Multifocal Ectopic Purkinje-Related Premature Contractions A New SCN5A-Related Cardiac Channelopathy

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:60

Article

Laurent, Gabriel¹  Saal, Samuel²  Amarouch, Mohamed Yassine^3,4,5  Beziau, Delphine M.^3,4,5  Marsman, Roos F. J.⁶  Faivre, Laurence²  Barc, Julien^3,4  Dina, Christian^3,4  Bertaux, Geraldine¹  Barthez, Olivier¹  Thauvin-Robinet, Christel²  Charron, Philippe^7,8  Fressart, Veronique^9,10  Maltret, Alice¹¹  Villain, Elisabeth¹¹  Baron, Estelle^3,4  Merot, Jean^3,4,5  Turpault, Rodolphe^4,12  Coudiere, Yves^4,12  Charpentier, Flavien^3,4,5,13  Schott, Jean-Jacques^3,4,13  Loussouarn, Gildas^3,4,5  Wilde, Arthur A. M.⁶  Wolf, Jean-Eric¹  Baro, Isabelle^3,4,5  Kyndt, Florence^3,4,14  Probst, Vincent^3,4,13 

[1] CHU Dijon, Serv Cardiol, Hop Bocage, F-21079 Dijon, France

[2] CHU Dijon, Ctr Genet, Hop Enfants, F-21079 Dijon, France

[3] INSERM, UMR1087, Inst Thorax, Nantes, France

[4] Univ Nantes, Nantes, France

[5] CNRS, UMR6291, Nantes, France

[6] Univ Amsterdam, Acad Med Ctr, Dept Expt Cardiol, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[7] GH Pitie Salpetriere, AP HP, Dept Cardiol, Paris, France

[8] Univ Paris 06, INSERM, Dept Genet, UMR S956, Paris, France

[9] GH Pitie Salpetriere, AP HP, UF Cardiogenet & Myogenet Mol & Cellulaire, Serv Biochim Metab, Paris, France

[10] Ctr Genet, Paris, France

[11] Univ Paris 05, Hop Necker Enfants Malad, Paris, France

[12] CNRS, UMR6629, Lab Math Jean Leray, Nantes, France

[13] CHU Nantes, Inst Thorax, Nantes, France

[14] CHU Nantes, Serv Genet Med, F-44035 Nantes 01, France

关键词: arrhythmia;    Purkinje fibers;    SCN5A;    ventricular tachycardia;   

DOI  :  10.1016/j.jacc.2012.02.052

来源: Elsevier

【 摘 要 】

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

【 授权许可】

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