Neuronal Na v 1.8 Channels as a Novel Therapeutic Target of Acute Atrial Fibrillation Prevention

Abstract

Background Ganglionated plexus have been developed as additional ablation targets to improve the outcome of atrial fibrillation ( AF ) besides pulmonary vein isolation. Recent studies implicated an intimate relationship between neuronal sodium channel Na v 1.8 (encoded by SCN 10A ) and AF . The underlying mechanism between Na v 1.8 and AF remains unclear. This study aimed to determine the role of Na v 1.8 in cardiac electrophysiology in an acute AF model and explore possible therapeutic targets. Methods and Results Immunohistochemical study was used on canine cardiac ganglionated plexus. Both Na v 1.5 and Na v 1.8 were expressed in ganglionated plexus with canonical neuronal markers. Sixteen canines were randomly administered either saline or the Na v 1.8 blocker A‐803467. Electrophysiological study was compared between the 2 groups before and after 6‐hour rapid atrial pacing. Compared with the control group, administration of A‐803467 decreased the incidence of AF (87.5% versus 25.0%, P <0.05), shortened AF duration, and prolonged AF cycle length. A‐803467 also significantly suppressed the decrease in the effective refractory period and the increase in effective refractory period dispersion and cumulative window of vulnerability caused by rapid atrial pacing in all recording sites. Patch clamp study was performed under 100 nmol/L A‐803467 in TSA 201 cells cotransfected with SCN 10A ‐ WT , SCN 5A ‐ WT , and SCN 3B ‐ WT . I N a,P was reduced by 45.34% at −35 mV, and I N a,L by 68.57% at −20 mV. Evident fast inactivation, slow recovery, and use‐dependent block were also discovered after applying the drug. Conclusions Our study demonstrates that Na v 1.8 could exert its effect on electrophysiological characteristics through cardiac ganglionated plexus. It indicates that Na v 1.8 is a novel target in understanding cardiac electrophysiology and SCN 10A ‐related arrhythmias.