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

Br J Pharmacol. 2015 May;172(9):2369-82. doi: 10.1111/bph.13062. Epub 2015 Mar 17.

Abstract

Background and purpose: The Ca(2+) 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 Ca(2+) channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from over-elevated cytoplasmic Ca(2+) through increased Ca(2+) entry by PDE3 inhibition under diminished sarcoplasmic reticulum Ca(2+) reuptake and increased Ca(2+) 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 Ca(2+) handling. Reduction of cytoplasmic Ca(2+) elevated by PDE3 inhibition might decrease this risk of sudden cardiac death.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling / drug effects
  • Cardiomyopathy, Dilated / drug therapy*
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / metabolism
  • Cardiomyopathy, Dilated / physiopathology
  • Cardiotonic Agents / pharmacology*
  • Cardiotonic Agents / toxicity
  • Death, Sudden, Cardiac / etiology
  • Death, Sudden, Cardiac / prevention & control
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Heart Failure / drug therapy*
  • Heart Failure / genetics
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Myocardial Contraction / drug effects*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Phosphodiesterase 3 Inhibitors / pharmacology
  • Pyridazines / pharmacology*
  • Pyridazines / toxicity
  • Risk Assessment
  • Risk Factors
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Time Factors
  • Troponin T / genetics
  • Ventricular Function, Left / drug effects
  • Ventricular Remodeling / drug effects

Substances

  • Calcium Channels, L-Type
  • Cardiotonic Agents
  • Phosphodiesterase 3 Inhibitors
  • Pyridazines
  • Troponin T
  • pimobendan