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

Ronny Alcalai, Hiroko Wakimoto, Michael Arad, David Planer, Tetsuo Konno, Libin Wang, Jon G. Seidman, Christine E. Seidman, Charles I. Berul

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Arrhythmia Prevention in CPVT. 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 Ca2+ 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 Ca2+-channel inhibitors, β-adrenergic inhibitors, or Mg2+. Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca2+ transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress-induced ventricular arrhythmia in mutant mice. The Ca2+ channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca2+ content in mutant myocytes, diminished diastolic Ca2+ overload, increased systolic Ca2+ amplitude, and prevented Ca2+ oscillations in stressed mutant myocytes. Conclusions: Ca2+ channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil-induced partial normalization of SR Ca2+ content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca2+ buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT.

Original languageEnglish
Pages (from-to)316-324
Number of pages9
JournalJournal of Cardiovascular Electrophysiology
Volume22
Issue number3
DOIs
StatePublished - Mar 2011

Funding

FundersFunder number
National Heart, Lung, and Blood InstituteR01HL080494
National Heart, Lung, and Blood Institute

    Keywords

    • CPVT
    • antiarrhythmia agents
    • calcium
    • calsequestrin-2
    • mouse model
    • sudden death

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