Stage-dependent benefits and risks of pimobendan in mice with genetic dilated cardiomyopathy and progressive heart failure

Miki Nonaka, Sachio Morimoto, Takashi Murayama, Nagomi Kurebayashi, Lei Li, Yuan Yuan Wang, Masaki Arioka, Tatsuya Yoshihara, Fumi Takahashi-Yanaga, Toshiyuki Sasaguri

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Background and Purpose The Ca2+ sensitizer pimobendan is a unique inotropic agent that improves cardiac contractility with less of an increase in oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia, compared with traditional inotropes. However, clinical trials report contradictory effects of pimobendan in patients with heart failure (HF). We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF. Experimental Approach 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. Key Results Pimobendan prevented myocardial remodelling in compensated HF and significantly extended life span in both compensated and end-stage HF, but dose-dependently increased sudden death in end-stage HF. In cardiomyocytes isolated from end-stage HF mice, pimobendan induced triggered activity probably because of early or delayed afterdepolarizations. The L-type Ca2+ channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from over-elevated cytoplasmic Ca2+ through increased Ca2+ entry by PDE3 inhibition under diminished sarcoplasmic reticulum Ca2+ reuptake and increased Ca2+ leakage from sarcoplasmic reticulum in end-stage HF. Conclusions and Implications Pimobendan was beneficial regardless of HF stage, but increased sudden cardiac death in end-stage HF with extensive remodelling of Ca2+ handling. Reduction of cytoplasmic Ca2+ elevated by PDE3 inhibition might decrease this risk of sudden cardiac death.

Original languageEnglish
Pages (from-to)2369-2382
Number of pages14
JournalBritish Journal of Pharmacology
Volume172
Issue number9
DOIs
Publication statusPublished - Jan 5 2015

All Science Journal Classification (ASJC) codes

  • Pharmacology

Fingerprint

Dive into the research topics of 'Stage-dependent benefits and risks of pimobendan in mice with genetic dilated cardiomyopathy and progressive heart failure'. Together they form a unique fingerprint.

Cite this