Anthracyclines are highly effective chemotherapeutics, but result in a clinically significant risk of heart failure (HF), left ventricular ejection fraction (LVEF) declines, and cardiomyopathy. The ongoing randomized clinical trial (RCT), The PREVENT (Preventing Anthracycline Cardiovascular Toxicity with Statins) study, is testing the hypothesis that atorvastatin 40 mg/day will prevent anthracycline-induced cardiomyocyte injury, HF, and cardiomyopathy. This RCT represents a rich and unique resource with banked blood samples and rigorously analyzed cardiac magnetic resonance (CMR) imaging-derived measures of CV function and structure. In this R21 application, we propose an ancillary biomarker study to PREVENT. Our fundamental objective is to determine if biomarkers of oxidative and nitrosative stress are clinically and mechanistically informative in cancer patients treated with anthracyclines. Our strong preliminary data support a role for biomarkers such as myeloperoxidase (MPO) and the arginine-NO metabolites asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) in predicting cardiac dysfunction with anthracyclines. Statin therapy has been shown to alter these markers, suggestive of a potential mechanistic link. We hypothesize that MPO, ADMA, MMA, and HDL-associated enzymes such as paraoxonase and arylesterase will be associated with changes in LVEF by CMR. We also hypothesize that statins will attenuate the adverse anthracycline-induced changes in these biomarkers, and these biomarkers can be used to identify ?statin responders,? i.e., those who derive the most cardioprotective benefit from statins. Cancer therapy associated cardiovascular disease is a significant clinical problem, and decreasing this growing public health burden is a high priority directive within the NCI and NHLBI, as evidenced by PA 16-036, the NHLBI Strategic Vision, and the Cancer Moonshot initiative. This R21 will efficiently and effectively leverage existent resources, build upon our initial observations of mechanistic biomarkers of oxidative and nitrosative stress; and advance an innovative paradigm in cardio-oncology of biomarker-guided, personalized delivery of cardioprotective strategies.

Public Health Relevance

Anthracyclines are an important therapy for various malignancies. However, this agent can result in significant adverse effects on the heart. Ongoing clinical trials, such as the PREVENT study, are rigorously studying the question of whether statin therapy can attenuate anthracycline-induced adverse cardiac effects. In PREVENT, we propose to test if circulating proteins of oxidative and nitrosative stress can be used to identify patients who are at risk of adverse cardiac outcomes, as well as those will derive the most benefit from statins. This work will improve the personalized delivery of cancer therapy and cardioprotective strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Cancer, Heart, and Sleep Epidemiology A Study Section (CHSA)
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Desvigne-Nickens, Patrice
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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