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

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198 Scopus citations

Abstract

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 Ca 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) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 and in 9% of 11 wild-type (P=0.03) littermates perfused with Caand isoproterenol; 66% of 12 RyR2/RyR2 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 mice. Under current clamp, single Purkinje cells from RyR2/RyR2 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.

Original languageEnglish (US)
Pages (from-to)1039-1048
Number of pages10
JournalCirculation research
Volume101
Issue number10
DOIs
StatePublished - Nov 1 2007

Keywords

  • Bidirectional ventricular tachycardia
  • CPVT
  • Ryanodine receptor
  • Sudden cardiac death
  • Transgenic mice

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    Cerrone, M., Noujaim, S. F., Tolkacheva, E. G., Talkachou, A., O'Connell, R., Berenfeld, O., Anumonwo, J., Pandit, S. V., Vikstrom, K., Napolitano, C., Priori, S. G., & Jalife, J. (2007). Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circulation research, 101(10), 1039-1048. https://doi.org/10.1161/CIRCRESAHA.107.148064