Published online before print September 13, 2007, doi: 10.1161/CIRCRESAHA.107.148064
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Submitted on January 9, 2007
Revised on August 21, 2007
Accepted on August 31, 2007
Arrhythmogenic Mechanisms in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
Marina Cerrone ;
From the Department of Pharmacology and Institute for Cardiovascular Research (M.C., S.F.N., E.G.T., A.T., R.O'C., O.B., J.A., S.V.P., K.V., J.J.), State University of New York, Upstate Medical University, Syracuse; and Molecular Cardiology (C.N., S.G.P.), Istituti di Ricovero e Cura a Carattere Scientifico Fondazione Maugeri, Pavia, Italy.
* To whom correspondence should be addressed. E-mail: jalifej{at}upstate.edu.
Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca2+ release through defective ryanodine receptor (RyR)2 channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol’s solution, and patch clamping in a knockin (RyR2/RyR2R4496C) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2R4496C and in 9% of 11 wild-type (P=0.03) littermates perfused with Ca2+and isoproterenol; 66% of 12 RyR2/RyR2R4496C and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (P=0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His–Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol’s solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2R4496C mice. Under current clamp, single Purkinje cells from RyR2/RyR2R4496C mouse hearts generated delayed afterdepolarization–induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His–Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT.
Key words: ryanodine receptor • CPVT • transgenic mice • bidirectional ventricular tachycardia • sudden cardiac death
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