Markers of Oxidative and Nitrosative Stress in Anthracycline Cardiotoxicity and Statin Cardioprotection

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY 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.