Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 60, Issue 2, Pages 144-156Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2012.02.052
Keywords
arrhythmia; Purkinje fibers; SCN5A; ventricular tachycardia
Categories
Funding
- Agence Nationale de la Recherche [ANR-07-JCJC-0141, ANR-09-GENO-003-01, ANR-05-MRAR-028-01]
- Leducq Foundation Trans-Atlantic Network of Excellence [05 CVD 01]
- European Community [FP7-HEALTH-2009-single-stage 241526]
- Association Francaise contre les Myopathies [14120]
- Fondation pour la Recherche Medicale [DVC20070409253]
- Agence Nationale de la Recherche (ANR) [ANR-07-JCJC-0141] Funding Source: Agence Nationale de la Recherche (ANR)
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Objectives The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease. Background Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias. Methods Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified. Results Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Conclusions A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine. (J Am Coll Cardiol 2012;60:144-56) (C) 2012 by the American College of Cardiology Foundation
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