Molecular and Functional Relevance of Na V 1.8-Induced Atrial Arrhythmogenic Triggers in a Human SCN10A Knock-Out Stem Cell Model.

In heart failure and atrial fibrillation, a persistent Na+ current (INaL ) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV 1.8 contributes to arrhythmogenesis by inducing a INaL . Genome-wide association studies indicate that mutations in the SCN10A gene (NaV 1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV 1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A -KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the INaL and action potential duration. Ca2+ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca2+ leak. The INaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of NaV 1.8. No effects on atrial APD90 were detected in any groups. Both SCN10A KO and specific blockers of NaV 1.8 led to decreased Ca2+ spark frequency and a significant reduction of arrhythmogenic Ca2+ waves. Our experiments demonstrate that NaV 1.8 contributes to INaL formation in human atrial CMs and that NaV 1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore NaV 1.8 could be a new target for antiarrhythmic strategies.