Abstract 8681: The Cardioprotective Role of Renin-Angiotensin System Antagonism in the Prevention of Doxorubicin and Trastuzumab Mediated Cardiac Dysfunction

Abstract

Background: In breast cancer patients, the administration of chemotherapeutic based agents, in particular Doxorubicin (Dox), is associated with an increased risk of cardiotoxicity. The introduction of novel monoclonal antibodies in breast cancer therapy, specifically Trastuzumab (Trz), further compounds this issue of drug induced cardiac dysfunction. Little is known about the use of renin-angiotensin system (RAS) antagonists in the prevention of Dox and Trz mediated cardiac dysfunction. Objective: To evaluate the cardioprotective effects of RAS antagonism in the prevention of Dox and Trz mediated cardiomyopathy in a chronic murine model. Methods: A total of 120 C57Bl/6 mice were randomized to three arms: (A) Trz; (B) Dox; or (C) Dox+Trz. The mice in each arm were further randomized to receive prophylactic treatment daily in their drinking water with either placebo, direct renin inhibitor (DRI), angiotensin converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). Serial murine echocardiography was performed weekly for 13 weeks, after which the hearts were removed for histopathologic analyses. Results: In arm A (Trz), there was no evidence of cardiotoxicity at week 13. In arms B (Dox) and C (Dox+Trz), prophylactic treatment with either RAS antagonist was partially cardioprotective. In arm C (Dox+Trz), mice prophylactic treated with either placebo, DRI, ACEI or ARB demonstrated a decrease in fractional shortening from 51±2% at baseline to 26±2%, 40±2%, 32±2% and 34±2% (p<0.05), at week 13, respectively. Survival analyses of each arm corroborated the echocardiographic findings (Figure 1). There was a decrease in histologic evidence of cardiac damage due to Dox+Trz pretreated with either RAS antagonist. Conclusion: Prophylactic administration of RAS antagonists is partially cardioprotective in a chronic murine model of chemotherapy induced cardiac dysfunction. Figure 1: