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(Circulation Research. 2007;101:1039.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Arrhythmogenic Mechanisms in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Marina Cerrone^*, Sami F. Noujaim^*, Elena G. Tolkacheva, Arkadzi Talkachou, Ryan O’Connell, Omer Berenfeld, Justus Anumonwo, Sandeep V. Pandit, Karen Vikstrom, Carlo Napolitano, Silvia G. Priori, José Jalife

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.

Correspondence to José Jalife, M.D., Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, 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 (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol’s solution, and patch clamping in a knockin (RyR2/RyR2^R4496C) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2^R4496C and in 9% of 11 wild-type (P=0.03) littermates perfused with Ca²⁺and isoproterenol; 66% of 12 RyR2/RyR2^R4496C 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/RyR2^R4496C mice. Under current clamp, single Purkinje cells from RyR2/RyR2^R4496C 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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