Abstract

ObjectiveTo understand the underlying pathways that promote cardiotoxicity following chemotherapy. BackgroundAnthracyclines are associated with cardiotoxicity which could be potentiated with use of complementary agents (like anti-ERBB2 inhibitors) which together afford robust anti-neoplastic effects. Anthracyclines lead to oxidative stress and thought to induce cardiotoxicity. However, interventions reducing oxidative stress in patients have been unsuccessful suggesting mechanisms beyond oxidative stress. Despite {beta}-adrenergic receptors ({beta}ARs) being key regulators of cardiac function, nothing is known about their role in chemotherapy-mediated cardiotoxicity. Methods{beta}1 and/or {beta}2-AR density was assessed in end-stage human heart failure patient samples either due to anthracycline cardiotoxicity or non-anthracycline dilated cardiomyopathy (DCM). Since ERBB2 inhibition is integral to overall chemotherapeutic arsenal, we assessed {beta}1- and/or {beta}2-AR density, cardiac function by echocardiography and immunohistochemistry in mice following ERBB2-specific inhibitor AG825. ResultsSelective increase in cardiac {beta}1AR density is observed in end-stage human heart failure patient samples due to anthracycline cardiotoxicity as well as in ERBB2 inhibitor-treated mice. ConclusionsElevated {beta}1AR density may be the key common underlying mechanism which is altered in response to chemotherapy promoting cardiac dilation of otherwise healthy hearts. HighlightsIn contrast to downregulation of {beta}1-adrenergic receptors ({beta}1AR) in end-stage human heart failure, anthracycline cardiotoxicity-mediated failure is associated with selective increase in {beta}1AR density. ERBB2 inhibitor (AG825) treatment in mice results in cardiac dilation and selective rise in {beta}1AR density showing that increased {beta}1AR density in the heart could be a common mechanism underlying cardiotoxicity.