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.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan. 

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

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Pearls and Quotes – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Cardiologist Perspective with Dr. Joerg Hermann

1. 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 Hermann

What 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 Hermann

Herrmann 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

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/.