Cardiooncology Archives - Cardionerds

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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.

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

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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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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:

Recommendations on the use of multimodality imaging, including advanced echocardiographic techniques and cardiac MRI, in patients receiving cardiotoxic therapies and long-term surveillance.
Role of nuclear imaging (MUGA scan) in monitoring left ventricular ejection fraction.
Use of computed tomography to identify and/or monitor coronary disease.
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.

CardioNerds Cardio-Oncology Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

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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 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.

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 Cardio-Oncology Page
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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

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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.

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 Cardio-Oncology Page
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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.

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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.

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 – 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.

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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.

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 – 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.

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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.

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 Cardio-Oncology Page
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 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

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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.

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 Cardio-Oncology Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
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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.

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CardioNerds CardioOncology Series Co-Chairs, Dr. Teodora Donisan and Dr. Dinu Balanescu, and FIT Lead Dr. Bala Pushparaji discuss Interventional CardioOncology with Prof. Cezar Iliescu. In this episode, we discuss the spectrum of cardiovascular diseases encountered by the interventional onco-cardiologist, with a focus on nuances in endovascular therapies tailored to cancer patients and their unique comorbidities […]

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CardioNerds cofounder Dr. Daniel Ambinder, series co-chair Dr. Dinu Balanescu (FIT, Mayo Clinic), and episode lead Dr. Anjali Rao (FIT, UTSW) discuss training in cardio-oncology with Dr. Stephanie Feldman from Rutgers University. In this episode, the group discusses some of the most burning questions about educating the next wave of cardio-oncologists. As Dr. Feldman mentions, […]

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In this episode, CardioNerds co-founder Amit Goyal joins Dr. Iva Minga, Dr. Kevin Lee, and Dr. Juan Pablo Salazar Adum from the University of Chicago – Northshore in Evanston, IL to discuss a case of primary cardiac diffuse large B-cell lymphoma. The ECPR for this episode is provided by Dr. Amit Pursnani (Advanced Cardiac Imaging, […]

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CardioNerds co-founder Amit Goyal, Dr. Dinu Balanescu, Dr. Teodora Donisan, and Dr. Anjali Agarwalla get the cardiologist perspective of Cancer Therapy-Related Cardiac Dysfunction (CTRCD) from Dr. Joerg Hermann. We previously learned from the oncologist perspective with Dr. Susan Dent in Episode #261! In this episode, we discuss the history of cancer therapies and our developing understanding of how these life-saving medications can cause cardiac toxicities. As we manage patients in the CardioNerds CardioOncology clinic, we ask Dr. Hermann how the general cardiologist should approach patients with a cancer diagnosis, when should a patient be referred to a cardiooncology specialist, and what are the common cardiotoxicities to look out for. We’ll also place a quick consult to our guest expert’s goldendoodle!

This episode is supported by a grant from Pfizer Inc.

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

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Pearls and Quotes – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Cardiologist Perspective with Dr. Joerg Hermann1. Patients with malignancy will incur several “hits” in addition to their malignancy and its subsequent treatment — these include their genetics, environment, and comorbidities. The role of the cardiologist is to identify how the combination of these “hits” can bring cardiovascular disease to the forefront and where we can intervene upon it. 2. The sooner we recognize cardiotoxicity, the better the outcome for our patients. Patients should receive baseline risk assessment with TTE and biomarkers with routine surveillance. 3. You cannot assign a percentage to cardiac risk in cancer. Patients require a multidisciplinary approach with constant monitoring and surveillance. 4. Consider exercise testing when conducting pre-treatment risk assessment and during monitoring. Peak VO2 abnormalities is often the first marker of cardiotoxicity — though note that it correlates well with global longitudinal strain (GLS). 5. If someone develops a cardiovascular complication of chemotherapy, this should prompt referral to cardiooncology.

Show notes – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Cardiologist Perspective with Dr. Joerg HermannWhat types of cardiovascular pathology occur in the setting of cancer and its treatment?

We conventionally thought of cardiotoxicities as being of two types:

Type 1: irreversible cardiac injury that does not improve despite withdrawal of offending chemotherapeutic (protype = classic anthracycline cardiotoxicity)
Type 2: reversible cardiac dysfunction that improves with discontinuation of chemotherapeutic (prototype = classic traztuzumab cardiotoxicity)

However, we have begun moving away from this thought process as it has become more evident that injuries historically thought of as “type 1” may not be as relentless as previously understood, and that patients with type 2 dysfunction may not actually be returning to completely normal after the offending agent is withdrawn. As such, this episode proposes two other ways to frame our understanding of cardiotoxicities: a clinical/practical approach, based on symptoms (symptomatic vs asymptomatic — this is the approach used by the ESC guidelines), and a mechanistic approach: direct effect on cardiac myocytes, indirect effects (e.g., effect on coronaries), and inflammatory effects.

The 2021 International Cardiooncology Society (ICOS) consensus statement defines five major forms of cancer therapy related cardiac dysfunction (CTRCD):

Cardiac dysfunction/heart failure:
- Asymptomatic: defined by changes in ejection fraction. This may be mild (LVEF >50% AND either new decline in GLS by >15% from baseline or new rise in troponin or NTproBNP), moderate (new LVEF reduction by ≥10 percentage points to 40 – 49% AND either new decline in GLS by >15% from baseline or new rise in troponin or NTproBNP), or severe (new LVEF reduction to < 40%).
- Symptomatic: defined by severity of symptoms and intensity of treatment required. This may be mild (mild HF symptoms, no intensification of therapy required), moderate (need for outpatient intensification of diuretic and HF therapy), severe (HF hospitalization), or very severe (requiring inotropic or mechanical circulatory support, consideration for transplant).
Vascular toxicity: namely, myocardial infarction or stroke. Three primary forms:
- Vasospasm
- Thrombosis
- Atherosclerosis
Arrhythmia/QTc prolongation
Hypertension
Myocarditis: made especially prominent by immune checkpoint inhibitors

Note that the definitions for these toxicities require a baseline assessment of LVEF, global longitudinal strain, and cardiac biomarkers. As such, these should be considered part of pre-treatment risk assessment for any patient planned to undergo therapy known to be cardiotoxic.

Who are the “usual suspects” in CTRCD?

The “five pillars” of cancer therapy can each cause a form of cardiotoxicity. These pillars are:

Conventional chemotherapeutics: designed to stop highly proliferative cells from proliferating by inhibiting DNA synthesis.
- Anthracyclines, such as doxorubicin, etoposide. Mechanism: intercalates into DNA, disrupting topoisomerase-mediated DNA repair and replication. Primary form of cardiotoxicity: cardiomyopathy (can also cause arrhythmia).
- Alkylating agents, such as cyclophosphamide. Mechanism: cross-links DNA. Primary form of cardiotoxicity: high doses can cause hemorrhagic pericarditis; we also see arrhythmia, cardiomyopathy, and arterial vascular disease.
- Antimetabolites, such as 5-fluorouracil, gemcitabine. Mechanism: replaces base pairs, preventing synthesis. Primary form of cardiotoxicity: cardiomyopathy, arterial vascular disease.
Targeted therapies: monoclonal antibodies that inhibit cell signaling pathways that are pivotal in tumor cells.
- HER2 inhibitors
- Tyrosine kinase inhibitors
- VEGF inhibitors, such as bevacizumab. Mechanism: inhibits angiogenesis via VEGF inhibition. Primary form of cardiotoxicity: hypertension, thrombosis, and occasionally cardiomyopathy.
Immune therapies: immunologic therapies that are “targeted” at receptors identified on specific tumor receptors
- CAR-T cell therapy
- Immune checkpoint inhibitors
Radiation therapy
Surgery

The first three of these — conventional chemotherapeutics, targeted therapies, and immune therapies — are the three classes we think about as causing CTRCD.

Pearls from the ESC 2022 guidelines

Cardiovascular risk in patients with cancer is a dynamic variable that requires a multidisciplinary team approach.
All patients with cancer who are scheduled to receive a potentially cardiotoxic anticancer therapy should receive a baseline cardiovascular risk assessment that includes transthoracic echocardiography with measurement of global longitudinal strain as well as baseline cardiac biomarkers.
In patients who are at high risk or very high risk of CTRCD as based on the risk stratification provided in the guidelines, efforts should be made to minimize the use of cardiotoxic agents (including the consideration of dexrazoxane and liposomal anthracyclines) and to initiate cardioprotective agents (like ACE-i/ARB, beta blockers, and statins).
In patients who develop asymptomatic, mild decreases in LVEF, especially in the setting of HER2 inhibitors, chemotherapy should be continued with the addition of cardioprotective therapy.
After the completion of chemotherapeutics, cardioprotective medications should be de-escalated in patients at low risk of future cardiovascular events.

Pearl from the ACC.23 meeting (March 4-6, 2023, New Orleans, LA) The STOP-CA trial is a multicenter, randomized, double-blind, placebo-controlled study presented at ACC.23. The study analyzed 286 patients with lymphoma undergoing treatment with anthracyclines. Baseline left ventricular ejection fraction (LVEF) was 63%. Patients were randomized into a group receiving atorvastatin 40 mg daily and a group receiving placebo. The primary endpoint of LVEF decline ≥10% at 12 months was seen in 9% of patients in the atorvastatin group and 22% of patients in the placebo group, with no difference in rates of adverse events. In conclusion, statins may have an important role in the prevention of anthracycline-associated cardiac dysfunction in lymphoma patients. For more on the STOP-CA trial, check out the ACC Fits-On-The-Go coverage by CardioNerds CardioOncology series co-chair Dr. Teodora Donisan, with lead authors Dr. Tomas Neilan and Dr. Marielle Scherrer-Crosbie. The STOP-CA trial was presented after the recording of this episode and is thus not addressed in the episode.

References – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Cardiologist Perspective with Dr. Joerg HermannHerrmann J, McCullough KB, Habermann TM. How I treat cardiovascular complications in patients with lymphoid malignancies. Blood. 2022;139(10):1501-1516. doi:10.1182/blood.2019003893

Herrmann J, Lenihan D, Armenian S, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022;43(4):280-299. doi:10.1093/eurheartj/ehab674

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. 2022;43(41):4229-4361. doi:10.1093/eurheartj/ehac244

Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010;7(10):564-575. doi:10.1038/nrcardio.2010.121

Yu AF, Flynn JR, Moskowitz CS, et al. Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer. JAMA Cardiol. 2020;5(3):309-317. doi:10.1001/jamacardio.2019.5586

Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol. 2020;17(8):474-502. doi:10.1038/s41569-020-0348-1

Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1 [published correction appears in J Am Coll Cardiol. 2018 Feb 6;71(5):587]. J Am Coll Cardiol. 2017;70(20):2536-2551. doi:10.1016/j.jacc.2017.09.1096

Chang HM, Okwuosa TM, Scarabelli T, Moudgil R, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 2. J Am Coll Cardiol. 2017;70(20):2552-2565. doi:10.1016/j.jacc.2017.09.1095

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Dr. Filip Ionescu (hematology-oncology fellow at Moffitt Cancer Center in Tampa, FL), Dr. Teodora Donisan (cardiology fellow at the Mayo Clinic in Rochester, MN and CardioNerds House Thomas chief), Dr. Sarah Waliany (internal medicine chief resident at Stanford University in Palo Alto, CA), Dr. Dinu Balanescu (internal medicine chief resident at Beaumont Hospital in Royal Oak, MI) and Dr. Amit Goyal (structural interventional cardiology fellow at the Cleveland Clinic, in Cleveland, OH and CardioNerds Co-Founder), discuss the cardiotoxicities of common cancer treatments with Dr. Susan Dent, a medical oncologist and one of the founders of the field of Cardio-Oncology. Using the recently published ESC Guidelines on cardio-oncology, they cover cardiovascular risk stratification in oncology patients, pretreatment testing, as well as prevention and management of established cardiotoxicity resulting from anthracyclines, trastuzumab, and fluoropyrimidines. They touch on the unique aspects of cardio-oncology encountered in patients with breast cancer, rectal cancer, and lung cancer, who are frequently the recipients of multiple cardiotoxic treatments. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah.

Access the CardioNerds Cardiac Amyloidosis Series for a deep dive into this important topic.

This episode is supported by a grant from Pfizer Inc.

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

Pearls • Notes • References • Production Team

CardioNerds Cardio-Oncology Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

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Pearls and Quotes – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent1. Formal cardiovascular risk stratification must be performed prior to initiating a potentially cardiotoxic anticancer treatment regimen. Considering both drug toxicity and patient-related factors (e.g., age, smoking, hypertension etc) is important. 2. Anthracyclines affect the cardiomyocyte in complex ways which lead to a largely irreversible cardiomyopathy. All patients should have a pretreatment echocardiogram and ECG. 3. Trastuzumab cardiotoxicity, by contrast, is more like stunning the myocardium, which manifests as a reversible decrease in left ventricular ejection fraction which generally normalizes upon discontinuation of the drug. 4. The treatment of chemotherapy-induced cardiomyopathy should involve interdisciplinary discussions and shared decision making with the patient. Beyond guideline-directed medical therapy of heart failure with reduced ejection fraction, management can include temporarily holding or permanently discontinuing the offending agent. 5. Fluoropyrimidine-associated cardiotoxicity manifests as cardiac ischemia from coronary vasospasm. A 5FU infusion is essentially a stress test as it tends to unmask clinically silent atherosclerosis.

Show notes 1. What is the basic pretreatment assessment of any oncology patient who is to receive a potentially cardiotoxic regimen?

Awareness and management of the cardiovascular toxicity of oncology treatments are of paramount importance to be able to deliver treatment safely and to achieve maximal efficacy guided by an expert multidisciplinary team. Thanks to Dr. Dent and her colleagues’ work, this year we have seen the publication of the first Cardio-Oncology guideline (1). Perhaps the most important recommendation is that cancer patients about to start a cardiotoxic regimen should undergo formal cardiovascular risk stratification by considering both the adverse profile of the planned treatment and patient-related factors (e.g., preexisting heart disease, hypertension, smoking). High-risk patients may be referred early to a cardio-oncologist who can anticipate and mitigate toxicities. In addition to risk stratification, specific treatment modalities may require additional imaging and biochemical testing as outlined next.

How does anthracycline-induced cardiotoxicity present and what are the risk factors to consider?

Anthracycline-induced cardiotoxicitygenerally manifests as a permanent decrease in left ventricular ejection fraction (LVEF) caused by direct toxic effect of the cytotoxic chemotherapy on the cardiomyocytes. The risk factors for developing anthracycline-induced cardiotoxicity are cumulative anthracycline dose, advanced age, pretreatment low-normal LVEF, prior cardiovascular disease, as well as other established cardiovascular risk factors (e.g., hypertension, diabetes, obesity, smoking).

What is included in the work-up of a patient about to begin an anthracycline-containing regimen?

All patients who are about to received anthracyclines require a baseline echocardiogram, ideally with global longitudinal strain, and an electrocardiogram. For patients who are at moderate-to-high risk of developing cardiomyopathy, B-type natriuretic peptide and Troponin can also be helpful for monitoring.

How is established anthracycline-induced cardiotoxicity typically managed?

When a decrease in LVEF below 50% is detected, management usually involves holding the anthracycline and repeating imaging. At this point, discussion with a cardio-oncologist about the initiation of ACC/AHA guideline-directed medical therapy (GDMT) is warranted. If there is improvement in the LVEF with this approach, the decision to rechallenge is nuanced and often part of a multidisciplinary and shared decision-making process with the patient.

What are some proven strategies to prevent or mitigate anthracycline-induced cardiotoxicity?

In the case of a rechallenge, two ways to mitigate the risk of cardiac damage are using liposomal doxorubicin, which is a less cardiotoxic anthracycline formulation, and co-administration of dexrazoxane, which is the only FDA-approved cardioprotectant for use in this setting.

What is trastuzumab and how does the cardiotoxicity associated with its use differ from that caused by anthracyclines?

Trastuzumab is a monoclonal antibody directed against the HER2 receptor molecule expressed on breast cancer cells. The actual mechanism of trastuzumab-associated cardiotoxicity is not clear, but it appears to be more akin to myocardial stunning and is generally reversible. If it occurs, a decrease in LVEF appears early and for most patients withholding the drug is effective in reversing the effect.

How is trastuzumab-associated cardiotoxicity managed?

For those patients with a nadir LVEF < 50%, there is evidence to support the efficacy of GDMT. For those with an LVEF decrease in the 40-49% range, trastuzumab can be continued concomitantly with GDMT and close monitoring of LVEF. In cases with severe LVEF decrease <40%, the decision to continue or rechallenge becomes more complicated and always should involve a multidisciplinary discussion of the risks and benefits of either approach. Depending on the goal of treatment (curative in the adjuvant setting or palliative in the metastatic setting), the actual predicted benefit and whether the cardiac function recovers with GDMT, trastuzumab could potentially be restarted.

How do novel antibody drug conjugates that contain trastuzumab differ in their cardiotoxicity profile from the naked antibody?

In recent years we have seen the advent of antibody drug conjugates (T-DM1, T-DXd) which in addition the antibody directed against HER2 (trastuzumab) also carry a cytotoxic payload (2). While the experience with these newer agents is still limited, early data suggest these are no more cardiotoxic than trastuzumab. However, the impact of long-term, sequential exposure to these agents on cardiovascular outcomes is unknown.

What are fluoropyrimidines and how does fluoropyrimidine-associated cardiotoxicity manifest clinically?

Fluoropyrimidines are analogs of nucleic acid bases which inhibit synthesis of DNA and RNA. These are some of the most widely use anticancer drugs and examples include 5-fluorouracil (5FU) and capecitabine (an oral prodrug of 5FU). Fluoropyrimidine-associated cardiotoxicity presents primarily with cardiac ischemia caused by coronary vasospasm or endothelial damage, although these are not the only mechanisms by which these drugs can damage the cardiovascular system (3). This is a phenomenon which typically occurs early in therapy after 1-2 cycles and its incidence varies greatly with the mode of administration, occurring in >10% of patients treated with a 5FU infusion (or continuous capecitabine) versus in 3-5% of those who receive the 5FU as a bolus.

What is the management of fluoropyrimidine-associated cardiotoxicity?

Rechallenge is possible in select patients who take active part in the decision-making process and who are deemed to derive substantially larger benefits than risks from continuing. When done, rechallenges usually take place in an inpatient setting with close monitoring and co-administration of calcium channel blockers and nitrates.

Is it possible to rechallenge patients with ischemic symptoms induced by fluoropyrimidine treatment?

Generally, presentations are clinically apparent with symptoms of ischemia and management necessarily includes holding the drug and performing an ischemic work-up which may require invasive testing such as coronary angiography. If there is a clear temporal association with fluoropyrimidine use and ischemic symptoms, a multidisciplinary discussion on whether treatment should be continued is warranted.

What is unique about the cardiotoxicity of oncology therapy in lung cancer patients?

Lung cancer patients are the perfect storm for cardiotoxicity. The prevalence of smoking is very high in this particular cohort which correlates with preexisting cardiovascular disease. Furthermore, radiation to the chest, tyrosine kinase inhibitors (TKIs) targeting EGFR or ALK, and immune checkpoint inhibitors are frequently part of the treatment schema and have defined cardiovascular toxicities (4). As such, these patients are very likely to benefit from cardiology consultation and optimization of cardiovascular risk factors prior to initiating cancer therapy.

What is the cardiovascular toxicity of TKIs?

These systemic treatments were initially developed for metastatic disease but are now making their way into the adjuvant setting. These drugs can maintain efficacy for a long time which translates into prolonged exposure and cardiovascular side effects such as hypertension and QT prolongation.

What is the cardiovascular toxicity of immune checkpoint inhibitors?

Immune checkpoint inhibitors can cause hyperactivation of the immune system resulting in immune attack of normal structures, such as the myocardium. While immune-mediated myocarditis is uncommon (1-2%), it can be very severe with mortality rates approaching 50%, underlining the importance of early recognition and treatment.

References – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent1. 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): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC). European Heart Journal. Published online August 26, 2022:ehac244. doi:10.1093/eurheartj/ehac244

Dent SF, Morse A, Burnette S, Guha A, Moore H. Cardiovascular Toxicity of Novel HER2-Targeted Therapies in the Treatment of Breast Cancer. Current Oncology Reports. 2021;23(11). doi:10.1007/s11912-021-01114-x
Sara JD, Kaur J, Khodadadi R, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. doi:10.1177/1758835918780140
Kunimasa K, Kamada R, Oka T, et al. Cardiac Adverse Events in EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib. JACC: CardioOncology. 2020;2(1):1-10. doi:10.1016/j.jaccao.2020.02.003

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The importance of recognition and diagnosis of cardiac amyloidosis is at an all-time high due to its high prevalence and improved therapeutic strategies. Here we discuss what CardioNerds need to know about the manifestations, diagnosis, and management of transthyretin (ATTR) and light chain (AL) cardiac amyloidosis. Join Dr. Dan Ambinder (CardioNerds Cofounder), Dr. Dinu-Valentin Balanescu (Series Cochair, Chief Resident at Beaumont Health, and soon FIT at Mayo Clinic), and Dr. Dan Davies (Episode FIT Lead and FIT at Mayo Clinic) as they discuss cardiac amyloidosis with Dr. Omar Siddiqi, cardiologist at the Boston University Amyloidosis Center and program director for the general cardiovascular fellowship program at Boston University, a CardioNerds Healy Honor Roll Program. Episode notes were drafted by Dr. Dan Davies. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah.

Access the CardioNerds Cardiac Amyloidosis Series for a deep dive into this important topic.

This episode is supported by a grant from Pfizer Inc.

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

Pearls • Notes • References • Production Team

CardioNerds Cardio-Oncology Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
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Become a CardioNerds Patron!

Pearls and Quotes 1. Cardiac amyloidosis is no longer considered a rare disease, especially transthyretin amyloidosis in older male patients with HFpEF and aortic stenosis. 2. Echocardiogram is the “gate keeper” of cardiac imaging and provides initial evidence of amyloid infiltration, while cardiac MRI can help refine the presence of an infiltrative cardiomyopathy versus other causes of increased wall thickness. 3. The most clinically important types of amyloid heart disease are transthyretin (ATTR) and light chain (AL) amyloidosis. The workup to differentiate these disorders includes a gammopathy panel to screen for the presence of potentially amyloidogenic light chains (serum and urine electrophoresis WITH immunofixation and serum free light chains), and cardiac scintigraphy with Technetium-99m-labeled bone-seeking tracers (PYP, DPD, etc.) to identify cardiac aTTR infiltration if the gammopathy panel is unrevealing. 4. There is still a role for endomyocardial biopsy in the diagnosis of cardiac amyloidosis! All patients in whom there is concern for cardiac amyloidosis and gammopathy panel indicates the presence of monoclonal light chains should have a biopsy to obtain a tissue diagnosis of likely AL amyloidosis. Alternatively, an endocardial biopsy may prove valuable in patients who have confusing phenotypic features between amyloid types, such as a patient with abnormal monoclonal protein and positive PYP imaging. 5. Be suspicious of heart failure patients that do not tolerate typical medications that lower heart rate. In the restrictive cardiomyopathy of cardiac amyloidosis, patients are reliant on higher heart rates to compensate for the inability to augment stroke volume. 6. Be suspicious of amyloidosis in patients with recurrent left atrial thrombi despite anticoagulation.

Show notes CardioNerds Cardiac Amyloid, updated 1.20.211. What is cardiac amyloidosis and how common is it?

Cardiac amyloidosis is adisorder caused by misfolding of proteins into insoluble forms which are deposited into extracellular spaces of the heart, commonly causing a stiff and thick heart with progressive diastolic dysfunction with restrictive hemodynamics and ensuing heart failure.
The two most common types of amyloid protein that affect the heart are transthyretin (ATTR) and light chain (AL). Transthyretin amyloidosis is caused by a misfolded transporter protein produced by the liver, while light chain amyloidosis is caused by a misfolded light chain immunoglobulin produced by clonal plasma cells.
ATTR cardiac amyloidosis may be present in 6-17% of older patients with HFpEF and increased wall thickness, as well as in 4-16% of patients undergoing intervention for severe aortic stenosis. AL amyloidosis is much rarer, with a prevalence of about 12 cases per million persons per year.

2. What are some non-cardiac clues to the presence of cardiac amyloidosis?

Non-cardiac clinical clues for transthyretin amyloidosis (ATTR) include spinal stenosis, biceps tendon rupture, carpal tunnel syndrome (particularly when bilateral), and peripheral neuropathy.
- Bilateral carpal tunnel syndrome may be present in up to 60% of ATTR-CA patients with over 40% having a history of biceps tendon rupture.
Non-cardiac clinical clues for light chain amyloidosis (AL) include renal disease (esp. nephrotic syndrome), macroglossia, autonomic and peripheral neuropathy, and periorbital purpura (racoon eyes).

3. What are common multimodality imaging features used for the diagnosis of cardiac amyloidosis?

For an in-depth discussion about the use of multimodality imaging in the diagnosis of cardiac amyloidosis, enjoy CardioNerds Episode #109 – Nuclear & Multimodality Imaging: Cardiac Amyloidosis.
Echocardiography (echo) is among the first test performed in patients for the diagnosis of cardiovascular symptoms and may provide initial clues to the diagnosis. Features of cardiac amyloidosis on echocardiogram include increased left ventricular wall thickness (>12 mm, classically concentric) with abnormal diastolic function, increased right ventricular free wall and interatrial septal thickness, as well as increased valve thickness. There may be a small pericardial effusion. Left ventricular strain is usually abnormal with a characteristic apical sparing pattern. A granular, or sparkling, appearance of the myocardium has been classically described but is poorly predictive.
Cardiac magnetic resonance (CMR) imaging is often used for differentiation of increased left ventricular wall thickness (infiltrative cardiomyopathies, hypertrophic cardiomyopathies, etc.) and in patients at increased risk of AL cardiac amyloidosis. Common features specific to CMR include abnormal myocardial nulling (blood pool nulls before the myocardium on inversion recovery sequences), elevated native T1 value, increased extracellular volume (ECV), and late gadolinium enhancement (classically in a diffuse, non-ischemic pattern).
Bone scintigraphy (technetium pyrophosphate [PYP] or DPD) is a nuclear imaging study used for the diagnosis of transthyretin amyloidosis. In the absence of an abnormal monoclonal protein, the sensitivity and specificity approach 100%, allowing for the “non-biopsy” diagnosis of ATTR-CA (specifically in the context of a negative gammopathy panel). The 2019 multi-society diagnostic guidelines recommend SPECT imaging be used in combination planar imaging for all cases to improve predictive characteristics.

4. How are heart failure and arrhythmias managed in patients with cardiac amyloidosis?

The mainstay of heart failure therapy in cardiac amyloidosis is loop diuretics with or without aldosterone antagonists. Spironolactone was shown to be effective in patients with a phenotype suggesting cardiac amyloidosis in a subgroup analysis of TOPCAT.
Patients often have poor tolerance of guideline directed medical therapies for heart failure, including beta blockers and calcium channel blockers, with ACEI/ARB/ARNI frequently limited by hypotension. The SGLT2 inhibitors appear to be tolerated in patients with cardiac amyloidosis but more research is needed to determine impact on cardiovascular outcomes.
Rate and rhythm control strategies for atrial arrhythmias can both be successful, but patients may be intolerant of medications. The risk of cardioembolic events in amyloid patients with atrial fibrillations is elevated, independent of CHA2DS2 -VASc score, and therefore all patients should be offered anticoagulation. Be suspicious of amyloidosis in patients with recurrent left atrial appendage thrombi despite anticoagulation.

5. What specific therapies can be used for transthyretin (ATTR) amyloidosis and light chain (AL) amyloidosis?

Tafamidis is a transthyretin stabilizer that inhibits tetramer dissociation and reduces amyloid deposition in extracellular tissue. It is the only FDA approved medication for transthyretin cardiac amyloidosis and was shown to be associated with reduced mortality and heart failure hospitalization compared to control in the ATTR-ACT trial.
Patisiran is a small interfering RNA that works as a gene silencer for ATTR protein production and is FDA approved for patients with polyneuropathy secondary to hereditary ATTR. Analysis of cardiac outcomes in the APOLLO trial suggest early stabilization of left ventricular wall thickness and reduction in natriuretic peptides in patients with features of concomitant cardiac involvement.
Specific therapies for AL amyloidosis are managed by hematologists with the goal of complete hematologic response to prevent further immunoglobulin production and amyloid deposition. These therapies typically include chemotherapy regimens (e.g. cyclophosphamide, bortezomib, dexamethasone [CyBorD]), daratumumab (an anti-CD38 antibody), with or without autologous stem cell transplantation.
There are many ongoing trials with novel therapies, with specific interest in treatments targeting removal of systemically deposited amyloid fibrils.

References 1. 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. J. Nucl. Cardiol. 26, 2065–2123 (2019). Link 2. 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 2 of 2—Diagnostic criteria and appropriate utilization. J. Nucl. Cardiol. 27, 659–673 (2020). Link 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. Link 4. Witteles RM, Liedtke M. AL Amyloidosis for the Cardiologist and Oncologist: Epidemiology, Diagnosis, and Management. JACC CardioOncol. 2019;1(1):117-130. Link 5. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. Link 6. Gertz, M. A., & Dispenzieri, A. (2020). Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review. Jama, 324(1), 79-89. https://jamanetwork.com/journals/jama/fullarticle/2767867 7. Cappelli, F., Zampieri, M., Fumagalli, C., Nardi, G., Del Monaco, G., Matucci Cerinic, M., Allinovi, M., Taborchi, G., Martone, R., Gabriele, M., Ungar, A., Moggi Pignone, A., Marchionni, N., Di Mario, C., Olivotto, I., & Perfetto, F. (2021). Tenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype. J Intern Med, 289(6), 831-839. https://pubmed.ncbi.nlm.nih.gov/33615623/ 8. Sperry, B. W., Hanna, M., Shah, S. J., Jaber, W. A., & Spertus, J. A. (2021). Spironolactone in Patients With an Echocardiographic HFpEF Phenotype Suggestive of Cardiac Amyloidosis: Results From TOPCAT. JACC Heart Fail, 9(11), 795-802. https://www.sciencedirect.com/science/article/pii/S2213177921003206?via%3Dihub 9. Dobner, S., Bernhard, B., Asatryan, B., Windecker, S., Stortecky, S., Pilgrim, T., Gräni, C., & Hunziker, L. (2022). SGLT2 inhibitor therapy for transthyretin amyloid cardiomyopathy: early tolerance and clinical response to dapagliflozin. ESC Heart Fail. https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14188

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CardioNerds Cofounder Dr. Amit Goyal is joined by an esteemed group of UCLA cardiology fellows – Dr. Patrick Zakka (CardioNerds Academy Chief), Dr. Negeen Shehandeh (Chief Fellow), and Dr. Adrian Castillo – to discuss a case of primary cardiac angiosarcoma. An expert commentary is provided by Dr. Eric Yang, beloved educator, associate clinical professor of […]

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CardioNerds (Dr. Patrick Azcarate, Dr. Teodora Donisan, and Amit Goyal) discuss Radiation-Associated Cardiovascular Disease (RACD) with Dr. Eric Yang, cardio-oncologist, assistant professor of medicine, and associate fellowship program director at UCLA. RACD is a consequence of radiation treatment for various mediastinal tumors (breast, lung, lymphoma). It is the second most common cause of morbidity and […]

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CardioNerds (Amit Goyal and Dan Ambinder), Series Co-Chair Dr. Dinu Balanescu (Academy House Faculty and Chief Resident at Beaumont Hospital), and Episode Lead Dr. Manu Mysore (Former CardioNerds Ambassador and Cardiologist at the University of Maryland) discuss The Need for Cardio-Oncology with Expert Faculty Dr. Bonnie Ky, Director of Penn Cardio-Oncology Translation Center of Excellence […]

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CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Phoo Pwint Nandar (former FIT Ambassador), Dr. Deep Shah (current FIT Ambassador), and Dr. Sugat Wagle from the Summa Health Cardiology Department for an afternoon at Cuyahoga National Valley Park. We discuss a case of a post-partum woman who presented with ventricular fibrillation arrest due to SCAD. She had ongoing […]

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CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Sonu Abraham (Cardiology fellow, Lahey Hospital and Medical Center), Dr. Amitoj Singh (Internal Medicine Resident, Lahey Hospital and Medical Center), Dr. Ahmed Ghoneem (Internal Medicine Resident, Lahey Hospital and Medical Center, CardioNerds Academy Chief) and Dr. Aanika Balaji (Internal Medicine Resident, Johns Hopkins) for a scrumptious meal on the Boston […]

The post 196. Case Report: What I C, I Remember: A Case of Acute Heart Failure – Lahey Hospital and Medical Center appeared first on Cardionerds.

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CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Loie Farina (Northwestern University CardioNerds Ambassador), Dr. Josh Cheema, and Dr. Graham Peigh from Northwestern University for drinks along the shores of Lake Michigan at North Avenue Beach. They discuss a case of a 52-year-old woman with limited cutaneous systemic sclerosis who presents with progressive symptoms of […]

The post 178. Case Report: Occam’s Razor or Hickam’s Dictum? Cardiogenic Shock With Severe Biventricular Heart Failure – Northwestern University appeared first on Cardionerds.

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CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Patrick Azcarate and Dr. Antoinette Birs from the University of California San Diego along with a guest host Dr. Christine Shen from Scripps Health for a hike along Torrey Pines. They discuss a case of a 30-year-old man with a history of malignant thymoma status post two partial lung resections […]

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Cardiooncology Archives - Cardionerds: Recent Episodes

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