TY - JOUR
T1 - Multifocal Ectopic Purkinje-Related Premature Contractions A New SCN5A-Related Cardiac Channelopathy
AU - Laurent, Gabriel
AU - Saal, Samuel
AU - Amarouch, Mohamed Yassine
AU - Béziau, Delphine M.
AU - Marsman, Roos F. J.
AU - Faivre, Laurence
AU - Barc, Julien
AU - Dina, Christian
AU - Bertaux, Geraldine
AU - Barthez, Olivier
AU - Thauvin-Robinet, Christel
AU - Charron, Philippe
AU - Fressart, Véronique
AU - Maltret, Alice
AU - Villain, Elisabeth
AU - Baron, Estelle
AU - Mérot, Jean
AU - Turpault, Rodolphe
AU - Coudière, Yves
AU - Charpentier, Flavien
AU - Schott, Jean-Jacques
AU - Loussouarn, Gildas
AU - Wilde, Arthur A. M.
AU - Wolf, Jean-Eric
AU - Baró, Isabelle
AU - Kyndt, Florence
AU - Probst, Vincent
PY - 2012
Y1 - 2012
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.jacc.2012.02.052
DO - https://doi.org/10.1016/j.jacc.2012.02.052
M3 - Article
C2 - 22766342
SN - 0735-1097
VL - 60
SP - 144
EP - 156
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 2
ER -