatic LV dysfunction with or without newly diagnosed HF. Accordingly, BNP or NT–proBNP–based screening followed by team-based care, including a cardiovascular specialist, has a Class 2a (LOE B-R) recommendation in patients at risk of developing HF to prevent the development of LV dysfunction or new-onset HF.Our patients should be counseled on healthy lifestyles, smoking cessation, and weight loss. Her anti-hypertensive regimen should be intensified for blood pressure optimization. Her ASCVD risk should be calculated, and counseling regarding statin use should be provided accordingly. If she develops overt diabetes, she should be started on an SGLT-2 inhibitor. Given her BNP level, she does not currently warrant further evaluation with an echocardiogram or referral to a specialist. | | Main Takeaway | Patients with Stage A HF are those who are at risk for HF but are without symptoms, structural heart disease, or cardiac biomarkers of stretch or injury. At this stage, the emphasis should be on identifying and modifying risk factors. | | Guideline Loc. | Sections 2.1 and 4.2 |

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CardioNerds (Dr. Dan Ambinder and Dr. Rick Ferraro) join Dr. Mansi Oberoi and Dr. Mohan Gudiwada from the University of Nebraska Medical Center discuss a case of constrictive pericarditis. Expert commentary is provided by Dr. Adam Burdorf, who serves as the Program Director for the Cardiovascular Medicine Fellowship at the University of Nebraska Medical Center.

The case discussed involves a 76-year-old woman with a history of monoclonal gammopathy of undetermined significance, chronic obstructive pulmonary disease, type 2 diabetes mellitus, and squamous cell carcinoma was admitted to the hospital for worsening shortness of breath, swelling in lower extremities, hyponatremia, and urinary tract infection. CT chest to evaluate for pulmonary embolism showed incidental pericardial calcifications; the heart failure team was consulted for the management of her decompensated heart failure. Echo images were nondiagnostic. Subsequent invasive hemodynamic monitoring showed elevated right and left-sided filling pressures, diastolic equalization of LV and RV pressures, and positive RV square root sign with ventricular interdependence. Cardiac MRI showed septal flattening on deep inspiration and septal bounce, suggestive of interventricular dependence. After a heart team discussion and with shared-decision making the patient opted for medical management owing to her comorbidities and frailty.

Enjoy this 2024 JACC State-of-the-Art Review to learn more about pericardial diseases and best practices for pericardiectomy (Al-Kazac et al., JACC 2024)

American Heart Association’s Scientific Sessions 2024 As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS* and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! “To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – Constrictive PericarditisEcho: Left Ventricular ejection fraction = 55-60%. Unclear septal motion in the setting of atrial fibrillation

MRI: Diastolic septal flattening with deep inspiration as well as a septal bounce suggestive of interventricular dependence and constrictive physiology

References 1. Garcia, M. Constrictive Pericarditis Versus Restrictive Cardiomyopathy. Journal of the American College of Cardiology, vol. 67, no. 17, 2016, pp. 2061–2076. 2. Pathophysiology and Diagnosis of Constrictive Pericarditis. American College of Cardiology, 2017. 3. Geske, J., Anavekar, N., Nishimura, R., et al. Differentiation of Constriction and Restriction: Complex Cardiovascular Hemodynamics. Journal of the American College of Cardiology, vol. 68, no. 21, 2016, pp. 2329–2347. 4. Constrictive Pericarditis. ScienceDirect. 5. Constrictive Pericarditis. Journal of the American College of Cardiology, vol. 83, no. 12, 2024, pp. 1500-1512.

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Dr. Amit Goyal, along with episode chair Dr. Dinu Balanescu (Mayo Clinic, Rochester), and FIT leads Dr. Sonu Abraham (University of Kentucky) and Dr. Natasha Vedage (MGH), dive into the fascinating topic of channelopathies with Dr. Michael Ackerman, a genetic cardiologist and professor of medicine, pediatrics, and pharmacology at Mayo Clinic, Rochester, Minnesota. Using a case-based approach, they review the nuances of diagnosis and treatment of channelopathies, including Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and long QT syndrome. Dr. Sonu Abraham drafted show notes. Audio engineering for this episode was expertly handled by CardioNerds intern, Christiana Dangas.

The CardioNerds Beyond the Boards Series was inspired by the Mayo Clinic Cardiovascular Board Review Course and designed in collaboration with the course directors Dr. Amy Pollak, Dr. Jeffrey Geske, and Dr. Michael Cullen.

American Heart Association’s Scientific Sessions 2024 As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS* and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

CardioNerds Beyond the Boards Series
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Become a CardioNerds Patron!

Pearls and Quotes – Channelopathies1. One cannot equate the presence of type 1 Brugada ECG pattern to the diagnosis of Brugada syndrome. Clinical history, family history, and/or genetic testing results are required to make a definitive diagnosis. 2. The loss-of-function variants in the SCN5A gene, which encodes for the α-subunit of the NaV1.5 sodium channel, is the only Brugada susceptibility gene with sufficient evidence supporting pathogenicity. 3. Exertional syncope is an “alarm” symptom that demands a comprehensive evaluation with 4 diagnostic tests: ECG, echocardiography, exercise treadmill test, and Holter monitor. Think of catecholaminergic polymorphic ventricular tachycardia (CPVT) in a patient with exertional syncope and normal EKG! 4. ICD therapy is never prescribed as monotherapy in patients with CPVT. Medical therapy with a combination of nadolol plus flecainide is the current standard of care. 5. Long QT syndrome is one of the few clinical scenarios where genetic testing clearly guides management, particularly with respect to variability in beta-blocker responsiveness.

Notes – Channelopathies1. What are the diagnostic criteria for Brugada syndrome (BrS)?

Three repolarization patterns are associated with Brugada syndrome in the right precordial leads (V1-V2):

• Type 1: Prominent coved ST-segment elevation displaying J-point amplitude or ST-segment elevation ≥2 mm, followed by a negative T wave.
• Type 2/3: Saddleback ST-segment configuration with variable levels of ST-segment elevation.

It is important to note that only a type 1 pattern is diagnostic for Brugada syndrome, whereas patients with type 2/3 patterns may benefit from further testing.

The Shanghai score acknowledges that relying solely on induced type 1 ECG changes has limitations. Therefore, one cannot equate the presence of a type 1 Brugada ECG pattern alone to the diagnosis of Brugada syndrome. The score suggests incorporating additional information—such as clinical history, family history, and/or genetic testing results—to achieve a definitive diagnosis.

2. What is the significance of genetic testing in Brugada syndrome?

There are 23 alleged Brugada syndrome susceptibility genes published with varying levels of evidence. However, only one gene mutation, the loss-of-function variants in the SCN5A gene encoding for the α-subunit of the NaV1.5 sodium channel, is considered to have sufficient evidence.

The overall yield of BrS genetic testing is 20%. The presence of PR prolongation (>200 ms) along with type I EKG pattern increases the yield to 40%. On the contrary, in the presence of a normal PR interval, the likelihood of SCN5A positivity drops to <10%.

3. How would you risk-stratify a patient with Brugada syndrome?

Serious arrhythmic events (SAE), including resuscitated cardiac arrest and sudden cardiac death, rarely represent the initial symptoms of Brugada syndrome. Thus, risk stratification is important.

Factors that increase risk include:

1. Resuscitated cardiac arrest or history of cardiogenic syncope and the presence of a spontaneous type 1 ECG.
2. Positive genetic test – certain SCN5A variants were independent predictors for SAE.
3. Inducibility during programmed ventricular stimulation (EP study) using a double stimulation protocol (annualized risk is 1.5% per year for a positive study and 0.5% per year for a negative study).

4. What are the treatment options for Brugada syndrome?

• The only drug with therapeutic potential in BrS is quinidine. The antiarrhythmic effect is achieved by prolonging the effective refractory period via inhibition of Ito potassium channel.
• BrS plus a history of cardiac arrest, sustained VT, or syncope judged to be caused by ventricular arrhythmia would warrant an ICD.
• In those refractory to first-line therapies, RVOT epicardial ablation is now an additional therapeutic option.

5. What are the four diagnostic tests to be done in a patient who presents with an episode of exertional syncope?

Exertional syncope is a high-risk presentation that demands a comprehensive evaluation! This includes:

1. EKG
2. Echocardiogram
3. Exercise treadmill test
4. Holter monitor

Do not stop at an EKG and echo alone!

Think of catecholaminergic polymorphic ventricular tachycardia (CPVT) in a patient with exertional syncope and a normal EKG!

6. What are the features on the exercise treadmill test that increase the suspicion for CPVT?

Bidirectional VT is considered a hallmark of CPVT, with digoxin toxicity being the only real imitator. This finding is specific in the absence of digoxin but not sensitive.

During exercise testing in CPVT, as the patient’s heart rate rises with increasing workload, PVCs begin to appear, progressing to bigeminy, couplets, and, in some instances, bidirectional couplets. The ectopy typically vanishes within 30 seconds of the recovery phase. This pattern increases suspicion of CPVT and warrants a detailed family history and genetic testing.

7. What are the genetic underpinnings of CPVT?

Mutations in the ryanodine receptor (RyR2 gene) render calcium release channels leaky, leading to diastolic calcium overload. This ultimately triggers arrhythmias in CPVT.

8. What are therapeutic interventions for a patient with CPVT?

Medical therapy is the mainstay of treatment in CPVT. Drugs include non-selective beta-blockers like nadolol or propranolol. Standard of care currently includes a combination of nadolol plus flecainide. An ICD is indicated only in the case of an aborted cardiac arrest. ICD therapy is never prescribed as monotherapy in these patients.

9. How do we correctly measure the QTc?

The QT interval is measured from the beginning of the QRS complex to the end of the T wave. The end of the T wave is determined using the maximum slope intercept method, in which a tangent line is drawn through the maximum down slope of the T wave. The point at which this tangent line crosses the isoelectric line is the end of the T wave. The U wave is excluded.

• Best measured in leads II or V5.
• Quick eyeball test: if the QT interval is more than ½ the RR interval, the QTc will be >460 ms.

10. What are the three primary mutations implicated in Long QT syndrome?

1. LQT1 (30-40% of cases)
   • Mutation: loss of function in potassium channel gene KCNQ1
   • ECG: broad-based T wave
   • Trigger: activity, adrenaline, exercise
   • BB responsiveness: +++ (nadolol or propranolol)
2. LQT2 (second most common)
   • Mutation: loss of function in potassium channel gene KCNH2
   • ECG: notched T wave
   • Trigger: auditory (alarm clock), post-partum
   • BB responsiveness: ++
3. LQT3
   • Mutation: gain of function or leakiness of sodium channel SCN5A (note: BrS is due to loss of function in the same gene)
   • ECG: normal T wave after prolonged isoelectric ST segment
   • Trigger: none, but typically happens during rest
   • BB responsiveness: + (propranolol); may consider combination therapy with mexiletine or mexiletine monotherapy.

References – Channelopathies1. Charles Antzelevitch, Gan-Xin Yan, Michael J. Ackerman, Arthur A.M. Wilde et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge, EP Europace, Volume 19, Issue 4, April 2017, Pages 665–694 2. Krahn AD, Behr ER, Hamilton R, Probst V, Laksman Z, Han HC. Brugada Syndrome. JACC Clin Electrophysiol. 2022 Mar;8(3):386-405. PMID: 35331438. 3. Chockalingam, P, Crotti, L, Girardengo, G. et al. Not All Beta-Blockers Are Equal in the Management of Long QT Syndrome Types 1 and 2: Higher Recurrence of Events Under Metoprolol. JACC. 2012 Nov, 60 (20) 2092–2099 4. Priori SG, Wilde AA, Tracy C et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013 Dec;10(12):1932-63. PMID: 24011539. 5. Viskin S, Rosovski U, Zeltser D et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm. 2005 Jun;2(6):569-74. PMID: 15922261. 6. Horner JM, Ackerman MJ. Ventricular ectopy during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm. 2008 Dec;5(12):1690. PMID: 19084807; PMCID: PMC3281579.

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The CardioNerds Academy is excited to present the 3rd Annual Sanjay V. Desai Lecture in Medical Education, featuring a deep dive into the evolving role of Artificial Intelligence in Medical Education. Join us as Dr. Kathryn Berlacher, Dr. Melissa McNeil, and Dr. Alfred Shoukry explore the transformative potential of AI in training future healthcare professionals and enhancing educational methodologies. Their insightful discussion sheds light on the integration of cutting-edge technologies to improve medical learning and patient care. The conversation is faciliated by Dr. Tommy Das, Program Director of the CardioNerds Academy, and CardioNerds Academy Chiefs: Dr. Callie Clark, Dr. Rachel Goodman, Dr. Ronaldo Correa Fabiano, and Dr. Claire Cambron, who bring their expertise and enthusiasm to this engaging discussion on the future of medical education. Special thanks to Pace Wetstein, CardioNerds academy intern, for his exceptional audio editing in this episode.

American Heart Association’s Scientific Sessions 2024 As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Dr. Kathryn Berlacher* is a graduate of The Ohio State University College of Medicine and completed her internal medicine residency, chief residency, and cardiology fellowship at UPMC, where she has been on faculty since 2012. She earned a master’s degree in medical education from the University of Pittsburgh and has served as the Program Director of the Cardiovascular Fellowship Program since 2015. In 2021, she was appointed Associate Chief of Education for the UPMC Heart and Vascular Institute. Additionally, Dr. Berlacher is the director of the McGee Women’s Heart Program and chief of medicine at McGee Women’s Hospital. Nationally, she serves as the chair for the American College of Cardiology’s Annual Scientific Sessions for 2025 and 2026, regularly speaking on women’s cardiology, medical education, diversity, inclusion, and health equity.

Dr. Alfred Shoukry graduated from Northwestern University with dual degrees in Neurobiology and Biomedical Engineering. He completed medical school and internal medicine residency at UPMC, where he also earned a certificate in medical education. Dr. Shoukry serves as core faculty at the University of Pittsburgh School of Medicine and cares for patients at the VA in Pittsburgh. As the course director for Population Health, he teaches on topics such as patient safety, quality improvement, and bioinformatics. He is an expert on the impact of large language models in medical education, presenting locally and nationally on the subject.

Dr. Melissa McNeil received her undergraduate degree from Princeton University, her MD from the University of Pittsburgh, and a Master of Public Health from the same institution. She is a professor emeritus of medicine at the University of Pittsburgh and recently joined the faculty at Brown University as a professor of medicine. Dr. McNeil serves as an academic hospitalist and senior consultant to the Women’s Health Division at Brown. Her expertise lies in developing training programs to foster leaders in women’s health education and research. She has been recognized nationally for her contributions, including being named the Society of General Internal Medicine Distinguished Professor of Women’s Health in 2014 and receiving their Career Achievement in Medical Education award in 2016.

Dr. Sanjay V Desai serves as the Chief Academic Officer, The American Medical Association and is the former Program Director of the Osler Medical Residency at The Johns Hopkins Hospital.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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CardioNerds Drs. Jason Feinman, Gurleen Kaur, and Rick Ferraro discuss the implementation of SGLT inhibitors in clinical practice with Dr. Alison Bailey. Notes were drafted by Dr. Jason Feinman.

In this episode, we discuss the implementation of SGLTi in clinical practice scenarios, including for individuals with heart failure regardless of ejection fraction, those with chronic kidney disease, and those with diabetes mellitus. The group also discusses important side effects to monitor for, as well as how to counsel patients when prescribing these medications.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

American Heart Association’s Scientific Sessions 2024 As heard in this episode, the American Heart Association’s Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It’s a special year you won’t want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here! * When registering, use code NERDS* and if you’re among the first 20 to sign up, you’ll receive a free 1-year AHA Professional Membership! Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls – Clinical Implementation of SGLT Inhibitors1. For patients with heart failure with reduced ejection fraction, SGLT inhibitors reduce the composite outcome of cardiovascular death or heart failure hospitalization by 25%. 2. SGLT inhibitors can be safely started in patients with an eGFR as low as 20. There are ongoing trials investigating the safety of these medications in individuals with eGFR lower than 20 or those who are receiving dialysis. 3. An eGFR decrease of 3-5 ml/min on average is expected after starting an SGLTi, but this will stabilize over time and provides protective effects of renal dysfunction in the long run. 4. Early data that suggested an association between SGLTi and bacterial UTI development hasn’t panned out in the long run, but there is an association between SGLTi and the development of either genital mycotic infections or yeast infections. Perineal hygiene is important to prevent the development of either. 5. A patient-centered, shared decision-making approach should guide the choice of agents for individuals with type 2 diabetes mellitus. In certain patients, it may be reasonable to choose an SGLTi as the first-line agent.

Show notes – Clinical Implementation of SGLT InhibitorsWhat is the data supporting the use of SGLTi in HFpEF?

• The EMPEROR-Preserved and DELIVER trials investigated the impact of empagliflozin and dapagliflozin, respectively, on cardiovascular outcomes in patients with mildly reduced or preserved ejection fraction.
• The SOLOIST-WHF trial investigated a combined SGLT1/2 inhibitor, sotagliflozin, in patients with recently worsening heart failure, irrespective of ejection.SGLTi have been demonstrated to reduce the risk of cardiovascular death or worsening heart failure, including heart failure hospitalization, in these individuals.
• A meta-analysis of the EMPEROR-Preserved and DELIVER trials demonstrated a hazard ratio of 0.80 for cardiovascular death or first hospitalization for heart failure for empagliflozin or dapagliflozin over placebo in the setting of HFpEF.

What is the data supporting the use of SGLTi in HFrEF?

• In addition to the SOLOIST-WHF trial that was previously discussed, the EMPEROR-HF and DAPA-HF investigated the impact of SGLTi medications in patients with HFrEF.
• In patients with HFrEF, SGLTi medications have been demonstrated to reduce the risk of either cardiovascular death or heart failure hospitalization.
• Dapagliflozin and empagliflozin had a pooled risk reduction of all-cause death of 13%, a pooled risk reduction of cardiovascular death of 14%, and a 26% reduction in the combination of CV death or first hospitalization for heart failure.

What is the expected impact of SGLTi on renal function?

• Dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, and canagliflozin have all been studied for their impact on renal dysfunction in individuals both with and without diabetes.
• In the CANVAS trial, canagliflozin was associated with an initial decrease in eGFR of 3.2ml/min compared to placebo but overall decreased change from baseline in eGFR compared to placebo at trial end.In a large meta-analysis, SGLTi medications reduced the progression of kidney disease by 37%.
• The risk of acute kidney injury was reduced by 23%.

What are the recommendations for SGLTi in patients with type 2 diabetes mellitus?

• ADA guidelines emphasize a patient-centered shared decision-making approach when choosing which pharmacologic agent to prescribe for an individual with diabetes mellitus.
• Factors in choosing which agent include the risk of cardiovascular disease, the risk of renal disease, and whether there is an emphasis on weight reduction.

What side effects should be monitored for when starting an individual on an SGLTi medication?

• Side effects with SGLTi medications are overall rare but include DKA, genital mycotic infections, necrotizing fasciitis, and volume status derangements.
• In the CANVAS trial, SGLTi was associated with an increased risk of amputation, but this has not been shown to be consistent in other trials. Nevertheless, in a meta-analysis including CANVAS, SGLTi medications were associated with a 15% relative risk of amputation over placebo medications.The relative risk of DKA in the same meta-analysis was 2.12.
• Careful assessment of an individual’s volume status and whether they are on any other diuretic medications when initiating an SGLTi medication may allow for upfront adjustment of these medications to reduce the risk of dehydration.

References – Clinical Implementation of SGLT Inhibitors1. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098. 2. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. 3. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384(2):117-128. 4. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400(10354):757-767. 5. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. 6. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. 7. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-829. 8. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. 9. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788-1801. 10. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S158-S178.

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CardioNerds (Amit Goyal) join Dr. Merna Hussien, Dr. Akhil Kallur, Dr. Abhinav Saxena, and Dr. Brody Deb from the MedStar Georgetown – Washington Hospital Center in DC for a stroll around Rock Creek Park as they discuss an unusual case of cobalt cardiomyopathy. Expert commentary is provided by Dr. Nana Afari Armah. Episode audio was edited by CardioNerds Intern Christiana Dangas.

The case is of a middle-aged woman with a past medical history of hypertension, hyperlipidemia, and bilateral hip replacements, who presented with subacute progressive exertional dyspnea, orthopnea, and constitutional symptoms and was found to have SCAI Stage C cardiogenic shock. Transthoracic echocardiogram showed severely reduced left ventricular ejection fraction (LVEF, 20-25%) and a moderate pericardial effusion. Cardiac catheterization revealed biventricular failure with elevated filling pressures. A cardiac MRI showed diffuse late gadolinium enhancement (LGE) in the left ventricle. Endomyocardial biopsy showed nonspecific chronic inflammation. However, the evidence of mitochondrial heavy metal toxicity and elevated cobalt levels made the diagnosis of cobalt cardiomyopathy. The patient underwent revision of hip joint implants to ceramic implants and started chelation therapy. However, due to persistent stage D heart failure despite normalization of cobalt levels, she underwent orthotropic heart transplantation.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Case MEdia – Cobalt CardiomyopathyPearls – Cobalt Cardiomyopathy* A good history goes a long way in diagnosing non-ischemic cardiomyopathy (NICM). * Common problems can have uncommon presentations requiring a high degree of suspicion for diagnosis. * Imaging features can overlap between causes of NICM. History helps in targeting further histological workup and uncovering the root cause. * Multidisciplinary effort is essential in making a rare diagnosis.

Taken from1 – Singh M, Krishnan M, Ghazzal A, Halushka M, Tozzi JE, Bunning RD, Rodrigo ME, Najjar SS, Molina EJ, Sheikh FH. From Hip to Heart: A Comprehensive Evaluation of an Infiltrative Cardiomyopathy. CJC Open. 2021 Nov 1;3(11):1392–5.

Notes – Cobalt CardiomyopathyHow common is cobalt cardiomyopathy? When should it be suspected?

• Cobalt cardiomyopathy is incredibly rare, with only a handful of reported cases. 2 It is also known as beer drinkers’ cardiomyopathy, as cobalt was added to beer for fortification in Quebec 3, where it was first reported. Cobalt cardiomyopathy is characterized by its rapidly progressive nature, the presence of low voltages on EKG, and diffuse infiltration. Patients also complained of a previous history of anorexia and weight loss and were found to have polycythemia and thyroid abnormalities on labs. This syndrome was very similar to wet beriberi except for the absence of a therapeutic response to thiamine.

Taken from – 2

• Later, this was noted in patients with total metal hip arthroplasty 4–6, especially in patients with metal-on-metal hip arthroplasty, which led to corrosion and leakage of cobalt into the bloodstream. The syndrome in these patients was similar to those in beer drinkers from Quebec.

This figure, taken from 2, shows the reports of Cobalt cardiomyopathy after cobalt alloy prostheses. [HX1]

What is the pathophysiology of cobalt cardiomyopathy?

• Cobalt has a variety of effects on the heart, both microscopically and biochemically.
  • Cobalt may have multiple calcium-mediated cardiac effects and may also interfere with the Krebs cycle and ATP generation by mitochondria. Histology may show modest changes with no inflammatory response on microscopy and ultrastructural changes, including vacuolar degeneration and swollen and distorted mitochondria with loss of cristae.
  • Remarkably, cardiac dysfunction does not correlate with serum cobalt levels. 2

How does cobalt cardiomyopathy present, and how do we diagnose it?

• Diagnosis is made with a consistent exposure history and high index of suspicion. Patients present with anorexia and cachexia and complain of rapid onset and progression of symptoms of cardiomyopathy.
  • Labs may show polycythemia and thyroid dysfunction. Cobalt levels should be elevated, but the severity of the disease does not correlate well with levels.
  • Cardiac workup: EKG shows low voltage from infiltration and pericardial effusion. Echocardiogram shows systolic dysfunction and pericardial effusion. MRI shows diffuse infiltrative pathology. Native heart pathology is often diagnostic. 2

How is cobalt cardiomyopathy managed?

• Medical management of heart failure, including guideline directed medical therapy (GDMT), inotropic support, and mechanical circulatory support, implantable device or transplant where appropriate.
• Oral chelating agents should be used.
• The mainstay of management is the removal of the prosthesis or source of exposure. 2

What is the prognosis of Cobalt Cardiomyopathy?

• In the beer-drinker population, the prognosis was bad. Patients in that population had rapid clinical progression leading to cyanosis, marked elevation of cardiac and hepatic enzymes, lactic acidosis, and shock, and a high mortality rate (of 10%–40%), which was proportional to the daily intake of beer. 2
  • Some patients may recover function after removal of the cobalt source and normalization of the levels. However, some patients, like our patient, continue to have deterioration of function despite lower Cobalt levels requiring mechanical support and heart transplant.

Infographic made by the team (Made with BioRender – license included)

References – Cobalt Cardiomyopathy1. Singh M, Krishnan M, Ghazzal A, et al. From Hip to Heart: A Comprehensive Evaluation of an Infiltrative Cardiomyopathy. CJC Open. 2021;3(11):1392-1395. https://www.ncbi.nlm.nih.gov/pubmed/34901809

1. Packer M. Cobalt Cardiomyopathy. Circ Heart Fail. 2016;9(12):e003604. https://www.ahajournals.org/doi/epub/10.1161/CIRCHEARTFAILURE.116.003604

2. Mercier G, Patry G. Quebec beer-drinkers’ cardiomyopathy: clinical signs and symptoms. Can Med Assoc J. 1967;97(15):884-888. https://pubmed.ncbi.nlm.nih.gov/6051257/

3. Oldenburg M, Wegner R, Baur X. Severe cobalt intoxication due to prosthesis wear in repeated total hip arthroplasty. J Arthroplasty. 2009;24(5):825.e15-20. https://www.ncbi.nlm.nih.gov/pubmed/18835128

4. Tower SS. Arthroprosthetic cobaltism: neurological and cardiac manifestations in two patients with metal-on-metal arthroplasty: a case report. J Bone Joint Surg Am. 2010;92(17):2847-2851. https://www.ncbi.nlm.nih.gov/pubmed/21037026

5. Casian M, Bica R, Ionescu V, Predescu V, Țincu R, Jurcuț R. Too young for an acquired cardiomyopathy? Cobalt metallosis as a cardiac amyloidosis mimicker. ESC Heart Fail. 2024;11(2):1236-1241. https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14695

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The following question refers to Section 2.2 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by University of Colorado internal medicine resident Dr. Hirsh Elhence, answered first by University of Chicago advanced heart failure cardiologist and Co-Chair for the CardioNerds Critical Care Cardiology Series Dr. Mark Belkin, and then by expert faculty Dr. Mark Drazner.

Dr. Drazner is an advanced heart failure and transplant cardiologist, Professor of Medicine, and Clinical Chief of Cardiology at UT Southwestern. He is the President of the Heart Failure Society of America.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #35

| A 50-year-old woman with a history of congestive heart failure, hypertension, type 2 diabetes mellitus, and obstructive sleep apnea presents to the outpatient clinic to follow up on her heart failure management. One year prior, echocardiogram showed an ejection fraction of 30% with an elevated BNP, for which she was started on appropriate GDMT. Repeat echocardiogram today showed an EF of 50%. Which of the following best describes her heart failure status? | | A | HFrEF (HF with reduced EF) | | B | HFimpEF (HF with improved EF) | | C | HFmrEF (HF with mildly reduced EF) | | D | HFpEF (HF with preserved EF) |

Answer #35

| Explanation | The correct answer is B – HFimpEF, or heart failure with improved ejection fraction, best describes her current heart failure status.Left ventricular ejection fraction is an important factor in classifying heart failure given differences in prognosis, response to treatment, and use in clinical trial enrollment criteria.The classification of heart failure by EF (adopted from the Universal Definition of HF):– HFrEF (HF with reduced EF): LVEF ≤40%– HFimpEF (HF with improved EF): previous LVEF ≤40%, a ≥10% increase from baseline LVEF, and a second measurement of LVEF >40%.– HFmrEF (HF with mildly reduced EF): LVEF 41%–49%, andevidence of spontaneous or provokable increased LV filling pressures (e.g., elevated natriuretic peptide, noninvasive and invasive hemodynamic measurement)– HFpEF (HF with preserved EF): LVEF ≥50%, and evidence of spontaneous or provokable increased LV filling pressures (e.g., elevated natriuretic peptide, noninvasive and invasive hemodynamic measurement)Patients with HFmrEF are usually in a dynamic state of improving from HFrEF or deteriorating towards HFrEF. Therefore, patients with HFmrEF may benefit from follow-up evaluation of systolic function and etiology of sub-normal EF.Improvements in EF are associated with better outcomes but do not indicate full myocardial recovery or normalization of LV function. Indeed, structural and functional abnormalities such as LV dilation and systolic or diastolic dysfunction often persist. Moreover, EF may remain dynamic with fluctuations in either direction depending on factors such as GDMT adherence and re-exposure to cardiotoxic agents. As such, the term heart failure with “improved EF” was deliberately chosen over “recovered EF” and “preserved EF”. Importantly, in patients with HFimpEF while on GDMT, the EF may decrease after withdrawal of GDMT. | | Main Takeaway | Classification of Heart failure helps direct and track management. | | Guideline Loc. | Section 2.2 |

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CardioNerds Cardio-Rheumatology Series Co-Chairs Dr. Rick Ferraro, Dr. Gurleen Kaur, and and Dr. Bree Hansen discuss how to decipher cardiovascular risk in patients with rheumatological conditions with cardio-rheumatology experts Dr. Brittany Weber and Dr. Michael Garshick.

In this episode, Drs. Weber and Garshick take us through the role of inflammation in patients with rheumatologic conditions and cardiovascular disease. They discuss the increased prevalence of traditional cardiac risk factors in this population and how these standard cardiac risk factors do not account for the full extent of cardiovascular risk. Dr. Bree Hansen drafted show notes. Audio editing by CardioNerds intern Christiana Dangas.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

This episode is supported by the5th Annual Going Back to the Heart of Cardiology (A MedscapeLIVE Conference). Join co-chairs Dr. Robert Harrington and Dr. Fatima Rodriguez January 24-26, 2025 at the Fontainebleau Hotel in Miami Beach, Florida.

The agenda will explore the latest advancements in cardiology including cardiovascular prevention, atherosclerosis and thrombosis, cardiovascular dysfunction, arrhythmias, and valvular heart disease. Network, attend engaging presentations by renowned cardiologists, visit the exhibit and poster hall, participate in an exclusive immersive experience, and earn up to 13 CME/CE credits.

Register today with code CARDIONERDS for 30% OFF your registration. Click here for more information.

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Pearls – Cardio-Rheumatology – Deciphering Cardiovascular Risk in Patients with Rheumatological Conditions1. Cardiovascular disease prevalence: cardiovascular disease is common in patients with autoimmune rheumatologic disease; therefore, we must take every opportunity to screen patients early. 2. Limitations of Traditional Scores: conventional risk calculators often underestimate cardiovascular risk for autoimmune disease patients, necessitating additional methods to assess risk accurately. 3. Integration of Disease-Specific Biomarkers: using biomarkers specific to autoimmune diseases, such as lupus, enhances risk assessment and helps in tailoring treatment strategies. 4. Value of Imaging and Risk Enhancers: incorporating imaging (like CAC scoring and carotid ultrasound) and evaluating additional risk factors (such as lipoprotein(a) and high-sensitivity CRP) provides a more comprehensive view of cardiovascular risk and guides more effective management.

Show notes – Cardio-Rheumatology – Deciphering Cardiovascular Risk in Patients with Rheumatological ConditionsShow notes (Drafted by Dr. Bree Hansen):

How does inflammation contribute to atherosclerosis, specifically in autoimmune rheumatologic diseases like psoriasis?

• Lipids need to enter the intimal space of blood vessels, which can be facilitated by endothelial damage caused by chronic cytokine stimulation, such as TNF or IL-6. Once in the intima, lipids are recognized as foreign, leading to the recruitment of monocytes that transform into macrophages to clear these lipids. However, this process often exacerbates the problem, leading to persistent inflammation and atherosclerotic plaque formation.
• Specifically, in psoriasis, the endothelial damage is particularly pronounced due to cytokines like TNF, IL-17, and interferons. The inflammasome pathway, which is highly active in psoriasis, also contributes to endothelial damage. Additionally, hyperactivated platelets in psoriasis can further damage the endothelium and contribute to atherosclerosis.
• Overall, atherosclerosis results from a combination of traditional risk factors and systemic inflammation, leading to the development of cardiovascular disease.

Which traditional cardiovascular risk factors are increased in patients with rheumatologic conditions?

• Patients with autoimmune diseases may be up to > three times more likely to develop cardiovascular disease, similar to the risk of type 2 diabetes; therefore, it is important to screen patients with autoimmune rheumatologic disorders for cardiovascular disease
• Most common cardiovascular risk factors, such as smoking, diabetes, hypertension, and dyslipidemia, are also increased in patients with autoimmune rheumatologic disorders. Smoking, specifically, is highly prevalent in psoriasis and exhibits a dose-response relationship with psoriasis severity.
• Hyperlipidemia is another common risk factor present in patients with autoimmune rheumatologic disease; however, a “lipid paradox” also exists. The “lipid paradox,” where lower LDL (low-density lipoprotein) levels are associated with higher inflammation, seems counterintuitive since lower LDL is often thought to indicate lower cardiovascular risk. This paradox is particularly well-documented in rheumatoid arthritis (RA) but may apply to various other conditions as well. In clinical practice, it’s important to assess lipid levels not only during periods of high inflammation but also when the patient is in a state of disease remission or stability. This is because lipid levels can fluctuate based on the level of inflammation and the medications a patient takes, such as biologics.

How can cardiovascular disease risk be estimated in patients with rheumatologic conditions beyond that of traditional risk factor calculators?

• Traditional cardiovascular risk scores like the Framingham Risk Score and ACC/AHA Pool Cohort Equation often underestimate risk, particularly for patients with autoimmune diseases. Risk calculators in women with RA underestimated cardiovascular risk at least 2‐fold.
• The Run-On Risk Score includes inflammatory markers like CRP but can still fall short in risk assessment. While some specialized calculators like The British SCORE2 system, which initially included rheumatoid arthritis (RA), and later QRISK3, which added lupus and steroid use, include these autoimmune conditions, no standard tool is universally applied for these diseases. Therefore, clinicians need to integrate multiple data sources to assess risk effectively
• Recent research, such as a study from Dr. Weber’s group, has highlighted that incorporating lupus-specific biomarkers such as persistently positive double-stranded DNA, low complement levels, and lupus anticoagulant into risk calculators improves risk prediction for lupus patients.
• Thus, beyond traditional risk factors, clinicians should assess disease duration, activity biomarkers, and the impact of treatments (including medications like hydroxychloroquine that have potential cardiotoxicity). Clinicians should also use other risk enhancers, like lipoprotein(a) and high-sensitivity CRP, and consider imaging techniques like coronary artery calcium (CAC) scoring to evaluate atherosclerotic burden. Elevated lipoprotein(a) levels and high CAC scores indicate higher risk, even if traditional risk scores suggest otherwise.

References – Deciphering Cardiovascular Risk in Patients with Rheumatological ConditionsConrad N, Verbeke G, Molenberghs G, et al. Autoimmune diseases and cardiovascular risk: a population‐based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK. Lancet. 2022;400:733–743.

Crowson CS, Liao KP, Davis JM 3rd, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166(4):622-628.e1. doi:10.1016/j.ahj.2013.07.010

Garshick MS, Ward NL, Krueger JG, Berger JS. Cardiovascular Risk in Patients With Psoriasis: JACC Review Topic of the Week. J Am Coll Cardiol. 2021;77(13):1670-1680. doi:10.1016/j.jacc.2021.02.009

Weber, B, Paik, J, Aghayev, A. et al. Novel Imaging Approaches to Cardiac Manifestations of Systemic Inflammatory Diseases: JACC Scientific Statement. JACC. 2023 Nov, 82 (22) 2128–2151. https://doi.org/10.1016/j.jacc.2023.09.819

Mortensen M, Jensen J, Sand N, et al. Association of Autoimmune Diseases with Coronary Atherosclerosis Severity and Ischemic Events. JACC. 2024. Jun, 83 (25) 2643-2654. Doi: 10.1016/j.jacc.2024.04.030

Choi M, Guan H, Yoshida K, et al. Personalizing cardiovascular risk prediction for patients with systemic lupus erythematosus. Seminars in Arthritis and Rheumatism. 2024. Aug:67:152468. Doi: 10.1016/j.semarthrit.2024.152468.

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CardioNerds Dan Ambinder and Dr. Devesh Rai join cardiology fellows and National Lipid Association lipid scholars Dr. Jelani Grant from Johns Hopkins University and Dr. Alexander Razavi from Emory University. They discuss a case involving a patient with familial hypercholesterolemia. Dr. Archna Bajaj from University of Pennsylvania provides expert commentary. Drs. Jelani Grant and Alexander Razavi drafted notes. CardioNerds Intern Pacey Wetstein engineered episode audio.

This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos.

A classic finding in patients with familial hypercholesterolemia is the presence of markedly elevated levels of total and low-density lipoprotein cholesterol (LDL-C) with an LDL-C concentration of 190 mg/dL or greater. However, severe hypercholesterolemia is not inevitably present, and many patients who carry this diagnosis may have lower LDL-C levels. This case history describes a young woman whose mother and brother met clinical and genetic criteria for heterozygous familial hypercholesterolemia but who had only a mild elevation in LDL-C, falling to 130 mg/dL after dietary intervention. Despite this finding, genetic testing revealed the presence of the same genetic variants as were noted in her mother and brother. In addition, a second genetic variant predisposing them to cholesterol gallstone formation was identified in all three family members. If genetic testing had not been performed, the diagnosis may have been missed or delayed, resulting in an increased risk for vascular complications associated with familial hypercholesterolemia. This case supports the value of genetic testing of family members of those with familial hypercholesterolemia, even when LDL-C levels are not severely elevated.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Pearls – Exposing an Unusual Presentation of Familial Hypercholesterolemia – National Lipid Association1. Familial hypercholesterolemia (FH) is among the most common autosomal co-dominant genetic conditions (approximately 1:200 to 1:300 for HeFH, 1:160,000 to 1:300,000 for HoFH). 2. Genetic testing has a role for all first-degree relatives when a family history of FH is strongly suggestive, regardless of LDL-C level. 3. Heterogeneity in ASCVD risk among individuals with FH is derived from background polygenic risk, clinical risk factors (e.g., timing of lipid-lowering initiation and adjacent risk factors), as well as subclinical atherosclerosis burden. 4. In clinical or genetically confirmed FH, an LDL-C goal of 55 mg/dL is recommended. 5. Beyond statins, FDA-approved non-statin therapies for FH include ezetimibe, PCSK9 mAb, bempedoic acid, inclisiran, evolocumab (only HoFH), lomitapide (only HoFH), and LDL apheresis.

Notes – Exposing an Unusual Presentation of Familial Hypercholesterolemia – National Lipid AssociationWhat are the diagnostic criteria for FH?

Dutch Lipid Clinic Network1

• Variables: family history, clinical history, physical exam, LDL-C level, DNA (LDLR, APOB, PCSK9)

Simon-Broome1

• Variables: total or LDL-C, physical exam, DNA (LDLR, APOB, PCSK9), family history
• Emphasis on clinical history and physical exam reduces sensitivity

U.S. Make Early Diagnosis Prevent Early Death (MEDPED) 1

• Only one of the three where no genetic testing is required, may work well in cascade screening
• Variables: age, total cholesterol, family relative (and degree) with FH
• Definite, probable, possible, unlikely
• Emphasis on clinical history and physical exam reduces sensitivity

How does FH affect CAD risk?

• There is about a 20-fold higher risk of premature CHD in FH without treatment2
• For any CHD3
  • As high as 100-fold greater risk in young men with FH
  • Risk is lower in women versus men (approximate 10-year age difference in development)
• Up to one-half of men and one-third of women with FH will suffer fatal or non-fatal coronary events before age 50 and 60 years old, respectively 4
• Despite this high risk, it is important to note heterogeneity in FH that can be attributable to:
  • Polygenic risk
  • Timing of lipid-lowering therapy initiation
  • Adjacent risk factors
  • Subclinical atherosclerosis burden 5 6 7

What is the role of genetic testing in FH?

• Clinical value of genetic testing:
  • Providing prognostic information
  • Promotes initiation and adherence of lipid-lowering therapies
  • Serves as a basis for more effective cascade screening
• Heterogeneity in FH may be attributable to other genes that regulate LDL-C, but which are not tested as part of the FH gene panel. For example, there are polygenic risk scoring systems to gauge the relative impact on LDL-C; however, this is not routinely done, but potentially impactful

Provide guideline-based recommendations for treatment

• Beyond statins, FDA-approved non-statin therapies for FH include: ezetimibe, PCSK9 mAb, bempedoic acid, inclisiran, evinacumab (only HoFH), lomitapide (only HoFH), and LDL apheresis8.
• Based on the 2022 ACC Expert Consensus Decision Pathway for Non-Statin Therapy, an LDL-C goal of <55 mg/dL is recommended for individuals with a clinical or genetic diagnosis of FH 8

When should a patient be referred to a lipid specialist?

*Based on 2022 ACC ECDP 8

• Any patient with ASCVD
• Baseline LDL >190 mg/dL
• Inadequate reduction of LDL-C (>50% and LDL-C <70 mg/dL or non-HDL-C <100 mg/dL)
• Intolerance to at least two statin therapies, with an attempt to initiate FDA-approved lowest dose of statin and a trial of an alternative statin therapy regimen such as every other day dosing

References1. Vallejo-Vaz AJ, Ray KK. Epidemiology of familial hypercholesterolaemia: Community and clinical. Atherosclerosis. 2018;277. doi:10.1016/j.atherosclerosis.2018.06.855
Link to article 2. Austin MA, Hutter CM, Zimmern RL, Humpries SE. Familial hypercholesterolemia and coronary heart disease: A HuGE association review. Am J Epidemiol. 2004;160(5). doi:10.1093/aje/kwh237
Link to article 3. Watts GF, Lewis B, Sullivan DR. Familial hypercholesterolemia: A missed opportunity in preventive medicine. Nat Clin Pract Cardiovasc Med. 2007;4(8). doi:10.1038/ncpcardio0941
Link to article 4. Marks D, Thorogood M, Neil HAW, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1). doi:10.1016/S0021-9150(02)00330-1
Link to article 5. Mszar R, Grandhi GR, Valero-Elizondo J, et al. Absence of Coronary Artery Calcification in Middle-Aged Familial Hypercholesterolemia Patients Without Atherosclerotic Cardiovascular Disease. JACC Cardiovasc Imaging. 2020;13(4). doi:10.1016/j.jcmg.2019.11.001
Link to article 6. Miname MH, Bittencourt MS, Moraes SR, et al. Coronary Artery Calcium and Cardiovascular Events in Patients With Familial Hypercholesterolemia Receiving Standard Lipid-Lowering Therapy. JACC Cardiovasc Imaging. 2019;12(9). doi:10.1016/j.jcmg.2018.09.019
Link to article 7. Sandesara PB, Mehta A, O’Neal WT, et al. Clinical significance of zero coronary artery calcium in individuals with LDL cholesterol ≥190 mg/dL: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. Published online 2020. doi:10.1016/j.atherosclerosis.2019.09.014
Link to article 8. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-1418. doi:10.1016/j.jacc.2022.07.006
Link to article

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CardioNerds Cofounder Dr. Amit Goyal, Chair of the CardioNerds Heart Failure Committee Dr. Jenna Skowronski, and Episode FIT Lead Dr. Shazli Khan discuss iron deficiency and its impact on heart failure with Dr. Robert Mentz, Chief of Heart Failure at Duke University and principal investigator of the HEART-FID trial. In this case-based discussion, they cover the diagnostic criteria of iron deficiency in heart failure, epidemiology, and strengths and limitations of different iron formulations. They also review clinical trials examining the impact of iron deficiency on quality of life, heart failure hospitalizations, and mortality. Importantly, they stress the relevance of iron metabolism in heart failure, irrespective of the presence of anemia. They also discuss the approach to addressing outpatient management of iron in heart failure and future directions of research needed in this domain.

Notes were drafted by Dr. Shazli Khan, and Dr. Daniel Ambinder engineered episode audio.

Click here for CME.

This episode was created in collaboration with the Cardiometabolic Health Congress and is supported by an educational grant from American Regent. Please follow the link in the show notes for free CME. All CardioNerds education is planned, produced, and reviewed by CardioNerds.

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Pearls – Iron Deficiency in Heart Failure Think about iron deficiency in ALL patients with heart failure and send appropriate diagnostic labs, even if there is no evidence of anemia! * Iron deficiency in heart failure* has a specific and distinguished definition, defined as a ferritin level of <100 ng/mL, or a ferritin level between 100-300 ng/mL with a transferrin saturation of <20%. * Data thus far suggests that treatment of iron deficiency in heart failure results in improved quality of life, as well as a probable reduction in heart failure hospitalizations, and that administration of intravenous iron has a favorable safety profile. * Not all formulations of iron are created equal – intravenous iron formulations have been shown to be effective in this population, but oral iron therapy has not. * Management of iron deficiency in the outpatient setting is an evolving area of research, but patients should typically receive surveillance labs and additional treatment with IV iron if indicated.

Show notes – Iron Deficiency in Heart FailureHow is iron deficiency in heart failure defined, and how prevalent is iron deficiency in this patient population?

• Iron deficiency is common in patients with heart failure, with an estimated prevalence of 50-60%.
  • Iron deficiency in heart failure is associated with worse outcomes, including increased hospitalization and mortality and poorer functional status and quality of life.
  • Iron deficiency in heart failure is defined as a ferritin level of <100 ng/mL or a ferritin level of 100-300 ng/mL plus a transferrin saturation of <20%.
  • There is an evolving school of thought that suggests transferrin saturation alone may be the best indicator of iron deficiency in heart failure, but more data are needed.

Importantly, iron deficiency in heart failure can be seen in patients with both reduced and preserved ejection fraction. Which patients should be screened for iron deficiency?

• There is a class I indication to send iron studies in all patients with heart failure as a part of the initial diagnostic work-up for the underlying etiology of the cardiomyopathy, as well as to assess for the presence of iron deficiency.
  • The presence of anemia is not required to check iron studies, as many patients with iron deficiency in heart failure may not have concomitant anemia.
  • That is, all patients with heart failure should be evaluated for iron deficiency, irrespective of the presence of anemia.

What are the hypothesized mechanisms of iron deficiency in heart failure, and how does iron deficiency impact patients with heart failure?

• Mechanisms causing iron deficiency in heart failure are multifactorial, including reduced oral intake, reduced gut absorption, reduced iron availability due to sequestration, and increased loss due to higher rates of bleeding.
  • Nutritional variation is one proposed mechanism, as patients living with heart failure tend to take in less iron in their diet, and the iron consumed tends to be less easily absorbed.
  • Due to chronic inflammation, there are increased levels of iron sequestration in cells in patients with heart failure, rendering the available iron stores unable to be used.
  • Patients with chronic heart failure also tend to be on anti-platelet agents and/or anticoagulants (due to often-occurring comorbidities), which may potentially lead to bleeding complications, consequently causing iron deficiency.
  • Iron deficiency has been associated with decreased exercise tolerance and functional status, worse quality of life, and increased risk of heart failure hospitalizations.

What are the key takeaways of the clinical trials done in patients with heart failure and iron deficiency?

• The FAIR-HF trial published in 2009 demonstrated that treatment with IV ferrous carboxymaltose (FCM) in patients with heart failure led to improved symptoms and quality of life with an acceptable safety profile. These benefits were verified in a follow-up study known as CONFIRM-HF, demonstrating improvement in 6MWT and functional capacity.
  • The AFFIRM-AHF trial investigated IV FCM in patients with iron deficiency and a left ventricular ejection fraction of <50%. It was a neutral trial with no significant improvement in their primary endpoint, a composite of hospitalization and death. The trial did demonstrate the safety of FCM and decreased hospitalizations. Of note, this trial was significantly impacted by the COVID pandemic, which may have affected the results.
  • The IRONMAN trial was similar in design to AFFIRM-AHF but used a different iron formulation (iron derisomaltose) and had similar findings.
  • The HEART-FID trial was a larger study including 3000 patients with HFrEF investigating treatment with IV ferric carboxymaltose every six months if the patients remained iron deficient. The primary endpoint was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. While it was considered a neutral trial with a p=0.019 with a prespecified significance level of 0.01, it demonstrated a trend to improved mortality and six-minute walk.

Which patients should we treat with iron, and with what formulation? What do the guidelines recommend?

• Patients who have chronic heart failure on maximally tolerated guideline-directed medical therapy with iron deficiency are candidates for intravenous iron supplementation with the goal of improving quality of life and reducing heart failure hospitalizations.
  • Intravenous iron has been shown to be effective, but oral iron therapy has shown no benefit in trials.
  • Per the updated 2023 ESC guidelines, there is a class IA recommendation to provide intravenous iron supplementation in symptomatic patients with heart failure with reduced and mid-range ejection fraction with iron deficiency to both alleviate HF symptoms and improve quality of life.
  • There is a class IIA recommendation to provide supplementation to reduce heart failure hospitalizations.
  • Surveillance labs in the outpatient setting, combined with continued treatment for persistent iron deficiency, are likely beneficial in patients with heart failure.

References – Iron Deficiency in Heart Failure1. Packer M, Anker SD, Butler J, et al. Identification of three mechanistic pathways for iron-deficient heart failure. Eur Heart J. 2024;45(26):2281-2293. doi:10.1093/eurheartj/ehae284. https://academic.oup.com/eurheartj/article/45/26/2281/7668668 * Salah HM, Savarese G, Rosano GMC, et al. Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis. ESC Heart Fail. 2023;10(2):1473-1480. doi:10.1002/ehf2.14310. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053151/ * Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895-1904. doi:10.1016/S0140-6736(20)32339-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32339-4/abstract * Kalra PR, Cleland JGF, Petrie MC, et al; IRONMAN Study Group. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400(10369):2199-2209. doi:10.1016/S0140-6736(22)02083
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02083-9/fulltext * Mentz RJ, Garg J, Rockhold FW, et al; HEART-FID Investigators. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. N Engl J Med. 2023;389(11):975-986. doi:10.1056/NEJMoa2304968. https://www.nejm.org/doi/full/10.1056/NEJMoa2304968 * McDonagh TA, Metra M, Adamo M, et al; ESC Scientific Document Group. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195. Erratum in: Eur Heart J. 2024;45(1):53. doi:10.1093/eurheartj/ehad613. https://academic.oup.com/eurheartj/article/44/37/3627/7246292?login=false * Anker SD, Comin Colet J, Filippatos G, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency. N Engl J Med. 2009;361(25):2436-2448. doi:10.1056/NEJMoa0908355. https://www.nejm.org/doi/full/10.1056/NEJMoa0908355 * Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657-668. doi:10.1093/eurheartj/ehu385. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359359/

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CardioNerds Cardio-Rheumatology Series Co-Chairs Dr. Rick Ferraro, Dr. Gurleen Kaur, and Episode Lead Dr. Ronaldo Correa discuss “The Role of Inflammation in Cardiovascular Disease” with Dr. Antonio Abbate.

Join the CardioNerds as they kick off the Cardio-Rheumatology series with Dr. Antonio Abbate. In this episode, Dr. Abbate, a leading expert in cardio-immunology, discusses the role of inflammation in cardiovascular disease. We explore the molecular mechanisms linking inflammation to atherosclerosis, the impact of chronic low-grade systemic inflammation on heart disease, and potential therapeutic targets. Dr. Abbate shares insights on how genes and lifestyle factors contribute to inflammation, the use of inflammatory markers in clinical practice, and emerging anti-inflammatory therapies in atherosclerotic cardiovascular disease. Tune in for an enlightening conversation on the intersection of inflammation and cardiovascular health.

Dr. Ronaldo Correa drafted the notes. Episode audio was engineered by Dr. Amit Goyal.

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Pearls – Cardio-Rheumatology: The Role of Inflammation in Cardiovascular Disease1. Inflammation is key in the pathogenesis and progression of atherosclerosis. Estimating systemic inflammation is part of a comprehensive preventive assessment (primary/secondary). 2. Patients with autoimmune inflammatory diseases are at a higher risk for cardiovascular events. 3. C-reactive protein (CRP) can estimate systemic inflammation and help assess residual inflammatory risk in patients with traditional intermediate/low cardiovascular disease, guiding management consideration with lipid-lowering therapy, aspirin, and colchicine. 4. The pharmacological management of atherosclerosis is evolving beyond primarily lipid-lowering therapies to focus on targeting the underlying residual inflammatory process. Colchicine (inflammasome blocker as an anti-mitotic drug) is approved for use in chronic stable CVD in selected cases, and interleukin pathway blockers, especially IL-1 and IL-6, are under clinical trial investigation. 5. First things first! Prioritize treating and optimizing traditional risk factors and comorbidities and emphasize lifestyle modifications to reduce cardiovascular disease (control diabetes and hypertension, reduce or cease smoking/alcohol, lose weight, and engage in regular physical activity). They all impact inflammation directly or indirectly

Show notes – Cardio-Rheumatology: The Role of Inflammation in Cardiovascular DiseaseNotes: Notes drafted by Dr. Ronaldo Correa.

What is the link between inflammation and cardiovascular atherosclerosis?

• Inflammation is involved both in the pathogenesis and progression of atherosclerosis.
  • Histopathological coronary atherosclerosis studies have demonstrated the presence of inflammatory mediators as well as a central role of factors of innate immunity such as macrophages and T cells which can interact with vascular smooth muscle cells in the progression of atherosclerotic plaque.
  • Patients with autoimmune inflammatory conditions have earlier and higher cardiovascular event rates (accelerated atherosclerosis due to residual inflammatory risk).
  • Elevated inflammatory markers (for example, high CRP) predict cardiovascular events.

How should inflammation be considered in the context of residual cardiovascular risk?

• Inflammation may be the inciting factor in atherosclerosis, or it may amplify the process driven primarily by other risk factors. Therefore, treating the comorbidities and traditional CVD contributors is key to reducing the vicious inflammatory cycle.
  • Assessing residual risk using inflammatory markers can assist in management. C-reactive protein (CRP) can estimate systemic inflammation and help assess residual inflammatory risk in patients with traditional intermediate/low cardiovascular disease, guiding management consideration with lipid-targeting therapies, aspirin, and colchicine.
  • Optimizing traditional risk factors, emphasizing appropriate treatment for hypertension, diabetes, dyslipidemia, weight loss, obstructive sleep apnea (OSA), depression, underlying inflammatory conditions, and lifestyle modifications such as consuming a Mediterranean diet, alcohol/smoking reduction/cessation, and getting regular physical activity can help directly and indirectly reduce inflammatory contributors.

How does inflammation contribute to thrombosis, and what are the implications for cardiovascular disease?

• Inflammation increases the expression of procoagulant factors through the inflammasome pathway, including mediators like IL-6.
  • Proinflammatory changes in endothelial cells, leukocytes, and platelets promote thrombosis.
  • The concept of immunothrombosis has emerged, especially highlighted by conditions like COVID-19.
  • Inflammation-induced thrombosis has significant implications for cardiovascular disease.

What are the key inflammatory pathways involved in atherosclerosis, and what therapeutic targets have emerged?

• The inflammatory process is complex, and we still have much to learn about it. Three inflammatory therapeutic targets are highlighted: NLRP3 inflammasome, IL-1, and IL-6.
  • Colchicine is an NLRP3 inflammasome blocker that is FDA-approved as an add-on medication for secondary ischemic prevention in patients with stable CAD who remain at higher risk despite optimal medical therapy with aspirin and statin.
  • The CANTOS trial showed a significant reduction in MACE and hsCRP in post-MI patients who received canakinumab (IL-1 inhibitor) as an add-on therapy.
  • The ZEUS trial is investigating Ziltivekimab (an IL-6 inhibitor) for secondary ASCVD prevention. Rilonacept (an IL-1 inhibitor) is FDA-approved for recurrent pericarditis based on the RHAPSODY trial. Ongoing trials are further exploring inflammation-targeting therapies for the treatment of cardiovascular disease.

References – Cardio-Rheumatology: The Role of Inflammation in Cardiovascular DiseaseEngelen SE, Robinson AJB, Zurke YX, Monaco C. Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?. Nat Rev Cardiol. 2022;19(8):522-542. doi:10.1038/s41569-021-00668-4

Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 2022;7(1):131. Published 2022 Apr 22. doi:10.1038/s41392-022-00955-7

Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387-401. doi:10.1038/s41569-020-0352-5

Sage AP, Tsiantoulas D, Binder CJ, Mallat Z. The role of B cells in atherosclerosis. Nat Rev Cardiol. 2019;16(3):180-196. doi:10.1038/s41569-018-0106-9

Suero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022;4(5):598-615. Published 2022 Dec 20. doi:10.1016/j.jaccao.2022.11.011

Zhao TX, Mallat Z. Targeting the Immune System in Atherosclerosis: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(13):1691-1706. doi:10.1016/j.jacc.2018.12.083

Geovanini GR, Libby P. Atherosclerosis and inflammation: overview and updates. Clin Sci (Lond). 2018;132(12):1243-1252. Published 2018 Jun 21. doi:10.1042/CS20180306

Fragoulis GE, Soulaidopoulos S, Sfikakis PP, Dimitroulas T, D Kitas G. Effect of Biologics on Cardiovascular Inflammation: Mechanistic Insights and Risk Reduction. J Inflamm Res. 2021;14:1915-1931. Published 2021 May 14. doi:10.2147/JIR.S282691

Giles JT, Sattar N, Gabriel S, et al. Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial. Arthritis Rheumatol. 2020;72(1):31-40. doi:10.1002/art.41095

Del Buono MG, Bonaventura A, Vecchié A, et al. Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1. Eur J Clin Invest. 2024;54(2):e14110. doi:10.1111/eci.14110

Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease. Circ Res. 2020;126(9):1260-1280. doi:10.1161/CIRCRESAHA.120.315937

Toldo S, Abbate A. The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nat Rev Cardiol. 2024;21(4):219-237. doi:10.1038/s41569-023-00946-3

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CardioNerds (Drs. Teodora Donisan, Jenna Skowronski, and Johnny Hourmozdi) discuss Cardiomyopathies with Dr. Steve Ommen. Through a case-based discussion, we review the diagnostic evaluation of suspected restrictive cardiomyopathy, and Dr. Ommen shares his expertise in the nuances of caring for patients with hypertrophic cardiomyopathy, from counseling to pharmacologic, device, and septal reduction therapies. We cover the foundations of diagnosis and management that will be helpful to CardioNerds preparing to encounter hypertrophic cardiomyopathy on the boards or on the wards.

Dr. Johnny Hourmozdi drafted notes. The audio was engineered by Dr. Atefeh Ghorbanzadeh.

The CardioNerds Beyond the Boards Series was inspired by the Mayo Clinic Cardiovascular Board Review Course and designed in collaboration with the course directors Dr. Amy Pollak, Dr. Jeffrey Geske, and Dr. Michael Cullen.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – Cardiomyopathies1. The presence of an S4 and a rapid y-descent in the jugular venous pulsation on exam should clue you to the presence of a restrictive filling pattern. Restrictive filling doesn’t necessarily mean restrictive cardiomyopathy and is more commonly due to dilated or ischemic cardiomyopathy. 2. The five main topics of counseling that every hypertrophic cardiomyopathy (HCM) patient should understand: (1) Prognosis, (2) Family Screening, (3) Risk of Sudden Death, (4) Treatments, and (5) Physical Activity. 3. Remember 1/3: In clinical trials of cardiac myosin inhibitors for HCM (mavacamten), about a third of patients had a tremendous improvement in symptoms, another third had some improvement, and the final third had no improvement or had to discontinue the drug due to negative inotropy. 4. When counseling patients about septal reduction therapy, consider the patient’s age. For younger patients, surgical myectomy at an experienced center offers a higher success rate and greater durability with lower rates of pacemaker placement when compared to alcohol septal ablation. 5. Historically, the conclusion that it was higher risk to be an athlete with HCM was unfortunately generalized to mean that it was high risk to exercise for patients with HCM. “And we turned a generation of HCM patients into HCM cardiometabolic syndrome patients, which is actually a worse combination.”

Notes – CardiomyopathiesWhat is the initial approach to evaluating a patient with new or suspected cardiomyopathy, including hypertrophic cardiomyopathy (HCM)?

• A history and physical exam, including a thorough past medical and family history, is always the first step and helps determine the patient’s risk for potential underlying etiologies, including genetic cardiomyopathies, hypertrophic cardiomyopathy, or those related to treatments of previous cancer.
• In terms of ECG findings, pay attention to QRS voltage (high or low) and the presence of any arrhythmias.
• TTE should be obtained in all patients and is often sufficient to diagnose many underlying cardiomyopathies, including HCM.
• Cardiac MRI (CMR) is helpful as an adjunct when TTE alone is inconclusive or imaging quality is poor. CMR can help provide a better idea of chamber sizes and wall thickness, and late gadolinium contrast enhancement (LGE) can also be helpful if present in a specific pattern, though often HCM patients may have non-specific patterns of LGE.
• Invasive hemodynamics assessment is reserved for patients with discordance between non-invasive testing and the clinical impression. It can also be useful to guide the management of heart failure, especially in advanced disease.

How do you treat patients with hypertrophic obstructive cardiomyopathy (HOCM)?

• In patients with HCM and LVOT obstruction (defined as a resting peak LVOT gradient >30 mmHg), we want to avoid medications that increase inotropy, reduce preload (diuretics), or reduce afterload (pure vasodilators).
• First-line medical therapies for symptomatic HOCM include non-vasodilating beta-blockers (e.g., metoprolol) and/or non-dihydropyridine calcium channel blockers (e.g., diltiazem, verapamil).
• For those with symptoms despite the above first-line medications, second-line therapies include the addition of disopyramide or the newer myosin inhibitors (e.g., mavacamten).
• In patients who don’t respond to medical therapies, a referral should be made for septal reduction therapy at an experienced center. Surgical myectomy involves open heart surgery and has a success rate of 90-95% with a durable result. Alcohol septal ablation can be done percutaneously and offers a shorter recovery time, but it has a lower success rate of 75-85%. Septal ablation comes with a similar risk of stroke and mortality compared to surgery (<0.5%) and with a higher rate of pacemaker implantation (5-10% vs 3%).

How should patients with HCM be counseled with regard to physical activity and exercise?

• Observational studies suggest an increased risk of sudden cardiac death among athletes with HCM as compared to those without HCM. Among patients with HCM, it is less clear whether there is an association between gradations of physical activity and risk for SCD.
• For patients with HCM, the safety and benefits of low to moderate-intensity exercise for cardiovascular health and fitness are established. The 2024 HCM guidelines recommend counseling patients to engage in 150-300 minutes of low-moderate intensity exercise per week in keeping with physical activity guidelines for the general population (Class 1, LOE B-R).
• For athletes looking to engage in vigorous exercise or competitive sport, shared decision-making with an expert in HCM is recommended. For most patients, universal restriction from this level of exercise is not indicated.

What is the approach to genetic testing and family screening for HCM?

• All patients with a clinical diagnosis of HCM should be offered genetic testing with a gene panel test. Genetic testing results can help with family screening and may inform prognosis but do not currently impact therapy decisions for the patient.
• In those where a pathogenic or likely pathogenic variant is identified, cascade testing for this variant should be offered to first-degree relatives. If no variant or a variant of unknown significance (VUS) is identified, then periodic echocardiographic screening should be performed instead in all first-degree relatives.
• For adults, screening ECG and TTE in first-degree relatives should begin when a family member has been diagnosed with HCM and be repeated every 3-5 years.
• For children and adolescents, initiation of screening should be no later than the onset of puberty and be repeated every 1-2 years.

Who should be offered an implantable cardiac defibrillator (ICD) for prevention of sudden cardiac death?

• There are “three layers of eligibility” for an ICD among patients with HCM, corresponding with the strength of the guideline recommendation based on indication (Class 1, 2a, and 2b, respectively).
• The “top layer” or Class 1 indication where there is broad agreement that every patient should get an ICD is when a patient has had a documented cardiac arrest or sustained ventricular tachycardia.
• The “second layer” or Class 2a indication are patients with one or more major risk factors for SCD, in whom it is reasonable to pursue an ICD:
  • Massive hypertrophy (LVH of 30 mm or greater in any segment)
  • A history of “scary” syncope that is suspected to be due to arrhythmia
  • A family history of sudden cardiac death
  • LV apical aneurysm with transmural scar
  • LV systolic dysfunction (EF <50%)
• The last layer or Class 2b indication where it is of uncertain benefit but may be offered in shared decision-making is when there is extensive LGE present on CMR or frequent nonsustained VT on ambulatory monitoring in the absence of any major clinical risk factor.
• Using an HCM risk calculator can be helpful for estimating individual patient risk for SCD by incorporating all of the above risk factors and can help to frame a shared decision-making discussion around ICD placement.

References – Cardiomyopathies1. Ommen SR, Ho CY, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology. 2024;83(23):2324-2405. doi:10.1016/j.jacc.2024.02.014

1. Saberi S, Wheeler M, Bragg-Gresham J, et al. Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy: A Randomized Clinical Trial. JAMA. 2017;317(13):1349-1357. doi:10.1001/jama.2017.2503

2. Desai MY, Owens A, Wolski K, et al. Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 56 Results From the VALOR-HCM Randomized Clinical Trial. JAMA Cardiology. 2023;8(10):968-977. doi:10.1001/jamacardio.2023.3342

3. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden Deaths in Young Competitive Athletes. Circulation. 2009;119(8):1085-1092. doi:10.1161/CIRCULATIONAHA.108.804617

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The following question refers to Sections 6.1 and 7.4 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by University of Colorado internal medicine resident Dr. Hirsh Elhence, answered first by University of Chicago advanced heart failure cardiologist and Co-Chair for the CardioNerds Critical Care Cardiology Series Dr. Mark Belkin, and then by expert faculty Dr. Mark Drazner.

Dr. Drazner is an advanced heart failure and transplant cardiologist, Professor of Medicine, and Clinical Chief of Cardiology at UT Southwestern. He is the President of the Heart Failure Society of America.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #34

| Question Stem | A 72-year-old woman with a history of hypertension, type 2 diabetes mellitus, and a recent myocardial infarction is seen in your clinic. Two months previously, she was hospitalized with a myocardial infarction and underwent successful revascularization of the left anterior descending artery with a drug-eluting stent. Following her myocardial infarction, an echocardiogram revealed an ejection fraction of 17%, and she was discharged on metoprolol succinate, lisinopril, spironolactone, and dapagliflozin with escalation to maximal tolerated doses over subsequent visits. A repeat echocardiogram performed today in your clinic reveals an ejection fraction of 26%. An electrocardiogram reveals normal sinus rhythm with a narrow QRS at a heart rate of 65 beats per minute. She is grateful for her cardiac rehabilitation program and reports no ongoing symptoms. Which of the following devices is indicated for placement at this time? | | Answer choices | A | Implantable loop recorder | | B | ICD | | C | CRT-D | | D | CRT-P |

Answer #34

| Explanation | The correct answer is B.This patient suffered a myocardial infarction more than 40 days ago and has been on appropriate guideline-directed medical therapy since that time. Her left ventricular ejection fraction has improved but remains under 30%. For patients who have suffered a myocardial infarction over 40 days prior with LVEF ≤ 30% and NYHA Class I symptoms while receiving GDMT and have a reasonable expectation of meaningful survival for >1 year, an ICD is recommended for primary prevention of sudden cardiac death to reduce total mortality (Class I, LOE B-R).The MADIT-II trial enrolled 1,232 patients with a prior myocardial infarction and LVEF ≤ 30% to prophylactic ICD or medical therapy. At a median follow-up of 20 months, the trial was terminated early for reduced all-cause mortality with prophylactic ICD. The DINAMIT trial later investigated the implantation of ICD in patients with MI and an LVEF of ≤ 35% at 6 to 40 days after the initial myocardial infarction. This trial found no differences in all-cause mortality between the two groups. Therefore, the current recommendation is to wait at least 40 days with GDMT prior to re-evaluation of left ventricular ejection fraction before proceeding with ICD implantation.Cardiac resynchronization therapy entails implanted pacemakers to simultaneously pace both the RV and LV in order to improve electrical synchrony and generally provides benefit in those with systolic dysfunction and a wide left bundle branch block. Specifically, for patients who have LVEF ≤35%, sinus rhythm, left bundle branch block (LBBB) with a QRS duration ≥150 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT, CRT is indicated to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL (Class I, LOE B-R). CRT implantation provides high economic value in this setting. CRT implantation carries a Class 2a recommendation for those with reduced LVEF (≤35%) and either a non-LBBB pattern with a QRS ≥150 ms or a LBBB with QRS duration 120-149ms. This patient with a narrow QRS does not have indications for CRT placement at this time. | | Main Takeaway | ICD implantation is recommended as primary prophylaxis against ventricular arrhythmias for patients with LVEF ≤30% after 40 days following myocardial infarction despite use of GDMT. | | Guideline Loc. | Section 6.1 and 7.4 |

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CardioNerds Dan Ambinder and Dr. Devesh Rai join cardiology fellows and National Lipid Association lipid scholars Dr. Oby Ibe from Temple University and Dr. Elizabeth Epstein from Scripps Clinic. They discuss a case involving a patient with elevated Lp(a). Dr. Jessica Pena provides expert commentary. Drs. Oby Ibe and Elizabeth Epstein drafted notes. CardioNerds Intern Christiana Dangas engineered episode audio. This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos.

This is a 63-year-old man with hypertension, hyperlipidemia, and active tobacco smoking who presented with acute dyspnea. He was tachycardic but otherwise initially hemodynamically stable. The physical exam demonstrated warm extremities with no murmurs or peripheral edema. Chest X-ray revealed diffuse pulmonary edema, and the ECG showed sinus tachycardia with T-wave inversions in the inferior leads. A bedside echocardiogram revealed a flail anterior mitral valve leaflet. The patient was taken for cardiac catheterization that revealed nonobstructive mid-RCA atheroma with a distal RCA occlusion, which was felt to reflect embolic occlusion from recanalized plaque. PCI was not performed. Right heart catheterization then demonstrated a low cardiac index as well as elevated PCWP and PA pressures. An intra-aortic balloon pump was placed at that time. A TEE was performed soon after which showed the posteromedial papillary muscle was ruptured with flail segments of the anterior mitral leaflet as well as severe posteriorly directed mitral regurgitation. The patient ultimately underwent a successful tissue mitral valve replacement and CABG.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls – Little (a), Big Deal – National Lipid Association1. You are never too young to see a preventive cardiologist! The field of preventive cardiology is shifting focus towards the identification of early upstream risk and intervention before the development of clinical ASCVD (1,5). Patients who have a strong family history of cardiovascular disease, a personal history of CVD at an early age, multiple risk factors, or genetic disorders such as familial hypercholesterolemia especially benefit from early cardiovascular risk assessment and reduction. 2. Female-specific risk factors to incorporate into a young woman’s cardiovascular risk assessment include polycystic ovarian syndrome, hormone contraceptive use, early menarche (age <10 years old), primary ovarian insufficiency, fertility therapy, hypertensive disorders of pregnancy (eclampsia, preeclampsia, gestational hypertension, preterm delivery, gestational diabetes, multi-parity >5 pregnancies), early menopause (age <45 years old), & post-menopausal hormone therapy. 3. Lp(a) testing for all! The most recent NLA scientific statement on the use of Lp(a) in clinical practice recommends measuring Lp(a) at least once in every adult for risk stratification. 4. While Lp(a) has not yet been incorporated into our risk calculators, we do know that elevated Lp(a) increases 10-year risk. The European Atherosclerosis Society published a consensus statement on Lp(a), which includes a handy table to quantify the degree to which a patient’s 10-year risk increases as Lp(a) increases. 5. Lifestyle changes are the first line and can reduce the risk of high Lp(a) by 66%. Next, we can consider the risks and benefits of LDL-lowering in a young patient and monitor closely for the development of plaque over time. Lp(a) lowering drugs such as olpasiran are on the horizon, and we can keep this patient in mind as a potential candidate for therapy in the future.

Notes – Little (a), Big Deal – National Lipid AssociationWhen should patients see a preventive cardiologist?

• Strong family history of cardiovascular disease – A positive family history of CVD was defined as a self‐reported diagnosis of CVD in parents, siblings, or children that occurred at 60 years or younger. A positive family history of CVD is an independent predictor of both myocardial infarction and stroke. Among individuals with hypertension, family history of CVD has been shown to be independently associated with mortality by ischemic heart disease and family history of CVD mortality with incidence of overall CVD. Family history of CVD modifies future CVD risk depending on the number and age of affected first-degree relatives. Siblings of patients with CVD have about a 40% risk increase, while offspring of parents with premature CVD have a 60% to 75% risk increase.
• Personal history of early CVD – A personal history of cardiovascular disease at an age younger than 60 years. For young and middle-aged adults, increases in heart disease between 2020 and 2021 explain more than 4% of the most recent shortening in life expectancy. In particular, hypertensive heart disease, heart failure, and endocarditis have increased in young adults, particularly among Black individuals, through 2018. Consequently, young adults make up a growing proportion of cardiovascular disease events, with the proportion of premature myocardial infarction among adults younger than 40 years increasing by 2% every year. The increasing event rates observed among younger adults can be attributed to the increasing prevalence and onset of risk factors such as obesity and hypertension at younger ages, which exacerbate cumulative exposure and cardiovascular disease risk over near- and long-term time horizons.
• Multiple cardiovascular risk factors – Risk factors include hyperlipidemia, high triglycerides, elevated lp(a), diabetes mellitus, obesity, tobacco use, unhealthy diet, and lack of physical activity. Unadjusted event rates were 8-fold to 30-fold higher in persons with adverse levels of risk factor exposure during young adulthood (age 20–39 years) compared with persons with optimal levels of exposure.
• Familial hypercholesterolemia – In primary prevention, patients with FH had incidences of ASCVD and coronary heart disease (CHD) of 14.9/1000 and 5.8/1000 person-years, respectively, compared to 7.1/1000 and 2.1/1000 person-years in the normolipidemic group. FH conferred a hazard ratio (HR) of 7.1 and 16.7 for ASCVD and CHD, respectively, in patients younger than 35 years. In secondary prevention, patients with FH had incidences of ASCVD and CHD of 89.7/1000 and 34.5/1000 person-years, respectively, compared to 90.9/1000 and 28.2/1000 person-years in the normolipidemic group

What are some female-specific risk factors for cardiovascular disease? (7)

• PCOS – Polycystic ovarian syndrome (PCOS) is a disorder characterized by hyperandrogenism and menstrual irregularities. Women affected by PCOS have a heightened risk of developing diabetes due to associated insulin resistance, central obesity, and hypertension. This adverse cardiovascular risk profile in women with PCOS may lead to premature atherosclerosis (8,20). Women with PCOS have been shown to have an increased risk for CVD events (21).
• Depression — Among 593,616 young adults (aged 18–49 years) from 2017 to 2020, depression was independently associated with CHD and suboptimal cardiovascular health (CVH), with a dose‐response relationship (CVH was determined using 7 cardiovascular risk factors: hypertension, hypercholesterolemia, overweight/obesity, current smoking, diabetes, physical inactivity, and inadequate fruit and vegetable intake) (13). Suboptimal CVH was defined as the presence of ≥2 of these 7 cardiovascular risk factors, whereas optimal CVH was 0 or 1 cardiovascular risk factor.
• Early menarche – Results from the Women’s Ischemia Syndrome Evaluation (WISE) study demonstrated that in comparison to women with menarche at age 12 years, there was an approximately 4-fold adjusted increased risk for major adverse cardiac events for menarche ≤ 10 years (15).
• African descent – Safford et al. found that among those at the highest CHD risk, Black women’s hyperlipidemia was the least likely to be treated or controlled. Lp(a) is significantly higher among Blacks versus Whites, and in both, increased Lp(a) correlates positively with LDL-C and negatively with triglycerides. Another study based on the MESA population demonstrated that Black participants showed a significant risk of CHD in those with Lp(a) levels ≥ 75 nmol/L as opposed to White and Hispanic participants who had a greater risk with Lp(a) levels ≥125 nmol/L.
• Elevated BMI – Obesity and higher measures of central adiposity are associated with significantly higher rates of CAD, CVD mortality, sudden cardiac death, heart failure, and arrhythmias (23). High BMI accounted for 4.0 million deaths in 2015, more than two-thirds of which were caused by cardiovascular disease. Marked increases in obesity prevalence among adolescents over the past 35 years ultimately contribute to CVD risk into young adulthood.

Who should be getting an Lp(a) measured?

• Per the most NLA-focused update to the 2019 scientific statement on the use of Lp(a) in clinical practice, we now have sufficient evidence to support measuring Lp(a) at least once in all adults for risk stratification.

What risk calculators would apply to a young adult?

• The American Heart Association recently released the PREVENT calculator (c-statistic 0.72) for 10- and 30-year risk estimation of total CVD (composite of atherosclerotic CVD and heart failure) in primary prevention patients (10). This improves upon the prior pooled cohort equation because it is based on newer data from a larger, more diverse sample (6,612,004 US adults 30 to 79 years of age) than the existing tool. The calculator also takes into account other health conditions, such as cardiovascular-kidney-metabolic risk factors, adjusts for competing risk of non-CVD death, and incorporates an indicator of social determinants of health. Race was not included because it is a social construct, not a biological risk factor, and could, therefore, create bias. Three research teams were awarded $150,000 from AHA to further study how the risk calculator performs among people of various ages, racial and ethnic backgrounds, locations, and socioeconomic levels.
• A universal calculator (c-statistic 0.747 and 0.691 for patients with and without CAD) was also recently published in JACC. This was unique because it can be used in patients both with and without CAD, doing away with the concepts of primary vs secondary prevention and placing everyone on the same spectrum of risk. The calculator incorporates ASCVD vs no ASCVD, age, diabetes, SBP, HTN treatment, TC, smoking history, CRP, NT Pro-BNP, hs Troponin T and provides a 5- and 10-year risk of MACE. The calculator was able to identify patients without CAD who had a higher risk than those with prior CAD. This calculator is not yet available online, but the authors did publish their formulae, which can be plugged into Excel to create a calculator. Unfortunately, this calculator may not apply to our patient because it was validated in a cohort of patients aged 45-64 years.
• QRISK3 (c-statistic 0.75) has been validated in patients aged 25-84 years, so it can be useful in predicting cardiovascular disease in both younger and older patients. It also incorporates a wider variety of risk-enhancing factors than most other calculators, including diagnosis of HIV/AIDS, inflammatory diseases, CKD stage, type 1 and type 2 diabetes, and erectile dysfunction. However, it is important to note that this calculator was validated in a primarily European population, and the risk prediction may not be as accurate in other ethnic groups.

How does elevated Lp(a) influence a patient’s 10-year risk, and can we quantify it?

• A recent observational study demonstrated that elevated Lp(a) is associated with long-term MACE in both patients with and without cardiovascular disease. Among patients with ASCVD, individuals in the 71st to 90th percentile group had a 21% increased hazard of MACE (adjusted HR: 1.21; P < 0.001), and among patients without ASCVD, individuals in the 91st to 100th Lp(a) percentile group had the highest relative risk with an adjusted HR of 1.93 (P < 0.001). In patients without ASCVD, there was a linear association between Lp(a) and CV events, whereas in patients with prior ASCVD, the association plateaued between 150-200 nmol/L.

• Similarly, the 2019 consensus statement from HEART UK categorized the impact of CV risk associated with Lp(a) as minor, moderate, high, or very high based on the level of Lp(a). The table from this paper is a clinically useful tool to categorize risk from Lp(a).

• The European Atherosclerosis Society has published a consensus statement on Lp(a) in the European Heart Journal which includes another useful table to adjust a patient’s 10-year risk based on the Lp(a) level(12).

How do we manage a young patient with elevated Lp(a)? Which patients might benefit from treatment with emerging Lp(a)-lowering therapies?

• Given we do not yet have Lp(a) lowering therapies available for clinical use, the mainstay of management for patients with elevated Lp(a) is intensive risk factor management. Beyond the question of LDL lowering, we know that lifestyle change plays a big role in patients with elevated Lp(a) specifically. While it was previously thought that lifestyle has no impact on ASCVD risk associated with elevated Lp(a), in fact, it very much does. It doesn’t lower Lp(a) directly but following the AHA Life’s Simple 8 lowers the risk of Lp(a) by 66%.

• There is some newer data suggesting that in patients with coronary artery disease, aggressive LDL lowering down to 50 can reduce the risk of Lp(a) by up to 50% (6). LDL of 50 mg/dL is a pretty aggressive treatment goal, which makes sense in very high-risk patients with existing CAD. However, we still need more data to guide LDL treatment goals in young patients(18).

• Novel Lp(a)-lowering therapies such as olpasiran are currently in clinical trials (19). We await the data from these trials in order to understand which patients would benefit most from treatment.

ReferencesAllen N, Wilkins JT. The Urgent Need to Refocus Cardiovascular Disease Prevention Efforts on Young Adults. JAMA. 2023;329(11):886-887. doi:10.1001/jama.2023.2308

https://jamanetwork.com/journals/jama/fullarticle/2802264

Baber, Usman, Roxana Mehran, Samantha Sartori, Mikkel Malby Schoos, Henrik Sillesen, Pieter Muntendam, Mario J. Garcia, et al. 2015. “Prevalence, Impact, and Predictive Value of Detecting Subclinical Coronary and Carotid Atherosclerosis in Asymptomatic Adults: The BioImage Study.” Journal of the American College of Cardiology 65 (11): 1065–74.

https://pubmed.ncbi.nlm.nih.gov/25790876

Bhatia, H. S., Trainor, P., Carlisle, S., Tsai, M. Y., Criqui, M. H., DeFilippis, A., & Tsimikas, S. (2024). Aspirin and Cardiovascular Risk in Individuals With Elevated Lipoprotein (a): The Multi‐Ethnic Study of Atherosclerosis. Journal of the American Heart Association, 13(3), e033562.

https://www.ahajournals.org/doi/10.1161/JAHA.123.033562

Coll, B., Betriu, A., Feinstein, S. B., Valdivielso, J. M., Zamorano, J. L., & Fernandez, E. (2013). The role of carotid ultrasound in assessing carotid atherosclerosis in individuals at low-to-intermediate cardiovascular risk. Revista Española de Cardiología (English Edition), 66(12), 929-934.

https://pubmed.ncbi.nlm.nih.gov/24774105

Devesa, A, Ibanez, B, Malick, W. et al. Primary Prevention of Subclinical Atherosclerosis in Young Adults: JACC Review Topic of the Week. J Am Coll Cardiol. 2023 Nov, 82 (22) 2152–2162.

https://www.jacc.org/doi/10.1016/j.jacc.2023.09.817

Dykun, Iryna, Jürgen Kampf, Tienush Rassaf, and Amir A. Mahabadi. 2023. “Interaction between Elevated Lipoprotein(a) and LDL Cholesterol on Mortality Risk in Patients with Coronary Artery Disease.” European Journal of Preventive Cardiology 30 (13): e64–65.

https://academic.oup.com/eurjpc/article-abstract/30/13/e64/7065497?redirectedFrom=PDF

Elder P, Sharma G, Gulati M, Michos ED. Identification of female-specific risk enhancers throughout the lifespan of women to improve cardiovascular disease prevention. Am J Prev Cardiol. 2020;2:100028. Published 2020 Jun 6. doi:10.1016/j.ajpc.2020.100028

https://www.sciencedirect.com/science/article/pii/S2666667720300283

Glintborg D, Rubin KH, Nybo M, Abrahamsen B, Andersen M. Cardiovascular disease in a nationwide population of Danish women with polycystic ovary syndrome. Cardiovasc Diabetol. 2018;17(1):37. Published 2018 Mar 8. doi:10.1186/s12933-018-0680-5

https://pubmed.ncbi.nlm.nih.gov/29519249

Guan, W., Cao, J., Steffen, B. T., Post, W. S., Stein, J. H., Tattersall, M. C., … & Tsai, M. Y. (2015). Race is a key variable in assigning lipoprotein (a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology, 35(4), 996-1001.

https://pubmed.ncbi.nlm.nih.gov/25810300

Khan, S. S., Coresh, J., Pencina, M. J., Ndumele, C. E., Rangaswami, J., Chow, S. L., … & American Heart Association. (2023). Novel prediction equations for absolute risk assessment of total cardiovascular disease incorporating cardiovascular-kidney-metabolic health: a scientific statement from the American Heart Association. Circulation, 148(24), 1982-2004.

https://www.ahajournals.org/doi/10.1161/CIR.0000000000001191

Kolber MR, Scrimshaw C. Family history of cardiovascular disease. Can Fam Physician. 2014;60(11):1016.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229162/#:~:text=Family%20history%20of%20CVD%20modifies,%25%20to%2075%25%20risk%20increase.

Kronenberg, Florian, Samia Mora, Erik S. G. Stroes, Brian A. Ference, Benoit J. Arsenault, Lars Berglund, Marc R. Dweck, et al. 2022. “Lipoprotein(a) in Atherosclerotic Cardiovascular Disease and Aortic Stenosis: A European Atherosclerosis Society Consensus Statement.” European Heart Journal 43 (39): 3925–46.

https://pubmed.ncbi.nlm.nih.gov/36036785

Kwapong YA, Boakye E, Khan SS, et al. Association of Depression and Poor Mental Health With Cardiovascular Disease and Suboptimal Cardiovascular Health Among Young Adults in the United States. J Am Heart Assoc. 2023;12(3):e028332. doi:10.1161/JAHA.122.028332

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973664

Lau, F. D., & Giugliano, R. P. (2022). Lipoprotein (a) and its significance in cardiovascular disease: a review. Jama Cardiology.

https://pubmed.ncbi.nlm.nih.gov/35583875

Lee, J. J., Cook‐Wiens, G., Johnson, B. D., Braunstein, G. D., Berga, S. L., Stanczyk, F. Z., … & Shufelt, C. L. (2019). Age at menarche and risk of cardiovascular disease outcomes: findings from the National Heart Lung and Blood Institute‐sponsored Women’s Ischemia Syndrome Evaluation. Journal of the American Heart Association, 8(12), e012406.

https://pubmed.ncbi.nlm.nih.gov/31165670

Masana L, Zamora A, Plana N, et al. Incidence of Cardiovascular Disease in Patients with Familial Hypercholesterolemia Phenotype: Analysis of 5 Years Follow-Up of Real-World Data from More than 1.5 Million Patients. J Clin Med. 2019;8(7):1080. Published 2019 Jul 23. doi:10.3390/jcm8071080

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678686

Mendieta, Guiomar, Stuart Pocock, Virginia Mass, Andrea Moreno, Ruth Owen, Inés García-Lunar, Beatriz López-Melgar, et al. 2023. “Determinants of Progression and Regression of Subclinical Atherosclerosis Over 6 Years.” Journal of the American College of Cardiology 82 (22): 2069–83.

https://pubmed.ncbi.nlm.nih.gov/37993199

Navar, A. M., Fine, L. J., Ambrosius, W. T., Brown, A., Douglas, P. S., Johnson, K., … & Lewis, C. E. (2022). Earlier treatment in adults with high lifetime risk of cardiovascular diseases: what prevention trials are feasible and could change clinical practice? Report of a National Heart, Lung, and Blood Institute (NHLBI) workshop. American journal of preventive cardiology, 12, 100430.

https://pubmed.ncbi.nlm.nih.gov/36439649

O’Donoghue, M. L., Rosenson, R. S., Gencer, B., López, J. A. G., Lepor, N. E., Baum, S. J., … & Sabatine, M. S. (2022). Small interfering RNA to reduce lipoprotein (a) in cardiovascular disease. New England Journal of Medicine, 387(20), 1855-1864.

https://www.nejm.org/doi/full/10.1056/NEJMoa2211023

Orio Jr, F., Palomba, S., Cascella, T., De Simone, B., Di Biase, S., Russo, T., … & Colao, A. (2004). Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism, 89(9), 4588-4593.

https://pubmed.ncbi.nlm.nih.gov/15356067

Osibogun O, Ogunmoroti O, Michos ED. Polycystic ovary syndrome and cardiometabolic risk: Opportunities for cardiovascular disease prevention. Trends Cardiovasc Med. 2020;30(7):399-404. doi:10.1016/j.tcm.2019.08.010

https://www.sciencedirect.com/science/article/pii/S1050173819301288?via%3Dihub

Pletcher MJ, Vittinghoff E, Thanataveerat A, Bibbins-Domingo K, Moran AE. Young Adult Exposure to Cardiovascular Risk Factors and Risk of Events Later in Life: The Framingham Offspring Study. PLoS One. 2016;11(5):e0154288. Published 2016 May 3. doi:10.1371/journal.pone.0154288

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854462

Powell-Wiley, T. M., Poirier, P., Burke, L. E., Després, J. P., Gordon-Larsen, P., Lavie, C. J., … & American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council. (2021). Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 143(21), e984-e1010.

https://pubmed.ncbi.nlm.nih.gov/33882682

Safford, M. M., Gamboa, C. M., Durant, R. W., Brown, T. M., Glasser, S. P., Shikany, J. M., … & Muntner, P. (2015). Race–Sex Differences in the Management of Hyperlipidemia: The REasons for Geographic And Racial Differences in Stroke Study. American journal of preventive medicine, 48(5), 520-527.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422177

Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89(11):5454-5461. doi:10.1210/jc.2003-032237

https://academic.oup.com/jcem/article/89/11/5454/2844369?login=false

Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association [published correction appears in J Clin Lipidol. 2022 Sep-Oct;16(5):e77-e95]. J Clin Lipidol. 2019;13(3):374-392. doi:10.1016/j.jacl.2019.04.010

https://www.lipidjournal.com/article/S1933-2874(22)00244-6/fulltext#seccesectitle0006

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The following question refers to Section 5.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by University of Colorado internal medicine resident Dr. Hirsh Elhence, answered first by advanced heart failure faculty at the University of Chicago and Co-Chair for the CardioNerds Critical Care Cardiology Series Dr. Mark Belkin, and then by expert faculty Dr. Biykem Bozkurt.

Dr. Bozkurt is the Mary and Gordon Cain Chair, Professor of Medicine, Director of the Winters Center for Heart Failure Research, and an advanced heart failure and transplant cardiologist at Baylor College of Medicine in Houston, TX. She is former President of HFSA, former senior associate editor for Circulation, and current Editor-In-Chief of JACC Heart Failure. Dr. Bozkurt was the Vice Chair of the writing committee for the 2022 Heart Failure Guidelines.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #33

| A 63-year-old man with a past medical history of hypertension and type 2 diabetes mellitus presents for routine follow-up. He reports feeling in general good health and enjoys 2-mile walks daily. A review of systems is negative for any symptoms. Which of the following laboratory studies may be beneficial for screening? | | A | NT-proBNP | | B | CK-MB | | C | Troponin | | D | C-reactive protein | | E | None of the above |

Answer #33

| Explanation | The correct answer is A – NT-proBNP.This patient is at risk for HF (Stage A) given the presence of risk factors (hypertension and type 2 diabetes mellitus) but the absence of signs or symptoms of heart failure.Patients at risk for HF screened with BNP or NT-proBNP followed by collaborative care, diagnostic evaluation, and treatment in those with elevated levels can reduce combined rates of LV systolic dysfunction, diastolic dysfunction, and HF.The STOP-HF (St Vincent’s Screening to Prevent Heart Failure) study was a large single-center trial of patients at risk of HF that showed BNP-based screening reduced the composite endpoint of incident asymptomatic LV dysfunction with or without newly diagnosed HF.Therefore, for patients at risk of developing HF, natriuretic peptide biomarker-based screening followed by team-based care, including a cardiovascular specialist optimizing GDMT, can be useful toprevent the development of LV dysfunction (systolic or diastolic) or new-onset HF (Class 2a, LOE B-R).There is no indication for measuring troponin, CK-MB, or CRP at this time. | | Main Takeaway | In patients at risk for HF, screening for pre-HF using natriuretic peptide testing followed by team-based care may be helpful for preventing disease progression. | | Guideline Loc. | Section 5.1 |

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CardioNerds Dr. Rick Ferraro, Dr. Gurleen Kaur, and Dr. Maryam Barkhordarian discuss the evidence and data supporting SGLT inhibition for cardiovascular and kidney health outcomes with expert faculty Dr. Muthu Vaduganathan. They discuss the role of SGLT inhibitors in different populations, including those with diabetes mellitus, heart failure, CKD, and myocardial infarction. Show notes and audio editing by CardioNerds Academy Fellow Dr. Maryam Barkhordarian.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls – The Data Supporting SGLT Inhibition with Dr. Muthiah Vaduganathan1. The benefit of SGLT inhibition extends beyond diabetes, and improves cardiovascular and kidney health outcomes independent of diabetes in appropriate patient populations. 2. SGLT inhibition decreases cardiovascular mortality and heart failure hospitalization independent of left ventricular ejection fraction. 3. SGLT inhibitors reduce clinically relevant events such as dialysis and transplantation in CKD patients irrespective of etiology and are now a cornerstone for the prevention of CKD progression. 4. The introduction of polypills in heart failure can simplify GDMT implementation.

Show notes – The Data Supporting SGLT Inhibition with Dr. Muthiah VaduganathanHow did SGLT inhibitors transition from “diabetes medication” to guideline-directed cardiovascular medicine?

• Most therapies in cardiology were developed for a particular purpose and ended up being indicated for a vastly different reason. The SGLT-2 inhibitors are no different.
• Cardiovascular safety concerns about diabetes medications led to a mandate to conduct cardiovascular outcomes trials for all novel diabetes medications. This federal requirement shed light on the cardiovascular benefits of SGLT inhibitors in patients with diabetes.
• These initial trials showed that not only are these medications safe but also, surprisingly, proved their role in preventing heart failure and delaying progression of chronic kidney disease.

What are the mechanisms of action of SGLT-2 and SGLT-1/2 inhibitors?

• The central mechanism(s) of how these medications confer health outcomes benefits patients is/are not well understood.
• The main organ involved in the action of SGLT-2 inhibitors is the kidney at the level of the proximal tubule, impacting the cardiovascular system by handling salt and water and improving kidney efficiency. Conversely, SGLT-1/2 inhibitors also act at the level of the gut, the predominant location of the SGLT-1 cotransporter.
• Their effects on the cardiovascular system are secondary, given there is no SGLT-1 or -2 cotransporters in the myocardium. These secondary effects can be impacted through blood pressure reduction, volume regulation, improved glycemic control, etc. to overall improve cardiovascular status.
• Whatever the underlying mechanisms, the empirical data for their use is strong and growing.

What is the role of SGLT inhibitors in preventing CKD progression?

• RAAS inhibitors (ACE inhibitors and ARBs) have been the cornerstone of CKD management for the past two to three decades.
• SGLT inhibitors have been the first add-on to this background therapy.
• Four trials, DAPA-CKD, EMPA-CKD, CREDENCE, and the SCORED, investigated the effects of SGLT-2 and SGLT-1/2 inhibitors in patients with CKD with or without diabetes.
• The outcomes of these trials include modifying the course of CKD and reducing events such as dialysis initiation and transplantation. These effects were regardless of participants’ diabetic status, CKD etiology, or individual patient profile.
• The addition of SGLT-2 inhibitors to ACEI or ARB can be considered as GDMT of CKD.

What is the role of SGLT-2 inhibitors in combination with other medications as polypill?

• Polypills have been beneficial in many areas such as cardiometabolic medicine, hypertension, and diabetes mellitus. In addition, a multi-drug regimen is strongly recommended in heart failure with reduced ejection fraction.
• Developing polypills in HFrEF has been challenging because adjacent compounds are not available in the armamentarium of sponsored pharmaceutical companies.
• Investigations of various polypills are underway for the management of heart failure.

References – The Data Supporting SGLT Inhibition with Dr. Muthiah Vaduganathan1. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816 2. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233 3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744 4. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021;384(2):129-139. doi:10.1056/NEJMoa2030186

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In this episode, Dr. Gurleen Kaur (Cardiology FIT at Brigham and Women’s Hospital and APD of the CardioNerds Academy) and Dr. Chelsea Amo-Tweneboah (Medicine Resident at Stonybrook and CardioNerds Academy Intern) discuss with Dr. Heval Kelli (Cardiologist at Northside Hospital Cardiovascular Institute) about his personal and professional journey in Cardiology. They discuss Dr. Kelli’s lifelong advocacy for serving those in need including refugee and immigrant communities, his character in the documentary Refuge, and fostering inclusivity within Cardiology. Audio editing and show notes were drafted by Dr. Chelsea Amo-Tweneboah.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

The PA-ACC & CardioNerds Narratives in Cardiology is a multimedia educational series jointly developed by the Pennsylvania Chapter ACC, the ACC Fellows in Training Section, and the CardioNerds Platform with the goal to promote diversity, equity, and inclusion in cardiology. In this series, we host inspiring faculty and fellows from various ACC chapters to discuss their areas of expertise and their individual narratives. Join us for these captivating conversations as we celebrate our differences and share our joy for practicing cardiovascular medicine. We thank our project mentors Dr. Katie Berlacher and Dr. Nosheen Reza.

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Video version – Advocacy for Refugee Health and Empowering First-Generation CardiologistsQuoatables – Advocacy for Refugee Health and Empowering First-Generation Cardiologists* “I have always believed that if someone opened the door for you, you have to hold the door for the next generation. Because if you just walk through the door and close it, you just close the door for many people behind you.” * “Instead of making luck a matter of luck, just make an opportunity for everyone else.” * “Hate makes us realize that no matter how privileged you are, you are not protected.” * “It is very hard to hate something you know.” * “Compassion starts with the neighbor next to you, and then you go out to the world and show it.” * “Your best intern wasn’t the smartest intern. Your best intern was the person ready to go for rounds, took care of everything, sharp early in the morning, stays late, and gets the work done.” * “Intelligence is relative. Hard work and dedication [are] the most important thing.”

Notes – Advocacy for Refugee Health and Empowering First-Generation CardiologistsAdvocacy for refugee health and empowering first-generation cardiologists

• Focusing on creating professionals from a given community can help increase their chances of returning to that community and helping to address health disparities.
• Refugees and immigrants come from countries and communities where, by and large, prevention is lacking. Seeing a healthcare provider is more appropriate in dire situations.
• When approaching immigrants, it is important to present medical information in ways in which they can understand and absorb properly.
• For many refugee families, there exists a language barrier and the children are most often the advocates for the family because they are most likely to understand the language of the community they live in.
• The vast number of students in the US medical school system come from privileged backgrounds; however, this same statistic is not true for the populations they end up serving.
• It is important to have health professionals reflect the populations they serve, and one of the methods to achieve this is through introducing as many individuals as possible to the field of medicine; one of the ways to overcome a leaky pipeline is to pack the pipeline. Strategies include encouraging medical students to serve as mentors for those junior to them.
• It is important to build more sustainable relationships with communities because it leads to more trust and success.
• Advocating for mental health in these communities is very important because they face these issues at an increased level. However, it is unfortunately under-addressed.
• Resource avenues such as the CDC provide substantial information regarding different refugee and immigrant profiles and the issues most pertinent to these communities.

Inclusivity in Cardiology

• It is important to normalize people feeling comfortable in having a discourse about differences and recognizing the challenges individuals face when pursuing a career in medicine or cardiology in order to promote inclusivity in this field. This is a major goal for the CardioNerds Narratives in Cardiology program.
• Within Cardiology, structural racism and hate are present.
• It is important to place yourself in a challenging environment or one different from what you are used to and attempt to find common ground with other individuals.

The Bridge Between Social Issues and Cardiology

• As a physician, it is important to create boundaries and choose what social issues you wish to engage in.
• If groups of people do not see eye to eye, steps should be taken to reach out to one another and establish and try to understand what these differences are.
• Physicians are the best advocates in the world because, for the most part, they are trusted by their patients. Recognizing the importance of the influence that physicians have and realizing this influence can extend beyond the medical space.
• Humor can be another means by which to make it easier to bring up important conversations that may otherwise be difficult.

Technology to Help Bridge the Gap

• Technology can serve as a means of being able to communicate with refugee families because they are likely to have access to a smartphone.
• Refugee families most often don’t understand the information given to them in paper or pamphlet form, and often important medical advice can be lost that way.
• Technology provides increased access to medicine and allows patients more individuality and control in keeping on top of their health.
• Artificial intelligence technology is the direction that health and medicine are heading in; thus, health professionals and patients must learn how to use this technology to their advantage.

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CardioNerds co-founder Dan Ambinder joins Dr. Lefan He, Dr. Sina Salehi Omran, and Dr. Neil Gupta from the University of Rochester Cardiovascular Disease Fellowship Program for a day sailing on Lake Ontario. Expert commentary is provided by Dr. Jeffrey Bruckel, and CV Fellowship Program Director Dr. Burr Hall shares insights on the University of Rochester fellowship. The episode audio was edited by CardioNerds intern Dr. Atefeh Ghorbanzadeh. They discuss the following case involving a patient with papillary muscle rupture.

This is a 63-year-old man with hypertension, hyperlipidemia, and active tobacco smoking who presented with acute dyspnea. He was tachycardic but otherwise initially hemodynamically stable. The physical exam demonstrated warm extremities with no murmurs or peripheral edema. Chest X-ray revealed diffuse pulmonary edema, and the ECG showed sinus tachycardia with T-wave inversions in the inferior leads. A bedside echocardiogram revealed a flail anterior mitral valve leaflet. The patient was taken for cardiac catheterization that revealed nonobstructive mid-RCA atheroma with a distal RCA occlusion, which was felt to reflect embolic occlusion from recanalized plaque. PCI was not performed. Right heart catheterization then demonstrated a low cardiac index as well as elevated PCWP and PA pressures. An intra-aortic balloon pump was placed at that time. A TEE was performed soon after which showed the posteromedial papillary muscle was ruptured with flail segments of the anterior mitral leaflet as well as severe posteriorly directed mitral regurgitation. The patient ultimately underwent a successful tissue mitral valve replacement and CABG.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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case MediaPearls – A Case of Papillary Muscle Rupture1. Most cases of papillary muscle rupture demonstrate only small areas of ischemia with preserved ventricular function, thus causing high shear force on the ischemic papillary muscle. 2. The posteromedial papillary muscle has a single blood supply from the posterior descending artery, while the anterolateral papillary muscle has a dual blood supply from the LAD and the circumflex. Therefore, the posteromedial papillary muscle is more vulnerable to ischemia and, hence, rupture. 3. A murmur may be absent in cases of papillary muscle rupture due to the rapid equalization of left atrial and left ventricular pressures caused by the acuteness of the severe MR. Papillary muscle rupture should always be on the differential for acute dyspnea when ACS is suspected. 4. While mostly associated with STEMIs, mechanical complications of acute myocardial infarctions can also occur after NSTEMIs. Always auscultate patients carefully after a myocardial infarction! 5. When evaluating patients with chest pain presenting with acute or rapidly progressive heart failure and a hypercontractile LVEF should raise suspicion for mechanical complications of MI. 6. Once a papillary muscle rupture is diagnosed, cardiac surgery should be immediately contacted. Temporizing measures prior to surgery include positive pressure ventilation, IV nitroglycerin/nitroprusside, and temporary mechanical circulatory support.

Notes – A Case of Papillary Muscle RuptureWhat is the clinical presentation of acute mitral regurgitation from papillary muscle rupture?

• Patients typically present 3-5 days after a transmural infarct. Roughly half of these patients present with pulmonary edema that may quickly progress to cardiogenic shock.
• Most cases are associated with STEMIs, but papillary muscle rupture is also possible with an NSTEMI.
• The classic murmur is a mid-, late-, or holosystolic murmur. However, due to the rapid equalization of pressures between the LA and LV, many patients may not present with a murmur!

What is the pathophysiology of papillary muscle rupture?

• The most common etiology is acute occlusion of the RCA causing infarct of the posteromedial papillary muscle, which then leads to a partial or complete tear 2-7 days later.
• The posteromedial papillary muscle has a single blood supply from the posterior descending artery, while the anterolateral papillary muscle has a dual blood supply from the LAD and the circumflex. Therefore, the posteromedial papillary muscle is more vulnerable to ischemia and, hence, rupture.

What are the echocardiographic features of acute mitral regurgitation?

• Typically, acute mitral regurgitation is caused by acute insult to the mitral valve or mitral valve apparatus. Examples include endocarditis with leaflet perforation, acute flail leaflet in the setting of mitral valve prolapse, and infarct-related papillary muscle rupture. Also, the LVEF can be hypercontractile.
• Left ventricular and left atrial dimensions tend to be normal in acute MR as the heart has not had time to remodel. This also leads to rapid equalization of the LV-LA pressure during systole, blunting both the Doppler signal and the audible murmur which may under-appreciate acute severe mitral regurgitation.
• Severe mitral regurgitation typically has a regurgitant volume of ≥60 mL or a regurgitant fraction of at least 50%. Additionally, an effective regurgitant orifice area of 0.4 cm^2 is typically indicative of severe mitral regurgitation. A complete multiparametric assessment is more important than any single parameter.
• Systolic flow reversal in the pulmonary veins is pathognomonic for severe mitral regurgitation. This may not be apparent in all pulmonary veins if the MR is eccentric, as is usually the case of papillary muscle or acute leaflet flail.

How should acute mitral regurgitation due to papillary muscle rupture be managed?

• Afterload reduction may help, but this may be limited by hypotension in the acute setting.
• Temporary mechanical circulatory support may be necessary, often with an intra-aortic balloon pump which can be effective in improving forward flow.
• The ultimate and definitive treatment is urgent cardiac surgery along with concomitant bypass grafting as appropriate. Transcatheter edge-to-edge repair may be considered sparingly when surgery is deemed very high risk.

What are the other mechanical complications of acute myocardial infarction?

• Ventricular septal rupture typically occur 3-5 days after an infarct but there is a bimodal distribution. The presentation can vary from an isolated systolic murmur all the way to cardiogenic shock. Echocardiography will show a left to right shunt and right heart cath will show a step-up in oxygenation between the RA and PA as well as an elevated Qp/Qs. VSRs require urgent surgical or percutaneous repair.
• Ventricular free wall rupture also occurs 3-5 days after an infarct and presents with elevated jugular venous distension, muffled heart sounds, and pulsus paradoxus. As blood irritates the pericardium, the patient’s ECG can show new ST-elevations. Management is emergent surgery.
• Pseudoaneurysms present weeks to years after an infarct. These occur when a cardiac rupture is contained by pericardial adhesions and typically involve the inferior or lateral walls. Patients may be asymptomatic, but once diagnosed, pseudoaneurysms should be urgently repaired, lest they expand or become unstable.

References 1. Damluji AA, van Diepen S, Katz JN, Menon V, Tamis-Holland JE, Bakitas M, Cohen MG, Balsam LB, Chikwe J; on behalf of the American Heart Association Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Surgery and Anesthesia; and Council on Cardiovascular and Stroke Nursing. Mechanical complications of acute myocardial infarction: a scientific statement from the American Heart Association. Circulation. 2021;144:e16–e35. doi: 10.1161/CIR.0000000000000985 2. Chang C et al. Transcatheter Edge-to-Edge Repair for Acute Mitral Regurgitation due to Postinfarction Papillary Muscle Rupture. JSCAI (2022) 100431. 3. Kilic A et al. Mitral Valve Surgery for Papillary Muscle Rupture: Outcomes in 1342 Patients From The Society of Thoracic Surgeons Database. The Annals of Thoracic Surgery Volume 110, Issue 6, December 2020, Pages 1975-1981 4. van Diepen S, Katz JN, Albert NM, Henry TD, Jacobs AK, Kapur NK, Kilic A, Menon V, Ohman EM, Sweitzer NK, Thiele H, Washam JB, Cohen MG; on behalf of the American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Mission: Lifeline. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association. Circulation. 2017;136:e232–e268. doi: 10.1161/CIR.0000000000000525 5. Zoghbi, W. A., Adams, D., Bonow, R. O., Enriquez-Sarano, M., Foster, E., Grayburn, P. A., Hahn, R. T., Han, Y., Hung, J., Lang, R. M., Little, S. H., Shah, D. J., Shernan, S., Thavendiranathan, P., Thomas, J. D., & Weissman, N. J. (2017). Recommendations for noninvasive evaluation of native valvular regurgitation. Journal of the American Society of Echocardiography, 30(4), 303–371. https://doi.org/10.1016/j.echo.2017.01.007

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CardioNerds (Drs. Gurleen Kaur and Richard Ferraro) and episode FIT Lead Dr. Saahil Jumkhawala (Cardiology Fellow at the University of Miami) discuss SGLT inhibitors, focusing on the biology of SGLT and its inhibition, with Dr. Katherine Tuttle (Executive Director for Research at Providence Healthcare, Co-Principal Investigator of the Institute of Translational Health Sciences, and Professor of Medicine at the University of Washington). Show notes were drafted by Dr. Saahil Jumkhawala. The episode audio was engineered by CardioNerds intern Christiana Dangas.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Lexicon Pharmaceuticals.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls – The Biology of SGLT Inhibition with Dr. Katherine Tuttle1. SGLT inhibitors, while initially developed as antidiabetic medications, have been shown to be beneficial for cardiovascular and renal outcomes. These benefits result from their on-target glucosuric effects and additional off-target effects. 2. The side effect profiles of SGLTis are primarily mediated by glucose reabsorption in their target tissues. The side effect profile of SGLTis must be considered when prescribing these medications and is generally favorable for SGLT2is versus SGLT1is. 3. Once SGLTis are prescribed, patients should be given specific attention to their eGFR, serum potassium, and clinical evaluations of volume status and blood pressure. 4. Strategies to increase implementation of and reduce clinical inertia for these important class of medication remain an area of active investigation

Show notes – The Biology of SGLT Inhibition with Dr. Katherine TuttleWhat should prompt consideration of starting an SGLT inhibitor?

• Considerations for SGLT inhibitor initiation are based on a history of heart failure, kidney disease, and diabetes status.
  • In the EMPA-KIDNEY trial, empagliflozin improved cardiovascular and kidney outcomes in those with low GFR (regardless of level of albuminuria).

What is the mechanism of action of SGLT2 inhibitors?

• SGLT2 inhibitors improve glycemic control by blocking SGLT2 receptor-mediated reabsorption of glucose in the proximal convoluted tubule, where 80-90% of this reuptake occurs, and increased downstream excretion of glucose and sodium chloride. SGLT2 inhibitors provide only a modest glucose-lowering effect, particularly for patients with GFR <45.

How do SGLT2 inhibitors improve cardiac function?

• Through corrected glomerular hyperfiltration, there is a reduction in blood pressure, a reduction in sympathetic neural activity, and increased glucosuria, improving diuresis. Systemically, there is an increase in erythropoietin, which raises red blood cell mass and oxygen-carrying capacity.
  • Beyond inhibition of the SGLT2 receptor, which is isolated to the proximal convoluted tubule, there are additional off-target effects. Through non-receptor-mediated mechanisms, glucose transport is blocked into cells by blocking GLUT1 and GLUT4 receptors. They also reduce the mTORC signal transduction pathway, thereby reducing inflammation and glycolysis, leading to a cardioprotective effect in myocytes.
  • In the DAPA-CKD and CREDENCE trials, GFR decreases of up to 30% were correlated with improved renal and cardiovascular outcomes.
  • The cardiovascular benefit of SGLT2 inhibitors is not dose-dependent.

Where are SGLT1 receptors located?

• SGLT1 receptors are found primarily in small and large bowel enterocytes, as well as the kidney proximal tubule, beyond the convoluted segment.
  • Around 10% of glucose re-uptake is mediated by SGLT1 receptors in the proximal tubule.

What are some common side effects of SGLT inhibitors?

• Given SGLT1 receptors’ presence in the gastrointestinal tract, the side effects of SGLT1 inhibition are primarily gastrointestinal upset through decreased glucose reabsorption in the gut.
  • SGLT2 inhibitors’ side effects are primarily sequelae of glucosuria, particularly those of genitourinary infections, volume depletion, and euglycemic ketoacidosis (most commonly in patients with diabetes who are longstanding insulin users).

Additionally, a GFR decline of >30% should be suggestive of other issues for patients taking these medications, most commonly volume depletion or hypotension.

References – The Biology of SGLT Inhibition with Dr. Katherine TuttleCowie M.R., Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020 Dec; 17(12):761-722.

Kuboto Y, Shimizu W. Clinical Benefits of Sodium-Glucose Cotransporter 2 Inhibitors and the Mechanisms Underlying their Cardiovascular Effects. JACC: Asia. 2022 Jun; 2:287-293.

Lopaschuk G.D., Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors. JACC Basic Trans Sci. 2020 Jun; 5(6):632-644.

Harrington J., Udell J.A., Jones W.S., Anker S.D., Bhatt D.L., Petrie M.C., & Butler J. Empagliflozin in patients post myocardial infarction: rationale and design of the EMPACT-MI trial. American Heart Journal. 2022; 253:86-98.

Talha K.M., Anker S.D., & Butler J. SGLT-2 inhibitors in heart failure: a review of current evidence. International Journal of Heart Failure. 2023; 5(2):82.

Tuttle K.R. Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors. J Clin Invest. 2023; 133(5).

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CardioNerds cofounder, Amit Goyal joins Dr. Belal Suleiman, Dr. Nkiru Osude, and Dr. David Elliott from Duke University. They discuss a case of severe mitral paravalvular regurgitation complicated by hemolytic anemia. Expert commentary is provided by Dr. Andrew Wang. Audio editing by CardioNerds Academy Intern, student doctor Adriana Mares.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – Severe Mitral Paravalvular Regurgitation Complicated by Hemolytic Anemia – Duke University

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CardioNerds Co-Founder Dr. Daniel Ambinder, Series Co-Chair Dr. Giselle Suero Abreu (FIT at MGH), and Episode Lead Dr. Iva Minga (FIT at the University of Chicago) discuss the use of multi-modality cardiovascular imaging in cardio-oncology with expert faculty Dr. Nausheen Akhter (Northwestern University). Show notes were drafted by Dr. Sukriti Banthiya and episode audio was edited by CardioNerds Intern and student Dr. Diane Masket.

They use illustrative cases to discuss:

1. Recommendations on the use of multimodality imaging, including advanced echocardiographic techniques and cardiac MRI, in patients receiving cardiotoxic therapies and long-term surveillance.
2. Role of nuclear imaging (MUGA scan) in monitoring left ventricular ejection fraction.
3. Use of computed tomography to identify and/or monitor coronary disease.
4. Imaging diagnosis of cardiac amyloidosis.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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References – Multi-modality Imaging in Cardio-Oncology1. Baldassarre L, Ganatra S, Lopez-Mattei J, et al. Advances in Multimodality Imaging in Cardio-Oncology. J Am Coll Cardiol. 2022 Oct, 80 (16) 1560–1578.

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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CardioNerds cofounders, Dan Ambinder joins Drs. Aishwarya Pastapur, Oyinkansola Osobamiro, and Rafik Issa from the University of Michigan for drinks in Ann Arbor. They discuss the following case of pericardial decompression syndrome. Expert commentary is provided by Dr. Brett Wanamaker. Notes were drafted by Dr. Aishwarya Pastapur and Dr. Rafik Issa. The episode audio was engineered by CardioNerds Intern student Dr. Atefeh Ghorbanzadeh.

A woman in her 50s with a past medical history of stage IV lung cancer (with metastatic involvement of the liver, bone, and brain), previous saddle pulmonary emboli, pericardial effusion, and malignant pleural effusions presents with dyspnea. She was found to have a pericardial effusion with tamponade physiology relieved by pericardiocentesis. We discuss the management of cardiac tamponade, indications for pericardiocentesis, how to monitor for post-pericardiocentesis complications, and what to keep on your differential diagnosis for decompensation after pericardiocentesis. We discuss the epidemiology, pathophysiology, diagnosis, and management of pericardial decompression syndrome.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – Pericardial Decompression SyndromePearls – Pericardial Decompression Syndrome* Diminished heart sounds, a low-voltage EKG with electrical alternans, elevated jugular venous pressure/pulsations (JVP), and the presence of pulses paradoxes are important findings that could suggest tamponade. * McConnell sign is strongly concerning for right ventricular failure and pulmonary hypertension, potentially due to acute pulmonary embolism. * Mechanical thrombectomy for pulmonary embolism is not feasible if the emboli are diffusely scattered without a central lesion to target. * For patients who experience decompensation following pericardiocentesis, consider perforation, tamponade re-accumulation, or pericardial decompression syndrome (PDS). * When possible, avoid draining more than 1L of pericardial fluid at once to minimize the risk of PDS.

Notes – Pericardial Decompression SyndromeWhat is Pericardial Decompression Syndrome (PDS), and how does it present?

• Pericardial decompression syndrome is a rare, life-threatening syndrome occurring in about 5-10% of cases with paradoxical worsening of hemodynamics after pericardial drainage.
  • The clinical presentation ranges from pulmonary edema to cardiogenic shock to death, occurring a few hours to days after a successful pericardiocentesis.

What is the underlying mechanism for PDS?

The pathophysiology behind PDS is debated, but there are three proposed mechanisms:

1. Paradoxical Hemodynamic Derangement: After pericardiocentesis, venous return to the RV rapidly increases, resulting in RV expansion and potentially septal deviation towards the LV. Subsequently, the LV experiences decreased preload while still facing increased afterload as a compensatory response to obstructive shock, leading to decompensation.
   1. Myocardial Ischemia: Increased intrapericardial pressure may impair coronary perfusion, leading to myocardial ischemia. Upon pericardiocentesis, there is myocardial stunning with increased demand due to increased venous return and cardiac output
   2. Sympathetic Withdrawal: Withdrawal of sympathetic activation after drainage of pericardial fluid can trigger cardiovascular collapse

What are the risk factors for developing PDS, and how can we mitigate those risks for prevention?

• Generally, patients with long-standing pericardial effusion with chronic compression of the heart, such as those with malignant pericardial effusions, are more vulnerable to developing PDS after pericardiocentesis.
  • Additionally, rapid fluid removal increases the risk. In terms of prevention, removing fluid to normalize CVP and MAP and letting the rest of the fluid drain slowly may mitigate the risk.

How do we manage a patient with PDS?

• The management of PDS is supportive, focusing on addressing hemodynamic and respiratory derangements.
  • The underlying pathophysiology should resolve in 24-48 hours.

What is the prevalence and prognosis of PDS?

• PDS affects 5-10% of pericardiocentesis procedures, although the exact frequency is difficult to ascertain.
  • It is a self-resolving process as the heart re-adapts to the new hemodynamics.
  • However, during the episode of PDS, mortality can be as high as 30% per some studies.

References – Pericardial Decompression Syndrome1. Schnur M. Understanding Pulsus Paradoxus. Accessed February 27, 2024. https://nursingcenter.com/ncblog/august-2021/understanding-pulsus-paradoxus 2. Carlini’ ’Caterina Chiara De, Maggiolini’ ’Stefano. Pericardiocentesis in cardiac tamponade: indications and practical aspects. Accessed February 27, 2024. https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-15/Pericardiocentesis-in-cardiac-tamponade-indications-and-practical-aspects 3. Angouras DC, Dosios T. Pericardial Decompression Syndrome: A Term for a Well-Defined but Rather Underreported Complication of Pericardial Drainage. The Annals of Thoracic Surgery. 2010;89(5):1702-1703. doi:10.1016/j.athoracsur.2009.11.073 4. Imazio M. Pericardial decompression syndrome: A rare but potentially fatal complication of pericardial drainage to be recognized and prevented. European Heart Journal Acute Cardiovascular Care. 2015;4(2):121-123. doi:10.1177/2048872614557771 5. Prabhakar Y, Goyal A, Khalid N, et al. Pericardial decompression syndrome: A comprehensive review. World Journal of Cardiology. 2019;11(12):282-291. doi:10.4330/wjc.v11.i12.282 6. Sobieski C, Herner M, Goyal N, et al. Pericardial Decompression Syndrome After Drainage of Chronic Pericardial Effusions. JACC: Case Reports. 2022;4(22):1515-1521. doi:10.1016/j.jaccas.2022.08.023 7. Chhabra L. Pericardial Decompression Syndrome. American College of Cardiology. Accessed February 27, 2024. https://www.acc.org/Latest-in-Cardiology/Articles/2020/04/13/09/05/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fArticles%2f2020%2f04%2f13%2f09%2f05%2fPericardial-Decompression-Syndrome 8. Pradhan R, Okabe T, Yoshida K, Angouras DC, DeCaro MV, Marhefka GD. Patient characteristics and predictors of mortality associated with pericardial decompression syndrome: a comprehensive analysis of published cases. European Heart Journal Acute Cardiovascular Care. 2015;4(2):113-120. doi:10.1177/2048872614547975 9. Amro A, Mansoor K, Amro M, et al. A Comprehensive Systemic Literature Review of Pericardial Decompression Syndrome: Often Unrecognized and Potentially Fatal Syndrome. Current Cardiology Reviews. 17(1):101-110.

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CardioNerds (Amit Goyal and Dan Ambinder), Dr. Jaya Kanduri, and Dr. Jason Feinman discuss foundations of cardiovascular prevention with Dr. Stephen Kopecky. In this episode, the CardioNerds and topic expert Dr. Stephen Kopecky tackle cardiovascular prevention. They focus on how to identify patients at risk for cardiovascular disease by using the pooled cohort equation and discuss how to incorporate additional risk-enhancing factors in risk estimation. Later, they discuss the role of non-invasive imaging and testing for further patient risk stratification. Last, they discuss the appropriate pharmacologic interventions for patient care, how to determine what LDL-c to target for each patient, and how to modify your treatment modalities in response to side effects or the need for further lipid-lowering therapies.

Notes were drafted by Dr. Jason Feinman. Audio was engineered by CardioNerds Intern Christiana Dangas.

The CardioNerds Beyond the Boards Series was inspired by the Mayo Clinic Cardiovascular Board Review Course and designed in collaboration with the course directors Dr. Amy Pollak, Dr. Jeffrey Geske, and Dr. Michael Cullen.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls and Quotes – Foundations of Cardiovascular Prevention1. The 2018 cardiovascular prevention guidelines indicate that a single equation, like the pooled risk equation, does not fit everyone. There are additional risk enhancers that are not factored into the pooled risk equation that can impact an individual’s risk 2. These factors are often conditions that increase inflammation but can also include family history, ethnicity, chronic kidney disease, metabolic syndrome, premature menopause or gestational diabetes, and rheumatologic conditions 3. Data from Get With The Guidelines demonstrates that the average LDL at the time of the first myocardial infarction is 105 mg/dL. 4. Coronary artery calcium scores or a carotid ultrasound can be used to further risk stratify patients. However, CAC is likely to be negative in young women. A CAC of zero can be used to “de-risk” some patients but should not be used to guide therapy in the setting of tobacco usage, diabetes mellitus, or familial hypercholesterolemia. 5. Strategies to mitigate risk include healthy lifestyle habits and selectively targeting key risk factors including LDL, hypertriglyceridemia, inflammation, and the GLP1-pathway. Upcoming medications may address elevated Lp(a).

Notes – Foundations of Cardiovascular PreventionNotes: Notes drafted by Dr. Jason Feinman.

How do you assess an individual’s risk for cardiovascular disease?

• The paramount role of primary prevention is the assessment and mitigation of an individual’s risk for ASCVD event.1
• The 10-year ASCVD risk calculator is a commonly used tool to assess an individual’s risk and to guide shared decision-making conversations and recommendations.2
• Individuals can be characterized as having low (less than 5%), borderline (5%-7.5%), intermediate (7.5%-20%), or high (greater than 20%) risk.2
• The 10-year ASCVD risk calculator has varying validation in ethnic minorities, and other risk calculators, such as the Framingham CVD risk score, may be considered in those groups.3-5
• Additional risk enhancers may be used to guide recommendations for individuals at borderline or intermediate risk.1

What additional imaging testing may be beneficial in the assessment of an individual’s risk?

• Individuals with intermediate or borderline risk may benefit from further non-invasive imaging to help guide therapeutic recommendations.2
• Coronary artery calcification is a marker of underlying atherosclerosis, which can help to reclassify patients to be at higher risk for ASCVD events and support interventions to help lower this risk.6
• Conversely, a score of zero can help to reclassify individuals into lower-risk groups
• A score of zero should be used with caution in young women who are more likely to have non-calcified plaque and should not be used as a marker of low risk in individuals with other risk factors, including diabetes mellitus and tobacco usage.1

What non-pharmacological interventions may be considered to lower an individual’s ASCVD risk?

• The 2019 guidelines give a class I recommendation for a diet of vegetables, fruits, nuts, whole grains, and fish to lower ASCVD risk factors.1
• Increased intake of sugar has been demonstrated to correlate with increased rates of type 2 diabetes mellitus and subsequent increased risk for cardiovascular events.7
• At least 150 minutes per week of moderate-intensity or 75 minutes of vigorous intensive is recommended to reduce the risk of ASCVD events.1

What pharmacological interventions can be considered for individuals with prior ASCVD events or at high risk for ASCVD?

• A moderate-intensity statin is recommended for individuals at intermediate risk of ASCVD events with risk enhancers with a goal reduction in LDL-c of 30% or more.1
• For individuals at a high 10-year risk for ASCVD events, a 50% reduction in LDL-C is recommended.1
• A doubling of a statin dose can be predicted to lead to a 6% further reduction in LDL-C
• Ezetimibe can be considered as adjunct therapy for individuals receiving statin therapy who do not reach their target LDL-C.2

How do you determine the goal LDL-c?

• LDL goal is based on a history of prior ASCVD events and the risk of future ASCVD events.
• For secondary prevention, especially for individuals at high risk for ASCVD events, an LDL goal of at least less than 70 mg/dL is recommended2

References – Foundations of Cardiovascular Prevention1. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019 Sep 10;140(11):e649-e650] [published correction appears in Circulation. 2020 Jan 28;141(4):e60] [published correction appears in Circulation. 2020 Apr 21;141(16):e774]. Circulation. 2019;140(11):e596-e646. doi:10.1161/CIR.0000000000000678 2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019 Jun 18;139(25):e1182-e1186] [published correction appears in Circulation. 2023 Aug 15;148(7):e5]. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625 3. Yang X, Li J, Hu D, et al. Predicting the 10-Year Risks of Atherosclerotic Cardiovascular Disease in Chinese Population: The China-PAR Project (Prediction for ASCVD Risk in China). Circulation. 2016;134(19):1430-1440. doi:10.1161/CIRCULATIONAHA.116.022367 4. Jung KJ, Jang Y, Oh DJ, et al. The ACC/AHA 2013 pooled cohort equations compared to a Korean Risk Prediction Model for atherosclerotic cardiovascular disease. Atherosclerosis. 2015;242(1):367-375. doi:10.1016/j.atherosclerosis.2015.07.033 5. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753. doi:10.1161/CIRCULATIONAHA.107.699579 6. DeFilippis AP, Young R, Carrubba CJ, et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med. 2015;162(4):266-275. doi:10.7326/M14-1281 7. Löfvenborg JE, Andersson T, Carlsson PO, et al. Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Eur J Endocrinol. 2016;175(6):605-614. doi:10.1530/EJE-16-0376

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This case report explores the intricacies of familial hypercholesterolemia (FH), delving into its genetic basis, atherosclerotic cascade, and early-onset cardiovascular complications. It examines established diagnostic criteria and emphasizes personalized management, including statins, novel therapies, and lifestyle modifications.

CardioNerds cofounders (Drs. Amit Goyal and Danial Ambinder) join Dr. Irfan Shafi, Dr. Preeya Prakash, and Dr. Rebecca Theisen from the Wayne State University/DMC and Central Michigan University at Campus Martius in Downtown Detroit for some holiday ice-skating! They discuss an interesting pediatric case (see case synopsis below). Dr. Luis C Afonso provides the Expert CardioNerd Perspectives & Review segment for this episode. Audio editing by CardioNerds academy intern, Pace Wetstein.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case SynopsisFH, a 9-year-old female with no previous medical history, recently moved back to the US from Iraq. She presented to establish care and discuss new-onset chest pain and dyspnea. A systolic ejection murmur was noted during her initial visit to the pediatrician, prompting cholesterol testing and a cardiology referral. Testing revealed, alarming cholesterol levels (Total Cholesterol: 802 mg/dL, LDL: 731 mg/dL, Triglycerides: 123 mg/dL) prompted concern for cardiac involvement.

Due to persistent symptoms, FH was transferred to Children’s Hospital of Michigan. Despite normal findings on EKG and chest x-ray, a 2/6 systolic murmur was noted. She was discharged with a cardiology clinic follow-up.

However, two days later, FH experienced severe chest pain at rest, sweating, and difficulty breathing. She was transported to Children’s Hospital again, and her troponin level measured 3000, and her total cholesterol was 695 mg/dL. An echocardiogram revealed valvar and supravalvar aortic stenosis, necessitating collaboration between Pediatric and Adult cardiology teams.

CTA thorax revealed severe supravalvular stenosis, a hypoplastic right coronary artery, and significant coronary artery obstructions. Diagnostic cardiac catheterization confirmed severe aortic stenosis and coronary artery disease, leading to the decision for surgical intervention.

FH underwent the Ross operation, left main coronary artery augmentation, and right coronary artery reimplantation. Intraoperatively, atherosclerotic plaques were observed in multiple cardiac structures.

FH’s recovery was uneventful, discharged on a regimen including Atorvastatin, Ezetimibe, evolocumab, and antiplatelet therapy. Persistent high LDL levels required regular plasmapheresis. Plans for evaluations in Genetics, Lipid Clinic, Endocrine, and Gastroenterology were made, potentially leading to a liver transplant assessment. Given the severity of her condition, a heart/liver transplant might be considered in the future.

Conclusion:

This case of FH highlights the complex presentation of severe aortic stenosis and coronary artery disease in a pediatric patient. Urgent diagnosis, interdisciplinary collaboration, and aggressive management were crucial. The case underscores the importance of comprehensive care for pediatric patients with rare cardiac conditions, emphasizing collaboration between specialties for optimal outcomes and long-term well-being.

Case MediaPearls – Familial Hypercholesterolemia * Mutations in LDLR, ApoB, or PCSK9 genes disrupt LDL-C clearance, leading to a cascade of events culminating in accelerated atherosclerosis and early-onset cardiovascular complications (e.g., CAD, aortic stenosis, PAD, stroke). * Diagnosis of familial hypercholesterolemia relies on a combination of clinical features (xanthomas, corneal arcus, high LDL-C), family history, and genetic testing guided by established criteria like DCLN or NLA recommendations. * Supravalvular aortic stenosis, while common in many congenital cases, should raise suspicion of homozygous familial hypercholesterolemia in the setting of extensively elevated LDL and unexpected coronary artery disease. * A multidisciplinary approach, including involvement of pediatric and adult cardiology teams, lipid specialists and cardiothoracic surgeons, should be involved in the overall evaluation and management of these patients, both at initiation of diagnosis, and in an outpatient setting. * In patients with FH, it is important to delineate between homozygous and heterozygous manifestations, as this can have extensive implications on treatment, management and the overall clinical prognosis and further disease sequelae that the patient may experience.

References – Familial Hypercholesterolemia 1. Shah, N. (2020). Familial hypercholesterolemia: Early diagnosis and treatment is key for cardiovascular prevention.Cleveland Clinic Journal of Medicine, 87(5), 109-120. https://pubmed.ncbi.nlm.nih.gov/23469913/ 2. Turgeon, R. D., Barry, A. R., & Pearson, G. J. (2023). Familial hypercholesterolemia: Review of diagnosis,screening, and treatment. American Journal of Health-System Pharmacy, 80(11), 917-929.https://pubmed.ncbi.nlm.nih.gov/26796832/ 3. Collins, R. T. (2018). Cardiovascular disease in Williams syndrome. Current Opinion in Pediatrics, 30(5), 609-615. https://www.ncbi.nlm.nih.gov/books/NBK544278/ 4. Collins, R. T., Kaplan, P., Somes, G. W., & Rome, J. J. (2010). Long-term outcomes of patients with cardiovascular abnormalities and Williams syndrome. American Journal of Cardiology, 105(6), 874-878.https://pubmed.ncbi.nlm.nih.gov/30045083/ 5. Honjo, R. S., Monteleone, V. F., Aiello, V. D., Wagenfuhr, J., Issa, V. S., Pomerantzeff, P. M. A., Furusawa, E. A.,Zanardo, E. A., Kulikowski, L. D., Bertola, D. R., & Kim, C. A. (2022). Cardiovascular findings in Williams-Beuren Syndrome: Experience of a single center with 127 cases. American Journal of Medical Genetics. Part A,188(3), 676-682. https://www.ncbi.nlm.nih.gov/books/NBK544278/ 6. Pham, P. P., Moller, J. H., Hills, C., Larson, V., & Pyles, L. (2009). Cardiac catheterization and operative outcomes from a multicenter consortium for children with Williams syndrome. Pediatric Cardiology, 30(1), 9-14.https://pubmed.ncbi.nlm.nih.gov/19052807/ 7. Olsen, M., Fahy, C. J., Costi, D. A., Kelly, A. J., & Burgoyne, L. L. (2014). Anaesthesia-related haemodynamic complications in Williams syndrome patients: A review of one institution’s experience. Anaesthesia and Intensive Care, 42(6), 619-624. https://pubmed.ncbi.nlm.nih.gov/25233176/ 8. Harada-Shiba, M., Arai, H., Ishigaki, Y., Ishibashi, S., Okamura, T., Ogura, M., Dobashi, K., Nohara, A., Bujo, H.,Miyauchi, K., Yamashita, S., & Yokote, K. (2018). Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. Journal of Atherosclerosis and Thrombosis, 25(8), 751-770.https://pubmed.ncbi.nlm.nih.gov/29877295/ 9. Alnouri, F., & Santos, R. D. (2022). New trends and therapies for familial hypercholesterolemia. Journal of Clinical Medicine, 11(22), 6638. https://pubmed.ncbi.nlm.nih.gov/36431115/

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In this episode, Dr. Katie Fell (General Cardiology Fellow at University of Michigan and CardioNerds Academy Fellow) and Dr. Gurleen Kaur (incoming General Cardiology fellow at Brigham and Women’s Hospital and Director of CardioNerds Internship) discuss with Dr. James Arrighi (General Cardiologist and CEO of ACGME-International) about developing as a clinician educator and the concept of competency-based education.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

The PA-ACC & CardioNerds Narratives in Cardiology is a multimedia educational series jointly developed by the Pennsylvania Chapter ACC, the ACC Fellows in Training Section, and the CardioNerds Platform with the goal to promote diversity, equity, and inclusion in cardiology. In this series, we host inspiring faculty and fellows from various ACC chapters to discuss their areas of expertise and their individual narratives. Join us for these captivating conversations as we celebrate our differences and share our joy for practicing cardiovascular medicine. We thank our project mentors Dr. Katie Berlacher and Dr. Nosheen Reza.

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Video version – Becoming a “Big E” Medical Educator as a Cardiologist with Dr. James ArrighiQuoatables – Becoming a “Big E” Medical Educator as a Cardiologist with Dr. James Arrighi* “You really have to have a passion or a love for what you do…that’s probably responsible for most of the success one has in life” (time 4:43) * “Sub-subspecialty societies in Cardiology represent [a] great opportunity for junior faculty or even trainees to get involved, even before getting involved in ACC.” (time 5:30) * “Competency-based medical education and time variable training are not synonymous.” (time 16:43) * “As Cardiology evolves into more and more subspecialties…it begs the question… ‘Is Cardiology a primary specialty?’” (time 27:30) * “We need to think about [a] more efficient ways for training.” (time 31:55) * “As a clinician educator, there’s variety, there’s innovation!” (time 41:22)

Notes – Becoming a “Big E” Medical Educator as a Cardiologist with Dr. James ArrighiHow might one develop as a clinician educator on a national level?

• Junior faculty and trainees should consider taking advantage of education opportunities in various Cardiology sub-specialty societies (ex: American Society of Nuclear Cardiology, ASNC). This may include involvement in different committees. These opportunities are great ways to build connections and establish a reputation on a national level. This can help lead to other opportunities with larger national organizations (ex: ACC, AHA).

Cardiology Training Oversight

• The Accreditation Council for Graduate Medical Education (ACGME) and American Board of Internal Medicine (ABIM) both have regulatory power over Cardiology training, providing the minimum clinical experience standards for Cardiology fellowship training programs.
  • The ACGME oversees accreditation for Cardiology fellowships.
  • The ABIM defines the requirements for eligibility for certification of individuals.
  • Over time, the ACGME has transitioned to placing an emphasis on quality improvement, with a particular focus on continuous programmatic improvement.
  • The American College of Cardiology (ACC) helps define more granular recommendations for Cardiology training programs and their curriculum.
    • Periodically the ACC releases training guidelines for Cardiology fellowship programs, called Core Cardiovascular Training Statements, or COCATS. This document provides more contemporary, detailed, and specialty-specific recommendations for Cardiology training as compared to ACGME.
    • While ACC has no regulatory authority over Cardiology training programs, COCATS documents provide a roadmap for program directors on how to structure training.
    • The most recent version of the document, COCATS 4, incorporated in the concept of competency-based education (CBME).

What is Competency-Based Education (CBME)?

• Medical education has evolved to focus more on outcome-based assessments of trainees structured around competency evaluations.
  • In 2002, the ACGME defined competencies by which training programs should evaluate their trainees. As a result, training shifted from a time-based structure to one in which trainees must demonstrate specific competencies within a specific time frame.
  • ACC further defined competencies for Cardiology training in the Core Cardiovascular Training Statement 4 (COCATS 4). This is the first COCATs document introducing aspects of CBME, including defining competencies, milestones, and tools to assess a Cardiology trainee’s performance.
  • Each of these documents focuses on optimizing fellow time while in training, targeting education to the learner’s goals and their future career trajectory.
  • Moving to a competency-based, time-variable training program in the U.S. would be challenging and would require significant restructuring of our current GME training system, including Medicare funding.

What is ACGME-International (ACGME-I)?

• Group within the ACGME dedicated to improving health care internationally by assessing and advancing the quality of resident physicians’ education through accreditation.
  • The organization is currently present in 12 countries at 23 sponsoring institutions (as of April 2024).
  • ACGME-I provides postgraduate medical education programs with standardized frameworks on how to improve the quality of teaching, learning, research, and clinical practice for their trainees.

References 1. Weissman G, Auseon AJ, Arrighi JA, et al. Perceptions and Utilization of the U.S. Core Cardiovascular Training Statement. J Am Coll Cardiol. 2019;73(22):2896-2899. 2. Halperin JL, Williams ES, Fuster V. COCATS 4 Introduction. J Am Coll Cardiol. 2015;65(17):1724-1733. 3. Arrighi JA, Kilic S, Haines PG. Perspectives on Current Training Guidelines for Cardiac Imaging and Recommendations for the Future. Curr Cardiol Rep. 2018;20(6):43. Published 2018 Apr 23. 4. ACGME Program Requirements for Graduate Medical Education in Cardiovascular Disease. Accessed February 2, 2024. 5. Mendes LA, Weissman G, Berlacher K, et al. Competency-Based Alternative Training Pathway in Cardiovascular Disease and Clinical Cardiac Electrophysiology. J Am Coll Cardiol. 2022;79(25):2540-2542.

Production TeamDr. Gurleen KaurAmit Goyal, MDDaniel Ambinder, MD

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CardioNerds (Dr. Jessie Holtzman, Chair for the CardioNerds Women’s Heart Disease Committee, and Dr. Naima Maqsood, Chair for the CardioNerds Electrophysiology Committee) join Dr. Ritika Gadodia, Dr. Namratha Meda, and Dr. Tsion Aberra from the Medstar Washington Hospital Center/Georgetown University Program for the National Cherry Blossom Festival. They discuss involving a patient with Chagas cardiomyopathy. Dr. Rachel Marcus provides the Expert CardioNerd Perspectives & Review segment for this episode. Episode audio was edited by Dr. Diane Masket.

A 79-year-old male with a history of cardiomyopathy presented with recurrent ventricular tachycardia (VT) post-CRT-D placement. On arrival, the patient was in cardiogenic shock. Initial treatment with amiodarone and milrinone failed, necessitating the addition of mexiletine. Imaging was suggestive of a left ventricular ejection fraction of 20-25% with severe global hypokinesis. Prior coronary angiogram had shown nonobstructive coronary artery disease. Further non-ischemic cardiomyopathy evaluation was unrevealing. Given his El Salvadorian origins, Chagas serology results revealed Chronic Chagas Cardiomyopathy (CCM) confirmed by CDC testing. This case underscores the importance of suspecting CCM in patients with risk factors. An early diagnosis of CCM, can prevent catastrophic events (heart blocks, ventricular arrhythmias, thromboembolic events).

In summary, this case takes the learner through the journey of a patient with non-ischemic cardiomyopathy and emphasizes the importance of approaching it with a wide range of differentials.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Case MediaPearls – Chronic Chagas Cardiomyopathy with Recurrent Ventricular Tachyarrhythmia1. Always consider Chagas cardiomyopathy when you have a patient from Latin America who presents with non-ischemic cardiomyopathy. 2. Chagas cardiomyopathy is associated with an unfavorable prognosis and serves as an independent predictor of mortality. 3. Chagas cardiomyopathy is arrhythmogenic and requires consideration for ICD and, when appropriate, catheter based ventricular tachycardia ablation. 4. It is crucial to treat patients with nifurtimox and benznidazole when appropriate. 5. Provide screening for first-degree family members or close relatives who may have lived in the same environment.

Show Notes – Chronic Chagas Cardiomyopathy with Recurrent Ventricular TachyarrhythmiaWhat is the disease progression in Chagas disease5?

• Acute Stage:
  • Initial infection occurs through contact with infected triatomine bug feces or contaminated blood products.
  • Symptoms may be mild or absent but can include fever, fatigue, body aches, and swelling at the injection site (chagoma).
  • Parasitemia is high during this stage.
• Intermediate/Indeterminate Stage:
  • The infection becomes chronic if left untreated.
  • Many individuals enter this stage with no noticeable symptoms.
  • Parasitemia levels decrease, but the parasite remains in the body, mainly in muscle and cardiac tissue.
  • This stage can last for years to decades.
• Chronic Stage:
  • Some individuals will remain asymptomatic throughout their lives.
  • Cardiac complications (chronic Chagas cardiomyopathy) can lead to arrhythmias, congestive heart failure, and sudden death.
  • Digestive complications can result in enlarged esophagus (megaesophagus) and colon (megacolon), leading to difficulties in swallowing and digestion.

When do we suspect, and who do we screen, for Chagas disease?

• The seroprevalence of CCM in the USA is as high as 19%16. Among patients with LVEF<50%, the rate of positive serology was 28%. Similarly, the seropositivity among patients who reported recognizing the reduviid bug was 31%.
• Individuals who have lived in endemic countries of Mexico, Central and South America, excluding the Caribbean islands.
• T. cruzi seroprevalence is highest in Bolivia, Argentina, Paraguay, Ecuador, El Salvador, and Guatemala6.
• Close relatives and those born to women from endemic countries7.
• Persons with a history of bite/exposure to the vector responsible for transmission.
• EKG abnormalities suggestive of infection even in the absence of symptoms.
• TTE changes: regional wall motion abnormalities (particularly basal inferolateral, apical aneurysm)4

What diagnostic tests can confirm the diagnosis of chronic Chagas cardiomyopathy?

• Serologic testing: no available assay has sufficient sensitivity and specificity to be used alone. Two serologic tests based on different antigens and/or techniques (e.g., ELISA and IFA) are used in parallel to increase the accuracy of the diagnosis8.
• EKG: RBBB, LAFB, AV block, atrial fibrillation, ventricular tachycardias
• TTE: dilated cardiomyopathy, reduced ejection fracture, regional wall motion abnormalities, left ventricular apical aneurysm
• Cardiac MRI: myocardial fibrosis is a striking feature of CCM and LGE is used to detect and qualify the extent. Myocardial fibrosis also plays a role in risk stratification of CCM9.

What are the indications for treatment of Chagas disease?

• Acute phase.
• Early chronic phase, including women of childbearing age.
• Reactivated infection (e.g., after immunosuppression).
• Adults <50 years of age who do not have advanced cardiomyopathy (stage B1)10.
• In all other cases, the potential benefit of medication in delaying the development of Chagas disease should be weighed against potential adverse reactions- benznidazole and nifurtimox should not be taken by pregnant women or people with kidney or liver failure.

What are the benefits of screening and early diagnosis?

• Effective treatment, particularly in the acute phase.
• The BENEFIT trial showed that Trypanocidal therapy with benznidazole in patients with CCM did not significantly reduce cardiac deterioration11.
• Screening of family members/friends who grew up in the same environment.
• Reduction of transmission due to blood transfusions and congenital transmission.
• Early initiation of GDMT (guideline-directed medical therapy) for clinical heart failure 2/2 CCM.
• Ongoing surveillance for cardiomyopathy can prevent catastrophic events (heart blocks, ventricular arrhythmias, thromboembolic events).
• Cost effectiveness: Early diagnosis and treatment may reduce healthcare costs compared to the treatment of complications that arise from the chronic phase of the disease. Early diagnosis may also reduce the number of endomyocardial biopsies.

How is the management of VT unique in chronic Chagas cardiomyopathy?

• In comparison to cardiomyopathies of other etiologies, CCM is associated with a higher risk of life-threatening ventricular arrhythmias and an unfavorable prognosis12,14.
• Per ESC guidelines, the greatest benefit of ICD in CCM is in patients with an LVEF ≤40%15.
• Per Gali et al, most patients with an ICD received appropriate ICD shocks/therapies regardless of their LV systolic function13.
• Ablation of VT requires extensive mapping because multiple discrete circuits are typically present. The most common site of origin is the LV basal inferolateral wall. However, 1/3rd of the foci is located on the epicardial surface. This necessitates epicardial mapping to achieve successful ablation6.

References – Chronic Chagas Cardiomyopathy with Recurrent Ventricular Tachyarrhythmia1. Ghzally Y, Mahajan K. Implantable Defibrillator. In: StatPearls. StatPearls Publishing; 2023. Accessed October 7, 2023. http://www.ncbi.nlm.nih.gov/books/NBK459196/ 2. Vrettos A, Panoulas V. Diagnosing STEMI in the presence of paced rhythm: dispelling the myth of the ‘uninterpretable paced ECG.’ BMJ Case Rep. 2021;14(7):e242546. doi:10.1136/bcr-2021-242546 3. 3. Bozkurt B, Colvin M, Cook J, et al. Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association. Circulation. 2016;134(23). doi:10.1161/CIR.0000000000000455 4. Forsyth CJ, Manne-Goehler J, Bern C, et al. Recommendations for Screening and Diagnosis of Chagas Disease in the United States. The Journal of Infectious Diseases. 2022;225(9):1601-1610. doi:10.1093/infdis/jiab513 5. CDC – Chagas Disease – Disease. Accessed October 7, 2023. https://www.cdc.gov/parasites/chagas/disease.html 6. Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association | Circulation. Accessed October 7, 2023. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000599 7. Montgomery SP, Parise ME, Dotson EM, Bialek SR. What Do We Know About Chagas Disease in the United States? The American Journal of Tropical Medicine and Hygiene. 2016;95(6):1225-1227. doi:10.4269/ajtmh.16-0213 8. Malone CJ. A Rapid Review on the Efficacy and Safety. Pan American Health Organization (PAHO) and the World Health Organization (WHO); 2021. 9. Nunes MCP, Badano LP, Marin-Neto JA, et al. Multimodality imaging evaluation of Chagas disease: an expert consensus of Brazilian Cardiovascular Imaging Department (DIC) and the European Association of Cardiovascular Imaging (EACVI). European Heart Journal – Cardiovascular Imaging. 2018;19(4):459-460n. doi:10.1093/ehjci/jex154 10. 10. Prevention CC for DC and. CDC – Chagas Disease – Resources for Health Professionals – Antiparasitic Treatment. Published April 11, 2022. Accessed October 7, 2023. https://www.cdc.gov/parasites/chagas/health_professionals/tx.html 11. 11. Morillo CA, Marin-Neto JA, Avezum A, et al. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. N Engl J Med. 2015;373(14):1295-1306. doi:10.1056/NEJMoa1507574 12. 12. Probability of Occurrence of Life‐Threatening Ventricular Arrhythmias in Chagas’ Disease versus Non‐Chagas’ Disease – FILHO – 2000 – Pacing and Clinical Electrophysiology – Wiley Online Library. Accessed October 7, 2023. https://onlinelibrary.wiley.com/doi/10.1111/j.1540-8159.2000.tb07058.x 13. 13. Implantable cardioverter-defibrillators for treatment of sustained ventricular arrhythmias in patients with Chagas’ heart disease: comparison with a control group treated with amiodarone alone | EP Europace | Oxford Academic. Accessed October 7, 2023. https://academic.oup.com/europace/article/16/5/674/484618?login=fals 14. 14. Barbosa MPT, Da Costa Rocha MO, De Oliveira AB, Lombardi F, Ribeiro ALP. Efficacy and safety of implantable cardioverter-defibrillators in patients with Chagas disease. EP Europace. 2013;15(7):957-962. doi:10.1093/europace/eut011 15. 15. Requena-Méndez A, Aldasoro E, De Lazzari E, et al. Prevalence of Chagas Disease in Latin-American Migrants Living in Europe: A Systematic Review and Meta-analysis. Rodrigues MM, ed. PLoS Negl Trop Dis. 2015;9(2):e0003540. doi:10.1371/journal.pntd.0003540 16. 16. Gadodia R, Kerai A, Aberra T, et al. SEROPREVALENCE OF CHAGAS CARDIOMYOPATHY IN LATIN AMERICAN IMMIGRANTS IN THE WASHINGTON DC METRO AREA. Journal of the American College of Cardiology. 2023;81(8):318. doi:10.1016/S0735-1097(23)00762-3

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CardioNerds Dr. Josh Saef and Dr. Tommy Das join Dr. Omkar Betageri, Dr. Andrew Geissler, Dr. Philip Lacombe, and Dr. Cashel O’Brien from the Maine Medical Center in Portland, Maine to enjoy an afternoon by the famous Portland headlight. They discuss a case of a patient who presents with obstructive cardiogenic shock. Dr. Bram Geller and Dr. Jon Donnelly provide the Expert CardioNerd Perspectives & Review segment for this episode. Dr. Maxwell Afari, the Maine Medical Center cardiology fellowship program director highlights the fellowship program. Audio editing by CardioNerds Academy Intern, student doctor Tina Reddy.

This is the case of a 42 year-old woman born with complicated Tetralogy of Fallot repair culminating in a 29mm Edwards Sapiens (ES) S3 valve placement within a pulmonary homograft for graft failure who was admitted to the cardiac ICU for progressive cardiogenic shock requiring vasopressors and inotropic support. Initial workup showed lactic acidosis, acute kidney injury, elevated NT-proBNP, and negative blood cultures. TTE showed at least moderate biventricular systolic dysfunction. She was placed on furosemide infusion, blood cultures were drawn and empiric antibiotics initiated. Right heart catheterization demonstrated elevated right sided filling pressures, blunted PA pressures with low PCWP, low cardiac index, and low pulmonary artery pulsatility index. Intracardiac echocardiography (ICE) showed a large mass within the ES valve apparatus causing restrictive valve motion with a low gradient across the pulmonic valve in the setting of poor RV function. Angiography revealed a large filling defect and balloon valvuloplasty was performed with immediate hemodynamic improvement. Blood cultures remained negative, she was gradually weaned off of inotropic and vasopressor support, and discharged. Despite empiric treatment for culture negative endocarditis and ongoing anticoagulation, she was readmitted for recurrent shock one month later at which time the pulmonic mass was revisualized on ICE. A valve-in-valve transcatheter pulmonary valve (29mm ES S3) was placed to compress what was likely pannus, with an excellent hemodynamic result and no visible mass on ICE.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case MediaPearls – Obstructive Cardiogenic ShocK1. Tetralogy of Fallot is the most common cyanotic defect and can lead to long term complications after surgical repair including chronic pulmonary insufficiency, RV dysfunction, residual RVOT obstruction and branch pulmonary artery stenoses. 2. Chronic RV failure may be more indicative of a structural defect and therefore require interventional or surgical management. 3. Valve thrombosis, infective endocarditis and obstructive pannus formation should be considered in the differential of a patient with obstructive shock with a prosthetic valve. 4. Bioprosthetic pulmonic valve obstruction may be effectively managed with balloon valvuloplasty in patients who present in acute extremis but TCPV will likely provide a more lasting result. 5. While valvular gradients are typically assessed via echocardiography, invasive hemodynamics can serve as a critical adjunctive tool in its characterization.

Show Notes – Obstructive Cardiogenic ShocKNotes were drafted by Drs. Omkar Betageri, Philip Lacombe, Cashel O’Brien, and Andrew Geissler.

What are the common therapies and management for Tetralogy of Fallot?

• Tetralogy of Fallot is the most common cyanotic defect in children beyond the age of one year
• Anatomic Abnormalities: Anterior and Superior deviation of the conal septum creating a SubAo VSD and encroachment on the RVOT. The Ao follows the conal septum anteriorly to override the VSD and RVH is a consequence of an RV chamber that is at systemic pressure.
• The need for medical intervention is dependent on the degree of RVOT obstruction, pulmonary regurgitation, and/or peripheral pulmonary artery obstruction.
• Many patients are minimally cyanotic in newborn period and clinical follow-up with elective surgical correction between 3 months and 6 months of age is a preferred approach.
• Total surgical correction typically involves placing patients on cardiopulmonary bypass, relieving right sided obstruction (sometimes utilizing trans-annular patch), and connecting left ventricular blood flow with aortic, with VSD closure.
• Hypercyanotic “Tet” spells can occur in the neonatal period when there is an acute muscular spasm in the RVOT, fall in SVR or increase in PVR to facilitate right to left shunting at the VSD. It is managed medically with a stepwise approach placing the patient in knee-chest position, administer oxygen, IV fluids and a dose of narcotics, IV beta blocker, IV phenylephrine, ECMO
• Long term complications post-surgical repair include chronic pulmonary insufficiency, RV dysfunction, residual RVOT obstruction, peripheral PA obstruction, aortic root dilation, endocarditis, arrhythmias, and sudden cardiac death.

How should we approach the management of chronic right ventricular failure?

• Briefly, RV failure can result in chamber dilatation, bowing of the interventricular septum to the LV, impairing LV stroke volume, and ultimately causing hemodynamic collapse. This is the frequently referenced “RV spiral”
• The primary step in management of RV cardiogenic shock should be to identify and reverse the primary etiology
• While patients in acute RV failure may respond well to therapies such as fluid resuscitation, inotropes and vasopressors, or inhaled nitric oxide, patients with chronic RV failure (such as in our case) are more likely to have structural defects driving their decompensation
• Chronic RV failure can result from etiologies related to preload (ASD, tricuspid and pulmonic insufficiency), afterload (pulmonic or pulmonary artery stenosis, pulmonary vascular disease, and left heart disease) or contractility (RV myopathy or ARVC).

VSD is not volume loading to RV and Eisenmenger’s would be a pressure load b/c of increased PVR and actually volume unload the RV with R to L VSD shunting. * In acute stabilization, it is reasonable to utilize methods used to manage acute RV failure, with the understanding that interventional/surgical management will ultimately be necessary for definitive management

When should bioprosthetic valve obstruction be suspected and what is the differential for this? What is the initial workup?

• Obstruction should be suspected in any patient with a history of prosthetic valve placement who presents with a new murmur, new history of exercise intolerance, syncope/presyncope, or evidence of heart failure on exam.
• Differential diagnosis includes pannus ingrowth, thrombus, and vegetation. The anterior location of a surgically replaced RVOT/PV also makes it susceptible to compressive forces from the chest wall anteriorly and dilated Ao posteriorly, particularly in growing children. For bioprosthetic valves pannus is more common than acute thrombosis. Age of the valve, risk factors for infection, and anticoagulation status are clinical signs that may help differentiate.
• Diagnosis is typically made by transthoracic echocardiology (TTE): Increased gradients across the PV, RV hypertrophy, dilatation or dysfunction, increasing TR volume with elevated gradients from RV to RA.
• Cardiac CT or CMRI can also be helpful in characterizing the stenosis (discreet or long-segment, singular or stenoses in series).
• Invasive hemodynamic assessment in the catheterization laboratory can be especially helpful to more specifically characterize the degree and location of the obstruction as well as perform intervention (balloon, stent placement, TCPV) to relieve the obstruction. It is not uncommon that distal pulmonary artery stenting is required at the time of ballooning of the valve or valve-in-valve TCPVR.
• Lab testing sometimes performed includes INR, hemoglobin level, hemolysis labs, NT-BNP. If acute thrombosis of the bioprosthetic valve is diagnosed, a hypercoaguable work-up to include familial thrombophilia should be performed
• FDG PET may be an adjunctive tool to help evaluate for prosthetic valve endocarditis by detection of acute inflammation.

What are the indications for management of valve obstruction? What are the primary management strategies?

• As previously discussed the differential diagnosis of bioprosthetic valve obstruction includes BPVT, pannus, and vegetation. Valve intervention is indicated for symptomatic severe stenosis and treatment strategy depends on the underlying cause.
  • BPVT: If stable, can trial anticoagulation therapy. If unstable immediate therapy is required which requires surgery or fibrinolytics.
  • Pannus: Severe stenosis caused by soft tissue overgrowth with degeneration and calcium requires stenting open the obstructive valve in the catheterization laboratory followed by a valve-in-valve TCPV placement. It is increasingly rare that an obstructed bioprosthetic PV cannot be managed in this fashion and surgical PVR is needed. Medical therapy is ineffective in treating the underlying cause although can treat consequences from heart failure.
  • Vegetation: Endocarditis with vegetation causing severe stenosis is usually treated with surgical intervention. Decisions regarding surgical indications for endocarditis are complex and a trial of medical therapy is reasonable in less severe disease.
• For native pulmonic valve obstruction many patients are amenable to balloon valvuloplasty and recurrent stenosis is rare. Patients are usually left with some degree of pulmonic insufficiency. Balloon valvuloplasty alone is rarely an effective long-term solution for bioprosthetic valve stenosis.

What is the role of right heart catheterization in valvular obstructive shock?

• Typically valve gradients are obtained by TTE in a parasternal short axis view but hemodynamic gradients measured in the cath lab can provide supportive information
• Additionally right heart catheterization can assist in the characterization of the degree of shock (through calculation of cardiac indices, pulmonary artery pulmonary index, and cardiac power output).
• In pulmonary stenosis, the narrowed valve creates a pressure differential between the RV and PA such that a peak pressure difference RVSP-PASP >64 mmHg is considered severe or mean difference of >35 mmHg
• As in this case, catheterization also allows for therapeutic intervention either through balloon valvuloplasty or TCPVP.

References – Obstructive Cardiogenic ShocK1. Egbe AC, Pislaru SV, Pellikka PA, et al. Bioprosthetic Valve Thrombosis Versus Structural Failure: Clinical and Echocardiographic Predictors. J Am Coll Cardiol. 2015;66(21):2285-2294. doi:10.1016/j.jacc.2015.09.022 2. McElhinney DB, Zhang Y, Levi DS, et al. Reintervention and Survival After Transcatheter Pulmonary Valve Replacement. J Am Coll Cardiol. 2022;79(1):18-32. doi:10.1016/j.jacc.2021.10.031 3. Nishimura RA, Carabello BA. Hemodynamics in the cardiac catheterization laboratory of the 21st century. Circulation. 2012;125(17):2138-2150. doi:10.1161/CIRCULATIONAHA.111.060319 4. Otto, Catherine M et al. “2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.” Circulation vol. 143,5 (2021): e35-e71. doi:10.1161/CIR.0000000000000932 5. Rao PS. Management of Congenital Heart Disease: State of the Art-Part II-Cyanotic Heart Defects. Children (Basel). 2019;6(4):54. Published 2019 Apr 4. doi:10.3390/children6040054 6. Stout, Karen K et al. “2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology vol. 73,12 (2019): 1494-1563. doi:10.1016/j.jacc.2018.08.1028 7. VARC-3 WRITING COMMITTEE et al. “Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research.” European heart journal vol. 42,19 (2021): 1825-1857. doi:10.1093/eurheartj/ehaa799 8. Arrigo, M., Huber, L. C., Winnik, S., Mikulicic, F., Guidetti, F., Frank, M., Flammer, A. J., & Ruschitzka, F. (2019). Right ventricular failure: Pathophysiology, diagnosis and treatment. Cardiac Failure Review, 5(3), 140–146. https://doi.org/10.15420/cfr.2019.15.2 9. Kanwar, M. K., Everett, K. D., Gulati, G., Brener, M. I., & Kapur, N. K. (2022). Epidemiology and management of right ventricular-predominant heart failure and shock in the cardiac intensive care unit. European Heart Journal. Acute Cardiovascular Care, 11(7), 584–594. https://doi.org/10.1093/ehjacc/zuac063

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CardioNerds Co-Founder Dr. Daniel Ambinder, Episode Chair Dr. Dinu Balanescu, and FIT Lead Dr. Natalie Tapaskar discuss advanced heart failure in CardioOncology with expert Dr. Richard Cheng. Audio editing by CardioNerds Academy Intern, Dr. Akiva Rosenzveig.

In this episode, we discuss the spectrum of advanced heart failure in patients with a history of cancer. We dissect cancer therapy-related cardiac dysfunction (CTRCD) cases and the imaging and biomarker tools available for risk stratification and disease monitoring. We delve into the data on the use of guideline-directed medical therapy (GDMT) and cardiac resynchronization therapy (CRT) in these patients. We discuss the risk of prior radiation and chemotherapy during cardiac surgery. Finally, we learn about the post-transplant risk of rejection, recurrent malignancy, and de-novo malignancies, as well as treatment strategies we can employ for these patients.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls and Quotes – Advanced Heart Failure in CardioOncology1. Use the HFA-ICOS risk tool to understand the baseline risk of developing cancer therapy-related cardiac dysfunction (CTRCD). Key factors are type of cancer therapy, baseline CV risk factors, and age. 2. A relative change in global longitudinal strain of more than 15% from baseline is a marker of early cardiac dysfunction and predicts the subsequent risk for systolic dysfunction in patients undergoing cardiotoxic chemotherapy. 3. Statins may be useful in prevention of cardiovascular dysfunction in patients receiving anthracycline chemotherapy. There is limited data on the 4 pillars of GDMT in prevention of CTRCD, but should be started early once CRTCD is suspected or diagnosed! 4. Mediastinal radiation causes adhesions and scarring which increase the risk of bleeding during cardiac surgery, lead to longer operative times, and can lead to RV failure and poor wound healing. 5. Patients with a pre-transplant history of malignancy have a higher risk of mortality due to post-transplant malignancy. And patients with active cancer should not be considered for heart transplant. Post-transplant malignancy risk can be mitigated by utilizing an mTOR based, CNI free immunosuppression regimen.

Show notes – Advanced Heart Failure in CardioOncologyHow do cardio-oncology and advanced heart failure intersect?

• There are 3 basic populations of patients to consider:
  • Patients with advanced heart failure who develop cancer.
  • Patients with pre-existing chemotherapy and radiation exposure for cancer treatment who later develop advanced heart failure
  • Heart transplant recipients who, in the long term are at very high risk of developing cancer
  • Cardio-oncologists must consider risk assessment and mitigation, long-term prognosis, and treatment strategies for each of these unique populations.

How can we assess the risk of developing cardiovascular disease during cancer treatment (CTRCD)?

• There are many proposed risk tools. However, the majority are not well-validated.
  • One of the most used tools is the HFA-ICOS risk tool.1
    • You can select the planned cancer therapy for the patient (anthracyclines, HER-2, VEGF, RAF/MEK inhibitors, Kinase inhibitors, multiple myeloma therapies) and then calculate their risk of developing CV disease during cancer treatment based on baseline variables:
      • 1) previous history of CV disease,
      • 2) biomarkers – troponin and NT-proBNP
      • 3)age,
      • 4) CV risk factors -HTN, DM, CKD,
      • 5) previous cardio-toxic treatments,
      • 6) lifestyle risk factors- smoking, obesity
    • The risk tool will then give you a ranking of very high, high, medium, or low risks.

How should we use imaging to evaluate cardiac dysfunction in patients undergoing cancer treatments?

• Echo with global longitudinal strainA relative change in global longitudinal strain of more than 15% from baseline is a marker of early cardiac dysfunction and predicts the subsequent risk for systolic dysfunction.Data are mixed on the benefit of intervening on drops in GLS without a concomitant drop in LVEF. Current vendor software has improved the consistency in GLS measurements across vendors, which used to be quite problematic.
  • Echo LVEF
    • Some centers prefer to use 3D LVEF to track patients over time.
    • For asymptomatic high-risk patients, we should obtain echocardiograms at 1, 3, and 5 years post-cancer therapies and then every 5 years thereafter.
    • But surveillance should occur on a case-by-case basis.
  • CPET
    • Can be used to risk stratify patients with lung or colon cancer before starting cancer treatment.
    • You can trend peak VO2 over time after cancer treatments.
    • However, this is generally a data-sparse zone!

Can we use serum biomarkers such as troponin or NT-proBNP in monitoring for the development of CTRCD?

• Elevations in BNP during cancer treatment are associated with subsequent cardiovascular disease.
  • Elevations in troponin and myeloperoxidase in breast cancer patients receiving anthracyclines can predict the risk of cardiotoxicity.
  • Novel biomarkers – data-free zone
    • CRP is a marker of inflammation and may be helpful in patients undergoing radiation therapy.
    • Immunoglobulins- baseline elevated IgE levels have a lower risk for cardiotoxicity.
    • Cell-free DNA – may be the future?

What is the role of cardiovascular medications and devices in preventing and treating CTRCD?

• Prevention:
  • Statins – The STOP-CA trial showed that use of atorvastatin 40 mg/day in patients with lymphoma receiving anthracycline chemotherapy reduced the incidence of cardiac systolic dysfunction compared to placebo.2
  • SGLT2i – limited retrospective data in patients with diabetes and anthracycline chemotherapy. May have lower rates of cardiac events on SGLT2i.
  • Currently there is not enough data to recommend routine use of SGLT2i, ARNI, and BB for cardioprotection before cancer therapies.
  • Treatment:
    • Treat these patients similarly to other heart failure patients. The four pillars of GDMT work! Early recognition is critical to confer better long-term outcomes.
    • CRT-D: MADIT-CHIC3 showed that CRT therapy improved LVEF at 6 months in patients with chemotherapy-induced cardiomyopathy.
      • Only consider ICD if life expectancy is >1 year.
      • There is a risk of device reset for radiation directly over the device. ICDs are more sensitive to ionizing radiation, leading to inappropriate shocks.
      • Can consider moving the device to a non-radiation field.

What do we need to consider when patients with a history of cancer are being evaluated for heart transplant and left ventricular assist device (LVAD)?

• Heart transplant
  • Patients with chemo-induced cardiomyopathy have no differences in post-transplant outcomes compared to patients with other causes of cardiomyopathy.
  • Patients with a pre-transplant history of malignancy have a higher risk of mortality due to post-transplant malignancy, particularly in those with a history of hematologic malignancy.
  • Patients with active cancer should not be considered for heart transplant.
  • The duration and interval of waiting after active cancer before a heart transplant depends on the type and stage of cancer.
  • LVAD
    • Patients with chemotherapy-induced cardiomyopathy have similar outcomes and rates of post-LVAD RV dysfunction as patients with other etiologies of cardiomyopathy.
    • Limited data on performing LVAD in patients with active cancer.

What risk does prior mediastinal radiation pose to cardiac surgery?

• Mediastinal radiation
  • Increases adhesions and scarring, increasing the risk of bleeding during cardiac surgery. Longer operative times may also increase the risk of RV failure.
  • There can also be atrophy of sternal muscles, which can lead to poor wound healing

What do the post-heart transplant rejection and malignancy profiles look like for patients with a history of chemotherapy-induced cardiomyopathy?

• Patients with prior chemotherapy have depressed immunosurveillance from their innate immune system and, thus, may have a lower risk of rejection. But there is limited data here.
  • Patients with a history of pre-transplant malignancy are at increased risk of recurrence and PTLD. You can consider decreasing immunosuppression or switching to mTOR inhibitor-based regimen to reduce the risk.

What must we know about de-novo malignancy post-heart transplant?

• Risk factors: history of prior malignancy, heavier immunosuppression, older recipient age, smoking history, radiation exposure, genetic variants.
  • Treatment: reduce immunosuppression as much as possible and switch to an mTOR-based regimen.
  • What about immune checkpoint inhibitors post-transplant?
    • These work by upregulating T cell activity, which counteracts our transplant immunosuppression. High risk of rejection, but some successful case reports of use.

References – Advanced Heart Failure in CardioOncology1. Lyon AR, Dent S, Stanway S, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the C ardio‐ O ncology S tudy G roup of the H eart F ailure A ssociation of the E uropean S ociety of C ardiology in collaboration with the I nternational C ardio‐ O ncology S ociety. Eur J Heart Fail. 2020;22(11):1945-1960. doi:10.1002/ejhf.1920 2. Neilan TG, Quinaglia T, Onoue T, et al. Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial. JAMA. 2023;330(6):528. doi:10.1001/jama.2023.11887 3. Singh JP, Solomon SD, Fradley MG, et al. Association of Cardiac Resynchronization Therapy With Change in Left Ventricular Ejection Fraction in Patients With Chemotherapy-Induced Cardiomyopathy. JAMA. 2019;322(18):1799. doi:10.1001/jama.2019.16658

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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CardioNerds, Dr. Richard Ferraro and Dr. Dan ambinder join Dr. Li Pang, Dr. Emily Hendricks, and Dr. Bei Jiang from West Virginia University to discuss the following case that features apical obliteration with biventricular thrombus. Dr. Christopher Bianco provides the Expert CardioNerd Perspectives & Review (E-CPR) for this episode. Audio editing by CardioNerds Academy Intern, student doctor Tina Reddy.

A 37-year-old Caucasian man with a history of tobacco smoking and hypertension who presented with chest pain and elevated troponin was admitted for non-ST elevation myocardial infarction (NSTEMI). Ischemic evaluation with an invasive coronary angiogram was negative. He was treated as NSTEMI and scheduled for outpatient cardiac MRI (CMR). The patient came back 2 months later with right arm weakness and confusion and was found to have an embolic stroke. Labs showed positive troponin with a flat trend and hypereosinophilia. Transthoracic echocardiogram (TTE) showed obliteration of LV and RV apex with thrombus and reduced LV systolic function. CMR was consistent with myocarditis with biventricular thrombus. The patient was started on corticosteroids and warfarin. Hypereosinophilia workup was positive for PDGFRA alpha rearrangement. He was diagnosed with primary hypereosinophila syndrome. Imatinib was initiated. The patient was followed up with the hematology clinic, achieved a complete hematologic response with normalized cell count, and remained free from any cardiovascular event at the 8-month follow-up.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Case MediaPearls – Apical Obliteration with Biventricular Thrombus1. Cardiac MRI is a valuable test for patients presenting with myocardial infarction with non-obstructive coronary arteries (MINOCA). 2. Obliterated apex with apical thrombus on TTE with hypereosinophilia should raise high suspicion for eosinophilic myocarditis. 3. Initiation of corticosteroids is the first-line treatment for eosinophilic myocarditis, which is associated with lower mortality in patients with myocarditis. For other potential complications, such as heart failure, intracardiac thrombus, arrhythmia, and pericardial effusion, the standard of care for each disorder is recommended. 4. Hypereosinophilia can be seen in parasitic infections, vasculitis, asthma, allergy, hematological malignancies, and as a primary disorder.

Show Notes – Apical Obliteration with Biventricular ThrombusWhat is the differential diagnosis for patients with elevated troponin and nonobstructive CAD?

• The occurrence of acute myocardial infarction (AMI) without significant CAD was reported 80 years ago. However, the term MINOCA (myocardial infarction with non-obstructive coronary arteries) has only been used recently to describe these patients. It involves ischemic and nonischemic etiologies. First, overlooked ischemic etiologies need to be ruled out by reconciling the angiogram images such as spontaneous coronary artery dissection (SCAD) and plaque disruption. Intracoronary imaging, such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), may be applied to evaluate for SCAD and subtypes of plaque disruption when indicated.
• The investigation continues with nonischemic causes such as stress cardiomyopathy, myocarditis, pulmonary embolism, demand ischemia from sepsis, anemia, chest trauma, heart failure exacerbation, arrhythmia, and stroke.
• The diagnosis of MINOCA is established when it fulfills the following criteria: First, it is AMI by the Fourth Universal Definition; Second, less than 50% of stenotic lesion on angiogram; Third, there is no alternate diagnosis. MINOCA etiologies include coronary artery spasms and microvascular dysfunction.
• It is recommended to perform CMR in all MINOCA patients without an obvious underlying cause.

What are the common causes of LV thrombus?

• The incidence of LV thrombus has been reported between 4-39% after anterior MI. The temporal incidence has been decreasing. It is also commonly seen in dilated cardiomyopathy with an incidence of 2-36%.
• The pathophysiology of intracardiac thrombus formation obeys Virchow’s triad rule, which states that endocardial injury, hypercoagulability/inflammation, and stasis lead to thrombogenesis.
• Other etiologies of LV thrombus include eosinophilic myocarditis and LV noncompaction.

What are the characteristic echocardiographic and CMR findings of eosinophilic myocarditis (EM)?

• During the acute necrotic stage, there is increased subendocardial echogenicity, wall thickening, impaired regional wall motion, and pericardial effusion; there is edema without fibrosis on CMR.
• During the thrombotic stage, intracardiac thrombus is often detected in the ventricles on TTE; on CMR, there is endomyocardial involvement and intracardiac thrombus.
• During the fibrotic stage, in addition to the cumulative findings from previous stages, restrictive physiology, valvular thickening, and restricted motion can occur on TTE; on CMR, endomyocardial fibrosis with LGE is present.

What is the management for eosinophilic myocarditis (EM)?

• Two aspects must be considered in the treatment of eosinophilic myocarditis: the management of acute cardiac conditions and the treatment of underlying causes.
• Corticosteroids are the first-line treatment for EM. A meta-analysis of 179 cases showed that steroid use is associated with a lower mortality rate. No clinical trial data are available for the treatment of eosinophilic myocarditis. The dose and duration of corticosteroids in each individual case can be different.
• For intracardiac thrombus, vitamin K antagonists (VKAs) are the drugs of choice. Complete gradual resolution of intracardiac thrombus with VKA in eosinophilic myocarditis was reported at the 18-month follow-up. The INR target was 2-3. Emerging data showed the noninferiority of using DOAC for LV thrombus compared to warfarin as an alternative for stroke prevention. There is an increased risk of stroke in patients on VKA but with subtherapeutic INR levels. The guidelines recommend DOAC as a reasonable alternative to VKA to treat LV thrombus.
• For other potential complications such as heart failure, intracardiac thrombus, arrhythmia, and pericardial effusion, the standard of care for each complication is recommended. There is no large data to suggest a specific approach in eosinophilic myocarditis. It has been reported to achieve full recovery with GDMT in addition to treating the underlying cause in a case report of eosinophilic myocarditis with severely reduced LV systolic function.

What is hypereosinophilic syndrome (HES)?

• HES is pleomorphic in clinical presentation and can be idiopathic or associated with a variety of underlying conditions, including allergic, rheumatologic, infectious, and neoplastic disorders.
• There are 4 groups. In primary HES, the hypereosinophilia is driven by a clonal process in stem cell or myeloid lineage. Patients usually present with a myeloid neoplasm and myeloid proliferative disorder. Besides eosinophilia, they may have other cytopenias, blasts, or dysplastic cells in peripheral blood. They can present with constitutional symptoms or hepatosplenomegaly. Some of these patients have disease-defining mutations or chromosome translocation. They require treatment for their underlying hematologic condition. Secondary HES usually have polyclonal eosinophilia secondary to some stimulus. The stimulus may be infections, rheumatology conditions, solid tumors, and lymphoid neoplasm. The underlying condition increases eosinophilic cytokines leading to an increase in eosinophil production. The third group is familial HES results from certain genetic factors. If no cause of HES can be identified, they fall into the category of idiopathic HES.
• Patients with HES secondary to myeloid and lymphoid disorders need to follow up with a hematology specialist. References – Apical Obliteration with Biventricular Thrombus1. Bondue A, Carpentier C, Roufosse F. Hypereosinophilic syndrome: considerations for the cardiologist. Heart 2022;108:164-171.
• Merlo M, Gagno G, Baritussio A et al. Clinical application of CMR in cardiomyopathies: evolving concepts and techniques : A position paper of myocardial and pericardial diseases and cardiac magnetic resonance working groups of Italian society of cardiology. Heart Fail Rev 2023;28:77-95.
• Murthy SB. Troponin Elevation After Ischemic Stroke and Future Cardiovascular Risk: Is the Heart in the Right Place? Journal of the American Heart Association 2021;10:e021474.
• Dhaliwal JSS, Ansari SA, Ghosh S, Chitkara A, Khizer U. Duet of Death: Biventricular Thrombus in a Methamphetamine User. Cureus 2023;15:e39917.
• Levine GN, McEvoy JW, Fang JC et al. Management of Patients at Risk for and With Left Ventricular Thrombus: A Scientific Statement From the American Heart Association. Circulation 2022;146:e205-e223.
• Parrillo JE. Heart Disease and the Eosinophil. New England Journal of Medicine 1990;323:1560-1561.
• Wright BL, Leiferman KM, Gleich GJ. Eosinophil Granule Protein Localization in Eosinophilic Endomyocardial Disease. New England Journal of Medicine 2011;365:187-188.
• Polte CL, Bobbio E, Bollano E et al. Cardiovascular Magnetic Resonance in Myocarditis. Diagnostics 2022;12:399.
• Ammirati E, Frigerio M, Adler ED et al. Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document. Circ Heart Fail 2020;13:e007405.
• Ito S, Isotani A, Yamaji K, Ando K. Follow-up magnetic resonance imaging of Löffler endocarditis: a case report. Eur Heart J Case Rep 2020;4:1-4.
• Miller T, Gabriel A, Bianco C, Hamirani Yasmin S. ACUTE EOSINOPHILIC MYOCARDITIS: AN ATYPICAL PRESENTATION DIAGNOSED BY COMBINED CARDIAC MAGNETIC RESONANCE IMAGING AND ENDOMYOCARDIAL BIOPSY WITH FULL RECOVERY. Journal of the American College of Cardiology 2022;79:2298-2298.

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CardioNerds (Drs. Richard Ferraro, Gurleen Kaur, and Rupan Bose) discuss the growing epidemic of obesity and dive into the role of its procedural management with Dr. Steve Nissen, Chief Academic Officer at the Cleveland Clinic HVTI and past president of the American College of Cardiology. This is an exciting topic that reflects a major inflection point in cardiovascular care. In this episode, we discuss the importance of addressing obesity in cardiovascular care, as it is a major driver of cardiovascular disease and the progression of associated cardiovascular comorbidities. We look at the role of bariatric surgery and its ability to produce sustained weight loss. Finally, we look into the emerging role of new medical therapies such as GLP1 and GIP agonist medications. Notes were drafted by Dr. Rupan Bose and episode audio was edited by CardioNerds Intern Dr. Atefeh Ghorbanzadeh.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls and Quotes – Procedural Management of Obesity with Dr. Steve Nissen1. Obesity is associated with adverse cardiovascular outcomes. Returning to a healthy weight can largely prevent the downstream consequences of obesity. 2. Regarding lifestyle modifications, diet alone is insufficient in sustaining prolonged weight loss. It is associated with short-term weight loss, but it is generally necessary to supplement with exercise and activity to ensure sustained weight loss. 3. Bariatric surgery should be considered for patients with BMI ≥40 kg/m2 or BMI ≥35 kg/m2 with obesity-related comorbid conditions who are motivated to lose weight and who have not responded to behavioral treatment with or without pharmacotherapy. 4. New emerging medications, including GLP1 receptor agonists, GIP receptor agonists, and glucagon receptor agonists, are beginning to approach weight loss levels that were previously only seen with bariatric surgery. Further research in this dynamic area is ongoing.

Show notes – Procedural Management of Obesity with Dr. Steve NissenNotes drafted by Dr. Rupan Bose.

What is the role of obesity in the burden of cardiovascular disease, and why is it so important for CardioNerds to address it?

• According to the AHA, approximately 2.8 to 3.5 billion people worldwide are either overweight or obese. It is estimated that by 2030, 30% of people in the US will have a BMI greater than 30.
• Adipose tissue is associated with cytokine release. Cytokines, in turn, can activate and increase levels of IL-1 beta, IL-6, and CRP, leading to an increased inflammatory state. This pro-inflammatory state then accelerates the rate of cardiovascular disease.
• Obesity is also associated with significant joint and orthopedic diseases, which further impact patients’ quality of life and morbidity.
• Additionally, obesity is associated with NASH cirrhosis. These adverse liver outcomes hold additional significant systemic implications and morbidity.

How do you determine one’s goal weight and goal BMI? Is BMI a good standard for measuring obesity?

• BMI is a variable of both weight and height. However, it cannot differentiate those whose weight is from adipose tissue versus from muscle mass. Therefore, BMI measurements can sometimes be misleading. Waist circumference may be a better measurement standard for obesity and risk assessment.
• The “apple shape” body type, with more abdominal fat, is associated with higher inflammation and cardiovascular risk than the “pear-shaped” body type, which is where there is more fat deposition in the buttocks and thighs. A fat distribution that is more centralized corresponds with greater cardiovascular risk.
• “Normal” BMI and “normal” waist circumference can differ based on ethnicity. For example, a BMI of 22.6 in South Asians carries a similar risk to a BMI of 30 in White European patients. Therefore, providers must remain cognizant of these differences when making individual patient recommendations.

Does childhood obesity correlate with obesity at later ages? At what age should we start screening for and addressing obesity?

• Childhood obesity, or obesity at a young age, often correlates with continued obesity later in life. But it is interesting that if one can return to a healthy body weight at some point in their life, one can largely prevent the downstream consequences of obesity
• The USPSTF recommends clinicians screen for obesity in children and adolescents age 6 and older and offer behavioral interventions to promote improvements in weight status (grade B recommendation)

What procedures or surgeries are available to patients with obesity?

• Bariatric surgery is an excellent option with great outcomes if done for the right patient.
• The 2013 AHA/ACC/TOS guidelines for the management of overweight and obesity in adults recommend bariatric surgery for patients with BMI ≥40 kg/m2 or BMI ≥35 kg/m2 with obesity-related comorbid conditions who are motivated to lose weight and who have not responded to behavioral treatment with or without pharmacotherapy.
• Several studies have shown that patients with bariatric surgery had a huge reduction in myocardial infarction, stroke, kidney disease, and death.
• Bariatric surgery can help address other cardiovascular comorbidities. For example, the STAMPEDE trial (Schauer, R et al.) demonstrated that bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing or, in some cases, resolving hyperglycemia.
• Additionally, the magnitude of weight loss from bariatric surgery is often greater than the absolute magnitude of weight loss through medical therapy alone. Therefore, for patients with a very high BMI, bariatric surgery may be better suited to achieve the necessary weight loss.

What emerging medications are available to patients with obesity? And what medications are just around the corner?

• GLP1 agonists, or dual GIP-GLP1 receptor agonists, drugs are associated with approximately 20% reduction in body weight.
• In the SELECT trial, semaglutide was associated with a 9.3% reduction in body weight (Please see GLP1 series for additional details!).
• In the SURMOUNT-1 trial, tirzepatide was associated with a 22% reduction in body weight.
• Future trials will look at triple agonists that combine GLP1, GIP, and glucagon agonist properties. One such drug is retatrutide, which previously demonstrated a 24% (and approximately 28.5% in females) reduction in body weight. These medications are approaching similar weight loss magnitudes to bariatric surgery (a Roux en Y procedure achieves approximately 25% weight loss on average), though additional studies are ongoing.

What other strategies can one use to lower body weight and maintain that weight loss?

• Diet alone is not sustainable in reducing weight and keeping weight off. Unfortunately, the body subconsciously activates adaptive responses that down-regulate metabolism, which in turn burns fewer calories.
• Therefore, exercise and activity play a key role in continuing to burn calories, allowing for sustained weight loss.
• All patients should, therefore, be counseled on both diet and exercise strategies to address obesity and weight loss.

Discussing weight and body image is often a sensitive subject and can carry a stigma for some patients. What are some recommendations on how we can address these topics in a safe and supportive manner?

• It is important to create a safe, supportive, and non-judgmental space when discussing weight with patients.
• We should also make an effort to understand the specific drivers of each individual patient’s weight gain. Some drivers include emotional stress, socio-economic factors, lifestyle barriers, etc. By understanding each specific driver, we can be more targeted in our approach and build more individualized plans with our patients.
• We can also recruit other clinical team members to assist the patient in their weight loss journey. Some such teammembers include dieticians, psychiatrists, social workers, etc.

References – Procedural Management of Obesity with Dr. Steve NissenJastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., … & Stefanski, A. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387(3), 205-216.

https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., … & Ryan, D. H. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine.

https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

Schauer, P. R., Bhatt, D. L., Kirwan, J. P., Wolski, K., Aminian, A., Brethauer, S. A., … & Kashyap, S. R. (2017). Bariatric surgery versus intensive medical therapy for diabetes—5-year outcomes. New England Journal of Medicine, 376(7), 641-651.

https://www.nejm.org/doi/full/10.1056/nejmoa1600869

Jensen, M. D., Ryan, D. H., Apovian, C. M., Ard, J. D., Comuzzie, A. G., Donato, K. A., … & Yanovski, S. Z. (2014). 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Journal of the American college of cardiology, 63(25 Part B), 2985-3023.

Powell-Wiley, T. M., Poirier, P., Burke, L. E., Després, J. P., Gordon-Larsen, P., Lavie, C. J., … & American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council. (2021). Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 143(21), e984-e1010.

Lopez-Jimenez, F., Almahmeed, W., Bays, H., Cuevas, A., Di Angelantonio, E., le Roux, C. W., … & Wilding, J. P. (2022). Obesity and cardiovascular disease: mechanistic insights and management strategies. A joint position paper by the World Heart Federation and World Obesity Federation. European Journal of Preventive Cardiology, 29(17), 2218-2237.

Sjöström, L., Peltonen, M., Jacobson, P., Sjöström, C. D., Karason, K., Wedel, H., … & Carlsson, L. M. (2012). Bariatric surgery and long-term cardiovascular events. Jama, 307(1), 56-65.

Liakopoulos, V., Franzén, S., Svensson, A. M., Sattar, N., Miftaraj, M., Björck, S., … & Eliasson, B. (2020). Renal and cardiovascular outcomes after weight loss from gastric bypass surgery in type 2 diabetes: cardiorenal risk reductions exceed atherosclerotic benefits. Diabetes Care, 43(6), 1276-1284.

Eisenberg, Dan, et al. 2022 American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) indications for metabolic and bariatric surgery. (2023): 3-14. doi: https://doi.org/10.1016/j.soard.2022.08.013

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CardioNerds (Drs. Gurleen Kaur and Richard Ferraro) and episode FIT Lead Dr. Spencer Carter (Cardiology Fellow at UT Southwestern) discuss the clinical implementation of GLP-1 receptor agonists with Dr. Neha Pagidapati (Faculty at Duke University School of Medicine). In this episode of the CardioNerds Cardiovascular Prevention Series, we discuss the clinical implementation of glucagon-like peptide-1 (GLP-1) receptor agonists. We cover the clinical indications, metabolic and cardiovascular benefits, and potential limitations of these emerging and exciting therapies. Show notes were drafted by Dr. Spencer Carter. Audio editing was performed by CardioNerds Academy Intern, student Dr. Pacey Wetstein.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

CardioNerds Prevention Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
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Check out CardioNerds SWAG!
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Pearls and Quotes – Clinical Implementation of GLP-1 Receptor Agonists1. GLP-1 agonists work through a variety of mechanisms to counteract metabolic disease. They increase insulin secretion, inhibit glucagon secretion, slow gastric motility, and increase satiety to limit excess energy intake. 2. Patients with type II diabetes and an elevated risk for atherosclerotic cardiovascular disease should be considered for GLP-1 agonist therapy regardless of hemoglobin A1c. 3. GLP-1 agonists offer significant ASCVD risk reduction even in the absence of diabetes. Newer data suggest a significant reduction in cardiovascular events with GLP-1 agonist therapy in patients who are overweight or obese and have a prior history of heart disease. 4. GLP-1 agonists should generally be avoided in patients with a history of medullary thyroid cancer or MEN2. As these medications slow gastric emptying, relative contraindications include history of recurrent pancreatitis and gastroparesis. 5. GLP-1 agonists should be initially prescribed at the lowest dose and slowly uptitrated to avoid gastrointestinal side effects.

Show notes – Clinical Implementation of GLP-1 Receptor AgonistsWhat were the groundbreaking findings of the STEP1 and SURMOUNT-1 trials and how these impact cardiovascular wellness?

• The STEP1 and SURMOUNT trials demonstrated sustained clinically relevant reduction in body weight with semaglutide and tripeptide, respectively, in patients with overweight and obesity. As obesity is an important risk factor for the development of cardiovascular disease, weight reduction meaningfully contributes to cardiovascular wellness.

What were the findings of the LEADER trial and their implications for patients with type II diabetes and high cardiovascular risk?

• The LEADER trial demonstrated a significant reduction in the rate of cardiovascular death, nonfatal MI, or nonfatal stroke in patients with type II diabetes treated with liraglutide. GLP-1 receptor agonist therapy should be considered in all patients with type II diabetes and elevated ASCVD risk regardless of A1c or current hyperglycemic therapy.

What are current indications for GLP1 agonists in the context of cardiometabolic disease.

• GLP-1 receptor agonists should be considered in patients with type II diabetes and high ASCVD risk OR patients without diabetes who are overweight/obese and have a history of cardiovascular disease.

What are important side effects or contraindications to GLP1 agents when used for cardiovascular risk reduction and wellness?

• GLP-1 receptor agonists should be avoided in patients with a history of medullary thyroid cancer or MEN2. Relative contraindications include recurrent pancreatitis, gastroparesis, or ongoing unexplained gastrointestinal symptoms.

What are practical concerns associated with GLP-1 use, and how can these be overcome?

• Affordability and availability remain the leading practical limitations for GLP-1 receptor agonist therapies. Many insurance companies will cover semaglutide and tirzepatide for patients with diabetes. Obtaining coverage may be difficult otherwise, but this is an evolving field as more clinical trial data emerge. Beware of unauthentic/alternate formulations of these medications, as they tend not to be FDA-regulated and can pose health risks. Some patients express concern about injectable therapies, but GLP-1 injectors are typically very well tolerated and easy to use.

References – Clinical Implementation of GLP-1 Receptor Agonists Brown, E., Heerspink, H. J., Cuthbertson, D. J., & Wilding, J. P. (2021). SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. The Lancet, 398(10296), 262-276. * https://www.sciencedirect.com/science/article/pii/S0140673621005365 * Wilding, J. P., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., … & Kushner, R. F. (2021). Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine. * https://www.nejm.org/doi/full/10.1056/NEJMoa2032183 * Müller, T. D., Blüher, M., Tschöp, M. H., & DiMarchi, R. D. (2022). Anti-obesity drug discovery: advances and challenges. Nature Reviews Drug Discovery, 21(3), 201-223. * https://www.nature.com/articles/s41573-021-00337-8 * Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., … & Stefanski, A. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387*(3), 205-216. * https://www.nejm.org/doi/full/10.1056/NEJMoa2206038 * Lincoff, M, Brown-Frandsen K, Colhoun H, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. (2023). 389(24):2221-2232. * https://www.nejm.org/doi/full/10.1056/NEJMoa2307563 * Eberly, L, Yang L, Essien U, et al. (2021). Racial, ethnic, and socioeconomic inequities in glucagon-like-peptide-1 receptor agonist use among patients with diabetes in the US; 2(12):e214182. * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796881/

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CardioNerds (Dr. Dan Ambinder), Dr. Nino Isakadze (EP Fellow at Johns Hopkins Hospital), and Dr. Karan Desai (Cardiology Faculty at Johns Hopkins Hospital) join Digital Health Experts, Dr. Alexis Beatty (Cardiologist and associate professor in the department of epidemiology and biostatistics at UCSF) and Dr. Seth Martin (Director of the Johns Hopkins Center for Mobile Technologies to Achieve Equity in Cardiovascular Health (mTECH), which is part of the American Heart Association (AHA) Strategically Focused Research Networks on Health Technology & Innovation) for another installment of the Digital Health Series. In this specific episode, we discuss pearls, pitfalls, and everything in between for emerging digital health innovators. This series is supported by an ACC Chapter Grant in collaboration with Corrie Health. Audio editing by CardioNerds Academy Intern, student doctor Shivani Reddy.

In this series, supported by an ACC Chapter Grant and in collaboration with Corrie Health, we hope to provide all CardioNerds out there a primer on the role of digital heath in cardiovascular medicine. Use of versatile hardware and software devices is skyrocketing in everyday life. This provides unique platforms to support healthcare management outside the walls of the hospital for patients with or at risk for cardiovascular disease. In addition, evolution of artificial intelligence, machine learning, and telemedicine is augmenting clinical decision making at a new level fueling a revolution in cardiovascular disease care delivery. Digital health has the potential to bridge the gap in healthcare access, lower costs of healthcare and promote equitable delivery of evidence-based care to patients.

This CardioNerds Digital Health series is made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Nino Isakadze and Dr. Karan Desai.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Immunotherapy is a type of novel cancer therapy that leverages the body’s own immune system to target cancer cells. In this episode, we focused on the most common type of immunotherapy: immune checkpoint inhibitors or ICIs. ICIs are monoclonal antibodies targeting immune “checkpoints” or brakes to enhance T-cell recognition against tumors. ICI has become a pillar in cancer care, with over 100 approvals and 5,000 ongoing trials. ICIs can lead to non-specific activation of the immune system, causing off-target adverse events such as cardiotoxicities. ICI-related myocarditis, though less common, can be fatal in 30% of cases. Clinical manifestations vary but can include chest pain, dyspnea, palpitations, heart failure symptoms, and arrhythmias. Diagnosis involves echocardiography, cardiac MRI, and endomyocardial biopsy. Treatment includes high-dose corticosteroids with potential additional immunosuppressants. Baseline EKG and troponin are recommended before ICI initiation, but routine surveillance is not advised. Subclinical myocarditis is a challenge, with unclear management implications. So let’s dive in and learn about cardiotoxicity of novel immunotherapies with Drs. Giselle Suero (series co-chair), Evelyn Song (episode FIT lead), Daniel Ambinder (CardioNerds co-founder), and Tomas Neilan (faculty expert). Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

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Pearls and Quotes – Cardiotoxicity of Novel Immunotherapies1. Immune checkpoint inhibitors (ICI) play a crucial role in current oncology treatment by enhancing T-cell recognition against tumors. 2. ICI-related cardiac immune-related adverse events (iRAEs) include myocarditis, heart failure, stress-cardiomyopathy, conduction abnormalities, venous thrombosis, pericardial disease, vasculitis, and atherosclerotic-related events. 3. ICI myocarditis can be fatal; thus, prompt recognition and treatment is crucial. 4. Management includes cessation of the ICI and treatment with corticosteroids and potentially other immunosuppressants. Close monitoring and collaboration with cardiology and oncology are crucial. 5. Rechallenging patients with immunotherapies after developing an iRAE is controversial and requires careful consideration of risks and benefits, typically with the involvement of a multidisciplinary team.

Show notes – Cardiotoxicity of Novel ImmunotherapiesWhat are immune checkpoint inhibitors (ICIs)?

• ICIs are monoclonal antibodies used to enhance the body’s immune response against cancer cells. Currently, there are four main classes of FDA-approved ICIs: monoclonal antibodies blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programed cell death protein-1 (PD-1), lymphocyte-activation gene 3 (LAG3), and programmed cell death ligand-1 (PD-L1).
• ICIs can lead to non-specific activation of the immune system, potentially causing off-target adverse events in various organs, including the heart, leading to myocarditis.
• The mechanisms of cardiac iRAEs are not fully understood, but they are believed to involve T-cell activation against cardiac antigens, which leads to inflammation and tissue damage.

What are the cardiotoxicities related to ICI therapies?

• ICI-related cardiac immune-related adverse events (iRAEs) include myocarditis, heart failure, stress-cardiomyopathy, conduction abnormalities, venous thrombosis, pericardial disease, vasculitis, and atherosclerotic-related events.
• ICI-related myocarditis is considered rare compared to other systemic IRAEs. While the incidence rate of ICI-myocarditis is around 0.7-2.0%, it can be fatal in 30% of cases.
• Clinical manifestations vary but can include chest pain, dyspnea, palpitations, heart failure symptoms, and arrhythmias. Severe cases of ICI myocarditis can present as cardiogenic shock or complete heart block (a fulminant myocarditis picture).
• The timing of adverse events is typically within the first three months of starting immunotherapy, with the majority occurring early on; however, some cases may present after three months.
• Increased clinical suspicion is key for early recognition and prompt diagnosis and treatment.

What is the general approach to the diagnosis of ICI-myocarditis?

• Diagnosis is based on clinical history and presentation, elevated troponin, and imaging findings. Echocardiography (with global longitudinal strain) and cardiac MRI (with T1 and T2 mapping as per the modified Lake Louise Criteria) are key diagnostic tools. If cardiac MRI is not diagnostic but suspicion remains high, an endomyocardial biopsy is the next diagnostic step.
• Baseline cardiac tests, such as ECG and troponin, are important before initiating ICIs in every patient to serve as a reference standard for comparison in case of troponin elevation during therapy. However, routine surveillance of asymptomatic patients on ICIs is not recommended.

How do endomyocardial biopsy findings for ICI-myocarditis compare to other types of autoimmune-mediated conditions such as transplant rejection?

• ICI-myocarditis is pathologically almost identical to transplant rejection; therefore, a similar grading system used for transplant rejection is applied to ICI-myocarditis to determine the severity and provide guidance on the intensity of immunosuppression.

What are the treatment strategies for ICI-myocarditis?

• In general, all patients with suspected ICI-myocarditis should have their immunotherapy held temporarily until the diagnosis is confirmed. Next, patients should be typically admitted to an inpatient unit with telemetry capabilities, given the risk of progression to complete heart block and cardiogenic shock.
• High-dose corticosteroids are the first-line pharmacological treatment, but the optimal dose varies between guidelines. An approach for severe life-threatening cases based on the NCCN and SITC guideline recommendations is a pulse of high-dose corticosteroids (consider 1000 mg methylprednisolone IV daily for 3–5 days until troponin normalizes) followed by a taper of 1–2 mg/kg methylprednisolone or oral prednisone for 4–6 weeks.
• For patients who do not respond to high-dose corticosteroids, additional immunosuppressive therapies can be considered, including intravenous immunoglobulin (IVIG), mycophenolate mofetil, anti-thymocyte globulin (ATG), alemtuzumab (monoclonal antibody to CD52), abatacept (CTLA-4 agonist), or plasmapheresis. This is an area where more data is needed to support guidelines for patient treatment. Currently, there are ongoing studies in this area, such as a phase 3 clinical of Abatacept for immune checkpoint inhibitor-associated myocarditis (ATRIUM, NCT053359280)
• High doses of corticosteroids used to treat ICI-associated myocarditis may adversely impact cancer outcomes. Further research is needed to understand the impact of cardiac toxicities and immunosuppressive treatments on cancer outcomes

Can patients be re-treated after an episode of ICI myocarditis?

• Patients who develop ICI-associated adverse events, including myocarditis, may have a second chance and be rechallenged with ICIs after resolution of the adverse event, but this decision should be made carefully considering the risks and benefits.

References – Cardiotoxicity of Novel Immunotherapies Zhang L, Reynolds KL, Lyon AR, Palaskas N, Neilan TG. The Evolving Immunotherapy Landscape and the Epidemiology, Diagnosis, and Management of Cardiotoxicity: JACC: CardioOncology Primer. JACC CardioOncology. 2021;3(1):35-47. doi:10.1016/J.JACCAO.2020.11.012 * Drobni ZD, Alvi RM, Taron J, et al. Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque. Circulation. 2020;142(24):2299-2311. doi:10.1161/CIRCULATIONAHA.120.049981 * Stein-Merlob AF, Rothberg M V., Holman P, Yang EH. Immunotherapy-Associated Cardiotoxicity of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T Cell Therapy: Diagnostic and Management Challenges and Strategies. Curr Cardiol Rep*. 2021;23(3):1-11. doi:10.1007/s11886-021-01440-3 * Suero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022 Dec 20;4(5):598-615. doi: 10.1016/j.jaccao.2022.11.011. PMID: 36636438; PMCID: PMC9830225.

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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CardioNerds join Dr. Inbar Raber and Dr. Susan Mcilvaine from the Beth Israel Deaconess Medical Center for a Fenway game. They discuss the following case: A 72-year-old man presents with two weeks of progressive dyspnea, orthopnea, nausea, vomiting, diarrhea, and right upper quadrant pain. He has a history of essential thrombocytosis, Barrett’s esophagus, basal cell skin cancer, and hypertension treated with hydralazine. He is found to have bilateral pleural effusions and a pericardial effusion. He undergoes a work-up, including pericardial cytology, which is negative, and blood tests reveal a positive ANA and positive anti-histone antibody. He is diagnosed with drug-induced lupus due to hydralazine and starts treatment with intravenous steroids, resulting in an improvement in his symptoms. Expert commentary is provided by UT Southwestern internal medicine residency program director Dr. Salahuddin (“Dino”) Kazi.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Case MediaPearls – A Drug’s Adverse Effect Unleashes the Wolf1. The differential diagnosis for pericardial effusion includes metabolic, malignant, medication-induced, traumatic, rheumatologic, and infectious etiologies. 2. While pericardial cytology can aid in securing a diagnosis of cancer in patients with malignant pericardial effusions, the sensitivity of the test is limited at around 50%. 3. Common symptoms of drug-induced lupus include fever, arthralgias, myalgias, rash, and/or serositis. 4. Anti-histone antibodies are typically present in drug-induced lupus, while anti-dsDNA antibodies are typically absent (unlike in systemic lupus erythematosus, SLE). 5. Hydralazine-induced lupus has a prevalence of 5-10%, with a higher risk for patients on higher doses or longer durations of drug exposure. Onset is usually months to years after drug initiation.

Show Notes – A Drug’s Adverse Effect Unleashes the Wolf1. There is a broad differential diagnosis for pericardial effusion which includes metabolic, malignant, medication-induced, traumatic, rheumatologic, and infectious etiologies. Metabolic etiologies include renal failure and thyroid disease. Certain malignancies are more likely to cause pericardial effusions, including lung cancer, lymphoma, breast cancer, sarcoma, and melanoma. Radiation therapy to treat chest malignancies can also result in a pericardial effusion. Medications can cause pericardial effusion, including immune checkpoint inhibitors, which can cause myocarditis or pericarditis, and medications associated with drug-induced lupus, such as procainamide, hydralazine, phenytoin, minoxidil, or isoniazid. Trauma can cause pericardial effusions, including blunt chest trauma, cardiac surgery, or cardiac catheterization. Rheumatologic etiologies include lupus, rheumatoid arthritis, systemic sclerosis, sarcoid, and vasculitis. Many different types of infections can cause pericardial effusions, including viruses (e.g., coxsackievirus, echovirus, adenovirus, human immunodeficiency virus, and influenza), bacteria (TB, staphylococcus, streptococcus, and pneumococcus), and fungi. Other must-not-miss etiologies include emergencies like type A aortic dissection and myocardial infarction. 2. In a retrospective study of all patients who presented with a hemodynamically significant pericardial effusion and underwent pericardiocentesis, 33% of patients were found to have an underlying malignancy(Ben-Horin et al). Bloody effusion and frank tamponade were significantly more common among patients with malignant effusion, but the overlap was significant, and no epidemiologic or clinical parameter was found useful to differentiate between cancerous and noncancerous effusions. Although this patient’s pericardial fluid cytology was negative, cytology is typically only positive in around 50% of malignant effusions (Ben-Horin et al). 3. The risk of drug-induced lupus (DIL) with hydralazine is high, approaching 10% of all treated patients. Another more commonly implicated cardiovascular drug is procainamide, with an incidence of 15-20%. Anti-histone antibodies are typically positive in DIL caused by hydralazine or procainamide, whereas anti-double stranded DNA antibodies are typically absent (in contrast to systemic lupus erythematosus). The most common symptoms of DIL include fever, arthralgias, myalgias, rash, and/or serositis with onset after months to years of drug exposure. If serositis is present, it is more often pleuritis, +/- pericarditis. 4. In addition to stopping the offending medication, treatment is extrapolated from the treatment of idiopathic systemic lupus and can include NSAIDs, hydroxychloroquine, and/or systemic steroids, depending on disease severity. References – A Drug’s Adverse Effect Unleashes the Wolf1. Ben-Horin, Bank, Guetta, & Livneh, A. (2006). Large symptomatic pericardial effusion as the presentation of unrecognized cancer – A study in 173 consecutive patients undergoing pericardiocentesis. Medicine (Baltimore), 85(1), 49–53. 2. Borchers, A.T., Keen, C.L. and Gershwin, M.E. (2007), Drug-Induced Lupus. Annals of the New York Academy of Sciences, 1108: 166-182. 3. Feng, Glockner, J., et al. (2011). Cardiac Magnetic Resonance Imaging Pericardial Late Gadolinium Enhancement and Elevated Inflammatory Markers Can Predict the Reversibility of Constrictive Pericarditis After Antiinflammatory Medical Therapy A Pilot Study. Circulation (New York, N.Y.), 124(17), 1830–1837

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Welcome back to the CardioNerds Cardiovascular Prevention Series, where we are continuing our discussion of Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RAs). This class of medications is becoming a household name, not only for their implications for weight loss but also for their effect on cardiovascular disease. CardioNerds Dr. Ty Sweeney (CardioNerds Academy Faculty Member and incoming Cardiology Fellow at Boston Medical Center), Dr. Rick Ferraro (CardioNerds Academy House Faculty and Cardiology Fellow at Johns Hopkins Hospital), and special guest Dr. Franck Azobou (Cardiology Fellow at UT Southwestern) sat down with Dr. Darren McGuire (Cardiologist at UT Southwestern and Senior Editor of Diabetes and Vascular Disease Research) to discuss important trial data on GLP-1 RAs in patients with heart disease, as well as recent professional society guidelines on their use. Show notes were drafted by Dr. Ty Sweeney. Audio editing was performed by CardioNerds Intern student Dr. Diane Masket.

If you haven’t already, be sure to check out CardioNerds episode #350 where we discuss the basics and mechanism of action of GLP-1 RAs with Dr. Dennis Bruemmer.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – GLP-1 Agonists: Diving into the Data1. Patients with diabetes and clinical atherosclerotic cardiovascular disease (ASCVD) or who are at high risk of ASCVD benefit from treatment with a GLP-1 RA. 2. For persons with sufficient ASCVD risk and type 2 diabetes, GLP-1 RAs and SGLT2 inhibitors can, and often should, be used in combination. “Just like we don’t consider ‘and/or’ for the four pillars of guideline-directed medical therapy for heart failure with reduced ejection fraction, we shouldn’t parcel out these two therapeutic options…it should be both.” 3. Setting expectations with your patients regarding injection practices, side effects, and expected benefits can go a long way toward improving the patient experience with GLP-1 RAs. 4. Utilize a multidisciplinary approach when caring for patients on GLP-1 RAs. Build a team with your patient’s primary care provider, endocrinologist, clinical pharmacist, and nurse. 5. “This is really a cardiologist issue. These are no longer endocrinology or primary care drugs. We need to be prescribing them ourselves just like we did back in the nineties when we took over the statin prescriptions from the endocrinology domain…we need to lead the way.”

Show notes – GLP-1 Agonists: Diving into the DataFor which patients are GLP-1 RAs recommended to reduce the risk of major cardiac events?

• For patients with type 2 diabetes and ASCVD, starting a GLP-1 RA carries a Class 1, Level of Evidence A recommendation in the most recent ESC and ACC guidelines.
• For patients without diabetes or clinical ASCVD with an estimated 10-year risk of CVD exceeding 10%, consideration of starting a GLP-1 RA carries a Class 2b, Level of Evidence C recommendation to reduce CV risk.
• The STEP-HFpEF trial showed that among patients with obesity and HFpEF, once-weekly semaglutide may be beneficial in terms of weight loss and quality of life.
• The results of the FIGHT and LIVE trials question the utility and safety of liraglutide in treating patients with advanced HFrEF. Of the over 17,000 patients enrolled in the SELECT trial, about 25% had heart failure, of which about one-third had HFrEF. Stay tuned for sub-analyses from that trial for more info!

Can we still prescribe GLP-1 Ras in patients with well-controlled T2DM?

• The recommendation to start GLP-1 RAs for cardiovascular benefit in eligible patients is made irrespective of HbA1C.
• If A1c is very low, or if the patient is experiencing episodes of hypoglycemia, consider backing off background diabetes therapy, especially if they don’t confer CV benefit.
  • Note, the recent ESC guidelines recommending SGLT2i and GLP-1RA therapy do so irrespective of background metformin therapy. This is supported by the ADA Standards of Care in Diabetes.

Is there evidence to suggest oral vs injectable GLP-1 RAs with respect to cardiac outcomes?

• The PIONEER-6 trial suggests cardiovascular benefit of oral semaglutide in patients with diabetes compared to placebo; however, the trial was only powered to assess safety.
• The ongoing SOUL trial is examining cardiovascular outcomes among patients being treated with oral semaglutide vs placebo with the primary outcome of time from randomization to the first occurrence of a major adverse CV event. Stay tuned!
• It is crucial that oral semaglutide be taken on an empty stomach, given its unique absorption and pharmacokinetics.

What side effects can patients expect when initiating GLP-1 RAs?

• Nausea is common after starting these medications, but this generally ameliorates after 1-2 weeks of therapy.
• Setting expectations with your patients ahead of time can go a long way to improving adherence.
• We do not have dose-response data to say whether sub-maximal doses of GLP-1 RAs (for example, in patients who do not want or cannot tolerate the full dose) are effective. That said, the SELECT trial suggests the benefits of starting GLP-1 RAs begin early, even at introductory doses. Therefore, if a patient truly cannot tolerate higher doses, it may be reasonable to titrate slowly or hold at a lower dose.

What does the literature say regarding the combined use of SGLT2 inhibitors and GLP-1 RAs?

• Sub-analyses examining the effect of background therapy when patients are randomized to receive the other vs. placebo suggest patients enjoy at least as good, if not better, outcomes from the combination of therapies.
• One of the first planned sub-analyses of SOUL will look at the potential additive effects of oral semaglutide alongside background SGLT2 inhibitor therapy.

References – GLP-1 Agonists: Diving into the Data Marx N, Federici M, Schütt K, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes: Developed by the task force on the management of cardiovascular disease in patients with diabetes of the European Society of Cardiology (ESC). European Heart Journal. 2023;44(39):4043-4140. https://academic.oup.com/eurheartj/article/44/39/4043/7238227?login=false * Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001168 * ElSayed NA, Aleppo G, Aroda VR, et al. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2023. Diabetes Care. 2022;46(Supplement_1):S158-S190. https://diabetesjournals.org/care/article/46/Supplement_1/S158/148038/10-Cardiovascular-Disease-and-Risk-Management * Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine*. 2019;381(9):841-851. https://www.nejm.org/doi/full/10.1056/NEJMoa1901118 * McGuire DK, Busui RP, Deanfield J, et al. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial. Diabetes Obes Metab. 2023;25(7):1932-1941. https://pubmed.ncbi.nlm.nih.gov/36945734/ * Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. https://pubmed.ncbi.nlm.nih.gov/37622681/ * Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19(1):69-77. https://pubmed.ncbi.nlm.nih.gov/27790809/ * Margulies KB, Hernandez AF, Redfield MM, et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;316(5):500-508. https://jamanetwork.com/journals/jama/article-abstract/2540402

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The following question refers to Section 13 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by Western Michigan University medical student and CardioNerds Intern Shivani Reddy, answered first by Mayo Clinic Cardiology Fellow and CardioNerds Academy Faculty Dr. Dinu Balanescu, and then by expert faculty Dr. Harriette Van Spall.

Dr. Van Spall is an Associate Professor of Medicine, cardiologist, and Director of E-Health at McMaster University. Dr Van Spall is a Canadian Institutes of Health Research-funded clinical trialist and researcher with a focus on heart failure, health services, and health disparities.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #32

| Palliative and supportive care has a role for patients with heart failure only in the end stages of their disease. | | TRUE | | FALSE |

Answer #32

| Explanation | The correct answer is FalsePalliative care is patient- and family-centered care that optimizes health-related quality of life by anticipating, preventing, and treating suffering and should be integrated into the management of all stages of heart failure throughout the course of illness. The wholistic model of palliative care includes high-quality communication, estimation of prognosis, anticipatory guidance, addressing uncertainty, shared decision-making about medically reasonable treatment options, advance care planning; attention to physical, emotional, spiritual, and psychological distress; relief of suffering; and inclusion of family caregivers in patient care and attention to their needs during bereavement.As such, for all patients with HF, palliative and supportive care—including high-quality communication, conveyance of prognosis, clarifying goals of care, shared decision-making, symptom management, and caregiver support—should be provided to improve QOL and relieve suffering (Class 1, LOE C-LD).For conveyance of prognosis, objective risk models can be incorporated along with discussion of uncertainty since patients may overestimate survival and the benefits of specific treatments – “hope for the best, plan for the worst.”For clarifying goals of care, the exploration of each patient’s values and concerns through shared decision-making is essential in important management decisions such as when to discontinue treatments, when to initiate palliative treatments that may hasten death but provide symptom management, planning the location of death, and the incorporation of home services or hospice.It is a Class I indication that for patients with HF being considered for, or treated with life-extending therapies, the option for discontinuation should be anticipated and discussed through the continuum of care, including at the time of initiation, and reassessed with changing medical conditions and shifting goals of care (LOE C-LD).Caregiver support should also be offered to family members even beyond death to help them cope with the grieving process.A formal palliative care consult is not needed for each patient, but the primary team should exercise the above domains to improve processes of care and patient outcomes.Specialist palliative care consultation can be useful to improve QOL and relieve suffering for patients with heart failure—particularly those with stage D HF who are being evaluated for advanced therapies, patients requiring inotropic support or temporary mechanical support, patients experiencing uncontrolled symptoms, major medical decisions, or multimorbidity, frailty, and cognitive impairment (Class 2a, LOE B). Studies have been mixed on if the palliative team itself improves quality of life and well-being so these interventions should be tailored to each patient and caregiver.For patients with HF, execution of advanced directives can be useful to improve documentation of treatment preferences, delivery of patient-centered care, and dying in a preferred place (Class 2a, LOE C-LD).In patients with advanced HF with expected survival < 6 months, timely referral to hospice can be useful to improve QOL (Class 2a, LOE C-LD) | | Main Takeaway | In summary, the core principles of palliative care that include communication, transparency on prognosis, clarification of goals of care, shared decision-making, symptom management, and caregiver support should be integrated into each patient’s treatment plan regardless of the stage of heart failure | | Guideline Loc. | Section 13, Figure 15, Table 32 |

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CardioNerds cofounder Dr. Dan Ambinder joins Dr. Angie Molina, Dr. Cullen Soares, and Dr. Andrew Lutz from the University of Maryland Medical Center for some beers and history by Fort McHenry. They discuss a case of disseminated haemophilus influenza
presumed fulminant bacterial myocarditis with mixed septic/cardiogenic shock. Expert commentary is provided by Dr. Stanley Liu (Assistant Professor, Division of Cardiovascular Medicine, University of Maryland School of Medicine). Episode audio was edited by Dr. Chelsea Amo-Tweneboah.

A woman in her twenties with a history of intravenous drug use presented with acute onset fevers and sore throat, subsequently developed respiratory distress and cardiac arrest, and was noted to have epiglottic edema on intubation. She developed shock and multiorgan failure. ECG showed diffuse ST elevations, TTE revealed biventricular dysfunction, and pleural fluid culture grew Haemophilus influenza. Right heart catheterization showed evidence of cardiogenic shock. She improved with supportive care and antibiotics.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls – Sore Throat, Fever, and Myocarditis – It’s not always COVID-191. The post-cardiac arrest ECG provides helpful information for diagnosing the underlying etiology.​ 2. Be aware of diagnostic biases – availability and anchoring biases are particularly common during respiratory viral (such as COVID-19, RSV) surges. 3. Consider a broad differential diagnosis in evaluating myocarditis, including non-viral etiologies. 4. Right heart catheterization provides crucial information for diagnosis and management of undifferentiated shock​. 5. When assessing the need for mechanical circulatory support, consider the current hemodynamics, type of support needed, and risks associated with each type.

Show Notes – Sore Throat, Fever, and Myocarditis – It’s not always COVID-191. ECG findings consistent with pericarditis include diffuse concave-up ST elevations and downsloping T-P segment (Spodick’s sign) as well as PR depression (lead II), and PR elevation (lead aVR). In contrast, regional ST elevations with “reciprocal” ST depressions and/or Q-waves should raise concern for myocardial ischemia as the etiology. 2. Biventricular dysfunction and elevated troponin are commonly seen post-cardiac arrest and may be secondary findings. However, an elevation in troponin that is out of proportion to expected demand ischemia, ECG changes (pericarditis, ischemic ST elevations), and cardiogenic shock suggest a primary cardiac etiology for cardiac arrest. 3. The differential diagnosis of infectious myopericarditis includes, most commonly, viral infection (respiratory viruses) and, more rarely, bacterial, fungal, or parasitic. Noninfectious myopericarditis may be autoimmune (such as lupus, sarcoidosis, checkpoint inhibitors), toxin-induced (alcohol, cocaine), and medication-induced (anthracyclines and others). 4. Right heart catheterization can help diagnose the etiology of undifferentiated shock, including distinguishing between septic and cardiogenic shock, by providing right and left-sided filling pressures, pulmonary and systemic vascular resistance, and cardiac output. 5. Mechanical circulatory support (MCS) is indicated for patients in cardiogenic shock with worsening end-organ perfusion despite inotropic and pressor support. MCS includes intra-aortic balloon pump, percutaneous VAD, TandemHeart, and VA-ECMO. The decision to use specific types of MCS should be individualized to each patient with their comorbidities and hemodynamic profile. Shock teams are vital to guide decision-making. References 1. Witting MD, Hu KM, Westreich AA, Tewelde S, Farzad A, Mattu A. Evaluation of Spodick’s Sign and Other Electrocardiographic Findings as Indicators of STEMI and Pericarditis. J Emerg Med. 2020;58(4):562-569. doi:10.1016/j.jemermed.2020.01.017 2. Ferrero P, Piazza I, Lorini LF, Senni M. Epidemiologic and clinical profiles of bacterial myocarditis. Report of two cases and data from a pooled analysis. Indian Heart J. 2020;72(2):82-92. doi:10.1016/j.ihj.2020.04.005 3. Pollack A, Kontorovich AR, Fuster V, Dec GW. Viral myocarditis–diagnosis, treatment options, and current controversies. Nat Rev Cardiol. 2015;12(11):670-680. doi:10.1038/nrcardio.2015.108 4. Hsu S, Fang JC, Borlaug BA. Hemodynamics for the Heart Failure Clinician: A State-of-the-Art Review. J Card Fail. 2022;28(1):133-148. doi:10.1016/j.cardfail.2021.07.012 5. Korabathina R., Heffernan K.S., Paruchuri V., Patel A.R., Mudd J.O., Prutkin J.M., et al: The pulmonary artery pulsatility index identifies severe right ventricular dysfunction in acute inferior myocardial infarction. Catheter Cardiovasc Interv 2012; 80: pp. 593-600. https://pubmed.ncbi.nlm.nih.gov/21954053/ 6. Drazner MH, Velez-Martinez M, Ayers CR, et al. Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail. 2013;6(2):264-270. doi:10.1161/CIRCHEARTFAILURE.112.000204

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CardioNerds Dr. Rick Ferraro (CardioNerds Academy House Faculty and Cardiology Fellow at JHH), Dr. Gurleen Kaur (Director of the CardioNerds Internship and Internal Medicine resident at BWH), and Dr. Alli Bigeh (Cardiology Fellow at the Ohio State) as they discuss the growing obesity epidemic and how it relates to cardiovascular disease with Dr. Ambarish Pandey (Cardiologist at UT Southwestern Medical Center). Show notes were drafted by Dr. Alli Bigeh. CardioNerds Academy Intern and student Dr. Shivani Reddy performed audio editing.

Obesity is an important modifiable risk factor for cardiovascular disease, and it is on the rise! Here, we discuss how to identify patients with obesity and develop an approach to address current lifestyle recommendations. We also discuss the spectrum of pharmacologic treatment options available, management strategies, and some therapy options that are on the horizon.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

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Pearls and Quotes – Lifestyle & Pharmacologic Management of Obesity1. Identify obese patients not just using BMI, but also using anthropometric measurements such as waist circumference (central adiposity). 2. Lifestyle modifications are our first line of defense against obesity! Current recommendations emphasize caloric restriction of at least 500kcal/day, plant-based and Mediterranean diets, and getting at least 150 minutes of moderate-intensity weekly exercise. 3. Dive into the root cause of eating and lifestyle behaviors. It is crucial to address adverse social determinants of health with patients to identify the driving behaviors, particularly among those individuals of low socioeconomic status. 4. Newer weight loss agents are most effective at achieving and maintaining substantial weight loss, in particular Semaglutide (GLP-1) and Tirzepatide (GLP-1/GIP). Initiate at a low dose and titrate up slowly. 5. Obesity is a risk factor and potential driver for HFpEF. Targeted treatment options for obese patients with HFpEF include SGLT-2 inhibitors and semaglutide, which recently showed improvement in quality of life and exercise capacity in the STEP-HFpEF trial.

Show notes – Lifestyle & Pharmacologic Management of ObesityHow do we identify and define obesity?

• The traditional definition of obesity is based on body mass index (BMI), defined as BMI greater than or equal to 30.0 kg/m2 (weight in kg/height in meters).
  • Recognize that BMI may not tell the whole story. A limitation of BMI is it does not reflect differences in body composition and distribution of fat.
  • Certain patients may not meet the BMI cutoff for obesity but have elevated cardiovascular risk based on increased central adiposity, specifically those that are categorized as overweight.
  • The devil lies in the details of anthropometric parameters. Include waist circumference measurements as part of an obesity assessment of visceral adiposity.
  • A waist circumference greater than 40 inches for men and greater than 35 inches for women is considered elevated.

What are some current lifestyle recommendations for obese patients?

• Lifestyle recommendations are the first line of defense against obesity.
  • Current ACC/AHA guidelines suggest a target of reducing caloric intake by 500 kcal per day. For patients with severe obesity, this number may be higher.
  • Emphasis on hypocaloric plant-based and Mediterranean diets
  • Reduce total carbohydrate intake to 50-130 grams per day.
  • Focus on a low-fat diet with less than 30% of total energy coming from fat with a high-protein diet to maintain lean mass and promote satiety.
  • The overarching theme of prevailing lifestyle recommendations is incorporating whole grains, vegetables, fruit, nuts, and fiber-rich foods while minimizing saturated fats, salt, and sugar intake.
  • ACC/AHA recommendations include 150 minutes of moderate-intensity exercise per week.

What are some tips for addressing lifestyle modifications with patients?

• Tailor the approach to each individual patient. Get to the root cause and identify barriers to addressing the behaviors.
  • Consider getting a psychosocial assessment and focus on behavior modification strategies. Eating behaviors can be associated with other behavioral disorders.
  • Patients with severe obesity have a higher risk of adverse cardiovascular events. A risk-based approach for these patients mandates a greater emphasis on weight reduction and caloric restriction.
  • Consider access to nutrient-dense food, socioeconomic status, cost of healthy foods, access to exercise resources, and safety of neighborhoods when making recommendations.

What are the current pharmacologic options for weight loss? Which are the most effective?

• Consider pharmacological agents once lifestyle modifications and social determinants of health have been addressed. We should not get hung up on lifestyle modifications and fail to progress to using pharmacotherapies or surgical therapies in patients with morbid obesity or cardiovascular disease.
• Pharmacological therapy can be considered in patients with BMI >30 or BMI >27 with comorbidities.
• There are a variety of agents such as Orlistat, Phentermine/Topiramate, Bupropion/Naltrexone, GLP-1 receptor agonists (Liraglutide, Semaglutide) and Tirzepatide (GLP-1/GIP).
• Tirzepatide has the highest amount of reported weight loss, with patients achieving 23% weight loss or up to 50 pounds of weight loss based on the latest SURMOUNT trial. Semaglutide can achieve 16% weight loss based on trial data. The remaining agents have reported weight loss between 6-10%.
• Bariatric surgery should also be considered, especially in patients with severe obesity (BMI >40).

Compare and contrast the GLP-1 agents, specifically semaglutide and liraglutide.

• GLP-1 receptor agonists activate GLP-1 receptors in the pancreas, which increases insulin release, slows gastric emptying, and reduces appetite.
  • Semaglutide has a greater weight reduction of up to 16% total weight loss compared to 6% for liraglutide.
  • There have been higher reported adverse effects with liraglutide as well. In the STEP-8 trial, the proportion of participants discontinuing treatment for any reason was 13.5% with semaglutide versus 27.6% with liraglutide. Gastrointestinal adverse events were the most common and reported by 84.1% with semaglutide and 82.7% with liraglutide.
  • The SELECT trial in patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg reduced the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by approximately 20%. Liraglutide has been shown to reduce cardiovascular outcomes in patients with established cardiovascular disease but only in patients with diabetes thus far.

What other newer agents are on the horizon for treatment of obesity?

• An oral formulation of semaglutide 50mg is currently being tested, with phase 3 results showing up to 15% weight reduction in participants.
  • Retatrutide is a new triple-hormone-receptor agonist (an agonist of the glucose-dependent insulinotropic polypeptide [GIP], glucagon-like peptide 1, and glucagon receptors). Phase 2 trial was recently published, reporting up to 25% weight loss in patients.

Discuss some strategies to mitigate the GI side effects when using GLP-1 receptor agonists.

• Most importantly- keep a close eye on patient’s symptoms and prepare them for potential side effects along with the mechanism through which they work (i.e., inducing early satiety).
  • Expect some degree of gastrointestinal discomfort so patients know what to expect. Side effects often dissipate with continued use of the medication. This can help minimize discontinuation.
  • Counsel on diet and nutrition. Patients should eat small food portions for better tolerability, given the effect of the medication to slow gastric emptying.
  • Providers should focus on starting at a low dose and titrating up slowly.
  • If side effects become intolerable, providers can consider using the last tolerated dose or switching medication classes (i.e. Tirzepatide).

References – Lifestyle & Pharmacologic Management of Obesity1. Chakhtoura M, Haber R, Malak G, Caline R, Raya T, Mantzoros CS. Pharmacotherapy of obesity: an update on the available medications and drugs under investigation. Pharmacotherapy of obesity: an update on the available medications and drugs under investigation. 2023;58:101882-101882. doi:https://doi.org/10.1016/j.eclinm.2023.101882 2. Després JP, Carpentier AC, Tchernof A, Neeland IJ, Poirier P. Management of Obesity in Cardiovascular Practice. Journal of the American College of Cardiology. 2021;78(5):513-531. doi:https://doi.org/10.1016/j.jacc.2021.05.035 3. ‌Dominguez LJ, Veronese N, Di Bella G, et al. Mediterranean diet in the management and prevention of obesity. Experimental Gerontology. 2023;174:112121. doi:https://doi.org/10.1016/j.exger.2023.112121 4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. 2022;387(3). doi:https://doi.org/10.1056/nejmoa2206038 5. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. Circulation. 2013;129(25 suppl 2):S102-S138. doi:https://doi.org/10.1161/01.cir.0000437739.71477.ee 6. Kosiborod M, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. The New England Journal of Medicine. 2023;389(12). doi:https://doi.org/10.1056/nejmoa2306963 7. ‌Lincoff MA, Brown‐Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. Published online November 11, 2023. doi:https://doi.org/10.1056/nejmoa2307563 8. Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes. JAMA. 2022;327(2):138. doi:https://doi.org/10.1001/jama.2021.23619

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CardioNerds join Dr. Ethan Fraser and Dr. Austin Culver from the MedStar Georgetown University Hospital internal medicine and cardiology programs in our nation’s capital. They discuss the following case involving an unusual case of rapidly progressive heart failure. Episode audio was edited by CardioNerds Academy Intern and student Dr. Pacey Wetstein. Expert commentary was provided by advanced heart failure cardiologist Dr. Richa Gupta.

A 55-year-old male comes to the clinic (and eventually into the hospital) for what appears to be a straightforward decompensation of his underlying cardiac disease. However, things aren’t as simple as they might appear. In this episode, we will discuss the outpatient workup for non-ischemic cardiomyopathy and discuss the clinical indicators that we as clinicians should be aware of in these sick patients. Furthermore, we will discuss the differential for NICM, the management of patients with this rare disease, and how this disease can mimic other cardiomyopathies.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – Rapidly Progressive Heart FailurePearls – Rapidly Progressive Heart Failure* The non-ischemic cardiomyopathy workup should incorporate targeted multimodal imaging, thorough history taking, broad laboratory testing, genetic testing if suspicion exists for a hereditary cause, and a deep understanding of which populations are at higher risk for certain disease states. + Key Point: Always challenge and question the etiology of an unknown cardiomyopathy – do not assume an etiology based on history/patient story alone. * Unexplained conduction disease in either a young or middle-aged individual in the setting of a known cardiomyopathy should raise suspicion for an infiltrative cardiomyopathy and set off a referral to an advanced heart failure program. + Key Point: Consider early/more aggressive imaging for these patients and early electrophysiology referral for primary/secondary prevention. * Giant Cell Myocarditis is a rapidly progressive cardiomyopathy characterized by high mortality (70% in the first year), conduction disease, and classically presents in young/middle-aged men. + Key Point: If you have a younger male with rapidly progressive cardiomyopathy (anywhere as quickly as 1-2 months, weeks in some cases) and conduction disease, consider early endomyocardial biopsy, even before other advanced imaging modalities. * The Diagnosis of Giant Cell Myocarditis is time-sensitive – early identification and treatment are essential to survival. + Key Point: The median timeframe from the time the disease is diagnosed to the time of death is approximately 6 months. 90% of patients are either deceased by the end of 1 year or have received a heart transplant. * The treatment of Giant Cell Myocarditis is still governed largely by expert opinion, but the key components include high-dose steroids and cyclosporine, largely as a bridge to transplantation or advanced heart failure therapies. + Key Point: Multi-disciplinary care is essential in delivering excellent care in the diagnostic/pre-transplant period, including involvement by cardiology, cardiac surgery, radiology, critical care, allergy/immunology, case management, advanced heart failure, and shock teams if necessary. * There remains significant clinical overlap between Giant Cell Myocarditis and sarcoidosis, making managing equivocal cases challenging. + Key Point: Consider early FDG-PET imaging in equivocal cases, as management during the pre-transplant period and evaluation of transplant candidacy can vary drastically between the two.

Show Notes – Rapidly Progressive Heart Failure1. What is Giant Cell Myocarditis?

Giant cell myocarditis is a rare and rapidly progressive cause of heart failure due to T-cell lymphocyte mediated myocardial inflammation. The pathogenesis of GCM is incompletely understood – histologically, there is infiltration of the myocardium by T-lymphocytes and macrophages, and there is typically evidence of upregulation of IL-17 and TNF-a. Classically, the disease state is associated with electrical (e.g., ventricular tachycardia, high-grade AV block) and hemodynamic instability – all of which typically progresses rapidly over a period of weeks to months. This male-predominant disease tends to occur in young and middle-aged patients – with a mean age between 42 and 60 based on several registries. While a rare disease, a high index of suspicion is necessary when patients present with rapidly progressive or fulminant heart failure, as a missed diagnosis of giant cell myocarditis is invariably fatal. Early and rapid identification of this uniquely high-risk group of heart failure patients and prompt initiation of therapy targeted towards the underlying autoimmune process, as well as management at a center with advanced heart failure and cardiovascular ICU support, is necessary.

2. How is Giant Cell Myocarditis Diagnosed?

Establishing a diagnosis requires an endomyocardial biopsy (EMB), although EMB has imperfect sensitivity for GCM. Cardiac biomarkers and imaging serve an adjunct role in diagnosis; TTE findings can be variable, with either normal or dilated LV cavity size and increased wall thickness, which may be related to acute edema and inflammation. Worse LVEF on presentation has been shown to correlate with shorter transplant-free survival time. Troponin levels may be elevated, but case series have shown a lack of correlation between prognosis and troponin elevation in GCM, and importantly, in some cases, troponin values have been negative in patients later found to have GCM by biopsy. Advanced imaging is not always practical as these patients are often hemodynamically unstable, but CMR can demonstrate findings typical of myocarditis (i.e. the 2018 Lake Louise criteria).

3. What is the treatment for Giant Cell Myocarditis, and what are the future steps for disease management?

Cyclosporine-based combination immunosuppressive therapy, in addition to standard heart failure guideline-directed medical and procedural therapy and management of arrhythmias, can improve outcomes in these patients. Typical regimens include cyclosporine, high-dose steroids as the mainstay, and azathioprine or alemtuzumab (an anti-CD52 monoclonal antibody) as adjunctive agents. Patients are often co-managed by advanced heart failure, cardiac intensivists, and rheumatology. As the disease progresses, patients often develop sustained or symptomatic ventricular tachycardia, conduction abnormalities refractory HF with a dilated LV phenotype and many require mechanical circulatory support and/or cardiac transplantation.

GCM can remit and relapse, sometimes many years after initial diagnosis; an advanced heart failure team should follow these patients and should continue some immunosuppression (usually a calcineurin inhibitor) for at least 2 years. Overall, our understanding of the mechanism and management of GCM continues to evolve; high-grade evidence such as randomized controlled trials are extremely difficult to perform due to the rarity and high acuity of these presentations, therefore enrolling these patients in shared multicenter registries where able is essential to shrinking our knowledge gaps of this rare disease state.

4. What else should one consider in presumed cases of Giant Cell Myocarditis?

There exists a significant clinical overlap between Giant Cell Myocarditis and Cardiac Sarcoidosis, so much so that some argue the two diseases exist on opposite ends of one disease spectrum. Both notably present with significant arrhythmia burden and advanced heart failure symptoms, although they are both treated quite differently and present with different time courses (mean time to onset of symptoms 0.3 months for GCM, 7 months for CS). Furthermore, data from Nordenswan et al. from Finland reveals that the diagnosis of GCM on histology was recategorized to CS in 62% of their studies reviewed upon secondary pathology review. To this end, it is important that clinicians consider further advanced imaging modalities (i.e., FDG-PET) in equivocal cases and consider expert pathology evaluation of endomyocardial biopsy samples as proper escalation of care and rapid identification can prevent significant treatment delays.

References – Rapidly Progressive Heart Failure1. Amancherla, Kaushik, Juan Qin, Yu Wang, Margaret L. Axelrod, Justin M. Balko, Kelly H. Schlendorf, Robert D. Hoffman, Yaomin Xu, JoAnn Lindenfeld, and Javid Moslehi. “RNA-Sequencing Reveals a Distinct Transcriptomic Signature for Giant Cell Myocarditis and Identifies Novel Druggable Targets.” Circulation Research 129, no. 3 (2021): 451–53. https://doi.org/10.1161/CIRCRESAHA.121.319317. 2. Bang, Vigyan, Sarju Ganatra, Sachin P. Shah, Sourbha S. Dani, Tomas G. Neilan, Paaladinesh Thavendiranathan, Frederic S. Resnic, et al. “Management of Patients With Giant Cell Myocarditis.” Journal of the American College of Cardiology 77, no. 8 (2021): 1122–34. https://doi.org/10.1016/j.jacc.2020.11.074. 3. Birnie, David H., Vidhya Nair, and John P. Veinot. “Cardiac Sarcoidosis and Giant Cell Myocarditis: Actually, 2 Ends of the Same Disease?” Journal of the American Heart Association 10, no. 6 (2021): e020542. https://doi.org/10.1161/JAHA.121.020542. 4. Bobbio, Emanuele, Marie Björkenstam, Bright I. Nwaru, Francesco Giallauria, Eva Hessman, Niklas Bergh, Christian L. Polte, Jukka Lehtonen, Kristjan Karason, and Entela Bollano. “Short- and Long-Term Outcomes after Heart Transplantation in Cardiac Sarcoidosis and Giant-Cell Myocarditis: A Systematic Review and Meta-Analysis.” Clinical Research in Cardiology 111, no. 2 (February 1, 2022): 125–40. https://doi.org/10.1007/s00392-021-01920-0. 5. Brailovsky, Yevgeniy, Amirali Masoumi, Rachel Bijou, Estefania Oliveros, Gabriel Sayer, Koji Takeda, and Nir Uriel. “Fulminant Giant Cell Myocarditis Requiring Bridge With Mechanical Circulatory Support to Heart Transplantation.” JACC: Case Reports 4, no. 5 (2022): 265–70. https://doi.org/10.1016/j.jaccas.2021.11.013. 6. Cooper, Leslie T., Gerald J. Berry, and Ralph Shabetai. “Idiopathic Giant-Cell Myocarditis — Natural History and Treatment.” New England Journal of Medicine 336, no. 26 (1997): 1860–66. https://doi.org/10.1056/nejm199706263362603. 7. Ekström K, Lehtonen J, Kandolin R, Räisänen-Sokolowski A, Salmenkivi K, Kupari M. Incidence, Risk Factors, and Outcome of Life-Threatening Ventricular Arrhythmias in Giant Cell Myocarditis. Circulation: Arrhythmia and Electrophysiology. 2016;9(12):e004559. doi:10.1161/CIRCEP.116.004559 8. Fallon, J. M., A. M. Parker, S. P. Dunn, and J. L. W. Kennedy. “A Giant Mystery in Giant Cell Myocarditis: Navigating Diagnosis, Immunosuppression, and Mechanical Circulatory Support.” ESC Heart Fail 7, no. 1 (February 2020): 315–19. https://doi.org/10.1002/ehf2.12564. 9. Ghaly, Medhat, Danise Schiliro, and Jadwiga Stepczynski. “Giant Cell Myocarditis: A Time Sensitive Distant Diagnosis.” Cureus 12, no. 1 (2020): e6712–e6712. https://doi.org/10.7759/cureus.6712. 10. Gilotra NA, Minkove N, Bennett MK, et al. Lack of Relationship Between Serum Cardiac Troponin I Level and Giant Cell Myocarditis Diagnosis and Outcomes. Journal of Cardiac Failure. 2016;22(7):583-585. doi:10.1016/j.cardfail.2015.12.022 11. Heymans S, Eriksson U, Lehtonen J, Cooper LT. The Quest for New Approaches in Myocarditis and Inflammatory Cardiomyopathy. Journal of the American College of Cardiology. 2016;68(21):2348-2364. doi:10.1016/j.jacc.2016.09.937 12. Kandolin, Riina, Jukka Lehtonen, Kaisa Salmenkivi, Anne Räisänen-Sokolowski, Jyri Lommi, and Markku Kupari. “Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression.” Circulation: Heart Failure 6, no. 1 (2013): 15–22. https://doi.org/10.1161/CIRCHEARTFAILURE.112.969261. 13. Kociol, Robb D., Leslie T. Cooper, James C. Fang, Javid J. Moslehi, Peter S. Pang, Marwa A. Sabe, Ravi V. Shah, Daniel B. Sims, Gaetano Thiene, and Orly Vardeny. “Recognition and Initial Management of Fulminant Myocarditis.” Circulation 141, no. 6 (2020): e69–92. https://doi.org/10.1161/CIR.0000000000000745. 14. Kondo, Toru, Takahiro Okumura, Naoki Shibata, Takahiro Imaizumi, Kaoru Dohi, Hideo Izawa, Nobuyuki Ohte, Tetsuya Amano, and Toyoaki Murohara. “Differences in Prognosis and Cardiac Function According to Required Percutaneous Mechanical Circulatory Support and Histological Findings in Patients With Fulminant Myocarditis: Insights From the CHANGE PUMP 2 Study.” Journal of the American Heart Association 11, no. 4 (2022): e023719. https://doi.org/10.1161/JAHA.121.023719. 15. Nordenswan, Hanna‐Kaisa, Jukka Lehtonen, Kaj Ekström, Anne Räisänen‐Sokolowski, Mikko I. Mäyränpää, Tapani Vihinen, Heikki Miettinen, et al. “Manifestations and Outcome of Cardiac Sarcoidosis and Idiopathic Giant Cell Myocarditis by 25‐Year Nationwide Cohorts.” Journal of the American Heart Association 10, no. 6 (2021): e019415. https://doi.org/10.1161/JAHA.120.019415. 16. Paitazoglou, Christina, Martin W. Bergmann, Katharina Tiemann, Andrea Wiese, Ulrich Schäfer, Arne Schwarz, Ingo Eitel, and Moritz Montenbruck. “Atrial Giant Cell Myocarditis as a Cause of Heart Failure.” JACC: Case Reports 4, no. 1 (2022): 66–71. https://doi.org/10.1016/j.jaccas.2021.11.007. 17. PALMER, HARLEY P., and ISAAC E. MICHAEL. “Giant-Cell Myocarditis With Multiple Organ Involvement.” Archives of Internal Medicine 116, no. 3 (1965): 444–47. https://doi.org/10.1001/archinte.1965.03870030124022. 18. Polte, Christian L., Entela Bollano, Anders Oldfors, Anna Dudás, Kerstin M. Lagerstrand, Jakob Himmelman, Emanuele Bobbio, Kristjan Karason, Martijn van Essen, and Niklas Bergh. “Somatostatin Receptor Positron Emission Tomography/Computed Tomography in Giant Cell Myocarditis: A Promising Approach to Molecular Myocardial Inflammation Imaging.” Circulation: Cardiovascular Imaging 15, no. 1 (2022): e013551. https://doi.org/10.1161/CIRCIMAGING.121.013551. 19. Sujino, Yasumori, Fumiko Kimura, Jun Tanno, Shintaro Nakano, Eriko Yamaguchi, Michio Shimizu, Nanami Okano, et al. “Cardiac Magnetic Resonance Imaging in Giant Cell Myocarditis.” Circulation 129, no. 17 (2014): e467–69. https://doi.org/10.1161/CIRCULATIONAHA.113.005059. 20. Xu, J., and E. G. Brooks. “Giant Cell Myocarditis: A Brief Review.” Arch Pathol Lab Med 140, no. 12 (December 2016): 1429–34. https://doi.org/10.5858/arpa.2016-0068-RS. 21. Yang, S., X. Chen, J. Li, Y. Sun, J. Song, H. Wang, and S. Zhao. “Late Gadolinium Enhancement Characteristics in Giant Cell Myocarditis.” ESC Heart Fail 8, no. 3 (June 2021): 2320–27. https://doi.org/10.1002/ehf2.13276.

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The following question refers to Section 9.5 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by Keck School of Medicine USC medical student & former CardioNerds Intern Hirsh Elhence, answered first by Vanderbilt Cardiology Fellow and CardioNerds Academy Faculty Dr. Breana Hansen, and then by expert faculty Dr. Javed Butler.

Dr. Butler is an advanced heart failure and transplant cardiologist, President of the Baylor Scott and White Research Institute, Senior Vice President for the Baylor Scott and White Health, and Distinguished Professor of Medicine at the University of Mississippi

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

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Question #31

| Mrs. Hart is a 70-year-old woman who was admitted to the CICU two days ago for signs and symptoms consistent with cardiogenic shock. Since her admission, she has been on maximal diuretics, requiring greater doses of intravenous dobutamine. Unfortunately, her liver and renal function continue to worsen, and urine output is decreasing. A right heart catheterization reveals elevated biventricular filling pressures with a cardiac index of 1.7 L/min/m2 by the Fick method.What is the next best step? | | A | Continue current measures and monitor for improvement | | B | Switch from dobutamine to norepinephrine | | C | Place an intra-aortic balloon pump (IABP) | | D | Resume guideline directed medical therapy |

Answer #31

| Explanation | The Correct answer is C – Place an intra-aortic balloon pump.This patient is between the SCAI Shock Stages C and D with elevated venous pressures, decreased urine output, and worsening signs of hypoperfusion. She has been started on appropriate therapies, including diuresis and inotropic support. The relevant Class 2a recommendation is that in patients with cardiogenic shock, temporary MCS is reasonable when end-organ function cannot be maintained by pharmacologic means to support cardiac function (LOE B-NR). Thus, the next best step is a form of temporary MCS. IABP is appropriate to help increase coronary perfusion and offload the left ventricle. In fact, for patients who are not rapidly responding to initial shock measures, triage to centers that can provide temporary MCS may be considered to optimize management (Class 2b, LOE C-LD).The guidelines further state that in patients presenting with cardiogenic shock, placement of a pulmonary arterial line may be considered to define hemodynamic subsets and appropriate management strategies (Class 2B, LOE B-NR). And so, if time allows escalation to MCS should be guided by invasively obtained hemodynamic data via PA catheterization. Several observational experiences have associated PA catheterization use with improved outcomes, particularly in conjunction with short-term MCS. Additionally, PA catheterization is useful when there is diagnostic uncertainty as to the cause of hypotension or end-organ dysfunction, particularly when the patient in shock is not responding to empiric initial measures, such as in this patient.There are additional appropriate measures at this time that are more institution-dependent. An institutional shock team would be very helpful here as they often comprise multidisciplinary teams of heart failure and critical care specialists, interventional cardiologists, surgeons, and palliative care specialists. As such, there is a Class 2a recommendation that in patients with cardiogenic shock, management by a multidisciplinary team experienced in shock is reasonable (LOE B-NR). Most documented experiences have suggested outcomes improve after shock teams are instituted. For instance, in one such experience, using a shock team was associated with improved 30-day all-cause mortality (HR, 0.61; 95% CI, 0.41–0.93) and reduced in-hospital mortality (61.0% vs. 47.9%; P=0.041).Choice A – Continue current measures and monitor for improvement – is incorrect. This patient has been deteriorating on current measures since admission and is at higher risk for SCAI Shock Stage E – extremis, refractory hypotension/hypoperfusion, and cardiac arrest and, therefore requires escalation of therapyChoice B- Switch from dobutamine to norepinephrine – is incorrect. The Class 1 LOE B-NR recommendation is that in patients with cardiogenic shock, intravenous inotropic support should be used to maintain systemic perfusion and maintain end-organ performance. Dobutamine is a more potent inotropic agent than norepinephrine. Stopping dobutamine in the setting of her low cardiac index would be incorrect.Choice D – Resume guideline-directed medical therapy – is incorrect. This patient’s shock is getting worse. The Class 1 LOE B-NR recommendation is that in patients with HFrEF, GDMT should be initiated during hospitalization after clinical stability is achieved. Restarting medications now would be premature. | | Main Takeaway | In patients with cardiogenic shock, temporary MCS is reasonable when end-organ function cannot be maintained by pharmacologic means to support cardiac function. | | Guideline Loc. | Section 9.5 |

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CardioNerds co-founder Dr. Dan Ambinder, series chair Dr. Teodora Donisan, and Dr. Sukriti Banthiya discuss cardiac tumors with Dr. Juan Lopez-Mattei, a nationally recognized expert in the fields of cardio-oncology and the director of cardiac imaging at the Lee Health Heart Institute. Here, we explore the topic of cardiac tumors, with a focus on distinguishing between primary and secondary tumors. We delve into the symptoms, diagnostic methods, and treatment options. Show notes were drafted by Dr. Sukriti Banthiya and episode audio was edited by CardioNerds Intern and student Dr. Diane Masket.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

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Pearls and Quotes – Cardiac Tumors1. Keep it simple when approaching an intracardiac mass; start with transthoracic echocardiography (TTE) and use transesophageal echocardiography (TEE) or cardiac magnetic resonance (CMR) based on the clinical context. Use TEE when suspecting valvular vegetations or thrombi & CMR for intracavitary cardiac masses. 2. Cardiac tumors can manifest with a variety of symptoms; however, they are more commonly diagnosed as an incidental finding! 3. When faced with the dilemma of selecting the most suitable imaging modality for evaluating a cardiac mass, consider the following hierarchy: begin with TTE as the first choice, followed by CMR. If the patient cannot undergo CMR, the next step is cardiac computed tomography (CT) or Fluorodeoxyglucose F18 positron emission tomography (FDG-PET). 4. TEE is especially useful for the evaluation of small, highly mobile cardiac masses! 5. Imaging cannot substitute a tissue diagnosis of cardiac masses. However, in cases of advanced malignancy, it may not always be necessary.

Show notes – Cardiac TumorsSegment One: A big “picture” Approach to Cardiac Tumors

Let’s start with an overview of cardiac masses

• Neoplastic vs non-neoplastic
  • Neoplastic lesions can be further classified into Primary Cardiac Tumors (PCT’s) & Secondary Cardiac Tumor (SCT’s)
  • A majority of PCTs are benign (up to 90%!); however, rarely, they may be malignant.
  • SCTs are more common than PCTs, and, by definition, they are malignant tumors.

Now, let’s look at the tools you can use to aid with the diagnosis of cardiac masses…

• Step 1: Investigate the cardiac mass initially with TTE.
• Step 2: Collect clues through history-taking & examination.
  • If suspecting valvular vegetations (as in infective endocarditis!) or left atrial appendage thrombus, characterize the mass further with TEE.
  • Consider the possibility of metastatic cardiac tumors in patients with a known malignancy, as they are more common than primary cardiac tumors.
  • In cases where it is uncertain if the mass is a cardiac tumor or thrombus, use CMR to differentiate the two entities.
    • Some findings on TTE that support the presence of a thrombus include left ventricular dysfunction with segmental wall motion abnormalities and/or apical aneurysm as these result in local pockets of stasis (think: Virchow’s triad)
• Step 3: Put it all together!
  • Think about whether a tissue biopsy will be needed. If yes, determine whether a negative margin or open biopsy will be required.

Segment Two: Symptoms, Symptoms, Symptoms!

Cardiac tumors may be symptomatic and present in the 3 key ways as outlined below (Think COD 🐟). However, they are more commonly identified as incidental findings!

• Constitutional symptoms (fever, arthralgias, weight loss, malaise/fatigue)
• Obstruction – Interfering with blood outflow, arrhythmias, interference with valves causing regurgitation, pericardial effusion +/- tamponade (presyncope, syncope, dyspnea, chest discomfort)
• Distal embolization (pulmonary or systemic thromboembolic phenomenon)

When a metastatic tumor is present, distinguishing symptoms originating from the heart becomes challenging due to potential overlap with symptoms caused by the primary malignancy. This stands in contrast to cases of primary cardiac tumors like myxomas, where symptom localization to the heart is more straightforward.

Segment Three: Multimodality Imaging

| Imaging modality | Best used for | Advantages | Disadvantages | | TTE | Initial diagnostic modality Masses arising from valves | Good spatial resolution Understanding of hemodynamic significance of mass | Lack of tissue characterization Poor acoustic window in select cases | | TEE | Small highly mobile valvular lesions (<1cm) | Visualization of structures with greater accuracy compared to TTE Use of enhancing agents can help differentiate vascular tumors from non-vascular & thrombus | Lack of tissue characterization | | CMR | Differentiates tumor from thrombus. Identifies non-tumor masses or “pseudo-masses,” e.g. cysts, lipomas | Tissue characterization w/ T1, T2 weighted imaging and gadolinium enhancement | Lower temporal resolution Limited availability Interference from implanted electrical devices | | CT & FDG-PET | Differentiates benign from malignant tumors | Alternative to CMR in pts. w/ claustrophobia & older generation cardiac devices | CT with limited soft tissue & temporal resolution compared to CMR Dietary preparation before FDG |

Segment Four: The Issue With Tissue!

Tissue diagnosis is essential for the diagnosis of primary cardiac tumors; however, it may be less important for metastatic tumors to the heart in cases of known advanced-stage malignancies such as melanoma, breast, and lung.

An overview of a rare primary cardiac malignancy: Carney Complex!

A complex hereditary syndrome that affects multiple organs, including the heart, skin & endocrine organs.

• Epidemiology:
  • Autosomal dominant
  • Young age groups in both sexes
• Clinical presentation
  • Intra-cardiac/extra-cardiac myxomas; intra-cardiac myxomas are multiple, bilateral (atrial and ventricular) & multicentric.
  • Skin findings commonly include lentigines and blue nevi.
  • Endocrine abnormalities include Cushing syndrome, pituitary & adrenal adenomas, thyroid dysfunction.
• Diagnosis
  • Clues on CMR
    • SSFP (dteady-state free precession) cine imaging, an association of punctiform areas of high & low signal intensity consistent with “Blackberry appearance”
    • Hypoperfused enhancement pattern at first-pass perfusion imaging
    • High signal T2-imaging, iso-intense on T1-weighted imaging
• Treatment
  • Surgical resection
  • Annual surveillance for Carney complex as they frequently recur (compared with surveillance every 3-5 years for non-Carney myxomas)
  • Genetic testing for PRKAR1 mutations in 1st degree family members

Segment Five: “Secondary” to None

Secondary cardiac tumors (SCT’s)

• Epidemiology:
  • Cardiac metastasis is 20-40 times more common than primary cardiac tumors.
• Etiology:
  • Routes of spread: hematogenous, lymphatic, transvenous, direct invasion
  • Most common malignancies to metastasize to heart include melanomas, carcinomas of breast, lung and esophageal.
• Clinical Presentation
  • Pericardial effusion, tamponade
  • Arrhythmias – “resistant” to antiarrhythmic drugs
  • Heart failure due to myocardial infiltration
  • Valvular dysfunction due to intracavitary masses that impede blood flow.
• Diagnosis
  • Echocardiography is the initial test of choice.
  • MRI
    • Most malignancies exhibit low signal on T1-weighted imaging & high signal intensity on T2-weighted imaging.
    • Exception, metastaticmelanoma, which appears hyperintense on T1-weighted imaging due to paramagnetic T1 shortening effects of melanin.
  • FDG-PET/CT
    • In cardiac metastasis, the myocardium has high metabolic activity and can mimic FDG uptake seen in a tumor.
    • Ensure adequate dietary preparation to suppress glucose uptake of normal healthy myocardium.
• Multi-disciplinary approach to management
  • Tissue diagnosis is necessary.
    • Referral to an interventional cardiologist for transvenous biopsy, or
    • Referral to a cardiac surgeon for minimally invasive surgery
    • Note – tissue diagnosis can come from another metastatic site.
  • Pathologist to confirm the malignant nature of the tumor.
  • Cardio-oncologist to facilitate multidisciplinary team discussion involving oncologist and cardiac surgeon on the best approach to treatment.
    • Neoadjuvant chemotherapy or radiotherapy vs. cardiac surgery

References – Cardiac Tumors1. Tyebally, Sara, Daniel Chen, Sanjeev Bhattacharyya, Abdallah Mughrabi, Zeeshan Hussain, Charlotte Manisty, Mark Westwood, Arjun K. Ghosh, and Avirup Guha. “Cardiac Tumors: JACC CardioOncology State-of-the-Art Review.” JACC. CardioOncology 2, no. 2 (June 2020): 293–311. https://doi.org/10.1016/j.jaccao.2020.05.009. * Basson, Craig T., and H. Thomas Aretz. “Case 11-2002: A 27-Year-Old Woman with Two Intracardiac Masses and a History of Endocrinopathy.” Edited by Richard C. Cabot, Nancy Lee Harris, William F. McNeely, Jo-Anne O. Shepard, Sally H. Ebeling, Stacey M. Ellender, and Christine C. Peters. New England Journal of Medicine 346, no. 15 (April 11, 2002): 1152–58. https://doi.org/10.1056/NEJMcpc010057. * Colin, Geoffrey C., Bernhard L. Gerber, Mihaela Amzulescu, and Jan Bogaert. “Cardiac Myxoma: A Contemporary Multimodality Imaging Review.” The International Journal of Cardiovascular Imaging 34, no. 11 (November 2018): 1789–1808. https://doi.org/10.1007/s10554-018-1396-z.

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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CardioNerds Atrial Fibrillation Series Co-Chairs Dr. Colin Blumenthal (University of Pennsylvania Cardiology fellow) and Dr. Kelly Arps (Duke University Electrophysiology Fellow) join the 2023 atrial fibrillation guideline writing committee Chair Dr. José Joglar (UT Southwestern) and Vice Chair Dr. Mina Chung (Cleveland Clinic). They review the key takeaways from the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation. Audio editing by CardioNerds academy intern, student doctor Pace Wetstein.

This podcast was developed in collaboration with the American Heart Association. For more on these guidelines, access the AHA Science News AF Guideline landing page.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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CardioNerds nerd out with Drs. Karishma Rahman (Mount Siani Vascular Medicine fellow), Shu Min Lao (Mount Sinai Rheumatology fellow), and Constantine Troupes (Mount Sinai Vascular Surgery fellow). They discuss the following case: A 20-year-old woman with a history of hypertension (HTN), initially thought to be secondary to a mid-aortic syndrome that resolved after aortic stenting, presents with a re-occurrence of HTN. The case will go through the differential diagnosis of early onset HTN focusing on structural etiologies of HTN, including mid-aortic syndrome and aortitis. We will also discuss the multi-modality imaging used for diagnosis and surveillance, indications and types of procedural intervention, and how to diagnose and treat an underlying inflammatory disorder leading to aortitis. The expert commentary was provided by Dr. Daniella Kadian-Dodov, Associate Professor of Medicine and Vascular Medicine specialist at the Icahn School of Medicine at Mount Sinai. Audo editing was performed by Dr. Chelsea Amo-Tweneboah, CardioNerds Academy Intern and medicine resident at Stony Brook University Hospital.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Case Media – Hypertension With a TwistPearls – Hypertension With a Twist1. Early onset hypertension (HTN) and lower extremity claudication should raise suspicion for aortic stenosis (including mid-aortic syndrome). Initial evaluation should include arterial duplex ultrasound and cross-sectional imaging such as CT or MR angiogram of the chest, abdomen, and pelvis to assess for arterial stenosis involving the aorta and/or branching vessels. 2. Mid-aortic syndrome can have multiple underlying etiologies. Concentric aortic wall thickening should raise suspicion for an underlying inflammatory disorder. Initial evaluation should include inflammatory markers such as ESR, CRP, and IL-6, but normal values do not exclude underlying aortitis. 3. While Takayasu arteritis is the most common inflammatory disorder associated with mid-aortic syndrome, IgG4-RD should also be a part of the differential diagnosis. IgG subclass panel can detect IgG4-RD with elevated serum IgG4 levels, but some cases can require pathology for diagnosis. 4. Catheter based intervention is a safe and effective treatment of aortic stenosis for both primary aortic stenosis and post-procedural re-stenosis. 5. Multi-modality imaging, including cross-sectional imaging and duplex ultrasound, plays a central role for the diagnosis, management, and post-procedural surveillance of aortic disease. 6. A multi-disciplinary team (as exemplified by the participants of this podcast!) is essential for the management of complex aortopathy cases to optimize clinical outcomes.

Show Notes – Hypertension With a Twist1. Early onset HTN can have multiple etiologies – aortic stenosis (including but not limited to secondary to congenital aortic coarctation and mid–aortic syndrome, as well as in stent re-stenosis if there is a history of aortic stenting), thrombosis, infection, inflammatory/autoimmune disorders, renovascular disease, polycystic kidney disease, and endocrine disorders.

1. Mid-aortic syndrome is characterized by segmental or diffuse narrowing of the abdominal and/or distal descending aorta with involvement of the branches of the proximal abdominal aorta (renal artery, celiac artery, superior mesenteric artery) and represents approximately 0.5 to 2% of all cases of aortic narrowing. Underlying etiologies include genetic syndromes, inflammatory, non-inflammatory, and idiopathic. It is important to have a high suspicion of underlying inflammatory disorders if cross-sectional imaging reveals concentric aortic wall thickening1,2.

2. The current treatment options for aortic stenosis (of the aorta here…not the aortic valve) include balloon angioplasty, aortic stenting, and surgical repair. While studies show the efficacy of balloon angioplasty and aortic stenting, data is limited as studies were mostly done in children3,4.

3. Aortitis5-16 can have multiple etiologies including infectious (such as TB, syphilis, HIV, bacterial, fungal), inflammatory disorders (such as large vessel vasculitis, IgG4-RD, Behcet syndrome, relapsing polychondritis, spondyloarthritis, SLE, and rheumatoid arthritis), and idiopathic. Sometimes, hereditary connective tissue disorders (such Marfan syndrome,, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome) are included in the differential diagnosis, however, they would present as an aortic intramural hematoma (IMH) that typically would appears as eccentric wall thickening (rather than concentric wall thickening more consistent with aortitis).

4. While Takayasu arteritis is the most common inflammatory disorder associated with mid-aortic syndrome, IgG4-RD should also be a part of the differential diagnosis. IgG4-RD is characterized by lymphoplasmacytic infiltrates featuring IgG4 positive plasma cells. It presents in predominantly males between ages 40-70 years of age. The rate of vascular involvement is approximately 8% for aortitis and 20-36% periaortitis. It can be diagnosed with elevated serum IgG4 levels or from tissue biopsy where pathology would show dense lymphoplasmacytic infiltrates in a storiform fibrosis pattern with obliterative phlebitis and >40% plasma calls and >10 positive plasma cells/high power field. It is treated initially treated with high dose steroids with transition to steroid sparing agents such as Rituximab (RTX), azathioprine, mycophenolate, and methotrexate with RTX being the preferred agent10,14.

5. In cases of re-stenosis after initial balloon angioplasty and stenting, indications for re-intervention include hypertension in the setting of imaging evidence of re-stenosis (e.g. > 50% percent aortic narrowing relative to the aortic diameter at the diaphragm level) and

pressure gradient across the coarctation > 20 mmHg. The timing of re-intervention in cases of aortitis secondary to underlying inflammatory disorders will require a multi-disciplinary discussion to determine when underlying inflammatory disorder is sufficiently controlled for re-intervention.

References – Hypertension With a Twist1. Bacha E, Hijazi ZM. Management of Coarctation of the Aorta. U: UpToDate, Fulton DR ed UpToDate [Internet] Waltham, MA: UpToDate. 2020. 2. Lazea C, Al-Khzouz C, Sufana C, et al. Diagnosis and management of genetic causes of middle aortic syndrome in children: a comprehensive literature review. Therapeutics and Clinical Risk Management. 2022:233-248. 3. Rodés-Cabau J, Miró J, Dancea A, et al. Comparison of surgical and transcatheter treatment for native coarctation of the aorta in patients≥ 1 year old. The Quebec Native Coarctation of the Aorta Study. American heart journal. 2007;154(1):186-192. 4. Meadows J, Minahan M, McElhinney DB, McEnaney K, Ringel R. Intermediate outcomes in the prospective, multicenter Coarctation of the Aorta Stent Trial (COAST). Circulation. 2015;131(19):1656-1664. 5. Nikiphorou E, Galloway J, Fragoulis GE. Overview of IgG4-related aortitis and periaortitis. A decade since their first description. Autoimmunity reviews. 2020;19(12):102694. 6. Kadian-Dodov D, Seo P, Robson PM, Fayad ZA, Olin JW. Inflammatory Diseases of the Aorta: JACC Focus Seminar, Part 2. Journal of the American College of Cardiology. 2022;80(8):832-844. 7. Sohrabi B, Jamshidi P, Yaghoubi A, et al. Comparison between covered and bare Cheatham-Platinum stents for endovascular treatment of patients with native post-ductal aortic coarctation: immediate and intermediate-term results. JACC: Cardiovascular Interventions. 2014;7(4):416-423. 8. Marvisi C, Buttini EA, Vaglio A. Aortitis and periaortitis: the puzzling spectrum of inflammatory aortic diseases. La Presse Médicale. 2020;49(1):104018. 9. Bossone E, Pluchinotta FR, Andreas M, et al. Aortitis. Vascular pharmacology. 2016;80:1-10. 10. Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Annals of the rheumatic diseases. 2015;74(6):1171-1177. 11. Wallace ZS, Perugino C, Matza M, Deshpande V, Sharma A, Stone JH. Immunoglobulin G4–related disease. Clinics in chest medicine. 2019;40(3):583-597. 12. Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European league against rheumatism classification criteria for IgG4‐related disease. Arthritis & Rheumatology. 2020;72(1):7-19. 13. Onen F, Akkoc N. Epidemiology of Takayasu arteritis. La Presse Médicale. 2017;46(7-8):e197-e203. 14. Ebbo M, Grados A, Samson M, et al. Long-term efficacy and safety of rituximab in IgG4-related disease: data from a French nationwide study of thirty-three patients. PLoS One. 2017;12(9):e0183844. 15. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of giant cell arteritis and Takayasu arteritis. Arthritis Care & Research. 2021;73(8):1071-1087. 16. Lupi-Herrera E, Sanchez-Torres G, Marcushamer J, Mispireta J, Horwitz S, Vela JE. Takayasu’s arteritis. Clinical study of 107 cases. American heart journal. 1977;93(1):94-103.

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CardioNerds Dr. Rick Ferraro (cardiology fellow at Johns Hopkins Hospital) and Dr. Eunice Dugan (cardiology fellow at the Cleveland Clinic) join episode lead Dr. Tiffany Brazile (cardiology fellow at the University of Texas Southwestern Medical Center and postdoctoral fellow at the Institute for Exercise and Environmental Medicine) to discuss the impact of obesity on cardiovascular disease risk, differential risk in specific populations, and effective strategies for counseling patients. They are joined by expert Dr. Jaime Almandoz, Medical Director of the Weight Wellness Program and an Associate Professor of Medicine at the University of Texas Southwestern Medical Center. Audio editing was performed by CardioNerds Academy Intern, student Dr. Tina Reddy.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

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Pearls and Quotes – Obesity & Cardiovascular Disease Risk1. The durability of metabolically healthy obesity (i.e., normal A1c, lipids, LFTs, BMP, normotensive) is limited. Within 5 years, a third of adults with “metabolically healthy” obesity will develop a cardiometabolic complication. 2. The biomechanical and psychosocial complications of obesity are just as important as the cardiometabolic complications. Biomechanical and psychosocial complications, including obstructive sleep apnea, joint pain, and mood disorders also influence cardiovascular disease risk. 3. Weight loss is not always the patient’s goal. Meet patients where they are and understand their challenges, concerns, and long-term goals with respect to their cardiovascular health and obesity. This information provides an opportunity to frame the conversation in a supportive and engaging way that allows for patient education. 4. Body mass index (BMI) is a screening tool for obesity, but is not sufficient for providing individualized care. 5. Obesity management methods that result in rapid weight loss may not be appropriate for all patients. These methods, such as bariatric surgery and GLP1-receptor agonists, require regular monitoring, follow-up, and multidisciplinary care (e.g., nutritionist, exercise physiologist, endocrinologist, cardiologist, psychologist, etc.).

Show notes – Obesity & Cardiovascular Disease RiskIs it possible to be healthy at any size?

• Whether an individual can be healthy at any size depends on the definition of health and its durability.
  • Approximately 10-15% of adults with obesity are metabolically healthy.
    • The risk for developing cardiometabolic disease is higher in obese versus non-obese adults. One in three adults with metabolically healthy obesity will develop cardiometabolic complications (i.e., insulin resistance/diabetes, hyperlipidemia, hypertension) within five years. Thus, metabolically healthy obesity may represent a transient phenotype with adverse long-term consequences.
  • Consider non-metabolic health consequences of obesity that also influence cardiovascular disease risk.
    • Obstructive sleep apnea, joint pain leading to decreased physical activity, and mood disorders are key considerations here and encompass the biomechanical and psychosocial consequences of obesity.

Does large, rapid weight loss result in poorer long-term weight loss than slower, gradual weight loss?

• When approaches to weight loss are not sustainable, such as extremely low-calorie diets or extreme fitness regimens, the results and associated health benefits are less likely to be durable.
• Rapid, large-magnitude weight loss is appropriate for some adults with obesity and can be achieved through bariatric surgery and/or anti-obesity medications. Safety and sustainability are supported by regular follow-up, monitoring, and multidisciplinary care to incorporate nutritional and physical activity recommendations.
• Obesity management must be individualized to meet patient needs and goals while accounting for comorbid conditions (e.g., frailty, fall risk, disordered eating, etc.)

What are some best practices for incorporating the diagnosis of obesity into a patient’s assessment, including cardiovascular disease risk?

• Seek to understand what the patient wants to achieve during the office visit.
• Inquire about the patient’s health journey, goals, concerns, and challenges.
• In addition to addressing the patient’s expressed goals, frame the conversation in terms of concerns you have about the patient’s health.
• Incorporate objective measures, such as body composition, waist circumference, cardiorespiratory fitness, and biomarkers that can help support your concerns and management goals.

Does obesity impact men and women differently?

• Prevalence: of adults with obesity, women are more likely than men to have severe obesity. Obesity is also more prevalent in women of certain racial/ethnic minorities as compared to men.
• Fat distribution: men tend to have more visceral or central adiposity, which is associated with increased cardiometabolic risk. Earlier in adulthood, women tend to have more body fat in the gluteofemoral region. With advancing age and menopause, the distribution of excess adipose tissue in women often shifts to the visceral/central region and may enhance cardiometabolic risk.

What are the practical methods for evaluating and measuring obesity during a patient visit?

• BMI is a screening tool for obesity. It is blind to body composition and fat distribution. Cut points for BMI and the association with cardiovascular disease risk vary by race/ethnicity. Consideration of different BMI cut points for patients of various racial/ethnic backgrounds is important when evaluating candidacy for bariatric surgery or anti-obesity medications.
• Waist circumference is a useful measure to estimate visceral/central adiposity. Cut points for men and women have been established that are associated with increased cardiovascular disease risk across multiple studies.
• Measures of body composition provide valuable information about fat and lean body masses. DEXA scans and MRIs also provide data on fat distribution; however, they are impractical and expensive for regular use in the clinical setting. Bioelectrical impedance can provide body composition data efficiently during a clinic visit.

What are alternative validated tools beyond the Pooled Cohort Equation that can be used to estimate ASCVD risk in various ethnic/racial groups?

• The QRISK3 calculator is an alternative assessment tool for 10-year ASCVD risk that has been validated in 9 different ethnic groups. The calculator includes novel variables, such as chronic kidney disease, history of migraines, severe mental illness, erectile dysfunction, and family history of premature ASCVD. https://www.qrisk.org/

What are the mechanisms by which obesity impacts the development of cardiovascular disease?

• Obesity and lipotoxicity can impact cardiovascular disease development through multiple mechanisms, including inflammation that can lead to a prothrombotic state, insulin resistance, and alterations in lipid metabolism that can promote atherosclerosis.
• The distribution of body fat is highly heterogeneous and is partially driven by genetics. Brown adipose tissue has a high mitochondrial load and is involved in adaptive thermogenesis. White adipose tissue is considered more of a storage form of adipose tissue that also functions as an endocrine organ and provides insulation/protection for vital organs.
• Ectopic fat depots, such as hepatic steatosis or epicardial adipose tissue, are metabolically active and can influence adjacent tissues through humoral and neurohormonal signals. These fat depots may also exert mechanical effects on the organs they surround. The ways in which individuals accrue fat in these different locations, the specific mechanisms by which they may increase cardiovascular disease development, and whether targeted therapies to reduce specific fat depots are incompletely understood.

References – Obesity & Cardiovascular Disease Risk Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183 https://pubmed.ncbi.nlm.nih.gov/33567185/ * Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827 https://pubmed.ncbi.nlm.nih.gov/27295427/ * Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141 https://pubmed.ncbi.nlm.nih.gov/27633186/ * Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet*. 2019;394(10193):121-130. doi:10.1016/S0140-6736(19)31149-3 https://pubmed.ncbi.nlm.nih.gov/31189511/

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CardioNerds co-founder Dr. Amit Goyal, series co-chair Dr. Colin Blumenthal, and episode lead Dr. Anushka Tandon to discuss pharmacologic anticoagulation options in atrial fibrillation with Drs. Ashley Lochman and Chris Domenico. The case-based review helps clarify some key concepts, such as when warfarin is preferred for anticoagulation, who may be a good DOAC (direct-acting oral anticoagulant) candidate, how to choose an appropriate DOAC agent, and how to manage anticoagulation therapy in patients already on antiplatelet therapies. Notes were drafted by Dr. Anushka Tandon. The episode audio was edited by student Dr. Shivani Reddy.

This CardioNerds Atrial Fibrillation series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Kelly Arps and Dr. Colin Blumenthal.

This episode was planned and recorded prior to the release of the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation. Please refer to this guideline document for the most updated recommendations.

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Pearls and Quotes – Anticoagulation Pharmacology1. Avoid potentially fatal errors with this terminology tip for correctly referencing non-warfarin oral anticoagulant agents: it’s DOAC (like, please DO use AntiCoagulation), not NOAC (imagine someone interpreting that as “NO AntiCoagulation for this patient” at discharge – yikes)! 2. Sometimes, an oldie really is a goodie – warfarin is recommended over DOACs for patients with mechanical heart valves, moderate-to-severe mitral stenosis, anti-phospholipid antibody syndrome (APLS), left ventricular (LV) thrombus, higher INR goals, or DOAC failure. Patient preference and medication costs should also be considered – at the end of the day, “the best drug is the drug that a patient is willing to take!” 3. Standard-dose rivaroxaban or apixaban may be considered for use in patients weighing >120kg or with BMI >40; use of other DOACs should be limited to pts weighing =/< 120kg or with BMI =/< 40. 4. The pharmacists involved in this podcast promise they don’t have stock in apixaban! It just often happens to be the preferred DOAC option in certain scenarios – think patients with severe renal impairment (including ESRD) or with an increased risk for bleeding events (including older adults, those with a history of GI bleed, etc). 5. In general, dual therapy (DOAC or warfarin + P2Y12 inhibitor) is non-inferior to triple therapy (oral anticoagulant + P2Y12 inhibitor + aspirin) at preventing thrombotic events but is associated with a lower risk of bleeding events. Most patients can be transitioned to dual therapy after 7-30 days on triple therapy post-percutaneous coronary intervention. 6. What’s that on the horizon? Factor XI inhibitors may become the breakout stars of anticoagulation – multiple investigational agents are being studied for their potential to reduce thrombotic risk without significantly increasing bleeding risk in patients with indications for anticoagulation therapy…at least that’s the theorize hope. Watch this space!

Notes – Anticoagulation PharmacologyIn which cases is warfarin preferred over DOACs in patients with atrial fibrillation?

• Long-term anticoagulation with warfarin is indicated in patients with atrial fibrillation and either a mechanical valve or moderate-to-severe mitral stenosis (i.e., valvular atrial fibrillation as defined in the 2019 AHA/ACC/HRS guidelines on atrial fibrillation [1]). The REALIGN trial [2] showed increased rates of thromboembolic and bleeding complications with dabigatran vs. warfarin in patients with mechanical valves, and the PROACT Xa trial [3] found similarly higher rates of thromboembolic events with apixaban vs. warfarin in patients with On-X mechanical valves. However, DOACs are appropriate for use in patients with bioprosthetic valves.
• Warfarin is preferred over DOACs in patients with APLS (antiphospholipid syndrome). In triple-positive patients, DOACs should absolutely be avoided (as supported by the TRAPS study [4], which was stopped early due to findings of increased thromboembolic events with rivaroxaban vs. warfarin). Warfarin should also be preferentially used in single- and double-positive patients as well (as suggested by findings from the ASTRO-APS study [5]).
• There are some newer data to suggest apixaban may be non-inferior to warfarin in treating patients with LV thrombus; however, data overall is very mixed, and anticoagulating these patients with warfarin currently remains the preferred and more cautious approach.
• Other situations in which warfarin may be preferred are when a higher INR goal or a customized anticoagulation approach is required, in instances of DOAC failure, or in cases where cost or patient preference are driving factors.

What patient-specific factors should be considered when deciding whether someone is a good candidate for DOAC therapy?

• Weight/BMI: previous guidance suggested against the use of DOACs in pts weighing >120kg or with a BMI >40. However, ISTH updated their guidance in 2021 [6] to support using rivaroxaban and apixaban for VTE treatment or prevention “regardless of body weight and BMI”; these DOACs are often used in patients with obesity for non-VTE indications (e.g., thromboprophylaxis in atrial fibrillation). Data to support this include a post-hoc analysis of the ARISTOTLE trial (apixaban in atrial fibrillation), which showed that patients weighing >120kg (~5% of the study population) had similar results to the overall study population. It’s important to use adjusted body weight when calculating CrCl to estimate renal function and determine DOAC dosing in obese patients. Other DOACs should be avoided in pts >120kg/with BMI >40 due to limited or unconvincing data at this time.
  • Hepatic impairment: DOACs have varying hepatic metabolism (apixaban is the most hepatically cleared and dabigatran the least), but limited data exist for DOAC dose adjustments in patients with hepatic impairment. DOACs should NOT be used in Child-Pugh Class C/severe hepatic disease, while rivaroxaban (and betrixaban)[GU1] should also NOT be used in moderate/CP Class B patients. DOACs should be avoided in patients with decompensated/unstable cirrhosis. Aside from these caveats, DOACs may be considered for use in mild-moderate (Class A/B) hepatic impairment (with exceptions as above).
  • Renal impairment: DOACs may be used in stable CKD with appropriate renal dose adjustments; DOAC therapies should be held in the context of AKI. Dabigatran is the most renally cleared and generally avoided for this reason. Apixaban is the least renally cleared and is generally the preferred agent in patients with renal impairment, including ESRD (in the context of which apixaban use is supported by data, including that from a 2022 cohort study [7] vs. warfarin).
  • Drug Interactions: rivaroxaban, apixaban, edoxaban, and dabigatran are all P-gp substrates that will be affected by P-gp inducers or inhibitors (e.g., dronedarone, amiodarone, digoxin, diltiazem, verapamil, antiepileptics, antifungals, chemotherapy agents, and St. John’s Wort). Rivaroxaban and apixaban are substrates of CYP450 enzymes, prominently 3A4, 3A5, and 2J2. Apixaban is also metabolized by 1A2 and 2C 8/9/19 to a lesser degree. Some DOACs may interact with atorvastatin or ticagrelor, but these interactions are not typically a barrier to concurrent therapy if clinically indicated. Running a drug interaction report or consulting a pharmacist to help evaluate and safely navigate drug interactions is extremely helpful in these scenarios.
  • *In addition to DOAC package inserts, the AHA guide to DOAC use [8] is a great resource that summarizes renal/hepatic dosing considerations, drug interactions, and anticoagulant transition recommendations.

What safety profile and bleeding risk considerations exist for warfarin versus DOACs?

• Warfarin has been studied versus individual DOACs; generally, DOACs are preferred from a safety standpoint due to lower risk of bleeding. The RE-LY trial [9] showed no difference in major bleeding but less intracranial hemorrhage (ICH) with dabigatran when compared to warfarin. The ROCKET-AF [10] trial showed a greater Hgb drop/need for transfusion with rivaroxaban but higher critical/fatal bleeding (including ICH) incidence with warfarin. In the ARISTOTLE [11] trial, apixaban was associated with significantly lower bleeding outcomes than warfarin, except for GI bleeding (for which there was no significant difference between groups). Edoxaban had a lower incidence of overall GI bleed (upper and lower GI bleeding combined), but not individual upper or lower GI bleeding, than warfarin in the ENGAGE [12] trial.
  • There are no direct head-to-head trials comparing DOACs, though some data suggest apixaban is associated with a lower bleeding risk than rivaroxaban (no difference in ICH), and that rivaroxaban may be associated with a higher risk of hemorrhagic stroke.
  • In older adults, DOACs can be used without safety concerns over warfarin, though avoiding dabigatran may be suggested due to a signal for increased bleeding outcomes in older adult patients. The ELDERCARE-AF [13] trial from Japan showed no difference in major bleeding, but higher rates of GI bleeding and all bleeding, with edoxaban vs. placebo in adults >/= 80 years. Overall, apixaban is generally considered safe to use/the preferred DOAC option in patients with a history of GI bleeding.

What is the recommended anti-thrombotic approach for patients with indications for both antiplatelet therapy and anticoagulation (for example, patients with atrial fibrillation undergoing PCI)?

• Assessing the appropriateness of dual vs. triple therapy involves balancing the risk of stent thrombosis vs. stroke risk.
• Among P2Y12 inhibitors, clopidogrel is typically recommended over ticagrelor or prasugrel due to its lower incidence of bleeding events and because clopidogrel was also the most commonly used P2Y12 inhibitor in dual versus triple therapy trials.
• The WOEST trial [14] found no increased thrombosis risk but a reduced bleeding risk in patients given dual therapy post-PCI with clopidogrel and warfarin vs. those given triple therapy with warfarin, clopidogrel, and aspirin. The REDUAL-PCI trial [15] found a similarly reduced bleeding risk without statistically increased thrombotic risk in patients receiving dual therapy with dabigatran + P2Y12i vs. continuing triple therapy with P2Y12i + aspirin + warfarin. The PIONEER-AF [16] trial found lower bleeding risk with rivaroxaban + P2Y12 therapy than with warfarin-DAPT triple therapy without differences in thrombotic outcomes; the caveat here is that the 15mg daily rivaroxaban dose used is not approved for stroke prevention (that dose is 20mg daily). The AUGUSTUS trial [17] showed dual apixaban + P2Y12i therapy to have lower bleeding risk and unchanged efficacy than VKA dual therapy or triple therapy with apixaban or VKA. Importantly, these trials were not powered to differentiate ischemic outcomes.
• As for when patients should be transitioned from triple (OAC + P2Y12 + ASA) to dual therapy (OAC + P2Y12), data from medication-specific trials can help guide the approach. For patients anticoagulated with warfarin or dabigatran, a triple therapy duration of 30 days may be appropriate based on WOEST (up to 1 year) and REDUAL-PCI trials (up to 3 months for patients with a DES). In PIONEER-AF, patients were randomized directly to rivaroxaban + P2Y12 therapy without first receiving triple therapy, but in clinical practice, triple therapy is often instituted for 7-30 days before transitioning to dual therapy with rivaroxaban and P2Y12 inhibitor. For apixaban, a shorter 7-day course of triple therapy appears appropriate.
• *The 2022 ACC ECDP is a fantastic reference resource to help guide the management of anticoagulation and antiplatelet therapy in patients with atrial fibrillation or VTE undergoing PCI or with ASCVD [18].

What’s the scoop on factor XI, which appears to be clinically important for thrombosis but not hemostasis, as a potential drug target? Might this be the future of anticoagulation pharmacotherapy?

• Factor XI is a part of the contact pathway of coagulation. It is activated by thrombin and factor XIIa and is thought to activate factor IX. Factor XI appears to contribute to thrombin generation and thereby amplify thrombus growth; it may also reduce fibrin degradation. Higher levels of factor XI appear correlated to increased clotting risk, while factor XI levels are poorly correlated with bleeding risk. The excitement around factor XI as a drug target stems from the thought that XI inhibition may decrease thrombotic risk without significantly changing bleeding risk.
• Currently, there are several drugs in development and multiple ongoing clinical trials examining therapeutic viability. Oral, intravenous, and subcutaneous formulations of factor XI inhibitors are all being studied, in forms including monoclonal antibodies, small molecules, and antisense oligonucleotides. Most data reported thus far relates to VTE prophylaxis in orthopedic surgery. However, ongoing/planned trials, like the PACIFIC and OCEANIC series, will look at factor XI inhibitors in the context of atrial fibrillation, stroke, and myocardial infarction. Comparator drugs in these studies include DOACs and enoxaparin.
• Long-term impact for this class of investigational therapeutics remains to be seen, and cost will likely be a limiting factor in using these agents (especially as DOACs are anticipated to go generic in 5-10 years). However, early data seems promising! [19, 20].

References – Anticoagulation Pharmacology1. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons [published correction appears in Circulation. 2019 Aug 6;140(6):e285]. Circulation. 2019;140(2):e125-e151. doi:10.1161/CIR.0000000000000665 2. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. doi:10.1056/NEJMoa1300615 3. Wang TY, Svensson LG, Wen J, et al. Apixaban or Warfarin in Patients with an On-X Mechanical Aortic Valve. NEJM Evid 2023;May 6:[Epub ahead of print]. doi:10.1056/EVIDoa2300067 4. Pengo V, Hoxha A, Andreoli L, et al. Trial of Rivaroxaban in AntiPhospholipid Syndrome (TRAPS): Two-year outcomes after the study closure. J Thromb Haemost. 2021;19(2):531-535. doi:10.1111/jth.15158 5. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv. 2022;6(6):1661-1670. doi:10.1182/bloodadvances.2021005808 6. Martin KA, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882. doi:10.1111/jth.15358 7. Ellenbogen MI, Ardeshirrouhanifard S, Segal JB, Streiff MB, Deitelzweig SB, Brotman DJ. Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end-stage kidney disease: A national cohort study. J Hosp Med. 2022;17(10):809-818. doi:10.1002/jhm.12926 8. Chen A, Stecker E, A Warden B. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. J Am Heart Assoc. 2020;9(13):e017559. doi:10.1161/JAHA.120.017559 9. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010 Nov 4;363(19):1877]. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561 10. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638 11. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039 12. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907 13. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med. 2020;383(18):1735-1745. doi:10.1056/NEJMoa2012883 14. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115. doi:10.1016/S0140-6736(12)62177-1 15. Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377(16):1513-1524. doi:10.1056/NEJMoa1708454 16. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423-2434. doi:10.1056/NEJMoa1611594 17. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019;380(16):1509-1524. doi:10.1056/NEJMoa1817083 18. Kumbhani D, Cannon C, Beavers C, et al. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2021 Feb, 77 (5) 629–658. https://doi.org/10.1016/j.jacc.2020.09.011 19. Nopp S, Kraemmer D, Ay C. Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence. Front Cardiovasc Med. 2022;9:903029. Published 2022 May 12. doi:10.3389/fcvm.2022.903029 20. Greco A, Laudani C, Spagnolo M, et al. Pharmacology and Clinical Development of Factor XI Inhibitors. Circulation. 2023;147(11):897-913. doi:10.1161/CIRCULATIONAHA.122.062353

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CardioNerds (Dr. Amit Goyal) join Dr. Anureet Malhotra, Dr. John Fritzlen, and Dr. Tarun Dalia from the University of Kansas School of Medicine for some of Kansas City’s famous barbeque. They discuss a case of Hydroxychloroquine induced cardiomyopathy. Notes were drafted by Dr. Anureet Malhotra, Dr. John Fritzlen, and Dr. Tarun Dalia. Expert commentary was provided by Dr. Pradeep Mammen. The episode audio was edited by Dr. Akiva Rosenzveig.

Drug-induced cardiomyopathy remains an important and under-recognized etiology of cardiomyopathy and heart failure.Hydroxychloroquine is a disease-modifying antirheumatic drug used for various rheumatological conditions, and its long-term use is well-known to have toxic effects on cardiac muscle cells. Multiple cardiac manifestations of these drugs have been identified, the most prominent being electrophysiological disturbances.

In this episode, we discuss a biopsy-proven case of hydroxychloroquine-induced cardiotoxicity with detailed histopathological and imaging findings. We develop a roadmap for the diagnosis of hydroxychloroquine-induced cardiomyopathy and discuss the various differentials of drug-induced cardiomyopathy. We highlight the importance of clinical monitoring and early consideration of drug-induced toxicities as a culprit for heart failure.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Case Media – Hydroxychloroquine induced cardiomyopathyPearls – Hydroxychloroquine induced cardiomyopathy1. Continued decline in left ventricular systolic function despite appropriate guideline directed medical therapy should prompt a thorough evaluation for unrecognized etiologies and warrants an early referral to advanced heart failure specialists. 2. Transthoracic echocardiogram is a valuable non-invasive screening tool for suspected pulmonary hypertension, but right heart catheterization is required for definitive diagnosis. 3. Cardiac MRI can be used for better characterization of myocardial tissue and can aid in the evaluation of patients with non-ischemic cardiomyopathy. 4. Hydroxychloroquine (HCQ) is a commonly used DMARD that remains an underrecognized etiology of cardiomyopathy and heart failure. In addition to ophthalmological screening, annual ECG, as well as echocardiography screening for patients on long-term HCQ therapy, should be considered in patients at risk for cardiovascular toxicity, including those with pre-existing cardiovascular disease, older age, female sex, longer duration of therapy, and renal impairment. 5. Management of hydroxychloroquine-associated cardiomyopathy consists of discontinuing hydroxychloroquine and standard guideline-directed medical therapy for heart failure. HCQ cardiomyopathy may persist despite medical therapy, and advanced therapy options may have to be considered in those with refractory heart failure.

Show Notes – Hydroxychloroquine induced cardiomyopathyWhat are the various cardiotoxic effects of hydroxychloroquine (HCQ) and the mechanism of HCQ-mediated cardiomyopathy?

One of the most frequently prescribed disease-modifying antirheumatic drugs (DMARDs), HCQ is an immunomodulatory and anti-inflammatory agent that remains an integral part of treatment for a myriad of rheumatological conditions. Its efficacy is linked to inhibiting lysosomal antigen processing, MHC-II antigen presentation, and TLR functions.8 The known cardiac manifestations of HCQ-induced toxicity include conduction abnormalities, ventricular hypertrophy, hypokinesia, and lastly, cardiomyopathy.

• Conduction Abnormalities – by binding to and inhibiting the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel, also known as Ikr channel, HCQ can lead to prolongation of corrected QT (QTc) interval. This can lead to an increased risk of drug-induced Torsades de pointes and other lethal ventricular arrhythmias.

• Cardiomyopathy – HCQ is a lipophilic drug that easily permeates myocytes and binds to lysosomal phospholipids, leading to lysosomal accumulation of phospholipids. Furthermore, by increasing the pH of the lysosome, HCQ inhibits lysosomal enzymes, which interferes with lysosomal function and exocytosis, leading to an acquired lysosomal storage disorder. This results in myofibrillar disorganization, atrophy, and fibrosis, which may lead to cardiomyopathy. Risk factors for the development of cardiotoxicity are thought to be pre-existing cardiovascular disease, older age, female sex, longer duration of therapy, and renal impairment. 8

• Extracardiac side effects – With long term use, HCQ can also lead to ocular toxicity, neuropathy, and myopathy with similar pathogenesis as cardiotoxicity, i.e., acquired lysosomal storage disorder.

What are the histopathological findings of HCQ induced Cardiomyopathy?

HCQ causes an acquired lysosomal storage disorder due to the inhibition of constitutive autophagy present in normal cardiac myocytes. On histopathology, this presents itself as cytoplasmic vacuoles, lamellar bodies and curvilinear inclusion bodies in cytoplasm that can be visualized with electron microscopy. Of these findings, curvilinear bodies are thought to be pathognomonic for HCQ induced cardiotoxicity. On histopathology, these findings can resemble inherited lysosomal storage disorders including Anderson- Fabry disease except for the presence of curvilinear bodies. 9

What is the differential diagnosis for HCQ induced cardiomyopathy?

Differentials of HCQ mediated cardiomyopathy include storage disorders like Fabry disease, adult-onset Pompe disease (acid maltase deficiency), and Danon disease. Many drug-induced myopathies such as amiodarone, rituximab, prednisone, cocaine, cobalt, and several chemotherapeutic agents can also resemble HCQ mediated cardiotoxicity.

Furthermore, amyloidosis, sarcoidosis and myocarditis also merit consideration as they can lead to restrictive physiology and present similar echocardiographic findings. They can be differentiated using advanced cardiac imaging such as cardiac MRI and histopathological findings on endomyocardial biopsy.

How can Cardiac MRI (CMR) assist in the work up of non-ischemic cardiomyopathy?

CMR can enhance visualization of cardiac structures that may be poorly seen on echocardiogram due to location or poor acoustic windows. CMR also uniquely provides detailed tissue characterization. CMR can be used for assessing many pathologies, including aortic disease, coronary artery disease, cardiomyopathies, pericardial disease, and congenital heart disease. 4 CMR is also considered the gold standard for assessing cardiac function and can be used to assess valvular pathologies with flow assessment.

Late gadolinium enhancement (LGE) refers to the discrimination of regions of scar, necrosis, or inflammation from normal tissue by the prolonged retention of gadolinium-based contrast agents. The pattern of LGE, as well as T1 and T2 mapping, aid in tissue characterization and accurate diagnosis. Key take-home points are as follows:

1. The presence of LGE in a coronary distribution can support the diagnosis of prior myocardial infarction and aid in the assessment of myocardial viability.
2. LGE in the mid-wall and sub-epicardium of the LV is characteristic of viral myocarditis. In addition, T1 mapping helps estimate the extracellular volume, and T2 weighted imaging can show myocardial edema in patients with myocarditis.
3. In amyloidosis, the classic CMR findings include thick LV walls, valves, and interatrial septum and the presence of a pericardial effusion. They may also have the existence of amyloid protein in the myocardial interstitium associated with characteristic patterns of circumferential subendocardial LGE.

What is the management of HCQ induced cardiomyopathy?

• Diagnosis – HCQ cardiomyopathy diagnosis requires a high level of suspicion. A detailed history is an essential first step. CMR can aid in tissue characterization and is a helpful non-invasive tool. Definitive diagnosis can be established by obtaining an endomyocardial biopsy, given its distinctive histopathological findings, and ruling out close mimics of HCQ-induced cardiotoxicity.
• Treatment – the potentially reversible nature of HCQ cardiomyopathy makes early diagnosis and discontinuation of the offending drug the mainstays of treatment along with guideline directed medical therapy for heart failure. Recovery is variable and may take months or even years for LV function to improve. In some cases, there may be partial or no recovery, requiring advanced therapies evaluations. References – Hydroxychloroquine induced cardiomyopathy1. Greiner S, Jud A, Aurich M, et al. Reliability of Noninvasive Assessment of Systolic Pulmonary Artery Pressure by Doppler Echocardiography Compared to Right Heart Catheterization: Analysis in a Large Patient Population. Journal of the American Heart Association.2014;3(4).10.1161/JAHA.114.001103
• Augustine DX, Coates-Bradshaw LD, Willis J, et al. Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography. Echo research and practice. 2018;5(3):G11-G24. 10.1530/ERP-17-0071
• Page RL, O’Bryant CL, Cheng D, et al. Drugs That May Cause or Exacerbate Heart Failure. Circulation. 2016;134(6).https://doi.org/10.1161/CIR.0000000000000426
• Kramer CM. Role of Cardiac MR Imaging in Cardiomyopathies. Journal of Nuclear Medicine. 2015;56(Supplement_4):39S45S.10.2967/jnumed.114.142729.
• Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. European Heart Journal Acute Cardiovascular Care. 2013;2(1):77-83. https://doi.org/10.1177/2048872612471215
• Ezzeddine FM, Giudicessi JR, Maleszewski JJ, Lin PT, Borlaug BA, Geske JB. Unmasking Hydroxychloroquine Cardiotoxicity in a Patient With Heart Failure and Chronotropic Incompetence. JACC: Case Reports. 2021;3(7):997-1001. https://doi.org/10.1016/j.jaccas.2021.03.003
• Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal. Published online August 26, 2022. https://doi.org/10.1093/eurheartj/ehac237
• Bansal P, Goyal A, Cusick A, et al. Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019. Annals of Medicine. 2020;53(1):117-134. 10.1080/07853890.2020.1839959.
• Roos JM, Aubry MC, Edwards WD. Chloroquine cardiotoxicity: Clinicopathologic features in three patients and comparison with three patients with Fabry disease. Cardiovascular Pathology. 2002;11(5):277-283. https://doi.org/10.1016/s1054-8807(02)00118-7

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CardioNerds meet with fellows from The Christ Hospital, Drs. Hanad Bashir, Hyunsoo Chung, and Dalia Aziz to discuss the following case that highlights angioleiomyoma:

A 60-year-old woman with a past medical history significant for breast cancer (on tamoxifen) presented as a transfer to our facility for a clot-in-transit. She had initially presented to the outside hospital after progressive dyspnea on exertion and recent syncope. She was found on an echocardiogram to have a right atrial mass spanning into the right ventricle. CTA of the chest and abdomen/pelvis demonstrated extensive thrombus burden spanning from the IVC into the right ventricle. She was transferred to our facility for intervention.

Endovascular attempts were unsuccessful, at which point she underwent surgical thrombectomy. Gross examination of the mass revealed a cylindrical shape, homogeneous tan color, rubbery soft tissue, measuring 25.5 cm in length and 2.3 cm in diameter. Histology confirmed the presence of angioleiomyoma. A second, smaller mass (5.2cm long and 4mm in diameter) was removed from under the tricuspid valve, with histology consistent with leiomyoma. Estrogen receptor and progesterone receptor staining were strongly positive, leading to the discontinuation of tamoxifen. Given the presence of uterine fibroids identified on the CT scan, there was concern about a uterine origin. A hysterectomy is planned for her in the near future.

Expert commentary is provided by Dr. Wojciech Mazur. Episode audio was edited by student Dr. Adriana Mares.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Case Media – The Tall Tail Heart: Angioleiomyoma – The Christ HospitalPearls – The Tall Tail Heart: Angioleiomyoma – The Christ Hospital1. Although evaluation of cardiac mass by echocardiography can provide information such as size, location, and morphology, adjunctive cross-sectional imaging may be used depending on the need for further temporal resolution (CT) or tissue characterization via cardiac MRI (CMR). If suspicious for elevated metabolic activity, there should be consideration of FDG-PET. 2. Tamoxifen (a selective estrogen receptor modulator) is an agent used for breast cancer therapy. However, its use has been associated with endometrial hyperplasia, uterine fibroids, endometrial and uterine malignancy. Increased risk of malignancy has been seen more often in post-menopausal women and is dose and time-dependent. 3. Clot in transient is a mobile thrombus, typically within the right heart structures. It is estimated to occur in 4-18% of patients with pulmonary embolism and is associated with elevated morbidity and mortality. Treatment includes surgical embolectomy, endovascular embolectomy, systemic thrombolysis, catheter-directed thrombolysis, or systemic anticoagulation. 4. Angioleiomyoma is a rare benign pericystic tumor that most commonly affects the extremities. There are case reports of other affected sites, including the uterus. Invasion into the cardiac structures is exceedingly rare. 5. The only established treatment for angioleiomyoma is surgical resection.

Show Notes – The Tall Tail Heart: Angioleiomyoma – The Christ HospitalSyncope

• Syncope is a transient loss of consciousness secondary to reduced blood flow to the brain. Often, certain presentations are mislabeled as syncope, such as seizure disorders, posttraumatic loss of consciousness, and cataplexy.
• An organized diagnostic approach should be used to reduce hospital admissions and medical costs and increase diagnostic accuracy.
• Syncope can be divided into five general subgroups.

1) Neurally mediated reflex syncope (carotid sinus syndrome, vasovagal)

2) Orthostatic syncope

3) Cardiac arrhythmias

4) Structural cardiac and pulmonary causes

5) Cerebrovascular disorders.

• Initial evaluation should include thorough H&P, including orthostatic vitals and ECG. If diagnosis remains uncertain after initial evaluation, patients’ syncope should be risk stratified into three groups: high, intermediate, and low risk.
• Additionally, the 2017 ACC/AHA/HRS guidelines stratify patient risk based on short-term (<30 days) and long-term (>30 days) morbidity and mortality based on initial examination and history.
• Patients presenting with high-risk and short-term syncope features should be immediately hospitalized for further diagnostic testing and treatment. High-risk features are usually indicative of underlying cardiovascular causes that could lead to sudden death; this includes but is not limited to life-threatening arrhythmias and acute coronary syndrome.
• Risk stratification also determines the selection of diagnostic tests. When underlying cardiac etiology is suspected, diagnostic tests such as echocardiography, CT angiography, cardiac magnetic resonance, electrophysiology study, exercise stress testing, and coronary angiography may be valuable in establishing timely diagnosis in high-risk patients.
• Choice of study modality varies greatly based on patient presentation and risk factors. In contrast to patients presenting with high-risk syncope, low-risk patients are discharged home with re-assurance and follow-up.

Strategy for Intracardiac Masses

• First, take into account the patient’s age at the time of presentation, as certain medical conditions like rhabdomyomas and fibromas are more commonly observed among pediatric patients.
• Second, assess the likelihood from an epidemiological perspective and consider the clinical probability. For instance, if a patient has recently experienced an anterior wall myocardial infarction and exhibits an akinetic ventricular apex, the presence of a cardiac mass during echocardiography could indicate the possibility of an intracardiac thrombus.
• Third, factor in the location of the tumor. If the mass is detected on the valves, potential diagnoses to consider include thrombus or vegetation. While masses within the heart chambers might still indicate thrombus, it’s also important to contemplate other possibilities, such as myxomas, lymphomas, and metastases.
• Fourth, delve into the tissue characteristics of the mass using additional diagnostic imaging methods like cardiac magnetic resonance imaging.

Imaging Modalities for Intracardiac Masses

• Transthoracic echocardiography (TTE) is readily available and non-invasive. Transesophageal echocardiography (TEE) offers insights into size, shape, attachment site, extension, and hemodynamic effects. Ultrasound-enhancing agents in echocardiography help differentiate various masses. Thrombi and benign tumors display a non or low-enhancing pattern. Malignancies and highly vascular tumors display a hyperenhancing pattern. Doppler velocities aid in assessing the hemodynamic impact.
• Cardiac MRI (CMR) is invaluable in the assessment of cardiac masses. In addition to anatomy, dimensions, and mass consistency, using different signal sequences like T1, T2, early and late gadolinium enhancement differentiate tissue characteristics and unveil fatty presence, necrosis, bleeding, inflammation, and vascularity within a mass.
• Cardiac CT provides high spatial and temporal resolution, multiplanar image reconstruction, and rapid acquisition. The broad field of view allows for the evaluation of the chest, lung tissue, vascular structures, and potential masses within the chest. Cardiac CT can be used to detect calcifications within the mass, although it has less soft tissue resolution compared with CMR.
• FDG-PET/CT can help gauge tumors’ metabolic activity. When CT alone doesn’t decisively determine benign or malignant nature, PET/CT steps in, aiding in malignancy diagnosis and guiding biopsy locations, staging, and cancer therapy planning.

Cardiac tumors

• Cardiac tumors can be categorized into primary and secondary tumors.
• Secondary tumors, arising from metastasis, are more prevalent and often stem from cancers like melanoma, breast, or lung cancer.
• Secondary tumors can lead to issues like pericardial effusion with or without cardiac tamponade, myocardial infiltration, obstruction, or embolization. Primary tumors include benign (about 80%) and malignant (about 20%) types.
• Malignant tumors are mainly sarcomas, such as angiosarcomas and rhabdomyosarcomas.
• Benign tumors encompass myxomas, gelatinous masses with scattered myxoma cells; papillary fibroelastomas, frond-like masses typically on valves; lipomas, composed of fat cells; fibromas, containing fibroblasts and mostly found in the left ventricle; and rhabdomyomas, made of maldeveloped cardiac myocytes and often seen in ventricles. Other rare tumors include Purkinje cell tumors. However, the latter three mentioned are more common in children.

Clot-in-transit

• Clot-in-transit (CIT) is the presence of mobile echogenic material in the right atrium or ventricle as seen on ultrasound.
• Right heart clots are classified into three types based on their morphology:
  • Type A (common and carries a high risk of pulmonary embolization)
  • Type B (assumed to originate from the atrium or ventricle)
  • Type C (rare and migratory, resembling cardiac myxomas)
• Intervention options for CIT include catheter-based thrombolysis, systemic (IV) thrombolysis, surgical/endovascular embolectomy, and anticoagulation therapy.
• Catheter-based thrombolysis involves high-frequency ultrasound exposure, catheter-directed thrombolysis, mechanical thrombectomy, and endovascular clot suction. It has a high success rate but may not work for bulky thrombi.
• Surgical embolectomy is recommended for hemodynamically unstable patients with CIT and provides an opportunity to address right-to-left heart communication. It requires substantial surgery and cardiopulmonary bypass.
• In cases of concomitant CIT and pulmonary embolism (PE), simultaneous treatment is essential to prevent further PE episodes.
• Anticoagulants are an option for patients in whom surgery is contraindicated, but they do not affect existing clots and may lead to bleeding or thrombus fragmentation.
• Systemic thrombolysis can improve right ventricular function, reduce pulmonary hypertension, and dissolve clots in multiple locations but carries a risk of thrombus embolization as well as bleeding complications.
• Management plans for CIT should consider individual patient factors like hemodynamic stability, right heart function, patent foramen ovale (PFO), and malignancy.
• There are no definitive guidelines. As a result, treatment decisions should be made on a case-by-case basis. An algorithm for CIT treatment may be helpful in clinical decision-making. PE response teams (PERT) are invaluable for complex decision making.

Angioleiomyoma

• These are rare, benign tumors that are classified as pericytic (perivascular) soft tissue tumors.
• There appears to be no consensus on incidence and prevalence, though there have been reports of this tumor accounting for around 5% of benign soft tissue tumors. Women are more affected than men. The age of diagnosis tends to be in the 4th to 6th decade.
• They typically arise in the extremities, particularly the lower extremities. However, the prevalence of uterine, cardiac, and major vascular deposition (IVC) is unknown.
• Typically, when present in the extremities, patients complain of discomfort due to the nodules. That said, location and size will determine symptoms. Pulmonary angioleiomyomas causing dyspnea have been reported. If involving the uterus, patients may present with menorrhagia, abdominal pain, and abdominal mass. Those masses can be submucosal, intramural, subserosal. As in this case, excessive burden in the IVC and right heart can lead to hemodynamic limitations, ultimately leading to symptoms of dyspnea and syncope.
• There is no agreement on the pathophysiology of this tumor. However, there are hypotheses, including trauma to the area, venous stasis, and hormonal factors causing the propagation of abnormal cell growth. Proposed histological types include capillary type (narrow vessels interlaced with thick fascicles of smooth muscles), venous type (thick vessels interspersed with fascicles of smooth muscle), and cavernous type (widened vessels with less smooth muscles).
• Although echo, CT, and MRI imaging could help evaluate the characteristics of this mass, pathology is required for a definitive diagnosis.
• The mainstay treatment is surgical excision of the tumor. This has been effective in preventing recurrence. However, in this case, the treating team should be cognizant of any potential medications leading to the proliferation of this tumor.

Benign metastasizing leiomyoma

• The origins of the tumor are typically uterine leiomyomas. These are inherently mitotically inactive smooth muscle cells without atypia, which have migrated to extra-uterine sites.
• Although rare, these are mostly seen in patients of reproductive age and frequently involve the lungs, whereby it is called pulmonary benign metastasizing leiomyoma.
• Patients may present with incidental extra-uterine leiomyoma found on exam. If there is hemodynamic change in the cardiac chambers or if involving the lungs, patients may present with symptoms including dyspnea, cough, and chest discomfort.
• There is evidence to suggest chromosome deletions, particularly in 19q and 22q, may predispose leiomyomas to metastatic potential.
• When present in the lung, this needs to be differentiated from pulmonary lymphangioleiomyomatosis (LAM), which on histology demonstrates perivascular epithelioid cells along bronchial interstitium.
• Leiomyomas beyond the uterus have been classified as intravenous, benign metastasizing, diffuse peritoneal, retroperitoneal, and parasitic. Incidence is approximately 0.25% to 0.4% for those with leiomyomas.
• For patients with symptomatic disease, resection of the leiomyoma, anti-hormonal agents, and anti-angiogenesis agents can be used for tumor treatment.

References – 1. Schaal SF, Nelson SD, Boudoulas H, Lewis RP. Syncope. Curr Probl Cardiol. 1992 Apr;17(4):205-64. doi: 10.1016/0146-2806(92)90002-6. PMID: 1563273. 2. Writing Committee Members; Shen WK, Sheldon RS, Benditt DG, Cohen MI, Forman DE, Goldberger ZD, Grubb BP, Hamdan MH, Krahn AD, Link MS, Olshansky B, Raj SR, Sandhu RK, Sorajja D, Sun BC, Yancy CW. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-e217. doi: 10.1016/j.hrthm.2017.03.004. Epub 2017 Mar 9. PMID: 28286247. 3. Sutton R, Ricci F, Fedorowski A. Risk stratification of syncope: Current syncope guidelines and beyond. Auton Neurosci. 2021 Dec 23;238:102929. doi: 10.1016/j.autneu.2021.102929. Epub ahead of print. PMID: 34968831. 4. Motwani M, Kidambi A, Herzog BA, Uddin A, Greenwood JP, Plein S. MR imaging of cardiac tumors and masses: a review of methods and clinical applications. Radiology. 2013 Jul;268(1):26-43. doi: 10.1148/radiol.13121239. PMID: 23793590. 5. Tyebally S, Chen D, Bhattacharyya S, Mughrabi A, Hussain Z, Manisty C, Westwood M, Ghosh AK, Guha A. Cardiac Tumors: JACC CardioOncology State-of-the-Art Review. JACC CardioOncol. 2020 Jun 16;2(2):293-311. doi: 10.1016/j.jaccao.2020.05.009. PMID: 34396236; PMCID: PMC8352246. 6. Lopez-Mattei JC, Lu Y. Multimodality Imaging in Cardiac Masses: To Standardize Recommendations, The Time Is Now! JACC Cardiovasc Imaging. 2020 Nov;13(11):2412-2414. doi: 10.1016/j.jcmg.2020.04.009. Epub 2020 Jun 17. PMID: 32563655 7. Patel AN, Amrutiya RJ, Manvar BN. A Proposed Approach for the Management of Clot-in-Transit. Cureus. 2022 Aug 27;14(8):e28481. doi: 10.7759/cureus.28481. PMID: 36176887; PMCID: PMC9512516. 8. Hu Y, Ren S, Tan S, Chen C, Wang X, Liang Q, Yu F, Liu W. Angioleiomyoma of the pulmonary artery: a case report and literature review. J Cardiothorac Surg. 2020 Aug 28;15(1):230. doi: 10.1186/s13019-020-01275-z. PMID: 32859240; PMCID: PMC7456385. 9. Sikora-Szczęśniak DL. Uterine angioleiomyoma – a rare variant of uterine leiomyoma: review of literature and case reports. Prz Menopauzalny. 2016 Nov;15(3):165-169. doi: 10.5114/pm.2016.63496. Epub 2016 Nov 15. PMID: 27980528; PMCID: PMC5137480. 10. Zhang JZ, Zhou J, Zhang ZC. Subcutaneous Angioleiomyoma: Clinical and Sonographic Features With Histopathologic Correlation. J Ultrasound Med. 2016 Aug;35(8):1669-73. doi: 10.7863/ultra.15.06056. Epub 2016 Jul 1. PMID: 27371376. 11. Kang BS, Shim HS, Kim JH, Kim YM, Bang M, Lim S, Park GM, Lee TY, Ha ND, Kwon WJ. Angioleiomyoma of the Extremities: Findings on Ultrasonography and Magnetic Resonance Imaging. J Ultrasound Med. 2019 May;38(5):1201-1208. doi: 10.1002/jum.14798. Epub 2018 Sep 12. PMID: 30208227. 12. Kumar S, Hasan R, Maddukuri SB, Mathew M. Angiomyoma presenting as a painful subcutaneous mass: a diagnostic challenge. BMJ Case Rep. 2014 Oct 16;2014:bcr2014206606. doi: 10.1136/bcr-2014-206606. PMID: 25323285; PMCID: PMC4202094. 13. Morimoto Y, Sato M, Yamada A, Gan K. Large right ventricle cardiac leiomyoma metastasis from uterine leiomyoma. BMJ Case Rep. 2022 Dec 8;15(12):e252389. doi: 10.1136/bcr-2022-252389. PMID: 36593619; PMCID: PMC9743285. 14. Galvin SD, Wademan B, Chu J, Bunton RW. Benign metastasizing leiomyoma: a rare metastatic lesion in the right ventricle. Ann Thorac Surg. 2010 Jan;89(1):279-81. doi: 10.1016/j.athoracsur.2009.06.050. PMID: 20103256. 15. Pacheco-Rodriguez G, Taveira-DaSilva AM, Moss J. Benign Metastasizing Leiomyoma. Clin Chest Med. 2016 Sep;37(3):589-95. doi: 10.1016/j.ccm.2016.04.019. Epub 2016 Jun 25. PMID: 27514603. 16. Barnaś E, Książek M, Raś R, Skręt A, Skręt-Magierło J, Dmoch-Gajzlerska E. Benign metastasizing leiomyoma: A review of current literature in respect to the time and type of previous gynecological surgery. PLoS One. 2017 Apr 20;12(4):e0175875. doi: 10.1371/journal.pone.0175875. PMID: 28426767; PMCID: PMC5398563. 17. Mustafa A, Obholz J, Ghanim M, Congello S. Clot in Transit: Therapy via Peripherally Inserted Central Catheter Line. Cureus. 2022 Jan 28;14(1):e21691. doi: 10.7759/cureus.21691. PMID: 35237484; PMCID: PMC8882343.

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Calling all those with a passion for cardiovascular prevention! In this episode of the CardioNerds Cardiovascular Prevention Series, we take a deep dive into the world of glucagon-like peptide-1 (GLP-1) receptor agonists. Along the way, you’ll hear about the biology of the GLP-1 molecule and its related peptides, learn more about how GLP-1 agonists promote glycemic control, weight loss, and cardiometabolic health, and explore the current body of literature supporting the individualized application of these medications to patients with diabetes, obesity, and/or ASCVD.

Join Dr. Christian Faaborg-Andersen (CardioNerds Academy Fellow and Internal Medicine Resident at MGH), Dr. Gurleen Kaur (Director of the CardioNerds Internship, Chief of House Einthoven, and Internal Medicine resident at BWH), and Dr. Rick Ferraro (CardioNerds Academy House Faculty and Cardiology Fellow at JHH) for a wide-ranging discussion on GLP-1 and GIP agonists with Dr. Dennis Bruemmer (Cardiologist and Director of the Center for Cardiometabolic Health in the section of Preventive Cardiology at the Cleveland Clinic).

Show notes were drafted by Dr. Christian Faaborg-Andersen. Audio editing was performed by CardioNerds Academy Intern, student Dr. Tina Reddy.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – GLP-1 Agonists: Mechanisms to Applications1. The selection and dosing of GLP-1 and GIP agonists (GLP-1s and GIPs) depends on their intended use as an anti-glycemic or anti-obesity agent. 2. The cardiovascular benefits of GLP-1s and GIPs may be independent of improvements in glycemic control, and in part be driven by reduction in inflammation, a key driver of arterial plaque formation. 3. In patients with comorbid coronary artery disease, obesity, and diabetes, GLP-1 agonists and SGLT-2 inhibitors should be used as first-line agents, over metformin. 4. Tirzepatide is a dual agonist that activates GIP and GLP-1 receptors. GIP is highly expressed in the brain, which may mediate satiety, promote energy expenditure, and enhance peripheral glucose metabolism. 5. Caution should be used with GLP-1 agonists in patients with long-standing diabetes complicated by gastroparesis, as well as incompletely treated diabetic retinopathy. 6. GI upset is not uncommon with GLP-1/GIP agonists, and switching to a different agonist is unlikely to help.

Show notes – GLP-1 Agonists: Mechanisms to ApplicationsWhat are the mechanisms of action by which GLP-1 and GIP controls blood sugar and body weight?

• Glucagon-like peptide-1 (GLP-1) is an endogenous hormone that is secreted in response to an oral glucose load. It promotes insulin release, inhibits glucagon secretion, and slows gastric emptying via the brain-intestine axis, leading to satiety. GLP-1 agonists are medications that mimic the effect of this hormone and, on average, lower hemoglobin A1C by 0.8% to 1.5%. These medications include semaglutide, liraglutide, and dulaglutide.
• Glucose-dependent insulinotropic polypeptide (GIP) is also an endogenous hormone, similarly secreted by the body in response to an oral glucose load such as a meal. GIP is highly expressed in the arcuate nucleus and hypothalamus, which may mediate satiety, promote energy expenditure, and enhance peripheral glucose metabolism. Tirzepatide is a dual GLP-1/GIP agonist.

What is the role of GLP-1/GIP agonists in patients with overweight/obesity and/or type 2 diabetes? How does the dosing of GLP-1/GIP medications change with their intended disease target?

• The STEP-1 trial showed that once-weekly semaglutide led to a net 15% weight loss in non-diabetic, obese/overweight patients. The SELECT trial builds on these results, showing that once-weekly semaglutide resulted in a 20% reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with pre-existing cardiovascular disease and BMI ≥ 27kg/m2. Other notable trials in this space include the LEADER trial (liraglutide), the SUSTAIN-6 trial (semaglutide), and the REWIND trial (dulaglutide).
• The dosing of GLP-1 agonists depends on their intended use as either an anti-glycemic or anti-obesity agent. For weight management, the current FDA-approved therapies are semaglutide 2.4mg weekly and liraglutide 3mg daily. For diabetes, the approved medications are semaglutide 2mg weekly, dulaglutide 4.5mg weekly, and tirzepadite 15mg weekly.

What are the cardiometabolic benefits of GLP-1/GIP agonist therapy, beyond glycemic control and/or weight loss? When are GLP-1/GIP agonists considered first-line therapy?

• The cardiovascular benefits of GLP-1s may be independent of improvements in glycemic control, and in part be driven by reductions in inflammation and cytokine response driving plaque formation in the arterial wall. In the SELECT trial, once weekly 2.4mg semaglutide led to a 20% reduction in MACE in non-diabetic, obese/overweight patients with established ASCVD.
• In patients with comorbid coronary artery disease, obesity, and diabetes, national guidelines recommend GLP-1 agonists and SGLT-2 inhibitors as first-line agents, over metformin.

How does tirzepatide differ from GLP-1 agonists?

• Tirzepetide is a dual GLP-1/GIP agonist. GIP is highly expressed in the arcuate nucleus and hypothalamus, which may mediate satiety, promote energy expenditure, and enhance peripheral glucose metabolism.
• The SURMOUNT trial showed 20% net weight loss with tirzepatide in patients with overweight/obesity, nearly as effective as metabolic surgery.

What are the absolute and relative contraindications to GLP-1/GIP agonist therapy?

• GLP-1/GIP agonists are contraindicated in patients with a personal or family history of medullary thyroid cancer.
• Caution should be used in patients with long-standing diabetes with neuropathy and gastroparesis, as well as incompletely treated diabetic retinopathy.
• Gallstone pancreatitis should not be considered a contraindication to GLP-1/GIP therapy after cholecystectomy, though a history of recent pancreatitis should give one pause in prescribing a GLP-1/GIP agonist.
• GLP-1 agonists should not be prescribed for type 1 diabetes, during pregnancy, or with breastfeeding.

What are the most common side effects of GLP-1 agonists?

• GI upset is the most common side effect with GLP-1/GIP agonist therapy, and the incidence of these side effects is similar between tirzepadite and semaglutide in randomized control trials.

References – GLP-1 Agonists: Mechanisms to Applications Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183 https://pubmed.ncbi.nlm.nih.gov/33567185/ * Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827 https://pubmed.ncbi.nlm.nih.gov/27295427/ * Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141 https://pubmed.ncbi.nlm.nih.gov/27633186/ * Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet*. 2019;394(10193):121-130. doi:10.1016/S0140-6736(19)31149-3 https://pubmed.ncbi.nlm.nih.gov/31189511/

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CardioNerds cofounder Dr. Amit Goyal and cardiology fellows from the Cleveland Clinic (Drs. Alejandro Duran Crane, Gary Parizher, and Simrat Kaur) discuss the following case: A 61-year-old man presented with symptoms of heart failure and left ventricular hypertrophy. He was given a diagnosis of obstructive hypertrophic cardiomyopathy. He eventually underwent septal myectomy, mitral valve replacement, aortic aneurysm repair, and aortic valve replacement with findings of Fabry’s disease on surgical pathology. The case discussion focuses on the differential diagnosis for LVH and covers Fabry disease as an HCM mimic. Expert commentary was provided by Dr. Angelika Ewrin. The episode audio was edited by student Dr. Diane Masket.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – An Unusual Cause of Hypertrophic Cardiomyopathy – Cleveland ClinicPearls – An Unusual Cause of Hypertrophic Cardiomyopathy – Cleveland Clinic1. Left ventricular hypertrophy is a cardiac manifestation of several different systemic and cardiac processes, and its etiology should be clarified to avoid missed diagnosis and treatment opportunities. 2. Fabry disease is a rare, X-linked inherited disease that can present cardiac and extra-cardiac manifestations, the former of which include hypertrophic cardiomyopathy, conduction defects, coronary artery disease, conduction abnormalities, arrhythmias, and heart failure. 3. The diagnosis of Fabry disease includes measurement of alpha-galactosidase enzyme activity as well as genetic testing to evaluate for pathogenic variants or variants of unknown significance in the GLA gene. Family members of patients diagnosed with Fabry disease should be screened based on the inheritance pattern. 4. Multimodality imaging can be helpful in the diagnosis of Fabry disease. Echocardiography can show left ventricular hypertrophy (LVH), reduced global strain, aortic and mitral valve thickening, and aortic root dilation with associated mild to moderate aortic regurgitation. Cardiac MRI can show hypertrophy of papillary muscles, mid-wall late gadolinium enhancement and low-native T1 signal. 5. The treatment of Fabry disease involves a multi-disciplinary approach with geneticists, nephrologists, cardiologists, nephrologists, and primary care doctors. Enzyme replacement therapy can delay the progression of cardiac disease.

Show Notes – An Unusual Cause of Hypertrophic Cardiomyopathy – Cleveland ClinicWhat are the causes of left ventricular hypertrophy?

LVH is extremely common. It is present in 15-20% of the general population, and is more common in Black individuals, the elderly, obese or hypertensive individuals, with most cases being secondary to hypertension and aortic valve stenosis. In general terms, it is helpful to divide the causes of LVH into three main groups: high afterload states, obstruction to LV ejection, and intrinsic myocardial problems. Increased afterload states include both primary and secondary hypertension and renal artery stenosis. Mechanical obstruction includes aortic stenosis, subaortic stenosis, and coarctation of the aorta. Lastly, several intrinsic problems of the myocardium can cause LV hypertrophy, such as athletic heart with physiological LVH, hypertrophic cardiomyopathy with or without outflow obstruction, and infiltrative or storage diseases such as cardiac amyloidosis, Fabry’s disease, or Danon disease, among others.

How does Fabry disease present?

Fabry disease is present in all races and is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene that result in reduced alpha-galactosidase enzyme activity, leading to accumulation of lysosomal globotriaosylceramide (Gb3) globotriaosylsphingosine (lyso-Gb3) in affected tissues, including the heart, kidneys, vasculature, and peripheral nervous system. The reported incidence of this disease is said to be between 1 in 40,000 and 1 in 117,000 individuals, but screening in newborns suggests that this incidence may be underestimated, as it is present in up to 1 in 8,800 newborns. Depending on the variant of the mutation or the presence of mosaicism in females, the disease can have variable expression with early-onset presentations in the classical form or late-onset presentations in individuals who have residual a-galactosidase enzyme activity.

Fabry disease can have multiple cardiac and extracardiac manifestations. Accumulation of Gb3 occurs in all cell types of the heart, including smooth muscle cells of the endothelium, myocytes, conduction cells, and valvular fibroblasts. Accumulation of glycosphingolipids also leads to biochemical changes in cell function that lead to apoptosis, cellular necrosis, inflammation, and altered membrane ion channel properties that may lead to increased conduction velocities. In the myocardium, cell damage produces LVH and diastolic dysfunction. Damage to endothelial cells leads to coronary artery disease and myocardial ischemia. Together, these changes may eventually lead to myocardial fibrosis and systolic dysfunction. Involvement of the conduction cells can manifest as conduction abnormalities and ventricular arrhythmias. Other electrocardiographic findings are a short PQ interval or chronotropic incompetence. Aortic remodeling in FD has been well described and often presents as sinus of Valsalva dilatation or ascending aortic aneurysm, which in turn may lead to secondary aortic regurgitation.

Extracardiac manifestations of Fabry disease include neuropathy, gastrointestinal symptoms, angiokeratomas, cornea verticillata (golden-brown or gray discoloration of the corneal epithelium), hypohidrosis and exercise intolerance, proteinuria and renal failure, juvenile or cryptogenic stroke, hearing loss, chronic white matter hyperintensities in brain MRI, and lymphedema.

How is Fabry disease diagnosed?

Diagnosis of Fabry disease should be suspected in patients with unexplained LVH, especially when there are any extracardiac red flags. LVH presents in more than half of men and more than a third of women after the third decade of life. Other electrocardiographic findings besides high QRS voltages may include inferolateral negative T-waves, short PQ intervals, and a reduced P wave duration. The diagnosis is confirmed through genetic testing that may identify pathogenic variants as well as variants of unknown significance. Enzymatic level activities should be measured as well for confirmation. Absent or reduced alpha-galactosidase activity levels coupled with pathogenic variants in genetic testing confirm a diagnosis of FD. Variants of uncertain significance might require confirmation by endomyocardial biopsy and by lyso-Gb3 level assessment.

What is the role of cardiovascular imaging in the diagnosis of Fabry disease?

Multimodality imaging may be helpful in the diagnosis and staging of FD. Echocardiography typically reveals LVH with disproportionate hypertrophy of the papillary muscles, loss of base-to-apex circumferential strain gradient, and right-ventricular hypertrophy with normal systolic function. There may also be abnormal thickening of the aortic and mitral valves. Global longitudinal strain and speckle tracking may allow for early detection of cardiac involvement in patients with pathogenic variants.

Cardiac MRI (CMR) may help with tissue characterization. Typical CMR findings of FD include late gadolinium enhancement (LGE), initially in the basal inferolateral wall, and low native T1 signal intensity, likely reflecting glycosphingolipid myocardial storage and occurring before the development of significant LVH. Tissue characterization by CMR also allows for staging of FD cardiomyopathy in different and progressive stages of accumulation, with progressive lowering of T1 signal intensity; inflammation and hypertrophy, with low T1, initial LVH, and T2 mapping showing inflammation in the basal inferolateral segment associated with LGE; and fibrosis, with increasing T1 values or pseudo-normalization and LGE with wall thinning in the basal inferolateral segment.

What is the management for Fabry disease?

The main objective in the treatment of FD is prevention of disease progression and end-organ damage. The mainstay of therapy is enzyme replacement therapy (ERT) with agalsidase-alfa or beta intravenous injections every other week. Agalsidase-alfa is produced in human cell lines, while the beta form of the enzyme is produced by recombinant DNA technology using mammalian cells.

ERT is indicated in patients with late-onset FD who have the presence of laboratory, histological, or imaging evidence of injury to the heart, kidney, or central nervous system. It can delay the progression of cardiac disease and reduce the cardiovascular event rate in patients with FD.

Another available pharmacological agent is the chaperone agent migalastat, which can be helpful for specific genetic variants of FD by stabilizing the translated form of alpha-galactosidase. This chaperone agent is given in oral tablets every other day. There is ongoing development of novel therapies for FD with second-generation ERTs, substrate reduction therapies, and gene and mRNA therapies.

References – An Unusual Cause of Hypertrophic Cardiomyopathy – Cleveland Clinic1. Weidemann F, Strotmann JM, Niemann M, et al. Heart Valve Involvement in Fabry Cardiomyopathy. Ultrasound in Medicine and Biology. 2009;35(5):730-735. doi:10.1016/j.ultrasmedbio.2008.10.010 2. Pieroni M, Moon JC, Arbustini E, et al. Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week. Journal of the American College of Cardiology. 2021;77(7):922-936. doi:https://doi.org/10.1016/j.jacc.2020.12.024 3. Barbey F, Qanadli SD, Juli C, et al. Aortic remodelling in Fabry disease. European heart journal. 2010;31(3):347-353. doi:10.1093/eurheartj/ehp426 4. Chimenti C, Morgante E, Tanzilli G, et al. Angina in fabry disease reflects coronary small vessel disease. Circulation Heart failure. 2008;1(3):161-169. doi:10.1161/CIRCHEARTFAILURE.108.769729 5. Linhart A, Germain DP, Olivotto I, et al. An expert consensus document on the management of cardiovascular manifestations of Fabry disease. European Journal of Heart Failure. 2020;22(7):1076-1096. doi:https://doi.org/10.1002/ejhf.1960 6. Tower-Rader A, Jaber WA. Multimodality Imaging Assessment of Fabry Disease. Circulation Cardiovascular imaging. 2019;12(11):e009013. doi:10.1161/CIRCIMAGING.119.009013 7. Germain DP, Charrow J, Desnick RJ, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. Journal of Medical Genetics. 2015;52(5):353 LP – 358. doi:10.1136/jmedgenet-2014-102797 8. Pieroni M, Moon JC, Arbustini E, et al. Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week. J Am Coll Cardiol. 2021;77(7):922-936. doi:10.1016/J.JACC.2020.12.024 9. Maron BJ, Desai MY, Nishimura RA, et al. Diagnosis and Evaluation of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(4):372-389. doi:10.1016/J.JACC.2021.12.002 10. Bornstein AB, Rao SS, Marwaha K. Left Ventricular Hypertrophy. StatPearls [Internet] Treasure Island (FL). Published online August 8, 2022. Accessed April 1, 2023. https://www.ncbi.nlm.nih.gov/books/NBK557534/

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CardioNerds (Daniel Ambinder) joins Dr. Priyanka Ghosh and Dr. Ahmad Lone from the Guthrie Robert Packer Hospital for a day in the Finger Lakes region of New York. They discuss the following case. A 35-year-old man with nonspecific symptoms of headache, fatigue, and chest wall pain was found to have elevated troponin levels, elevated inflammatory markers, EKG with inferior and anterolateral ST depressions, and no obstructive coronary artery disease on cardiac catheterization. His peripheral eosinophilia, cardiac MRI results, and bone marrow biopsy revealed eosinophilic myocarditis from acute leukemia with eosinophilia. This episode discusses this rare type of myocardial inflammation, its potential causes, and the diagnostic workup with the mention of how this patient was ultimately treated for his acute leukemia and myocarditis. Expert commentary is provided by Dr. Saurabh Sharma. Audio editing by CardioNerds academy intern, student doctor Pace Wetstein.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

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Case Media – Guthrie Robert Packer HospitalPearls – Guthrie Robert Packer Hospital1. Myocarditis, especially eosinophilic myocarditis, requires a high level of clinical suspicion. 2. Eosinophilic myocarditis should be considered in a patient presenting with chest pain, normal coronary arteries, and pronounced eosinophilia levels. 3. Causes of eosinophilic myocarditis can vary, and diagnosis requires a thorough, detailed history, which cannot be determined many times. 4. Treatment of eosinophilic myocarditis focuses on the underlying etiology, acute management, and therapy for concomitant heart failure or cardiomyopathy. 5. Consider the whole-patient and cardiac manifestations of non-cardiac illnesses.

Show Notes – Guthrie Robert Packer HospitalWhat is eosinophilic myocarditis?

Eosinophilic myocarditis is a type of myocardial inflammation involving eosinophilic cell infiltration and an entity that is likely under-recognized. It requires a high level of suspicion as, many times, patients may not initially present with peripheral eosinophilia, which may develop over the course of their disease process. The presentation can vary from mild cardiac injury to fulminant cardiogenic shock depending on the degree of infiltration and concurrent other organ involvement. The presentation can include heart failure symptoms as well as electrical conduction abnormalities.

How is eosinophilic myocarditis diagnosed?

Eosinophilic myocarditis is diagnosed by a thorough history including new medications, exposures, travel, prior allergy history, physical exam, lab work including a complete blood count differential, inflammatory markers, cardiac biomarkers, and cardiac diagnostics which should include a 12-lead ECG and transthoracic echocardiogram as well as potentially cardiac MRI and/or endomyocardial biopsy.

What are the causes of eosinophilic myocarditis?

The causes of eosinophilic myocarditis include medication-induced, hypersensitivity reactions, infections, malignancy, and immune-mediated disorders such as eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndromes. The hypersensitivity subtype has been reported to be the most common cause. Potential offending medications can include antibiotics, sulfonamides, anticonvulsants, anti-inflammatory medications, and diuretics.

What is the treatment for eosinophilic myocarditis?

Treatment for eosinophilic myocarditis is multi-faceted, including focusing on the etiology and withdrawal of any potential offending agents, management of the acute clinical presentation, and treatment of any concomitant heart failure or cardiomyopathy. Immunosuppressive therapy has been controversial; however, many case reports have successfully used methylprednisolone, and some patients with cardiogenic shock from eosinophilic myocarditis have received therapy with azathioprine.

References 1. Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol. 2006 Dec;22(14):1233-7. doi: 10.1016/s0828-282x(06)70965-5. PMID: 17151774; PMCID: PMC2569073. 2. Takkenberg JJ, Czer LS, Fishbein MC, Luthringer DJ, Quartel AW, Mirocha J, Queral CA, Blanche C, Trento A. Eosinophilic myocarditis in patients awaiting heart transplantation. Crit Care Med. 2004 Mar;32(3):714-21. doi: 10.1097/01.ccm.0000114818.58877.06. PMID: 15090952. 3. Morimoto S, Kubo N, Hiramitsu S, Uemura A, Ohtsuki M, Kato S, Kato Y, Sugiura A, Miyagishima K, Mori N, Yoshida Y, Hishida H. Changes in the peripheral eosinophil count in patients with acute eosinophilic myocarditis. Heart Vessels. 2003 Sep;18(4):193-6. doi: 10.1007/s00380-003-0721-0. PMID: 14520487. 4. Burke AP, Saenger J, Mullick F, Virmani R. Hypersensitivity myocarditis. Arch Pathol Lab Med. 1991 Aug;115(8):764-9. PMID: 1863186. 5. Fozing T, Zouri N, Tost A, Breit R, Seeck G, Koch C, Oezbek C. Management of a patient with eosinophilic myocarditis and normal peripheral eosinophil count: case report and literature review. Circ Heart Fail. 2014 Jul;7(4):692-4. doi: 10.1161/CIRCHEARTFAILURE.114.001130. PMID: 25028351. 6. Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, Ammirati E. Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes. J Am Coll Cardiol. 2017 Nov 7;70(19):2363-2375. doi: 10.1016/j.jacc.2017.09.023. PMID: 29096807. 7. Cheung CC, Constantine M, Ahmadi A, Shiau C, Chen LYC. Eosinophilic Myocarditis. Am J Med Sci. 2017 Nov;354(5):486-492. doi: 10.1016/j.amjms.2017.04.002. Epub 2017 Apr 6. PMID: 29173361. 8. Aggarwal A, Bergin P, Jessup P, Kaye D. Hypersensitivity myocarditis presenting as cardiogenic shock. J Heart Lung Transplant. 2001 Nov;20(11):1241-4. doi: 10.1016/s1053-2498(01)00313-8. PMID: 11704488. 9. Kounis NG, Zavras GM, Soufras GD, Kitrou MP. Hypersensitivity myocarditis. Ann Allergy. 1989 Feb;62(2):71-4. PMID: 2645814. 10. Li H, Dai Z, Wang B, Huang W. A case report of eosinophilic myocarditis and a review of the relevant literature. BMC Cardiovasc Disord. 2015 Feb 26;15:15. doi: 10.1186/s12872-015-0003-7. PMID: 25887327; PMCID: PMC4359588.

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CardioNerds (Dr. Josh Saef and Dr. Sumeet Vaikunth) join Dr. Sheng Fu, Dr. Payton Kendsersky, and Dr. Aniqa Shahrier from the Medical University of South Carolina for some off-shore fishing. They discuss the following featuring a patient with D-TGA and Eisenmenger’s syndrome treated with a Heartmate 3. Expert commentary was provided by Dr. Brian Houston. The episode audio was edited by student Dr. Adriana Mares.

A 39-year-old woman with a history of D-transposition of the great arteries (D-TGA) with prior atrial switch repair (Mustard) was admitted from the clinic with cardiogenic shock. She underwent right heart catheterization which demonstrated elevated biventricular filling pressures and low cardiac index. An intra-aortic balloon pump was placed, and the patient was evaluated for advanced therapies. A liver biopsy showed grade 3 fibrosis, which, in combination with her shock state, made her a high-risk candidate for isolated heart or combined heart-liver transplantation. After a multi-disciplinary discussion, the patient underwent a Heartmate III left ventricular assist device (LVAD) implant in her systemic right ventricle. Although she did well post-operatively, she was admitted after a month with recurrent cardiogenic shock, with imaging showing her inflow cannula had become perpendicular to the septum. The patient and family eventually decided to pursue comfort measures, and the patient passed.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – D-TGA and Eisenmenger’s syndrome treated with a Heartmate 3Pearls – D-TGA and Eisenmenger’s syndrome treated with a Heartmate 3* Early diagnosis of cyanotic congenital heart disease is paramount for treatment and prevention of future complications. * Adult congenital heart disease requires a multi-disciplinary team for management in consultation with an adult congenital cardiology specialist. * Eisenmenger syndrome is related to multiple systemic complications and has a high rate of mortality. * Advancement in PAH medical management can offer noninvasive treatment options for some patients. * Transthoracic echocardiography is the cornerstone for diagnosis. Other modalities (e.g. cardiac CT, cardiac MRI, invasive catheterization) can aid in diagnosis and management.

Pearls – D-TGA and Eisenmenger’s syndrome treated with a Heartmate 31. While advances in pediatric surgery have allowed many patients born with congenital heart disease to survive into adulthood, adult congenital heart disease (ACHD) patients are complex and prone to numerous adverse sequalae including arrhythmias, heart failure, valvular disease, and non-cardiac organ dysfunction. 2. Heart failure can be a challenging presentation in ACHD patients due to a longstanding history of clinical compensation. 3. Their unique and complex anatomy, as well as highly variable clinical presentation, present unique challenges when it comes to advanced heart failure options such as durable left ventricular assist devices (LVAD) or transplantation. 4. While durable LVAD implantation is possible in patients with systemic right ventricles, anatomic compatibility is paramount and poses ongoing challenges in their management. 5. Goals of care discussions should be had early, as options for treatment may be limited.

Show Notes – D-TGA and Eisenmenger’s syndrome treated with a Heartmate 3What are some common sequelae in ACHD patients?

ACHD patients are a heterogeneous population, but atrial tachycardias are extremely frequent in this patient population, often due to re-entrant pathways around surgical suture lines. These can often be treated with radiofrequency ablation while paying close attention to their challenging anatomy. Heart failure is also extremely common (up to 40% incidence) but has variable incidence dependent on the specific anatomy. Valvular heart disease, including infective endocarditis as well as non-cardiac organ dysfunction, are also important contributors to the overall prognosis of ACHD patients.

How does heart failure present in ACHD patients?

Heart failure presentations in ACHD patients tend to be subacute and insidious, as patients often have become accustomed to their symptoms. They are often unable to identify clear exercise limitations due to the slow, subacute nature of symptoms. However, acute presentations and shock can also be seen. Heart failure is the leading cause of death in ACHD patients.

What are the challenges for advanced therapies in the ACHD population?

First and foremost, risk stratification for these patients is often difficult due to often unreliable self-reporting of symptoms. Thus, early recognition becomes key, but even then, may not be enough. Several anatomic and physiological challenges remain. ACHD patients have often undergone multiple cardiac surgeries, increasing the surgical risk of redo sternotomies with severe adhesions. Due to the longstanding nature of their disease, ACHD patients often develop irreversible pulmonary hypertension (making transplant prohibitive) or end-organ dysfunction secondary to right heart failure (necessitating dual organ transplant).

Is durable LVAD a feasible option for patients with systemic right ventricles?

Isolated case reports demonstrate the feasibility of the off-label use of durable LVADs in systemic right ventricles. The complex anatomy of these patients has led to reports of alternative implant sites for the inflow cannula to minimize obstruction. Alternative surgical approaches, such as lateral thoracotomy, have also been described to try to avoid the adhesions that are often seen in these patients as a result of multiple prior cardiac surgeries. While the surgery is technically feasible, long-term data is not available, and this remains a “bail-out” therapy with current-generation LVAD designs.

What is the role of goals of care discussions in ACHD patients?

Advanced care planning is rarely discussed in routine clinic visits, and most providers wait until the condition has deteriorated significantly. Most ACHD patients want to discuss advanced care early before the disease progresses, but some do not, so it is important to ask about patient preferences. The majority of ACHD patients prefer to have advanced care discussions with their ACHD provider due to an already established and trusting relationship.

References 1. Gatzoulis MA, Webb GD, F. DPE, Hornung T, O’Donnell C. Transposition of the Great Arteries. In: Diagnosis and Management of Adult Congenital Heart Disease: Expert Consult – Online and Print. 3rd ed. Elsevier; 2018:513-527. 2. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(14). 3. Schwerzmann M, Goossens E, Gallego P, et al. Recommendations for advance care planning in adults with congenital heart disease: A position paper from the ESC Working Group of adult congenital heart disease, the Association of Cardiovascular Nursing and Allied Professions (ACNAP), the European Association for Palliative Care (EAPC), and the International Society for Adult Congenital Heart Disease (ISACHD). European Heart Journal. 2020;41(43):4200-4210. doi:10.1093/eurheartj/ehaa614 4. Khairy P, Clair M, Fernandes SM, et al. Cardiovascular outcomes after the arterial switch operation for D-transposition of the great arteries. Circulation. Jan 22 2013;127(3):331-9. doi:10.1161/CIRCULATIONAHA.112.135046 5. Piran S, Veldtman G, Siu S, Webb GD, Liu PP. Heart failure and ventricular dysfunction in patients with single or systemic right ventricles. Circulation. Mar 12 2002;105(10):1189-94. doi:10.1161/hc1002.105182 6. Zandstra TE, Palmen M, Hazekamp MG, Meyns B, Beeres SLMA, Holman ER, Kiès P, Jongbloed MRM, Vliegen HW, Egorova AD, Schalij MJ, Tops LF. Ventricular assist device implantation in patients with a failing systemic right ventricle: a call to expand current practice. Neth Heart J. 2019 Dec;27(12):590-593. 7. Burchill LJ. Heart transplantation in adult congenital heart disease. Heart. 2016;102:1871–1877. doi: 10.1136/heartjnl-2015-309074.

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CardioNerds co-founder Dr. Dan Ambinder, series chair Dr. Giselle Suero Abreu, and episode FIT Lead Dr. Rachel Ohman discuss disparities in cardiooncology with Dr. Javier Gomez Valencia, the Director of Cardio-Oncology services at John H. Stronger Jr. Hospital of Cook County. Dr. Rachel Ohman drafted show notes. Audio editing by student doctor Shivani Reddy.

A disproportionate burden of both cancer and cardiovascular disease affects racial and ethnic minority groups as well as lower-income communities. Similar patterns of vulnerability exist among cancer survivors with cardiovascular disease, although further investigation in these subpopulations is needed. We discuss a comprehensive approach to the cardio-oncology patient, our current understanding of the social and structural determinants of disparities in cardio-oncology populations, and other contributions to inequity in the field. Given the growing population of cancer survivors and limited accessibility to cardio-oncology specialists, these topics are of critical importance to anyone caring for cancer patients who have or are at risk for cardiovascular disease.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – Disparities in CardioOncology1. Social and structural determinants of health are drivers of cardiovascular and cancer disparities. Existing data on cardiotoxicity outcomes suggests these determinants also contribute to disparities in cardio-oncology. 2. Assessing social and structural determinants of health should be a routine part of evaluating a patient with an active or prior history of cancer. 3. Customs, country of origin, and immigration status matter. Differential risk profiles among Hispanic/Latinx sub-populations require further investigation. 4. Black patients, particularly black women with breast cancer, have elevated morbidity and mortality from cardiotoxicity. Data suggest contributions from social determinants of health. 5. Representation in clinical trials must be diversified for applicability to our diverse patient populations. Concerted efforts should be made to recruit diverse clinical trial participants and help patients from diverse communities effectively participate in the research process, contributing to the advancement of science.

Show notes – Disparities in CardioOncologyHow do you approach the evaluation of a new patient in cardio-oncology? How do social and structural determinants of health impact treatment-associated cardiotoxicity?

• The evaluation of a new patient should include an assessment of a patient’s intrinsic risk factors, risks associated with cancer treatment, and consideration of cardioprotective therapeutic strategies
• Social and structural vulnerabilities should also be assessed routinely as a part of risk stratification. Providers should take stock of a patient’s demographic (e.g., race/ethnicity, gender), socioeconomic (e.g., occupation, insurance status, food security, housing security), environmental (e.g., transportation, proximity to health resources, neighborhood safety), and sociocultural (e.g., psychosocial stressors, discrimination, acculturation) determinants that are in turn modulated by larger systemic forces like structural racism.
• This comprehensive risk assessment can guide the strategies to mitigate cardiovascular risk before, during, and after cancer treatment.

What barriers to cardio-oncology care are unique to the Hispanic/Latinx population?

• The Hispanic/Latinx population now comprises 19% of the US population. A disproportionate fraction of the Hispanic/Latinx population is uninsured (about 20%).
• In addition to insurance barriers, some members of this population can face difficulties from language barriers and limited access to preventative care.
• Existing data suggest differential risk profiles for sub-populations of Hispanic/Latinx patients based on country of origin, customs, and immigration status. Further research is needed to investigate disparities among different sub-populations.

What disparities are faced by Black patients with cancer?

• Black patients have an elevated risk of morbidity and mortality from cancer and are more likely to develop cardiotoxicity than their White counterparts. Black patients with breast cancer who receive anthracycline or HER2-directed therapy have a two- to three-fold risk of cardiotoxicity when compared to their White counterparts.
• Black patients with HER2+ breast cancer treated with trastuzumab are more likely to develop LV dysfunction than White counterparts, even after controlling for age, disease state, and cardiovascular risk factors. This suggests a role for social determinants of health that have yet to be elucidated.

How can patients’ sexual orientation and gender identity influence disparities in cardio-oncology, particularly for LGBTQIA+ patients?

• Some of the barriers this population faces are related to social stigmatization as well as structural discrimination (e.g., lack of providers with appropriate expertise).
• Difficulties with accessing trusted providers can impair patients’ ability to have longitudinal care and optimal cardiotoxicity surveillance.

What other areas of cardio-oncology might contribute to ongoing outcomes disparities, and how should we approach those disparities?

• Underrepresentation of minority groups in clinical trials is an ongoing issue. It results in our extrapolating data from homogenous populations and applying it to more diverse populations not represented adequately.
• Clinical trial enrollment requires more diverse and inclusive recruitment and visibility. However, we also should help patients and communities feel included in the research process, particularly given historical examples of medical exploitation.
• The landscape of cardiology providers also requires diversification. A diverse workforce benefits patients as well as providers.
• Cardiologists and healthcare providers also need to engage in political advocacy to help advocate for underrepresented vulnerable groups to combat socioeconomic disparities and public health crises that create barriers to optimal care.

References – Disparities in CardioOncology1. Addison D, Branch M, Baik AH, et al. Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association. Circulation. 2023;148(3):297-308. doi:10.1161/CIR.0000000000001158. 2. Ahmad J, Muthyala A, Kumar A, Dani SS, Ganatra S. Disparities in Cardio-oncology: Effects On Outcomes and Opportunities for Improvement. Curr Cardiol Rep. 2022 Sep;24(9):1117-1127. doi: 10.1007/s11886-022-01732-2. Epub 2022 Jun 27. PMID: 35759170; PMCID: PMC9244335. 3. Branch B and Cosway D. Health Insurance Coverage by Race and Hispanic Origin: 2021. American Community Survey Briefs. 2022 Nov 22. https://www.census.gov/content/dam/Census/library/publications/2022/acs/acsbr-012.pdf. 4. Ohman RE, Yang EH, Abel ML. Inequity in Cardio-Oncology: Identifying Disparities in Cardiotoxicity and Links to Cardiac and Cancer Outcomes. J Am Heart Assoc. 2021 Dec 21;10(24):e023852. doi: 10.1161/JAHA.121.023852. Epub 2021 Dec 16. PMID: 34913366; PMCID: PMC9075267. 5. Sirufo MM, Magnanimi LM, Ginaldi L, De Martinis M. Overcoming LGBTQI+ Disparities in Cardio-Oncology: A Call to Action. JACC CardioOncol. 2023 Mar 7;5(2):267-270. doi: 10.1016/j.jaccao.2022.11.017. PMID: 37144105; PMCID: PMC10152199. 6. Suero-Abreu GA, Patel S, Duma N. Disparities in Cardio-Oncology Care in the Hispanic/Latinx Population. JCO Oncol Pract. 2022 May;18(5):404-409. doi: 10.1200/OP.22.00045. PMID: 35544659.

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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CardioNerds (Dr. Josh Saef, Dr. Agnes Koczo) join Dr. Iva Minga, Dr. Kifah Hussain, and Dr. Kevin Lee from the University of Chicago – NorthShore to discuss a case of unrepaired congenital heart disease that involves D-TGA complicated by Eisenmenger syndrome. The ECPR was provided by Dr. Michael Earing. Audio editing by Dr. Akiva Rosenzveig.

A 25-year-old woman with an unknown congenital heart disease that was diagnosed in infancy in Pakistan presents to the hospital for abdominal pain and weakness. She is found to be profoundly hypoxemic, and an echocardiogram revealed D-transposition of the great arteries (D-TGA) with a large VSD. As this was not repaired in childhood, she has unfortunately developed Eisenmenger syndrome with elevated pulmonary vascular resistance. She is stabilized and treated medically for her cyanotic heart disease. Unfortunately given the severity and late presentation of her disease, she has limited long-term options for care. CardioNerds discuss the diagnosis of D-TGA and Eisenmenger’s syndrome, as well as long-term management and complications associated with this entity.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

CardioNerds Case Reports Page
CardioNerds Episode Page
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Subscribe to The Heartbeat Newsletter!
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Case Media – Unrepaired Congenital Heart DiseasePearls – Unrepaired Congenital Heart Disease* Early diagnosis of cyanotic congenital heart disease is paramount for treatment and prevention of future complications. * Adult congenital heart disease requires a multi-disciplinary team for management in consultation with an adult congenital cardiology specialist. * Eisenmenger syndrome is related to multiple systemic complications and has a high rate of mortality. * Advancement in PAH medical management can offer noninvasive treatment options for some patients. * Transthoracic echocardiography is the cornerstone for diagnosis. Other modalities (e.g. cardiac CT, cardiac MRI, invasive catheterization) can aid in diagnosis and management.

Show Notes – Unrepaired Congenital Heart DiseaseCyanotic congenital heart disease is often diagnosed in infancy and timely treatment is paramount. As these diseases progress over time, pulmonary over-circulation often pulmonary hypertension (PH), elevated pulmonary vascular resistance, and Eisenmenger syndrome will develop, which preclude definitive treatment. For D-TGA, before PH develops, there are surgical options such as the arterial switch procedure that can treat the disease. Unfortunately, once Eisenmenger syndrome develops, there are multiple systemic complications including hyperviscosity, thrombosis, bleeding, kidney disease, iron deficiency, arrhythmias, etc. that can occur. Management requires a multi-disciplinary team including an adult congenital cardiology specialist, but mortality rates remain high, with median survival reduced by 20 years, worse with complex cardiac defects. Bosentan is a first line treatment for patients with Eisenmenger syndrome, with PDE-5 inhibitors as a second line either by themselves or in combination with bosentan. Data are currently limited for latest-generation PH treatments in Eisenmenger syndrome and further study is still underway.

References 1. Ferencz C. Transposition of the great vessels. Pathophysiologic considerations based upon a study of the lungs. Circulation. 1966 Feb;33(2):232-41. 2. Arvanitaki A, Gatzoulis MA, Opotowsky AR, Khairy P, Dimopoulos K, Diller GP, Giannakoulas G, Brida M, Griselli M, Grünig E, Montanaro C, Alexander PD, Ameduri R, Mulder BJM, D’Alto M. Eisenmenger Syndrome: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022 Mar 29;79(12):1183-1198. 3. Earing MG, Webb GD. Congenital heart disease and pregnancy: maternal and fetal risks. Clin Perinatol. 2005 Dec;32(4):913-9, viii-ix 4. Østergaard L, Valeur N, Ihlemann N, Bundgaard H, Gislason G, Torp-Pedersen C, Bruun NE, Søndergaard L, Køber L, Fosbøl EL. Incidence of infective endocarditis among patients considered at high risk. Eur Heart J. 2018 Feb 14;39(7):623-629 5. Opotowsky AR, Moko LE, Ginns J, Rosenbaum M, Greutmann M, Aboulhosn J, Hageman A, Kim Y, Deng LX, Grewal J, Zaidi AN, Almansoori G, Oechslin E, Earing M, Landzberg MJ, Singh MN, Wu F, Vaidya A. Pheochromocytoma and paraganglioma in cyanotic congenital heart disease. J Clin Endocrinol Metab. 2015 Apr;100(4):1325-34. 6. Jaïs X, D’Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, Hoeper MM, Lang IM, Mayer E, Pepke-Zaba J, Perchenet L, Morganti A, Simonneau G, Rubin LJ; Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008 Dec 16;52(25):2127-34. 7. Gatzoulis MA, Landzberg M, Beghetti M, Berger RM, Efficace M, Gesang S, He J, Papadakis K, Pulido T, Galiè N; MAESTRO Study Investigators. Evaluation of Macitentan in Patients With Eisenmenger Syndrome. Circulation. 2019 Jan 2;139(1):51-63. 8. McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, Palazzini M, Park MH, Tapson VF, Sitbon O. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D73-81. 9. Stoica SC, McNeil KD, Perreas K, Sharples LD, Satchithananda DK, Tsui SS, Large SR, Wallwork J. Heart-lung transplantation for Eisenmenger syndrome: early and long-term results. Ann Thorac Surg. 2001 Dec;72(6):1887-91.

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CardioNerds (Drs. Amit Goyal, Jason Feinman, and Tiffany Dong) discuss Beyond the Boards: Diseases of the Peripheral Arteries with Dr. Amy Pollak. We review common presentations of peripheral vascular disease, ranging from aortic disease to the more distal vessels in an engaging case-based discussion. Dr. Pollack talks us through these cases, including the diagnosis and management of peripheral vascular diseases. Show notes were drafted by Dr. Matt Delfiner and episode audio was edited by student doctor Tina Reddy.

The CardioNerds Beyond the Boards Series was inspired by the Mayo Clinic Cardiovascular Board Review Course and designed in collaboration with the course directors Dr. Amy Pollak, Dr. Jeffrey Geske, and Dr. Michael Cullen.

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Pearls and Quotes – Disease of the Peripheral Arteries 1. Risk factors for abdominal aortic aneurysm include traditional atherosclerotic risk factors such as age, hypertension, hyperlipidemia, and tobacco use. 2. Screening for AAA should be for men over the age of 65 years with a history of tobacco use. If present, medical management includes blood pressure and lipid lowering therapies to decrease the risk of expansion. Decision for surgical intervention relies on size and rate of growth of AAA, with clear indications if it grows> 10 mm in a year or diameter of 5.5 cm in men and 5.0 cm in women. 3. When diagnosis of PAD is not straightforward (presence of symptoms but ABI is normal), an exercise ankle-brachial index (ABI) test can be useful. An exercise-induced decrease in ABI by 20% or in ankle pressure by 30 mmHg is consistent with PAD. 4. For PAD, treatment with low dose rivaroxaban and aspirin yields lower event rates than with antiplatelet therapy alone. This in combination with lifestyle therapies (diet + exercise) and risk factor management (hypertension and hyperlipidemia) are the cornerstones of therapy. Revascularization is indicated for continued PAD symptoms despite conservative therapy. 5. Acute limb ischemia is an “acute leg attack” and is a life-threatening emergency. Common symptoms include pain, pallor, pulselesess, parasthesias, cold temperature (poikilothermia), and paralysis. Restoration of blood flow is paramount, and emergent or urgent revascularization is the first line therapy for those with symptoms < 2 weeks.

Notes – Disease of the Peripheral Arteries Learning Objectives:

1. Describe screening and therapeutic strategy for AAA management.
2. Understand the risk factors and diagnosis of peripheral arterial disease.
3. Compare different management approaches for PAD.
4. Be able to recognize acute limb ischemia.
5. Describe the overall treatment strategy for acute limb ischemia.

Abdominal Aortic Aneurysms

Abdominal aortic aneurysms are a source of high morbidity and mortality. The US Preventative Services Task Force recommends one time screening ultrasound for AAA in men older than 65 years of age with a tobacco use history. Risk factors include age, hypertension, hyperlipidemia, and tobacco use. Patients with AAA between 3-3.9 mm should be monitored every 2-3 years. Sizes 4-5 cm should be re-imaged every 6-12 months. Additional screening can be done for individuals < 65 years who have a first degree relative with AAA.

Women are more likely to have aortic dissection at smaller diameters than men, which is why intervention (open vs endovascular repair) is recommended at 5 cm diameter for women versus at 5.5 cm for men. Additionally, repair is also warranted if a AAA grows more than 5 mm in 6 months or 10 mm in one year.

Risk factor management is key with AAA, including blood pressure, glucose, and lipid targeting. The presence of an AAA should be treated as secondary ASCVD prevention like coronary arterial disease, since AAA is an atherosclerotic disease equivalent. Tobacco cessation is of the utmost importance here.

Regarding strategy for repair: if the patient is not a surgical candidate, then endovascular repair is a reasonable option. If they are a surgical candidate, then the location of the aneurysm comes into play. Infrarenal or juxtarenal disease are more likely to require open repair.

Peripheral Arterial Disease

When a patient presents with claudication, in addition to thorough history and physical exam, checking for ABIs is important. Risk factors include known coronary disease, hypertension, hyperlipidemia, and diabetes. Women often report cramping in their calves/legs rather than outright pain.

ABI < 0.9 are consistent with PAD, with > 1.3 consistent with calcified and non-compressible vessels. Toe brachial index (TBI) cutoff is 0.7. If there is strong clinical suspicion but normal ABI, then performing the test after a period of exercise (calf raises, treadmill) can be clinically useful. An exercise induced decrease in ankle pressure by 30 mm or change in ABI by 20% is consistent with PAD.

Therapy for PAD includes supervised exercise training, lifestyle changes (e.g., tobacco cessation) and risk factor modification (blood pressure/lipids/glucose). Additionally, low dose rivaroxaban (2.5 mg twice daily) plus aspirin has been shown to decrease events compared to aspirin alone.

If there are continued symptoms despite the above therapy, then invasive management can be considered. This includes percutaneous or surgical revascularization. This would be proceeded with CTA imaging for further guidance. Invasive angiography is reasonable for someone with a higher likelihood of a single lesion amenable to percutaneous repair. Discrete and singular lesions are usually repaired percutaneously while more diffuse or multivessel disease, then surgical management may be indicated.

Acute Limb Ischemia

ALI can present with the 6 Ps: pain, pallor, pulselessness, parasthesias, poikilothermia, and paralysis. Limbs may (rarely) remain viable, with signs being a clear Doppler-able pulse without sensory or muscle loss. Otherwise, a limb is salvageable if there is a faint arterial Doppler signal. If there is muscle weakness, then the limb is considered threatened. If an arterial Doppler signal is completely lost, then the limb is considered non-viable.

ALI is an “acute leg attack.” The initial therapy is systemic anticoagulation with unfractionated heparin. If symptoms have been present for less than two weeks, then endovascular therapy with either thrombectomy or catheter-directed lysis are indicated. Major contraindications to lytic therapy include recent surgery, any history of intracranial bleeding or neoplasm, or if they are otherwise at a high bleeding risk. Non-viable limbs may better be served with amputation rather than revascularization.

References – Disease of the Peripheral Arteries 1. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-1330. doi:10.1056/NEJMoa1709118

https://www.nejm.org/doi/full/10.1056/NEJMoa1709118

1. Criqui MH, Matsushita K, Aboyans V, et al. Lower Extremity Peripheral Artery Disease: Contemporary Epidemiology, Management Gaps, and Future Directions: A Scientific Statement From the American Heart Association Circulation. 2021;144(9):e171-e191. doi:10.1161/CIR.0000000000001005

https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000001005?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003𝔯_id=ori%3Arid%3Acrossref.org

1. Lanzi S, Belch J, Brodmann M, et al. Supervised exercise training in patients with lower extremity peripheral artery disease. Vasa. 2022;51(5):267-274. doi:10.1024/0301-1526/a001024

https://econtent.hogrefe.com/doi/full/10.1024/0301-1526/a001024

1. Sabouret P, Cacoub P, Dallongeville J, et al. REACH: international prospective observational registry in patients at risk of atherothrombotic events. Results for the French arm at baseline and one year. Arch Cardiovasc Dis. 2008;101(2):81-88. doi:10.1016/s1875-2136(08)70263-8

https://www.sciencedirect.com/science/article/pii/S1875213608702638?via%3Dihub

1. Zucker EJ, Misono AS, Prabhakar AM. Abdominal Aortic Aneurysm Screening Practices: Impact of the 2014 U.S. Preventive Services Task Force Recommendations. J Am Coll Radiol. 2017;14(7):868-874. doi:10.1016/j.jacr.2017.02.020

https://www.jacr.org/article/S1546-1440(17)30200-4/fulltext

1. Hensley SE, Upchurch GR Jr. Repair of Abdominal Aortic Aneurysms: JACC Focus Seminar, Part 1. J Am Coll Cardiol. 2022;80(8):821-831. doi:10.1016/j.jacc.2022.04.066

https://www.jacc.org/doi/abs/10.1016/j.jacc.2022.04.066

1. Shishehbor MH, White CJ, Gray BH, et al. Critical Limb Ischemia: An Expert Statement. J Am Coll Cardiol. 2016;68(18):2002-2015. doi:10.1016/j.jacc.2016.04.071

https://www.jacc.org/doi/full/10.1016/j.jacc.2016.04.071

1. Kinlay S. Management of Critical Limb Ischemia. Circ Cardiovasc Interv. 2016;9(2):e001946. doi:10.1161/CIRCINTERVENTIONS.115.001946

https://www.ahajournals.org/doi/full/10.1161/CIRCINTERVENTIONS.115.001946

1. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2017 Mar 21;135(12 ):e791-e792]. Circulation. 2017;135(12):e726-e779. doi:10.1161/CIR.0000000000000471

https://www.ahajournals.org/doi/10.1161/CIR.0000000000000471?url_ver=Z39.88-2003𝔯_id=ori:rid:crossref.org𝔯_dat=cr_pub%20%200pubmed

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CardioNerds (Dr. Daniel Ambinder, Dr. Giselle Suero Abreu, Dr. Kahtan Fadah, and Dr. Colin Blumenthal) discuss arrhythmias in CardioOncology with Dr. Michael Fradley.

In this episode, Dr. Michael Fradley joins us in the CardioNerds CardioOncology clinic where he uses his unique dual training in cardio-oncology and electrophysiology to walk us through the complex interplay and management of these disorders. We discuss the incidence and pathophysiology of these arrhythmias, including the link with various cancer treatments, screening and detection, and complex management including rate vs rhythm control in atrial fibrillation, need for anticoagulation, effects on the QTc and so much more. Given the unique challenges with this population we also delve into how this affects their oncology care and how to approach changes to their cancer treatment.

Show notes were drafted by Dr. Kahtan Fadah and episode audio was edited by student Dr. Tina Reddy.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls and Quotes – Arrhythmias in CardioOncology1. Arrhythmias are common in cancer patients due to shared risk factors and bi-directional risk between cardiac and oncologic disorders. Many cancer therapeutics can be directly arrhythmogenic or lead to cardiotoxicities that pre-dispose to arrhythmias. 2. Though incidence of arrhythmia can be significant increased with some cancer therapeutics (e.g. ibrutinib), there is not specific data to support proactive ambulatory monitoring for arrhythmia without evidence of clear symptoms. 3. Atrial fibrillation is the most common arrhythmia in cancer patients and management of atrial fibrillation, as well as other tachyarrhythmias, is unchanged from management in non-cancer patients. General principles of when to start anticoagulation or rate vs rhythm control are not significantly different (e.g. still use CHA2DS2-VAsC, monitor for symptoms etc), but providers should be more mindful of drug-drug interactions with cancer therapeutics. 4. Cancer therapeutics as well as common medications used to treat side effects or complications (e.g. antiemetics, antibiotics, etc) can prolong the QT interval and increase risk of Torsades de pointes (TdP). The QTc should be monitored with an ECG for patients on these medications. If a patient does develop a serious arrhythmia like TdP, management is similar to that in non-cancer patients. 5. The goal of arrhythmia management in cardio-oncology is to prevent cardiovascular disease from becoming a barrier to appropriate cancer therapy. Though cancer therapeutics should be temporarily or permanently discontinued in potentially fatal events (e.g TdP from QTc prolonging meds), the overall goal is to manage the arrhythmias appropriately to allow cancer therapeutics to be continued or restarted.

Show notes – Arrhythmias in CardioOncologyWhat is the prevalence of arrhythmias in patients with cancer?

Arrhythmias are common in patients with cancer due to a multitude of factors. Atrial fibrillation is the most common arrhythmia in this population and occurs in approximately 5% of patients with cancer. The driving forces are multifactorial and include the direct arrhythmogenic effects of cancer therapeutics and cardiotoxicities of cancer therapeutics that make arrhythmogenesis more likely. Additionally, there is a bi-directional link between cancer and cardiac disorders. For example, not only is atrial fibrillation more common in patients with cancer, but there is also a higher incidence of cancer in patients with atrial fibrillation, likely due to shared risk factors. Risk factors in patients with cancer that make arrhythmias more likely include advanced age, metabolic disturbances, electrolyte abnormalities, and elevated levels of inflammation and catecholamines.

(How) Do cancer therapeutics increase the risk of arrhythmias?

Many cancer therapies are either directly or indirectly arrhythmogenic. Though therapies like the BTK inhibitor ibrutinib have a direct link to an increase incidence of atrial fibrillation, other medications like immune checkpoint inhibitors can cause myocarditis, reduce cardiac function, and predispose to arrhythmias. The following table includes broad categories of cancer therapeutics that are linked to arrhythmia:

What is the appropriate arrhythmia monitoring strategy for patients receiving cancer therapy?

Though there is a clear increased risk of arrhythmia in many patients with cancer receiving specific therapeutics, there is not specific data to support proactive monitoring in these patients. One meta-analysis showed that when compared to alternative regimens, ibrutinib increased the risk of incident AF compared to alternative therapies (RR 3.9, 95% CI 2.0-7.5, P <0.0001), with overall AF incidence of 3.3 per 100 person-years compared to 0.84 per 100 person-years in the ibrutinib and non-ibrutinib groups, respectively. Though proactive monitoring might lead to more or earlier detection of AF in this population, there is a lack of data to support improved outcomes with monitoring asymptomatic patients. Additionally, the clinical relevance of subclinical and/or short episodes of atrial fibrillation remains uncertain. Because of this, there are no current recommendations for broad proactive monitoring, though monitoring should be considered in patients with signs or symptoms that could be consistent with arrhythmia.

What is the management of arrhythmias in patients with cancer?

Management of arrhythmias in patients with cancer is similar to general management in non-cancer patients. For AF, a rhythm control strategy is preferred for patients with paroxysmal AF and in patients who are symptomatic. For other patients who are asymptomatic, a rate control strategy is reasonable. One notable exception is when control of the AF becomes a barrier to the oncology team. In these situations, more aggressive rhythm control is preferred to facility oncologic care. Anticoagulation is also approached in a similar way to non-cancer patients. Patients with a CHA2DS2-VAsC score >2 for men and >3 for women warrant anticoagulation. Many patients with cancer are anemic, thrombocytopenic, or prone to bleeding, which should also be taken into account when prescribing anticoagulation. Left atrial appendage closure may be a consideration for select patients.

As for medications that cause QT prolongation, malignant arrhythmias are quite rare and mostly occur in patients with QTc > 500 ms. This can be multifactorial as many patients with cancer may have episodic metabolic or electrolyte abnormalities in addition to cancer therapeutics or symptom/complication management medications (e.g. antiemetics, antibiotics, etc) which can prolong the QTc or lower the threshold for arrhythmogenesis. Life threatening arrhythmias like Torsades de pointes (TdP) are treated similar to that in non-cancer patients, which can include magnesium, increasing HR with isoproterenol or transvenous pacing, anti-arrhythmic drugs, or cardioversion in addition to addressing the underlying cause.

Balancing arrhythmia risk with cancer therapeutics

An important goal in cardio-oncology is to prevent cardiovascular disease from becoming a barrier for a patient to receive appropriate cancer therapy. The goal is to facilitate the treatment plan that the oncologist thinks is optimal for their cancer, not to protect the heart at the expense of appropriate oncologic care. This is a difficult balancing act and, in the case of serious or potentially fatal events (e.g. Torsades from QTc prolonging meds, vasospasm with ischemia from 5FU, severe myocarditis from immune checkpoint inhibitors etc.), it is often necessary to discontinue the cancer therapeutic temporarily or permanently. Ideally, the arrhythmia should be treated and controlled allowing the patient to continue therapy while minimizing the cardiac symptoms and side effects.

References – Arrhythmias in CardioOncology1. Leiva O, AbdelHameid D, Connors JM, Cannon CP, Bhatt DL. Common Pathophysiology in Cancer, Atrial Fibrillation, Atherosclerosis, and Thrombosis: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2021;3(5):619-634. doi:10.1016/j.jaccao.2021.08.011 2. Fradley MG, Beckie TM, Brown SA, et al. Recognition, Prevention, and Management of Arrhythmias and Autonomic Disorders in Cardio-Oncology: A Scientific Statement From the American Heart Association. Circulation. 2021;144(3):e41-e55. doi:10.1161/CIR.0000000000000986 3. Leong DP, Caron F, Hillis C, et al. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood. 2016;128(1):138-140. doi:10.1182/blood-2016-05-712828

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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CardioNerds join Dr. Tony Li Yi Wei, Dr. Rodney Soh Yu Hang, and Dr. Zan Ng Zhe Yan from the National University Heart Centre Singapore for a cocktail drink on the top of marina bay sands. They discuss the following case featuring a young woman with recurrent ACS ultimately found to have Takayasu Arteritis. The ECPR for this episode is provided by Dr. Teng Gim Gee and Professor Tan Huay Cheem. Episode audio was edited by student Dr. Shivani Reddy.

A 37-year-old woman presents with chest pain. She has a background history of Hashimoto thyroiditis, gestational diabetes, and anemia of chronic disease and possible iron deficiency. Her significant medical history includes ischemic heart disease with prior coronary angiogram showing triple vessel coronary artery disease for which she underwent coronary artery bypass graft surgery (CABG) with LIMA-LAD, SVG-OM, SVG-RCA. After CABG, she had recurrent admissions in the subsequent year with acute coronary syndromes where she underwent percutaneous coronary intervention (PCI) to SVG-OM, RI, proximal LAD, and distal LAD. She was a non-smoker and had been compliant with her medications. For her current presentation, she underwent myocardial perfusion imaging which showed a large sized area of inducible ischemia in the LCx territory. Repeat coronary evaluation showed occluded SVG-OM, occluded LIMA-LAD where she underwent PCI. Clinically, she was noted to have weak brachial and radial pulses on the left side with systolic blood pressure difference between both arms. CT Thoracic Angiogram demonstrated concern for underlying large vessel vasculitis such as Takayasu arteritis. ESR was elevated at 34. Rheumatology was consulted and she was diagnosed with Takayasu arteritis and started on prednisolone and azathioprine. Given her young age, absence of traditional atherosclerotic risk factors, and progressive coronary disease, Takayasu arteritis was deemed the underlying etiology of her coronary disease.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.” – Sir William Osler. CardioNerds thank the patients and their loved ones whose stories teach us the Art of Medicine and support our Mission to Democratize Cardiovascular Medicine.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Case Media – Recurrent ACSPearls – Recurrent ACS1. Approach to accelerated CAD and/or CAD in the young: Causes of MI in young patients can be divided into four groups, although a considerable overlap exists between all groups. (1) atheromatous CAD, (2) non-atheromatous process such as spontaneous coronary artery dissection, vasculitides such as Takayasu disease, (3) hypercoagulable states leading to recurrent arterial and venous thrombosis and/or thromboembolism, and (4) recreational drug use. 2. Clinical Presentation of Takayasu and prevalence of cardiac involvement: Takayasu’s arteritis is classified as a large-vessel vasculitis because it primarily affects the aorta and its primary branches. It has a worldwide distribution; however, the greatest prevalence is seen in Asia. Women are affected in 80 to 90 percent of cases, with an age of onset that is usually between 10 and 40 years. 3. Management of Takayasu arteritis: As for systemic anti-inflammatory therapy, the mainstay of treatment would be systemic glucocorticoids guided by the care of a rheumatologist. A steroid sparing agent may be given in conjunction for long term suppressive therapy to achieve longer-term disease control. The choice of additional agents depends on several factors including considerations regarding comorbidities, a patient’s plans for conceiving a child, cost of treatments, and availability of specific agents. Options include methotrexate, azathioprine as well as mycophenolate. There are also growing studies into anti-TNF-alpha agents such as etanercept or infliximab.

Show Notes – Recurrent ACSFocusing on young patients presenting with myocardial infarction (MI), the definition is often arbitrary, with most studies using an age cut off of around 40-45 years. As we know, the risk factor profile of the younger population is different with lower prevalence of traditional cardiovascular risk factors, and women of this age group are generally premenopausal.

Causes of MI among such patients can be divided into four groups, although a considerable overlap exists between all groups.

The first etiology is that of atheromatous CAD, which is linked to conventional risk factors in older patients that we are familiar with. This includes smoking, lipid abnormalities including familial hyperlipidemia, insulin resistance, hypertension, and obesity. Other more novel risk factors include hyperhomocysteinemia and elevated lipoprotein (a).

Secondly, there are non-atheromatous coronary pathologies. These include conditions such as spontaneous coronary artery dissection especially prevalent in peripartum females. Other considerations include vasculitides with coronary artery involvement such as Kawasaki disease with coronary artery aneurysms as well as Takayasu disease, coronary vasospasm, and microvascular dysfunction

The third etiology is that of hypercoagulable states leading to recurrent arterial and venous thrombosis. Examples include antiphospholipid syndrome and Factor V Leiden mutations. Acquired hypercoagulable states like nephrotic syndrome, thrombotic thrombocytopenic purpura, solid organ malignancy, and myeloproliferative disorders have possible associations with arterial disease in the form of MI (REF). Embolic phenomenon may also cause coronary obstruction (from thrombi, infective vegetations, cardiac masses, etc).

Finally, recreational drug use must be considered, although it is the least common etiology in Singapore because of strict laws prohibiting it. Cocaine use is associated with MI by inducing coronary vasospasm as well as hypercoagulability, and long term cocaine use also leads to accelerated atherosclerosis as well as nonischemic cardiomyopathy.

Takayasu’s arteritis is classified as a large-vessel vasculitis because it primarily affects the aorta and its primary branches. It has a worldwide distribution; however the greatest prevalence is seen in Asia. Women are affected in 80-90% of cases, with an age of onset that is usually between 10 and 40 years.

The onset of symptoms in Takayasu arteritis (TAK) tends to be subacute and diagnosis is often only made at the point where there is significant vascular disease leading to symptoms due to resultant ischemia in the affected vascular territory.

Physical examination is what led to the clinical suspicion of a large vessel vasculitis in our patient.

Measurement of BP should be done in all four extremities to evaluate for arterial stenoses. Many patients with TAK will have partial or complete occlusion of one or both subclavian, axillary, or brachial arteries, or the brachiocephalic artery, leading to low-pressure readings in the ipsilateral arm. Similarly, femoral or more distal arterial stenoses will lower leg blood pressures and stenosis of the aorta may lead to bilateral low blood pressure readings.

Bruits may be heard over the bilateral carotid, subclavian, axillary, renal, and femoral arteries, as well as the abdominal aorta. Cardiac auscultation may reveal signs of aortic valvular disease, pulmonary hypertension, or heart failure. Pulses should be felt for and evaluated at bilateral temporal, carotid, brachial, femoral, and dorsal pedal arteries, and any arterial tenderness should also be noted. Signs of limb ischemia should be sought.

In most cases, a clinical diagnosis of Takayasu arteritis can be made in a patient with both suggestive clinical findings (eg, constitutional symptoms, hypertension, diminished or absent pulses, and/or arterial bruits) and imaging showing narrowing of the aorta and/or its primary branches.

There are no specific diagnostic laboratory tests for TAK. As a disease with systemic inflammatory process, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated but normal values do not exclude Takayasu arteritis.

Patients with suspected TAK should undergo imaging of the arterial tree by MR or CT angiogram to evaluate the arterial lumen, looking out for smoothly tapered luminal narrowing or occlusion that is sometimes accompanied by thickening of the wall of the vessel. 18 F-FDG – Positron emission tomography (PET), often in combination with CT (PET-CT) or MR (PET-MR) is an increasingly utilized test to evaluate for possible large-vessel vasculitis. The finding of “hot” segments (ie, those with increased standardized uptake values of fludeoxyglucose-F18) in the right clinical setting may be suggestive of large-vessel vasculitis. There is increasing use of PET to aid in the diagnosis of TAK.

Although definitive, getting a histological diagnosis via biopsy of the large arteries is impractical and rarely done. However, occasionally arterial tissue may become available after a revascularization procedure or aneurysm repair

American College of Rheumatology classification criteria were developed to help distinguish one form of vasculitis from another, however they are limited in terms of their use in clinical practice. The criteria are

• Age at disease onset ≤ 40 years
• Claudication of the extremities
• Decreased pulsation of one or both brachial arteries
• Difference of at least 10 mmHg in systolic blood pressure between the arms
• Bruit over one or both subclavian arteries or the abdominal aorta
• Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or other causes

Patients are said to have TAK if at least three of the six criteria are present. Although these criteria have been widely used by clinical researchers and clinicians to help diagnose patients, accurate diagnostic criteria have yet to be developed.

Management is targeted at tackling the inflammation in the various vascular territories and also endovascular or surgical procedures for critical areas of stenosis that have contributed to irreversible ischemia or aneurysm.

For example, as in this case, significant coronary artery disease leading to myocardial infarctions were addressed with surgical and/or percutaneous revascularization as per usual care for atherosclerotic CAD. Significant peripheral arterial disease can be treated in a similar fashion.

As for systemic anti-inflammatory therapy, the mainstay of treatment would be systemic glucocorticoids guided by the care of a rheumatologist.

• The initial dose of steroids would depend on the nature and severity of disease activity. The typical initial dose for prednisone is 1 mg/kg per day, up to a maximum daily dose of 60 to 80 mg, and should be continued for two to four weeks, at which time tapering of the dose should begin if patients demonstrate clinical improvement.
• In patients with more critical diseases such as aortitis or carotidynia, pulsed intravenous glucocorticoids can be considered as well.
• However, given the chronic, relapsing nature of the disease and the imperative to avoid glucocorticoid-related toxicities, patients are often prescribed a steroid sparing agent in conjunction for long term suppressive therapy to achieve longer-term disease control.
• No specific agent has been well-proven to be effective in trials, and it is common that patients are prescribed a series of medications, sometimes in combination.
• The choice of an additional agent depends on several factors including considerations regarding comorbidities, a patient’s plans for conceiving a child, cost of treatments, and availability of specific agents. Options include methotrexate, azathioprine as well as mycophenolate. There are also growing studies looking into anti-TNF-alpha agents such as etanercept or infliximab.
• Again, a rheumatologist with experience in treating Takayasu arteritis should be involved in multidisciplinary care.

In terms of long-term follow-up, monitoring disease activity and response to therapy may be challenging for clinicians, given the absence of specific laboratory tests or validated assessment criteria for disease activity.

• Expert consensus is that we can monitor for a decrease and eventual disappearance of constitutional symptoms, arthralgias, and claudication symptoms, accompanied by a decrease in acute phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels.
• CT or MR angiography can also be repeated at regular intervals to evaluate for progressive disease.
• Given the regularity at which repeat imaging may be needed, serial MR angiography is preferred whenever possible to avoid the additive exposure to radiation and iodinated contrast dye. References 1. Joseph G, Goel R, Thomson VS, Joseph E, Danda D. Takayasu Arteritis: JACC Focus Seminar 3/4 [published online ahead of print, 2022 Dec 13]. J Am Coll Cardiol. 2022;S0735-1097(22)07305-3. doi:10.1016/j.jacc.2022.09.051
• Soulaidopoulos S, Madenidou AV, Daoussis D, et al. Cardiovascular Disease in the Systemic Vasculitides. Curr Vasc Pharmacol. 2020;18(5):463-472. doi:10.2174/1570161118666200130093432
• Kim H, Barra L. Ischemic complications in Takayasu’s arteritis: A meta-analysis. Semin Arthritis Rheum. 2018;47(6):900-906. doi:10.1016/j.semarthrit.2017.11.001
• Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Rheumatol. 2021;73(8):1349-1365. doi:10.1002/art.41774
• Esatoglu SN, Hatemi G. Takayasu arteritis. Curr Opin Rheumatol. 2022;34(1):18-24. doi:10.1097/BOR.0000000000000852

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The following question refers to Section 4.9 of the 2021 ESC CV Prevention Guidelines. The question is asked by Dr. Christian Faaborg-Andersen, answered first by UCSD fellow Dr. Patrick Azcarate, and then by expert faculty Dr. Melissa Tracy.

Dr. Tracy is a preventive cardiologist, former Director of the Echocardiography Lab, Director of Cardiac Rehabilitation, and solid organ transplant cardiologist at Rush University.

The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #35

| In patients with a low risk of cardiovascular disease, which of the following is true? | | A | Aspirin does not affect the risk of ischemic stroke | | B | Aspirin increases the risk of fatal bleeding. | | C | Aspirin reduces the risk of non-fatal MI. | | D | Aspirin reduces cardiovascular mortality |

Answer #35

| Explanation | In 2019, an updated meta-analysis of aspirin for primary prevention of cardiovascular events found that patients with a low risk of CVD taking aspirin did not have a reduction in all-cause or cardiovascular mortality. There was a lower risk of non-fatal MI (RR 0.82) and ischemic stroke (RR 0.87). However, aspirin was also associated with a higher risk of major bleeding (RR 1.50), intracranial bleeding (RR 1.32), and major GI bleeding (RR 1.52). There was no difference in the risk of fatal bleeding (RR 1.09).Accordingly, the ESC does not recommend antiplatelet therapy in individuals with low/moderate CV risk due to the increased risk of major bleeding (Class III, LOE A).Although aspirin should not be given routinely to patients without established ASCVD, we cannot exclude that in some patients at high or very high CVD risk, the benefits may outweigh the risks. | | Main Takeaway | In patients with low/moderate risk of CVD, aspirin for primary prevention is not recommended due to the higher risk of bleeding. For those at higher risk of CVD, low-dose aspirin may be considered for prevention in the absence of contraindications. | | Guideline Loc. | Section 4.9.1, Page 3291 |

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The following question refers to Section 8.5 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by Western Michigan University medical student & CardioNerds Intern Shivani Reddy, answered first by University of Southern California cardiology fellow and CardioNerds FIT Trialist Dr. Michael Francke, and then by expert faculty Dr. Shashank Sinha.

Dr. Sinha is an Assistant Professor of Medical Education at the University of Virginia School of Medicine and an advanced heart failure, MCS, and transplant cardiologist at Inova Fairfax Medical Campus. He currently serves as both the Director of the Cardiac Intensive Care Unit and Cardiovascular Critical Care Research Program at Inova Fairfax. He is also a Steering Committee member for the multicenter Cardiogenic Shock Working Group and Critical Care Cardiology Trials Network and an Associate Editor for the Journal of Cardiac Failure, the official Journal of the Heart Failure Society of America.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #30

| Ms. V. Tea is a 55-year-old woman with a history of cardiac sarcoidosis, heart failure with mildly reduced ejection fraction (HFmrEF – EF 40%), and ventricular tachycardia with CRT-D who presents with recurrent VT. She has undergone several attempts at catheter ablation of VT in the past and previously had been trialed on amiodarone which was discontinued due to hepatotoxicity. She now continues to have episodic VT requiring anti-tachycardia pacing and ICD shocks despite medical therapy with mexiletine, metoprolol, and sotalol. Her most recent PET scan showed no active areas of inflammation. Currently, her vital signs are stable, and labs are unremarkable. What is the best next step for this patient? | | A | Evaluation for heart transplant | | B | Evaluation for LVAD | | C | Dobutamine | | D | Prednisone | | E | None of the above |

Answer #30

| Explanation | The correct answer is A – evaluation for heart transplant.For selected patients with advanced heart failure despite GDMT, cardiac transplantation is indicated to improve survival and quality of life (Class 1, LOE C-LD). Heart transplantation, in this context, provides intermediate economic value.Clinical indicators include refractory or recurrent ventricular arrhythmias with frequent ICD shocks. Patient selection for heart transplant includes assessment of comorbidities, goals of care, and various other factors. The United Network of Organ Sharing Heart Transplant Allocation Policy was revised in 2018 with a 6-tiered system to better prioritize unstable patients and minimize waitlist mortality. VT puts the patient as a Status 2 on the transplant list. There was a contemporary analysis of patients with end-stage cardiomyopathy due to cardiac sarcoidosis, published in Journal of Cardiac Failure, in 2018 that demonstrated similar 1-year and 5-year survival after heart transplant between patients with and without cardiac sarcoidosis.Choice B (evaluation for LVAD) is incorrect. While bridge to transplant with LVAD is definitely a potential next step in patients with cardiac sarcoidosis, it is not recommended in patients presenting primarily with refractory ventricular arrhythmias due to granuloma-induced scarring. In this situation, patients benefit from direct heart transplant rather than bridge to transplant LVAD approach. The same study, described before in the Journal of Cardiac Failure, also showed similar 1-year and 5-year survival after bridge-to-transplant mechanical circulatory support between patients with and without cardiac sarcoidosis. Since cardiac sarcoidosis is not just limited to the left ventricle, patients being considered for LVAD need hemodynamic assessment to determine the risk of post-LVAD RV failure.Choice C (dobutamine) is incorrect. The patient is currently not decompensated in terms of contractility nor is showing signs of cardiogenic shock. Further, dobutamine may worsen arrhythmia burden.Choice D (prednisone) is incorrect as there is no sign of active inflammation on the PET scan. The recurrent ventricular arrhythmias are being driven by granuloma-induced scar. | | Main Takeaway | Cardiac transplantation has a Class 1 (LOE C-LD) recommendation for eligible patients with advanced HF despite GDMT to improve survival and quality of life. Specifically, direct heart transplantation is the best next step in patients with cardiac sarcoidosis and refractory ventricular arrhythmias rather than a bridge-to-transplant approach. | | Guideline Loc. | Section 8.5 |

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CardioNerds (Amit Goyal and Daniel Ambider) ACHD series co-chair Dr. Daniel Clark (Vanderbilt University), cardiology FIT lead Dr. Stephanie Fuentes (Houston Methodist Hospital), and Dr. Frank Fish, a Pediatric Electrophysiologist and the Director of the Pediatric Electrophysiology (EP) Lab at Monroe Carrell Jr Children’s Hospital at Vanderbilt University. He is a board certified Adult Congenital Heart Disease (ACHD) physician and has a wealth of experience performing EP procedures in adults living with congenital heart disease. Audio editing was performed by student Dr. Shivani Reddy.

In this episode, we discuss key concepts and management of electrophysiologic issues that we can encounter when caring for adults with congenital heart disease. Arrythmias in adults with congenital heart disease can be intrinsic due to the defect itself or as a consequence of the interventions that they have undergone to palliate and/or repair these defects. The complex anatomy of these patients and the years of pressure and volume load make them not only exquisitely hemodynamically sensitive to arrhythmias (that may otherwise not be of much consequence to the general population) but they also make interventions (catheter ablation or device implant) complex. We therefore embark in a case-based discussion of patients with ACHD (Fontan circulation, Ebstein’s anomaly and Tetralogy of Fallot) in an effort to highlight the presentation of arrythmias and the management strategy in this very important group of patients.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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The CardioNerds Adult Congenital Heart Disease (ACHD) series provides a comprehensive curriculum to dive deep into the labyrinthine world of congenital heart disease with the aim of empowering every CardioNerd to help improve the lives of people living with congenital heart disease. This series is multi-institutional collaborative project made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Josh Saef, Dr. Agnes Koczo, and Dr. Dan Clark.

The CardioNerds Adult Congenital Heart Disease Series is developed in collaboration with the Adult Congenital Heart Association, The CHiP Network, and Heart University. See more

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Pearls – Electrophysiology in ACHD1. Patients with Fontan circulation have a high risk of developing atrial (and ventricular) arrhythmias and they are highly sensitive to the hemodynamic consequences that these arrythmias ensue. The goal of therapy then should be to achieve sinus or atrial paced rhythm. Rate control should NOT the goal. 2. Patients with Ebstein’s anomaly have high arrhythmic potential. They can have multiple accessory pathways (especially right sided) which can in turn be associated with sudden cardiac death. We should have low threshold for EPS +/- catheter ablation in patients with WPW pattern. 3. Patients with Tetralogy of Fallot have a unique risk for SCD that warrant ICD implant apart from the standard criteria (LVEF <=35% and NYHA II-III symptoms). This involves the pump (RV dilation/dysfunction), electricity (QRSd>180 ms) and surgical repair approach. 4. Patient’s anatomy is the major consideration when implanting devices (PPM/ICD). We ought to assess for residual intracardiac shunt at the atrial level and consider closing if feasible prior to placing a device. CRT has merit in systemic LV but less so in systemic RV.

Notes- Electrophysiology in ACHDWhat should we know about atrial arrhythmias in a Fontan patient?

• Intraatrial re-entrant tachycardia (IART) is slower than typical atrial flutter with atrial rates generally <300 bpm. It does not have typical flutter waves and when it is slow enough, it may be confused with sinus tachycardia. A simple maneuver to help discern between sinus tachycardia or AT/AFl is to stand the patient up. If there’s no variability in heart rate, then it is less likely for it be sinus. With intact AV conduction, atrial flutter or IART can conduct 1:1.
  • IART is usually a harbinger of issues among patients with Fontan circulation. These patients are dependent on passive pulmonary blood flow. So, loss of AV synchrony in these patients may raise left atrial pressures, impede forward flow and subsequently compromise cardiac output. Tachycardia reduces diastolic filling, thus further limiting systemic venous return. IART can be associated with systemic illness, worsening pump function, obstruction in the Fontan circuit, etc. Once it’s present, it warrants full investigation into the trigger and a management plan to prevent recurrence.

How should we manage atrial arrhythmias in a Fontan patient?

• The goal of therapy is to achieve sinus (or A-paced) rhythm. Rate control should not be the goal.
  • If hemodynamically unstable-> DCCV
  • Chemical options include ibutilide but would use with caution if one does not know sinus function as post conversion bradycardia can put patient at risk for torsades. Amiodarone or Procainamide are helpful in patients that are requiring frequent cardioversions acutely. However, would avoid amiodarone if patients are heading to EP lab for catheter ablation as this medication affects defibrillation thresholds.

How should we approach catheter ablation in a Fontan patient?

• Catheter ablation should be considered in centers with expertise with managing ACHD patients.
  • Operators should understand patient’s anatomy, ventricular function and systemic issues such as renal or hepatic function. Prior to intervening, venous/arterial access issues ought to be assessed. In cases where there’s femoral vein or IVC occlusion, trans-hepatic approach can be considered. Presence of atrial thrombi ought to be assessed prior to ablation as well. Given slower atrial rate leading to less degree of stasis compared to Afib, left atrial thrombi are less common.
  • When ablating, first assess the Fontan itself (lateral tunnel in this case) as it can become dilated overtime and this leads to an area of scar that can be source of arrythmias. If Fontan is not the source, then one has to go through it to reach the atria. In extra-cardiac Fontan, this may require the use of a radiofrequency-powered needle to cross the conduit and thereby reach the atria. A retrograde approach from the aorta, into the systemic RV, and then into the atria is much less ideal given that this would entail placing catheters in the systemic circulation for prolonged periods of time, raising thromboembolic risk, not to mention the trajectory that is required with this approach.

How should we approach anticoagulation in Fontan patients?

• CHADS2VASC for CVA prevention risk stratification is not as heavily applicable in this patient population as compared to the general population.
  • The Fontan circuit is highly susceptible to thrombosis. Each element of Virchow’s triad is present in patients with Fontan circulation: (1) Venous stasis – from the passive pulmonary flow and venous hypertension necessary to maintain this forward flow, (2) Activation of blood coagulation – underlying liver disease, prostheses, and inflammation may all play a role in making these patients hypercoagulable, and (3) Venous damage – surgical reconstruction of the venous tree and chronic venous hypertension lead to venous damage. Together, all these factors increase the risk of thrombosis. Let’s not forget that there are often residual right-to-left shunts that present opportunities for paradoxical emboli to the systemic circulation. So, not only is clotting more common, the stakes are often higher in this population.
  • All adults with Fontan palliation are on at least anti-platelets (aspirin) and many on systemic anticoagulation. Special circumstances that prompt consideration of systemic anticoagulation include prior clots in the Fontan circuit, atrial arrhythmias, thrombi in hypoplastic chambers when there are systemic communications or if they have other indications like: DVT/PE, mechanical valve prosthesis.

What arrhythmias are associated with patients who are born with Ebstein’s anomaly and when should we pursue EP study and/or catheter ablation?

• Approximately 1/3 of adults with Ebstein’s anomaly have multiple accessory pathways (particularly right sided) and atrial tachyarrhythmias are very common in these patients.
  • In the setting of ventricular preexcitation (Wolf Parkinson White syndrome), atrial tachyarrhythmias may expose the patient to a higher risk of lethal ventricular arrhythmias. This is why we don’t give nodal blockers to WPW patients in atrial fibrillation, as this can precipitate 1:1 conduction down the accessory pathway. In patients with Ebstein’s anomaly, without WPW, EKG shows right bundle branch block.
  • Ventricular myocardium that lies between the true AV groove and displaced tricuspid valve is thin-walled and unhealthy thus prone to ventricular tachycardia
  • The 2018 ACC/AHA ACHD guidelines give EPS with or without catheter ablation a IIA indication for diagnostic evaluation of adults with Ebstein anomaly and ventricular preexcitation (WPW pattern), even without SVT. Likewise, these guidelines give a IIA indication for EPS +/- CA prior to surgical intervention on the tricuspid valve regardless of a history of preexcitation or SVT.

In which ACHD patients should we consider the use of Holter monitor when they are asymptomatic?

• To screen for abrupt loss of pre-excitation in patients with Ebstein’s anomaly.
  • In Fontan patients to screen for junctional rhythm as this loss of AV synchrony would lead to long term hemodynamic consequences.
  • In patients with tetralogy of Fallot, to identify patients with non-sustained VT
  • In patients with D-TGA and atrial switch, to screen for sinus node dysfunction
  • In patients with CC-TGA, to screen for AV conduction abnormalities.

How should we approach ICD implant for primary sudden cardiac death prevention in patients who are born with Tetralogy of Fallot (ToF)?

• In general, primary prevention ICD for ToF is indicated for patients meeting standard criteria (LVEF <=35% and NYHA II-III symptoms). There have been many studies to better understand SCD risk among patients living with ToF. We can think of the risks in 3 categories: (1) The pump – how hypertrophied, dilated, and/or weak is the RV? Is RV dilatation so bad it is affecting the LV? If so, this confers a greater risk of SCD. (2) Electrical – has the patient had prior VT/VF (are we talking secondary prevention?)? How wide and fractionated is the QRS? We think of QRSd >=180 msec as a cut-point for increased risk and there’s new data from France last year that a fractionated QRS may matter even more (DAI-T4F registry). (3) Surgical/RVOT – what was the original repair? Did they use an LV vent or a RV ventriculotomy? Was there a transannular patch or RVOT aneurysm post-operatively? What’s the current status of the pulmonary valve?

What are the technical considerations that ACHD patients warrant when having an ICD/PPM implanted compared to the general population?

• Patient’s anatomy is the major consideration when implanting devices. We need to first assess if there’s remaining intracardiac shunting at the atrial level and consider closure prior to implanting a device.
  • CRT has merit in systemic LV. CRT in systemic RV like patients with D-TGA with atrial switch has less merit and is more technically challenging as it may require epicardial lead.

References – Electrophysiology in ACHD1. Stout KK et al. 2018 AHA/ACC Guideline for the management of adults with congenital heart disease: A report of the American college of cardiology/American heart association task force on clinical practice guidelines. Circulation.2019;139:e698-e800. Doi:10.1161/CIR. 0000000000000603 2. Khairy P et al. PACES/HRS Expert consensus Statement on the recognition and management of arrhythmias in adult congenital heart disease. Heart Rhythm.2014(11): e102-e165. 3. Baumgartner H et al. 2020 ESC Guidelines for the management of adult congenital heart disease, European Heart Journal. 2021; 42:563-645 doi:10.1093/eurheartj/ehaa554 4. Walsh EP, Cecchin F. Arrhythmias in adult patients with congenital heart disease. Circulation. 2007 Jan 30;115(4):534-45. 5. Waldmann et al. Long-Term Follow-Up of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator: The DAI-T4F Nationwide Registry. Circulation. 2020 Oct 27;142(17):1612-1622. doi:10.1161/CIRCULATIONAHA.120.046745.Epub 2020 Oct 1.

Meet Our Collaborators!Adult Congenital Heart AssociationFounded in 1998, the Adult Congenital Heart Association is an organization begun by and dedicated to supporting individuals and families living with congenital heart disease and advancing the care and treatment available to our community. Our mission is to empower the congenital heart disease community by advancing access to resources and specialized care that improve patient-centered outcomes. Visit their website (https://www.achaheart.org/) for information on their patient advocacy efforts, educational material, and membership for patients and providers

CHiP Network

The CHiP network is a non-profit organization aiming to connect congenital heart professionals around the world. Visit their website (thechipnetwork.org) and become a member to access free high-quality educational material, upcoming news and events, and the fantastic monthly Journal Watch, keeping you up to date with congenital scientific releases. Visit their website (https://thechipnetwork.org/) for more information.

Heart University
Heart University aims to be “the go-to online resource” for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of educational material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practicing provider. The site provides free content to a global audience in two broad domains: 1. A comprehensive curriculum of training modules and associated testing for trainees. 2. A curated library of conference and grand rounds recordings for continuing medical education. Learn more at www.heartuniversity.org/

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Join CardioNerds Co-Founder Dr. Dan Ambinder, Dr. Nino Isakadze (EP Fellow at Johns Hopkins Hospital), Dr. Karan Desai (Cardiology Faculty at Johns Hopkins Hospital and Johns Hopkins Bayview) join Digital Health Experts, Dr. Francoise Marvel (Co-Founder of Corrie Health and Co-Director of Johns Hopkins Digital Health Lab) and Dr. David Cho (Chair of the ACC Health Care Innovation Council) for another installment of the Digital Health Series. In this specific episode, we discuss pearls, pitfalls and everything in between for the emerging digital health innovator. This series is supported by an ACC Chapter Grant in collaboration with Corrie Health. Notes were drafted by Dr. Karan Desai. Audio editing was performed by student Dr. Shivani Reddy.

In this series, supported by an ACC Chapter Grant and in collaboration with Corrie Health, we hope to provide all CardioNerds out there a primer on the role of digital heath in cardiovascular medicine. Use of versatile hardware and software devices is skyrocketing in everyday life. This provides unique platforms to support healthcare management outside the walls of the hospital for patients with or at risk for cardiovascular disease. In addition, evolution of artificial intelligence, machine learning, and telemedicine is augmenting clinical decision making at a new level fueling a revolution in cardiovascular disease care delivery. Digital health has the potential to bridge the gap in healthcare access, lower costs of healthcare and promote equitable delivery of evidence-based care to patients.

This CardioNerds Digital Health series is made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Nino Isakadze and Dr. Karan Desai.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – Tips for the Digital Health Innovator 1. A critical first step in developing a digital health intervention is defining the clinical problem rather than developing the technology itself. 2. Most digital transformations – whether in medicine or other industries – require several iterations for the technology to develop and demonstrate value. A key aspect of this iterative process was human-centered design: involving patients, their families, and other end-users early in the development of the digital health intervention. 3. Dr. Marvel and colleagues have developed a 6-step process for innovators to consider in taking a concept to product.

Notes – Tips for the Digital Health Innovator 1. In this episode, we discussed with Dr. Marvel and Dr. Cho some general concepts on how to develop digital health interventions (DHI). DHIs have a broad definition, including any software or hardware application used to improve access, quality, efficacy or efficiency and they exist in various modalities (e.g., text message, mobile apps, wearables). 2. Dr. Marvel has previously authored a roadmap for digital health intervention that provides guidance for an interdisciplinary approach to developing effective and evidence-based DHIs. As discussed on the episode, a critical first step is defining the clinical problem an innovator is attempting to solve instead of attempting to develop the technology solution first and then adapting it to the problem. 3. Drs. Marvel and Cho emphasized that most digital transformations – whether in medicine or other industry – require several iterations for the technology to develop and demonstrate value. Frequent assessment in a structured manner will help the intervention mature over time. Dr. Marvel noted that a key aspect of this iterative process was human-centered design: involving patients, their families, and other end-users early in the development of the DHI. 4. For instance, with Corrie Health, Dr. Marvel noted that patients who had suffered acute myocardial infarction were involved in a Patient Advisory Board, demonstrations were held for the Patient Advisory board, and patients invited to participate on the research team. 5. Our experts also noted there is a wealth of literature on the common barriers in DHI adoption, including regulatory and cost requirements. Data security and interoperability are other major concerns for digital health innovators. An understanding of the healthcare ecosystem can help innovators recognize these barriers early in the design process. 6. In the aforementioned article, Dr. Marvel and colleagues define a stepwise process to help innovators bring their concept to product: * Early multidisciplinary accelerators compromised of a variety of stakeholders * Establishment of institutional navigators who can provide a pathway through institutional roadblocks and operational factors * Encouraging mentorship and championship from faculty-level and administration * Devotion of administrative/business/finance leadership to create sustainable business models to address the reimbursement and policy landscapes * Creation of expedited IRB pathways for low-risk DHIs * The design of systematic processes to access patient evaluations of new technologies and consumer-centered design.

References – Tips for the Digital Health Innovator 1. Marvel FA, Wang J, Martin SS. Digital Health Innovation: A Toolkit to Navigate From Concept to Clinical Testing. JMIR Cardio. 2018 Jan 18;2(1):e2. doi: 10.2196/cardio.7586 2. Glaser J and Shaw S. Digital Transformation Success: What Can Health Care Providers Learn from Other Industries. NEJM Catalyst. 2022 Mar 22. doi: 10.1056/CAT.21.0434

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CardioNerds (Drs. Amit Goyal, Matthew Delfiner, and Tiffany Dong) discuss infective endocarditis with distinguished clinician-educator Dr. Michael Cullen. We dive into the nuances of infective endocarditis, including native valve endocarditis, prosthetic valve endocarditis, and right-sided endocarditis.

Notes were drafted by Dr. Tiffany Dong, and audio editing was performed by student Dr. Adriana Mares.

The CardioNerds Beyond the Boards Series was inspired by the Mayo Clinic Cardiovascular Board Review Course and designed in collaboration with the course directors Dr. Amy Pollak, Dr. Jeffrey Geske, and Dr. Michael Cullen.

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Pearls and Quotes1. The physical exam is crucial in the evaluation of infective endocarditis and includes cardiac auscultation and a search for sequelae of endocarditis, such as immunologic and embolic phenomena. 2. The modified Duke Criteria categorizes the diagnosis of infective endocarditis into four different buckets: definite endocarditis by pathology, definite endocarditis by clinical criteria, possible endocarditis, and rejected. 3. The diagnosis of endocarditis may involve several different imaging modalities, including transthoracic echocardiogram, transesophageal echocardiogram, 4D CT, and nuclear imaging. 4. For left-sided endocarditis, indications to operate include endocarditis due to S. aureus or fungi, heart failure, evidence of perivalvular complications, persistent bacteremia, and large vegetations. 5. The management of endocarditis often involves multiple teams, including cardiology, infectious disease, addiction medicine, neurology, anesthesiology, and cardiothoracic surgery.

Notes What signs/complications of endocarditis are apparent on physical exam and labs?

• A new or worsening cardiac murmur with possible signs of volume overload.
• Vascular phenomena encompass splinter hemorrhages, conjunctival hemorrhages, Janeway lesions, mycotic aneurysms, and TIA/strokes.
• Immunologic phenomena include glomerulonephritis, Roth spots, and Osler nodes.
• Positive blood cultures with 2-3 samples collected.
• Elevated inflammatory markers.

How does the modified Duke criteria assist in the diagnosis of infective endocarditis?

• The modified Duke criteria separate the diagnosis of endocarditis into four categories: definite endocarditis by pathology, definite endocarditis by clinical criteria, possible endocarditis, and rejected endocarditis.
• Definitive endocarditis by pathology requires pathologic confirmation of “bugs under the microscope.”
• Definitive endocarditis by clinical criteria requires two major criteria, one major and two minor criteria, or all five minor criteria.
• Possible endocarditis requires one major and one minor or three minor criteria.
• Major criteria:
  • Positive blood culture for typical organism
  • Evidence of endocardial involvement (e.g., vegetation on echo)
• Minor Criteria
  • Predisposing clinical factors (e.g., intravenous drug use, known valvulopathy)
  • Fever
  • Immunologic phenomena
  • Vascular phenomena
  • Blood culture for atypical organism

What is the role of TTE compared to TEE in endocarditis?

• TTE and TEE both have their roles in the workup for endocarditis.
• TTE can provide a baseline screen and yield a better understanding of ventricular size and function than transesophageal.
• The strength of TEE is the ability to visualize smaller vegetations along with perivalvular complications that may be missed on TTE.
• If clinical suspicion is high for endocarditis, repeat echocardiography is warranted.

What are other tools to evaluate for endocarditis in prosthetic valves?

• TTE and TEE remain important and should be commonly utilized for the diagnosis of endocarditis.
• FDG-PET can detect inflammation that could be suggestive of endocarditis. Patients should be at least six weeks after valve implantation; otherwise, FDG PET may detect normal postsurgical inflammation.
• Gated 4D CT can also screen for perivalvular involvement and aid with surgical planning, especially in these patients who may undergo redo surgery.

What are the indications for surgery in infective endocarditis?

• It is important to separate left-sided and right-sided endocarditis because the indications are different.
• For left-sided endocarditis, indications for surgery include persistent bacteremia/fevers despite appropriate antibiotic therapy, S. aureus or fungal endocarditis, heart failure symptoms, perivalvular complications, and vegetations >20mm.
• For right-sided endocarditis, indications for surgery include infection with a fungal organism, heart failure due to severe tricuspid regurgitation, vegetations >10mm with embolic phenomenon, persistent bacteremia despite appropriate therapy, and perivalvular involvement.
• Often, medical therapy alone for right-sided endocarditis will be sufficient.

What is the role of multidisciplinary teams for endocarditis?

• Endocarditis teams can involve cardiology, infectious disease, cardiothoracic surgery, neurology, anesthesiology, and addiction medicine.
• Addiction medicine is a very important group, particularly in cases where endocarditis is related to IVDU. It is a class 1 indication to consult addiction medicine to give the patient the best long-term outcome.
• Even if surgery is not warranted at initial hospitalization, it may be appropriate to have cardiac surgery weigh in and follow up with the patient in case there arises an indication for surgery.

References1. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). European heart journal. Nov 21 2015;36(44):3075-3128. doi:10.1093/eurheartj/ehv319 https://academic.oup.com/eurheartj/article/36/44/3075/2293384 2. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Feb 2 2021;143(5):e35-e71. doi:10.1161/cir.0000000000000932
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000923#d1e11386 3. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. Oct 13 2015;132(15):1435-86. doi:10.1161/cir.0000000000000296
https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000296

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The following question refers to Section 4.7 of the 2021 ESC CV Prevention Guidelines. The question is asked by student Dr. Shivani Reddy, answered first by NP Carol Patrick, and then by expert faculty Dr. Eileen Handberg.

Dr. Handberg is an Adult Nurse Practitioner, Professor of Medicine, and Director of the Cardiovascular Clinical Trials Program in the Division of Cardiovascular Medicine at the University of Florida. She has served as Chair of the Cardiovascular Team Section and the Board of Trustees with the ACC and is the President Elect for the PCNA.

The CardioNerds Decipher The Guidelines Series for the 2021 ESC CV Prevention Guidelines represents a collaboration with the ACC Prevention of CVD Section, the National Lipid Association, and Preventive Cardiovascular Nurses Association.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #34

| Ms. BW presents after her best friend was diagnosed with hypertension and is interested in measuring her own blood pressure.According to the ESC Guidelines, what BP screening approach is recommended for making a diagnosis of hypertension? | | A | Repeated measurements in one visit | | B | A single measurement in a single visit | | C | Repeated measurements in more than one visit | | D | Reported patient history |

Answer #34

| Explanation | The correct answer is C – Repeated measurements in more than one visit.It is recommended to base the diagnosis of hypertension on repeated office BP measurements on more than one visit except when hypertension is severe (e.g., Grade 3—defined as SBP > 180 and/ or DBP >110mmHg—and especially in high-risk patients) (Class I, LOE C). In addition to recommending repeat measurements across visits, the guidelines provide a number of considerations for appropriately measuring blood pressure, such as taking measurements when seated in a quiet environment for 5 minutes and measuring in both arms at the first visit and using the higher-level value arm for visits thereafter (see Table 14 on page 3283).Additionally, home blood pressure monitoring is recommended as an alternative to repeated office measurements. Blood pressure measurements are taken with a semiautomated, validated cuff for 3 consecutive days – and 6-7 days being preferred – in the morning and at night, averaged over that period. Notably, home blood pressure thresholds for the diagnosis of hypertension are lower than for that of in-office measurements, with a daytime systolic of 135mmHg or diastolic of 85mmHg given as the level at which hypertension is diagnosed, as opposed to 140mmHg and 90mmHg for systolic and diastolic levels, respectively, given for in-office diagnosis. | | Main Takeaway | With the exception of those with severely elevated blood pressures, the diagnosis of hypertension requires repeated measurements across multiple office visits. | | Guideline Loc. | Sections 4.7.1 and 4.7.2, Table 13 and 14, Figure 14 |

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The following question refers to Section 7.8 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by Stony Brook University Hospital medicine resident and CardioNerds Intern Dr. Chelsea Tweneboah, answered first by Mayo Clinic Cardiology Fellow and CardioNerds Academy Chief Dr. Teodora Donisan, and then by expert faculty Dr. Michelle Kittleson.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #29

| A 69-year-old man was referred to the cardiology clinic after being found to have a reduced left ventricular ejection fraction and left ventricular hypertrophy. For the last several months he has been experiencing progressively worsening fatigue and shortness of breath while getting to the 2nd floor in his house. He has a history of bilateral carpal tunnel syndrome and chronic low back pain. He takes no medications. On exam, his heart rate is 82 bpm, blood pressure is 86/60 mmHg, O2 saturation is 97% breathing ambient air, and BMI is 29 kg/m2. He has a regular rate and rhythm with normal S1 and S2, bibasilar pulmonary rales, and 1+ pitting edema in both legs. EKG shows normal sinus rhythm with a first-degree AV delay and low voltages. Transthoracic echocardiogram shows a moderately depressed LVEF of 35-39%, severe concentric hypertrophy with a left ventricular posterior wall thickness of 1.5 cm and strain imaging showing globally reduced longitudinal strain with apical sparring. There is also biatrial enlargement and a small pericardial effusion. A pharmacologic nuclear stress test did not reveal any perfusion defects. A gammopathy panel including SPEP, UPEP, serum and urine immunofixation studies, and serum free light chains are unrevealing. A 99mTc-Pyrophosphate scan was positive with grade 3 uptake. In addition to starting diuretics, what is the next most appropriate step for managing for this patient? | | A | Start metoprolol succinate | | B | Start sacubitril/valsartan | | C | Perform genetic sequencing of the TTR gene | | D | Perform endomyocardial biopsy |

Answer #29

| Explanation | The correct answer is C – perform genetic sequencing of the TTR gene.This patient has findings which raise suspicion for cardiac amyloidosis. There are both cardiac (low voltages on EKG and echocardiogram showing marked LVH with biatrial enlargement and small pericardial effusion as well as a characteristic strain pattern) and extra-cardiac (bilateral carpal tunnel syndrome and low back pain) features to suggest amyloidosis. The diagnosis of cardiac amyloidosis requires a high index of suspicion and most commonly occurs due to a deposition of monoclonal immunoglobulin light chains (AL-CM) or transthyretin (ATTR-CM). ATTR may cause cardiac amyloidosis as either a pathogenic variant (ATTRv) or as a wild-type protein (ATTRwt).Patients for whom there is a clinical suspicion for cardiac amyloidosis should have screening for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and serum free light chains (Class 1, LOE B-NR). Immunofixation electrophoresis (IFE) is preferred because serum or urine plasma electrophoresis (SPEP or UPEP) are less sensitive. Together, measurement of serum IFE, urine IFE, and serum FLC is >99% sensitive for AL amyloidosis. Negative studies as in our patient essentially exclude AL amyloidosis from consideration.In patients with high clinical suspicion for cardiac amyloidosis, without evidence of serum or urine monoclonal light chains, bone scintigraphy should be performed to confirm the presence of transthyretin cardiac amyloidosis (Class 1, LOE B-NR). As in this patient’s case, the 99mTc-Pyrophosphate scan with a grade 2/3 cardiac uptake in the absence of a serum or urinary monoclonal protein has a very high specificity and positive predictive value for ATTR-CM. This allows for a noninvasive diagnosis of ATTR-CM, obviating the need for an endomyocardial biopsy and so option D is inaccurate.In patients for whom a diagnosis of transthyretin cardiac amyloidosis is made, genetic testing with TTR gene sequencing is recommended to differentiate hereditary variant from wild-type transthyretin cardiac amyloidosis (Class 1, LOE B-NR). Differentiating ATTRv from ATTRwt is important because confirmation of ATTRv would trigger genetic counseling and potential cascade screening of family members and TTR silencer therapies, such as inotersen and patisiran (currently only approved for the treatment of polyneuropathy caused by ATTRv amyloidosis).Routine guideline-directed medical treatment (GDMT) for neurohormonal blockade may be poorly tolerated in patients with ATTR-CM and EF ≤40%. Due to restrictive physiology, they may be predisposed to more hypotension with ARNi, ACEi, and ARB. Similarly, patients with ATTR-CM rely on their heart rate response to preserve the cardiac output, thus BB may worsen HF symptoms. In this case, our patient already has a borderline blood pressure without these medications. Both options A and B are false. | | Main Takeaway | In patients for whom a diagnosis of transthyretin cardiac amyloidosis is made, TTR gene sequencing is recommended to differentiate pathologic variant (ATTRv) from wild-type transthyretin cardiac amyloidosis (ATTRwt). This has implications in terms of screening for family members and management options for ATTRv.For patients with ATTR-CM and EF ≤40%, GDMT may be poorly tolerated. | | Guideline Loc. | Section 7.8, Figure 13 |

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The following question refers to Section 7.3 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The question is asked by Palisades Medical Center medicine resident & CardioNerds Academy Fellow Dr. Maryam Barkhordarian, answered first by Hopkins Bayview medicine resident & CardioNerds Academy Faculty Dr. Ty Sweeny, and then by expert faculty Dr. Gregg Fonarow.

Dr. Fonarow is the Professor of Medicine and Interim Chief of UCLA’s Division of Cardiology, Director of the Ahmanson-UCLA Cardiomyopathy Center, and Co-director of UCLA’s Preventative Cardiology Program.

The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Question #28

| Mr. Gene D’aMeTi, a 53-year-old African American man with ischemic cardiomyopathy and heart failure with reduced ejection fraction (LVEF 30-35%), is recently admitted with acutely decompensated heart failure and acute kidney injury on chronic kidney disease stage III. His outpatient regiment includes sacubitril-valsartan 97-103mg BID, carvedilol 25mg BID, and hydralazine 50mg TID.Sacubitril-valsartan was held because of worsening renal function. Despite symptomatic improvement with diuresis, his renal function continues to decline. He is otherwise well perfused & with preservation of other end organ function.Throughout this hospitalization, he has steadily become more hypertensive with blood pressures persisting in the 170s/90s mmHg. What would be an appropriate adjustment to his medication regimen at this time? | | A | Resume Losartan only | | B | Start Amlodipine | | C | Increase current Hydralazine dose | | D | Start Isosorbide dinitrate therapy | | E | Both C & D |

Answer #28

| Explanation | The correct answer is E – both increasing the current hydralazine dose (C) and starting isosorbide dinitrate therapy (D).Although ACEI/ARB therapy (choice A) has shown a mortality and morbidity benefit in HFrEF, caution should be used in patients with renal insufficiency. In this patient with ongoing decline in renal function, RAAS-inhibiting therapies (ACEi, ARB, ARNI, MRA) should be avoided. In this case, as his RAAS-I has been stopped, it would be reasonable to increase current therapies to target doses (or nearest dose tolerated), as these demonstrated both safety and efficacy in trials (Class 1, LOE A). Considering that his high dose ARNI was stopped, it is unlikely that either hydralazine or isosorbide dinitrate alone, even at maximal doses, would be sufficient to control his blood pressure (Options C and D, respectively). Interestingly, in the original study by Massie et. Al (1977), the decision was made to combine these therapies as the result was thought to be superior to either medication alone. ISDN would provide preload reduction, while Hydralazine would decrease afterload. Consequently, we do not have data looking at the individual benefit of either medication in isolation.In self-identified African Americans with NYHA class III or IV HFrEF already on optimal GDMT, the addition of hydralazine & isosorbide dinitrate is recommended to improve symptoms and reduce mortality and morbidity (Class 1, LOE A). In this case, as the patient has evidence of progressive renal disfunction, we are limited in using traditional RAAS-I, such as ACEI, ARB, or ARNI. In patients with current or previously symptomatic HFrEF who cannot be given first-line agents (like ARNi, ACEi, ARB) due to intolerance or renal insufficiency, combination therapy of hydralazine & isosorbide dinitrate might be considered to reduce morbidity and mortality (Class 2b, LOE C-LD).Dihydropyridine calcium channel blockers such as Amlodipine (choice B) are not recommended for treatment of HFrEF (COR 3, LOE A), though may be considered for treating elevated blood pressure despite optimization of GDMT. | | Main Takeaway | In self-identified African Americans, the addition of hydralazine & isosorbide dinitrate to GDMT has additional mortality & morbidity benefits.Should a patient have drug intolerances or renal dysfunction that precludes the use of ACEi/ARB/ARNi, hydralazine & isosorbide dinitrate is a reasonable alternative. | | Guideline Loc. | · Section 7.3.5-8· Table 14, Table 15 |

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In this episode, CardioNerds Dr. Daniel Ambinder, Dr. Giselle Suero Abreu, and Dr. Saahil Jumkhawala discuss thromboembolic disease in cardio-oncology with faculty expert Dr. Joshua Levenson, the Associate Program Director of the cardiology fellowship and an Assistant Professor of Medicine at the University of Pittsburg School of Medicine. Venous (VTE) and arterial thromboembolic (ATE) events are precipitants of morbidity and mortality in patients with cancer. Here, we discuss the pathophysiology of thromboembolism, risk factors and epidemiology for ATE and VTE, the role of risk prediction and patient stratification, and the approach to treatment for and prophylaxis of thromboembolic events with anticoagulation. Show notes were drafted by Dr. Saahil Jumkhawala and episode audio was edited by CardioNerds Intern Dr. Tina Reddy.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here.

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Pearls and Quotes – Thromboembolic Disease in Cardio-oncology1. Patients with cancer are at higher risk of developing both arterial and venous thromboembolic events compared to the general population. 2. Certain cancer subtypes are associated with a relatively higher risk of developing thromboembolic complications. 3. Anticoagulation type and duration should be dependent on patient characteristics and risk factors, with shared decision-making between the patient and their providers. 4. Subgroups of patients may benefit from more aggressive management of their atherosclerotic cardiovascular risk factors while being treated for cancer to reduce the risk of thromboembolic complications.

Show notes – Thromboembolic Disease in Cardio-oncologyWhat are the incidence and main manifestations of thromboembolic events (venous and arterial) in patients with active malignancy?

Approximately 10% of outpatients with active cancer have venous thromboembolic events, many of which are asymptomatic. Clinically relevant VTEs are predominantly deep venous thrombosis (DVTs) with pain and/or swelling of the involved extremities or pulmonary emboli (PEs) resulting in chest pain and/or shortness of breath. VTE is the number one preventable cause of death for all hospitalized patients, and the ability to prevent and treat these events is crucial, particularly in high-risk populations such as patients with cancer.

Are there any high-risk associations with specific cancer subtypes?

Patients with metastatic disease and those receiving chemotherapy are more likely to develop arterial or venous thromboembolic events. Patients with acute myelogenous leukemia (AML) and thrombocytopenic patients are at the lowest risk for thromboembolic events. Multiple myeloma patients on medication such as proteasome inhibitors or lenalidomide appear at particular risk. Patients with localized, early-stage cancers such as breast, prostate, and melanoma are also at lower risk.

What are the main risk factors to identify patients at a higher risk of developing thrombotic complications?

Patients with a sedentary lifestyle, deconditioning, and undergoing active treatment with chemotherapy are at the highest risk of developing DVT or PE.

How should we approach choosing the optimal type and duration of anticoagulation for acute pulmonary embolism (PE) in the setting of malignancy?

This remains an area of active research. Historically, patients would receive systemic anticoagulation with heparin followed by warfarin. Low molecular weight heparin (LMWH) has been found to be superior to warfarin in this patient population. In the recent trials comparing LMWH to direct oral anticoagulants (DOACs), particularly apixaban, edoxaban, and rivaroxaban, a similar incidence of VTEs and relatively equivalent bleeding events have been found. This has transitioned the field towards the higher use of DOACs, except for gastric cancers, in which DOACs have been found to have higher bleeding risk. Dabigatran has been found to be associated with a higher incidence of bleeding and gastrointestinal side effects compared to other DOACs. Important considerations for the use of DOACs are the patient’s renal function and the ability to take oral medications or issues with gastrointestinal absorption.

For acute PE, three months of treatment is the minimum for the standard of care. For patients with ongoing treatment with systemic chemotherapy or radiation, treatment for at least six months may be considered, or even indefinitely, if risk factors for recurrence persist. Shared decision-making with patients regarding the relevant risks and benefits of ongoing anticoagulation remains critical.

What are some risk assessment models to help identify patients at high risk for developing recurrent thrombotic events?

The Khorana score, which includes prechemotherapy platelet count ≥350 x109/L, elevated WBC >11 x109/L, low hemoglobin <10g/dL, or BMI ≥35 kg/m2 may help risk-stratify higher-risk patients. Certain types of cancers place patients at different risks; for example, gastric and pancreatic cancers confers higher risk, while patients with lung cancers, lymphoma, or genitourinary cancers confer a mildly elevated risk.

Patients with no risk factors have less than <1% risk of PE or DVT in the following 2.5 months, those with 1 or 2 points have about 2% risk of PE or DVT in the following 2.5 months, and those with >3 points have about 7% risk of PE or DVT in the following 2.5 months.

How does one manage recurrent thrombotic events, particularly while patients are already on an oral anticoagulant?

One major consideration in patients with recurrent thrombotic events is ensuring adherence, as there may be concerns with patient education, access, or cost which need to be addressed. Once compliance is confirmed, a patient can be switched from one DOAC to another DOAC or from one DOAC to LWMH, with the twice-daily dose having the strongest evidence for efficacy.

Rarely, concurrent treatment with antiplatelet therapy and LWMH may be considered in patients at very high risk for recurrent thrombotic events, particularly in patients with widely disseminated cancers with vascular complications. Notably, workup for underlying hypercoagulability should be considered in patients with localized malignancies with recurrent thromboembolic events.

What are considerations for scenarios with high bleeding risk when there is a strong indication for anticoagulation?

For patients with chemotherapy-induced thrombocytopenia, thromboelastography (“TEG” scan) may be valuable in guiding whether patients are hyper- or hypo-coagulable. Patients with platelet count <20K should generally not be on anticoagulation. For patients anticipated to have thrombocytopenia sustained through treatment, discussion with the treating oncology team may guide towards withholding ongoing anticoagulation. Mobility and sequential compression devices (SCDs) should be advised for patients to avoid the development of DVTs while patients are in the hospital. As platelet counts rise, consideration of subtherapeutic doses of heparin may be considered.

Any lesion with metastasis to the brain is at risk for bleeding. Discussion with oncology, neuro-oncology, and neurosurgery is crucial in identifying the risk of hemorrhage of these lesions. Primary brain tumors, such as glioblastoma, are associated with an elevated risk of DVT, likely attributable in part to reduced mobility and VEGF-targeted treatment.

Management of malignant pericardial effusions varies by etiology. Patients with local malignant pericardial effusion may be managed with pericardiocentesis with catheter drainage versus pericardial window, depending on clinician availability and expertise.

What is the role of inferior vena cava (IVC) filters in the management of patients at high risk for developing thromboembolic events?

For patients with active DVT and PE burden with active or very high risk for bleeding, it may be considered to place a retrievable IVC filter with the goal of removal within 4-6 weeks, and anticoagulation restarted as soon as possible. Of note, IVC filters that remain in place for longer periods of time place the risk of the development of thrombi and distal embolization.

How does the management of arterial thrombotic events for patients with active malignancy differ from the treatment of venous thromboembolic disease?

Arterial thrombotic events may be sequelae of atherosclerotic cardiovascular disease, dysfunction of the coagulation cascade, or both. Patients with atherosclerotic cardiovascular disease are at higher risk for developing cardiovascular events when treated for cancer. Certain patients, such as men with prostate cancer, appear to be at higher risk related to hormonal derangements during treatment. Proactive management of atherosclerotic risk factors in these patients is imperative with modalities such as coronary computed tomography (CT) scans to identify the burden of atherosclerotic coronary disease with coronary calcium scoring. These patients may benefit from more aggressive treatment with statin therapy and antiplatelet therapy. Patients with preexisting coronary disease being treated with endocrine therapies or VEGF tyrosine kinase inhibitors (TKIs) may be at higher risk for atherosclerotic cardiovascular events during treatment and, therefore indicated for more aggressive lifestyle and risk factor modification.

References – Thromboembolic Disease in Cardio-oncology1. Lyon, A. R., López-Fernández, T., Couch, L. S., Asteggiano, R., Aznar, M. C., Bergler-Klein, J., … & Zamorano, J. L. (2022). 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC). European heart journal, 43(41), 4229-4361. 2. Gervaso, L., Dave, H., & Khorana, A. A. (2021). Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology state-of-the-art review. JACC: CardioOncology, 3(2), 173-190. 3. Streiff, M. B., Abutalib, S. A., Farge, D., Murphy, M., Connors, J. M., & Piazza, G. (2021). Update on guidelines for the management of cancer‐associated thrombosis. The Oncologist, 26(1), e24-e40. 4. O’Connell, C., Escalante, C. P., Goldhaber, S. Z., McBane, R., Connors, J. M., & Raskob, G. E. (2021). Treatment of Cancer‐Associated Venous Thromboembolism with Low‐Molecular‐Weight Heparin or Direct Oral Anticoagulants: Patient Selection, Controversies, and Caveats. The Oncologist, 26(1), e8-e16. 5. Agnelli, G. (2019). Direct oral anticoagulants for thromboprophylaxis in ambulatory patients with cancer. N Engl J Med, 380(8), 781-783.

Meet Our Collaborators International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

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Join CardioNerds Co-Founder Dr. Dan Ambinder, Dr. Nino Isakadze (EP Fellow at Johns Hopkins Hospital), Dr. Karan Desai (Cardiology Faculty at Johns Hopkins Hospital and Johns Hopkins Bayview) join Digital Health Expert, Dr. La Princess Brewer (Associate Professor of Medicine Mayo Clinic Rochester) for another installment of the Digital Health Series. In this specific episode, we discuss how digital health can both reduce and amplify health disparities. This series is supported by an ACC Chapter Grant in collaboration with Corrie Health. Notes were drafted by Dr. Karan Desai. Audio editing was performed by student Dr. Shivani Reddy.

In this series, supported by an ACC Chapter Grant and in collaboration with Corrie Health, we hope to provide all CardioNerds out there a primer on the role of digital heath in cardiovascular medicine. Use of versatile hardware and software devices is skyrocketing in everyday life. This provides unique platforms to support healthcare management outside the walls of the hospital for patients with or at risk for cardiovascular disease. In addition, evolution of artificial intelligence, machine learning, and telemedicine is augmenting clinical decision making at a new level fueling a revolution in cardiovascular disease care delivery. Digital health has the potential to bridge the gap in healthcare access, lower costs of healthcare and promote equitable delivery of evidence-based care to patients.

This CardioNerds Digital Health series is made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Nino Isakadze and Dr. Karan Desai.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes1. Digital redlining occurs when a particular group has limited access to key services based on race and ethnicity, perpetuating inequities. Throughout this podcast episode, Dr. Brewer emphasizes how community engagement early in the creation of digital health technologies can mitigate structural inequities. 2. Dr. Brewer spoke about methods to develop innovative digital health tools that are culturally sensitive and inclusive, specifically community-based participatory research (CBPR). In CBPR, community members are partners with researchers in each step of the intervention. 3. While certain individuals and communities may have physical access to digital health tools, they still may remain inaccessible for several reasons.

Notes1. In this episode, we focus on achieving digital health equity and how the very technologies meant to reduce health disparities can widen them. We started by discussing a paper from Dr. Brewer and colleagues that crystallized how digital health disparities can occur with the example of Pokémon Go. As described in this paper, this mobile application was one of the most used applications worldwide. It incentivized users to collect virtual goods at various physical locations termed PokéStops. For public health professionals, this mobile app represented an engaging way to promote physical activity amongst users. However, some racial and ethnic minority groups in low-income, urban areas quickly took notice of the lack of PokéStops within their neighborhoods. As researchers noted, this could be considered examples of digital redlining, or limiting a particular group from key services based on race and ethnicity. As Dr. Brewer notes in the paper, the Pokémon Go developers relied on maps that were crowdsourced from a majority white male demographic. While it may not have been deliberate, the development process created a structural digital inequity placing certain communities at a home-court disadvantage. Throughout this podcast episode, Dr. Brewer emphasizes how community engagement early in the creation of digital health technologies can mitigate structural inequities. 2. Dr. Brewer spoke about methods to develop innovative digital health tools that are culturally sensitive and inclusive, specifically community-based participatory research (CBPR). In CBPR, community members are equal partners with researchers and included at every phase of the project (or development of a digital health tool. Learn more about CBPR from Dr. Brewer and her FAITH! application by listening to our Narratives in Cardiology Series with Episode #131. As demonstrated by in Dr. Brewer’s own research and digital health tool creation, early and consistent community involvement led to high recruitment and retention rates of study participants (100% and 98%, respectively). 3. We also discussed that one of the misunderstood aspects of the discussion around digital health equity is the concept of access. Access can mean many different things including broadband internet infrastructure or internet-enabled devices. But even if the infrastructure is available – as Dr. Brewer has noted in her research for instance, African Americans have similar smartphone ownership to the general populations – digital health tools may be inaccessible because digital health interventions are not tailored to specific populations

References 1. Brewer LC, Fortuna KL, Jones C, Walker R, Hayes SN, Patten CA, Cooper LA. Back to the Future: Achieving Health Equity Through Health Informatics and Digital Health. JMIR Mhealth Uhealth. 2020 Jan 14;8(1):e14512. 2. Brewer LC, Hayes SN, Jenkins SM, Lackore KA, Breitkopf CR, Cooper LA, Patten CA. Improving cardiovascular health among African-Americans through mobile health: the FAITH! app pilot study. J Gen Intern Med. 2019 Aug;34(8):1376–8. 3. Brewer LC, Jenkins S, Lackore K, Johnson J, Jones C, Cooper LA, Breitkopf CR, Hayes SN, Patten C. mHealth intervention promoting cardiovascular health among African-Americans: recruitment and baseline characteristics of a pilot study. JMIR Res Protoc. 2018 Jan 31;7(1):e31. 4. Israel BA, Schulz AJ, Parker EA, Becker AB. Review of community-based research: Assessing partnership approaches to improve public health. Annu Rev Public Health. 1998;19:173–202. 5. Weinstein JN, Geller A, Negussie Y, Baciu A. Communities in Action: Pathways to Health Equity. Washington, DC: National Academies Press; 2017.

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