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

Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying calsequestrin-2 Mutation

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Free PMC article

Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying calsequestrin-2 Mutation

Ronny Alcalai et al. J Cardiovasc Electrophysiol. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1. Typical ventricular arrhythmias recorded in CASQ2-/- mice
(A) Representative traces of normal sinus rhythm at baseline, (B) ventricular bigeminy after epinephrine IP injection, (C) sustained polymorphic ventricular tachycardia with bidirectional pattern after epinephrine IP injection.
Figure 2
Figure 2. Effect of IP injection of several drugs on arrhythmia and heart rate in CASQ2-/- mice
(A) Percentage of time in sustained ventricular arrhythmia during 10 minutes of recording after IP injection of Epinephrine. Recording were made without treatment and 2 minutes after test drug injection as indicated. * - p< 0.05 compare to no treatment, # - p< 0.05 compare to propranolol treatment. (B) Mean heart rate at baseline and after test drug IP injection as indicated. * - p< 0.05 compare to baseline, # - p< 0.05 compare to propranolol treatment.
Figure 3
Figure 3. Effect of oral treatment of Propranolol and Verapamil on arrhythmia rate in CASQ2-/- mice
Each line represents the percentage of time in sustained ventricular arrhythmia during 10 minutes of recording after IP injection of epinephrine in one mutant mouse at baseline and after two weeks of oral drug treatment as indicated.
Figure 4
Figure 4. SR Ca2+ transients of CASQ2-/- myocytes
Representative traces from CASQ2 mutant myocytes during constant epinephrine infusion for 5 minutes with electrical pacing at 1 Hz (ticks in the upper panel). The recordings were made in Tyrode solution (upper panel), in High Mg2+ (3mM) solution (middle panel) and in solution containing 1μM Verapamil (lower panel). Note elevation of diastolic Ca2+ levels (arrow), reduction of transient peak height, and development of Ca2+ oscillation after 4 minutes of epinephrine infusion (right side of upper panel). These pathologic responses to epinephrine were prevented by Mg2+ and more effectively by verapamil.
Figure 5
Figure 5. Verapamil increased SR Ca2+ content of CASQ2-/- myocytes
(A) Representative traces of caffeine-induced (20 mM) Ca2+ transients in wild type (WT) and CASQ2-/- myocytes with and without pre-treatment with verapamil. (B) Bars denote pooled data from 10 untreated wild-type cells (white), 23 untreated CASQ2-/- cells (black) and 22 treated CASQ2-/- cells (gray) from at least 3 independent myocyte preparations. *- p<0.01 compare to wildtype cells, #- p<0.05 compare to CASQ2-/- cells.

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