title: Atrial Fibrillation andSCN5AVariants.
abstract: Although atrial fibrillation (AF) is clinically and genetically a highly heterogeneous disease, recent studies suggest that the arrhythmia may arise because of interactions between genetic and acquired risk factors - the so called "double-hit" hypothesis. Genome-wide association studies have identified common AF susceptibility loci, and linkage analysis and candidate gene approaches have identified mutations in genes that encode for cardiac ion channels and signaling proteins; however, most of the heritability of AF still remains unexplained. The voltage-dependent cardiac sodium channel, encoded bySCN5A, conducts the main cardiac inward sodium current (INa) and is responsible for the upstroke of the atrial action potential. Mutations inSCN5A, which encodes the α-subunit of the NaV1.5 channel, have been linked with increased susceptibility to not only AF but also ventricular arrhythmias (long QT syndrome, Brugada syndrome), progressive cardiac conduction disease, and overlap syndromes with mixed arrhythmia phenotypes. Over the last decade, functional characterization ofSCN5Amutations by expressing the channel in heterologous expression systems and applying cellular electrophysiological techniques has not only advanced our understanding of molecular mechanisms of AF but also potentially identified a mechanism-based approach to treating this common and morbid condition.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Savio-Galimberti
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
keywords: SCN5A; SCN5A mutations; action potential; atrial fibrillation; electrophysiology; gain of function; loss of function; “two-hit” hypothesis