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Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying Calsequestrin‐2 Mutation
Author(s) -
ALCALAI RONNY,
WAKIMOTO HIROKO,
ARAD MICHAEL,
PLANER DAVID,
KONNO TETSUO,
WANG LIBIN,
SEIDMAN JON G.,
SEIDMAN CHRISTINE E.,
BERUL CHARLES I
Publication year - 2011
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/j.1540-8167.2010.01877.x
Subject(s) - catecholaminergic polymorphic ventricular tachycardia , calsequestrin , ryanodine receptor 2 , verapamil , ryanodine receptor , medicine , myocyte , ventricular tachycardia , calcium , endocrinology , dantrolene , voltage dependent calcium channel , cardiology
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 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 . (J Cardiovasc Electrophysiol, Vol. 22, pp. 316‐324, March 2011)