title: Stage-dependent benefits and risks of pimobendan in mice with genetic dilated cardiomyopathy and progressive heart failure.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nonaka
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Wang
authors.forename: Masaki
authors.initials: M
authors.lastname: Arioka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshihara
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000633:toxicity; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology* / Q000633:toxicity; D018570:Risk Assessment; D012307:Risk Factors; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D020107:Troponin T / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D011724:Pyridazines; D020107:Troponin T; C041648:pimobendan