Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions

Simple Summary Atrial fibrillation (AF) represents a worldwide medical problem contributing to substantial morbidity, mortality and social-economic burden. Gap junctions and their constituent components, connexins, are involved in the pathogenesis of AF, though the specific mechanisms have not been fully elucidated. We reviewed the current knowledge on the roles of connexin distribution and abundance in the pathogenesis of AF and the AF-related connexin mutations and polymorphisms as well as their pathogenic mechanisms. We also summarized the potential therapeutic targets and introduced connexin gene therapy for AF. Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have been causally linked to AF, of which the majority encode ion channels, cardiac structural proteins, transcription factors and gap junction channels. In the heart, gap junctions comprised of connexins (Cxs) form intercellular pathways responsible for electrical coupling and rapid coordinated action potential propagation between adjacent cardiomyocytes. Among the 21 isoforms of connexins already identified in the mammal genomes, 5 isoforms (Cx37, Cx40, Cx43, Cx45 and Cx46) are expressed in human heart. Abnormal electrical coupling between cardiomyocytes caused by structural remodeling of gap junction channels (alterations in connexin distribution and protein levels) has been associated with enhanced susceptibility to AF and recent studies have revealed multiple causative mutations or polymorphisms in 4 isoforms of connexins predisposing to AF. In this review, an overview of the genetics of AF is made, with a focus on the roles of mutant myocardial connexins and gap junctions in the pathogenesis of AF, to underscore the hypothesis that cardiac connexins are a major molecular target in the management of AF.