Molecular and Functional Relevance of Na1.8-Induced Atrial Arrhythmogenic Triggers in a Human Knock-Out Stem Cell Model.

In heart failure and atrial fibrillation, a persistent Na current (I) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na1.8 contributes to arrhythmogenesis by inducing a I. Genome-wide association studies indicate that mutations in the gene (Na1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial -KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I and action potential duration. Ca measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca leak. The I was significantly reduced in atrial KO CMs as well as after specific pharmacological inhibition of Na1.8. No effects on atrial APD were detected in any groups. Both KO and specific blockers of Na1.8 led to decreased Ca spark frequency and a significant reduction of arrhythmogenic Ca waves. Our experiments demonstrate that Na1.8 contributes to I formation in human atrial CMs and that Na1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na1.8 could be a new target for antiarrhythmic strategies.