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


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.
Alcalai
Ronny
R
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Wakimoto
Hiroko
H
Arad
Michael
M
Planer
David
D
Konno
Tetsuo
T
Wang
Libin
L
Seidman
Jon G
JG
Seidman
Christine E
CE
Berul
Charles I
CI
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002155:Calsequestrin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004110:Diltiazem / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography; D055879:Gene Knock-In Techniques; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; D011433:Propranolol; D014700:Verapamil; D004110:Diltiazem; D008274:Magnesium
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