Prevention of ventricular arrhythmia and calcium dysregulation in a catecholaminergic polymorphic ventricular tachycardia mouse model carrying calsequestrin-2 mutation

J Cardiovasc Electrophysiol. 2011 Mar;22(3):316-24. doi: 10.1111/j.1540-8167.2010.01877.x. Epub 2010 Aug 30.


Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmic syndrome caused by mutations in genes encoding the calcium-regulation proteins cardiac ryanodine receptor (RyR2) or calsequestrin-2 (CASQ2). Mechanistic studies indicate that CPVT is mediated by diastolic Ca(2+) overload and increased Ca(2+) leak through the RyR2 channel, implying that treatment targeting these defects might be efficacious in CPVT.

Method and results: CPVT mouse models that lack CASQ2 were treated with Ca(2+) -channel inhibitors, β-adrenergic inhibitors, or Mg(2+) . Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca(2+) transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress-induced ventricular arrhythmia in mutant mice. The Ca(2+) channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca(2+) content in mutant myocytes, diminished diastolic Ca(2+) overload, increased systolic Ca(2+) amplitude, and prevented Ca(2+) oscillations in stressed mutant myocytes.

Conclusions: Ca(2+) channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil-induced partial normalization of SR Ca(2+) content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca(2+) buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Calcium Channel Blockers / pharmacology*
  • Calcium Signaling / drug effects*
  • Calsequestrin / deficiency
  • Calsequestrin / genetics
  • Calsequestrin / metabolism*
  • Diltiazem / pharmacology
  • Disease Models, Animal
  • Electrocardiography
  • Gene Knock-In Techniques
  • Magnesium / pharmacology
  • Mice
  • Mice, Knockout
  • Mutation*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Propranolol / pharmacology
  • Ryanodine Receptor Calcium Release Channel / drug effects
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / prevention & control
  • Time Factors
  • Verapamil / pharmacology*


  • Adrenergic beta-Antagonists
  • Anti-Arrhythmia Agents
  • Calcium Channel Blockers
  • Calsequestrin
  • Ryanodine Receptor Calcium Release Channel
  • casq2 protein, mouse
  • Propranolol
  • Verapamil
  • Diltiazem
  • Magnesium

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia