Stage-Dependent Benefits and Risks of Pimobendan in Genetic Dilated Cardiomyopathy Mice with Progressive Heart Failure

Abstract

The Ca2+ sensitizer pimobendan is a unique inotropic agent that, compared with traditional inotropes, improves cardiac contractility with less oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia. However, clinical trials report contradictory effects of pimobendan in heart failure (HF) patients. We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF.A knock-in mouse model of human genetic dilated cardiomyopathy, which shows a clear transition from compensatory to end-stage HF at a fixed time during growth, was used to evaluate the efficacy of pimobendan and explore the underlying molecular and cellular mechanisms.Pimobendan prevented myocardial remodelling in compensated HF and significantly extended the life span in both compensated and end-stage HF, but dose-dependently increased the sudden death in end-stage HF. In cardiomyocytes isolated from end-stage HF mice, pimobendan induced triggered activity probably due to early or delayed afterdepolarizations via markedly up-regulated electrogenic sodium/calcium exchanger 1 activation. The L-type Ca2+ channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from overly elevated cytoplasmic Ca2+ through increased Ca2+ entry by phosphodiesterase 3 inhibition under diminished sarcoplasmic reticulum Ca2+ reuptake and increased Ca2+ leakage from sarcoplasmic reticulum in end-stage HF.Pimobendan is beneficial irrespective of HF stage, but increases sudden cardiac death in end-stage HF with extensive remodelling ofCa2+ handling. Reduction of cytoplasmic Ca2+ elevated by phosphodiesterase 3 inhibition may decrease the risk of sudden cardiac death.