Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density

Abstract

AbstractObjectiveTo 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 β-adrenergic receptors (βARs) being key regulators of cardiac function, nothing is known about their role in chemotherapy-mediated cardiotoxicity.Methodsβ1 and/or β2-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 β1- and/or β2-AR density, cardiac function by echocardiography and immunohistochemistry in mice following ERBB2-specific inhibitor AG825.ResultsSelective increase in cardiac β1AR density is observed in end-stage human heart failure patient samples due to anthracycline cardiotoxicity as well as in ERBB2 inhibitor-treated mice.ConclusionsElevated β1AR 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 β1-adrenergic receptors (β1AR) in end-stage human heart failure, anthracycline cardiotoxicity-mediated failure is associated with selective increase in β1AR density.ERBB2 inhibitor (AG825) treatment in mice results in cardiac dilation and selective rise in β1AR density showing that increased β1AR density in the heart could be a common mechanism underlying cardiotoxicity.