Journal of the American College of Cardiology · 2012
Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Laurent Gabriel, Saal Samuel, Amarouch Mohamed Yassine, Béziau Delphine M, Marsman Roos F J, Faivre Laurence, Barc Julien, Dina Christian, Bertaux Geraldine, Barthez Olivier, Thauvin-Robinet Christel, Charron Philippe, Fressart Véronique, Maltret Alice, Villain Elisabeth, Baron Estelle, Mérot Jean, Turpault Rodolphe, Coudière Yves, Charpentier Flavien, Schott Jean-Jacques, Loussouarn Gildas, Wilde Arthur A M, Wolf Jean-Eric, Baró Isabelle, Kyndt Florence, Probst Vincent
Аннотация
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.
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.
Предметные рубрики MeSH
AdolescentAdultAnti-Arrhythmia AgentsArrhythmias, CardiacCardiomyopathy, DilatedChildDNA Mutational AnalysisDeath, Sudden, CardiacElectrophysiologic Techniques, CardiacFemaleGenetic Association StudiesHumansInfantInfant, NewbornMaleMiddle AgedMutationMyocardial ContractionNAV1.5 Voltage-Gated Sodium ChannelPatch-Clamp TechniquesPedigreePhenotypePurkinje FibersQuinidineSodium ChannelsSyndromeVentricular Premature ComplexesYoung Adult