Statins to Prevent Cardiotoxicity from Anthracyclines

Survival among patients with non-Hodgkins Lymphoma (NHL) has improved, in part due to a combination of earlier diagnosis, improved characterization, and improved treatments. Anthracyclines are an integral part of most chemotherapy regimens for patients with NHL and have contributed to this improved survival. However, the use of anthracyclines is limited by the well recognized and frequent occurrence of cardiotoxicity. In comparison to other patients receiving anthracycline-based chemotherapy, patients with NHL are at the highest risk of adverse cardiac events. Statins reduce inflammation, decrease oxidative stress, improve vascular function, and attenuate myocardial fibrosis, all key pathophysiological processes implicated in the development of anthracycline cardiotoxicity. Therefore, in this randomized clinical trial, we will determine whether statins preserves left ventricular (LV) ejection fraction (EF) 12 months after the initiation of chemotherapy in patients with NHL undergoing anthracycline-based chemotherapy. Conventional measurement of LVEF using 2-dimensional (2-D) echocardiography is limited by temporal variability; therefore we will test the effect of statin therapy on cardiac magnetic resonance (CMR)-derived LVEF. We are not powered to detect a difference in clinical events; however, as statin therapy has been shown to reduced heart failure hospitalization, and this will be a key goal of subsequent studies, we will capture this data. We also propose to provide mechanistic insights, by using the additive tissue characterization available with CMR imaging, to evaluate the effect of statin therapy on myocardial fibrosis. Finally, cardiotoxicity occurs beyond a reduction in LVEF. Therefore, we propose to test whether statin therapy limits the increase in markers of myocardial injury (cardiac troponin) and sensitive markers of myocardial function (myocardial strain). At the completion of this proposal, we will have characterized the effect of statins on anthracycline-induced LV dysfunction in patients with NHL, established their safety, and gained insights into the mechanisms by which statins limits cardiotoxicity. The demonstration of a beneficial effect of statins on cardiac function will allow the design of a larger clinical trial testing the ability of statins to prevent cardiovascular morbidity and mortality in patients being treated with anthracyclines.