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

• Published in: Journal of the American College of Cardiology Vol. 60; no. 2; pp. 144 - 156
• Main Authors: LAURENT, Gabriel, SAAL, Samuel, THAUVIN-ROBINET, Christel, CHARRON, Philippe, FRESSART, Véronique, MALTRET, Alice, VILLAIN, Elisabeth, BARON, Estelle, MEROT, Jean, TURPAULT, Rodolphe, COUDIERE, Yves, CHARPENTIER, Flavien, MOHAMED YASSINE AMAROUCH, SCHOTT, Jean-Jacques, LOUSSOUARN, Gildas, WILDE, Arthur A. M, WOLF, Jean-Eric, BARO, Isabelle, KYNDT, Florence, PROBST, Vincent, BEZIAU, Delphine M, MARSMAN, Roos F. J, FAIVRE, Laurence, BARC, Julien, DINA, Christian, BERTAUX, Geraldine, BARTHEZ, Olivier
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 10.07.2012
• Subjects: Adolescent; Adult; Anti-Arrhythmia Agents - therapeutic use; Arrhythmias, Cardiac - genetics; Biological and medical sciences; Cardiology. Vascular system; Cardiomyopathy, Dilated - genetics; Child; Death, Sudden, Cardiac; Diseases of mother, fetus and pregnancy; DNA Mutational Analysis; Electrophysiologic Techniques, Cardiac; Female; Genetic Association Studies; Gynecology. Andrology. Obstetrics; Humans; Infant; Infant, Newborn; Male; Medical sciences; Middle Aged; Mutation; Myocardial Contraction - drug effects; Myocardial Contraction - genetics; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Pedigree; Phenotype; Pregnancy. Fetus. Placenta; Purkinje Fibers - physiopathology; Quinidine - analogs & derivatives; Quinidine - therapeutic use; Sodium Channels - genetics; Sodium Channels - physiology; Syndrome; Ventricular Premature Complexes - drug therapy; Ventricular Premature Complexes - genetics; Ventricular Premature Complexes - physiopathology; Young Adult; Heart; Premature; Circulatory system; Ectopia; Cardiology; Contraction
• DOI: 10.1016/j.jacc.2012.02.052
• ISSN: 0735-1097; 1558-3597

The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease. Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias. 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. 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. 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.