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

Publisher: Blackwell Country of Publication: United States NLM ID: 9010756 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-8167 (Electronic) Linking ISSN: 10453873 NLM ISO Abbreviation: J Cardiovasc Electrophysiol Subsets: MEDLINE

Publication: Malden, MA : Blackwell
Original Publication: Mt. Kisco, N.Y. : Futura Pub., c1990-

Mutation*; Anti-Arrhythmia Agents/*pharmacology ; Calcium Channel Blockers/*pharmacology ; Calcium Signaling/*drug effects ; Calsequestrin/*metabolism ; Myocytes, Cardiac/*drug effects ; Verapamil/*pharmacology; Adrenergic beta-Antagonists/pharmacology ; Animals ; Calsequestrin/deficiency ; Calsequestrin/genetics ; Diltiazem/pharmacology ; Disease Models, Animal ; Electrocardiography ; Gene Knock-In Techniques ; Magnesium/pharmacology ; Mice ; Mice, Knockout ; 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 ; Polymorphic Catecholaminergic Ventricular Tachycardia

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.
(© 2010 Wiley Periodicals, Inc.)

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PL1 HL092552-01 United States HL NHLBI NIH HHS; R01 HL080494 United States HL NHLBI NIH HHS; P50 HL052320-070006 United States HL NHLBI NIH HHS; P50 HL052320 United States HL NHLBI NIH HHS; P01 HL059139-010009 United States HL NHLBI NIH HHS; R01 HL084553 United States HL NHLBI NIH HHS; R01 HL080494-01 United States HL NHLBI NIH HHS; P01 HL059139 United States HL NHLBI NIH HHS; P50 HL052320-030006 United States HL NHLBI NIH HHS; U01 HL098166 United States HL NHLBI NIH HHS; R01 HL084553-01A1 United States HL NHLBI NIH HHS; U01 HL098166-01 United States HL NHLBI NIH HHS; PL1 HL092552 United States HL NHLBI NIH HHS

0 (Adrenergic beta-Antagonists)
0 (Anti-Arrhythmia Agents)
0 (Calcium Channel Blockers)
0 (Calsequestrin)
0 (Ryanodine Receptor Calcium Release Channel)
0 (casq2 protein, mouse)
9Y8NXQ24VQ (Propranolol)
CJ0O37KU29 (Verapamil)
EE92BBP03H (Diltiazem)
I38ZP9992A (Magnesium)

Date Created: 20100903 Date Completed: 20110624 Latest Revision: 20250103

20250114

PMC3053436

10.1111/j.1540-8167.2010.01877.x

20807279