Journal Article

Molecular and Functional Relevance of Nasub.V1.8-Induced Atrial Arrhythmogenic Triggers in a Human ISCN10A/I Knock-Out Stem Cell Model

Hasenfuß, Gerd, Maurer, Wiebke, Knierim, Maria, Streckfuss-Bömeke, Katrin, Dybkova, Nataliya, Sossalla, Samuel, Hartmann, Nico

2023

Overview

In heart failure and atrial fibrillation, a persistent Na[sup.+] current (I[sub.NaL]) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na[sub.V]1.8 contributes to arrhythmogenesis by inducing a I[sub.NaL]. Genome-wide association studies indicate that mutations in the SCN10A gene (Na[sub.V]1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na[sub.V]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 I[sub.NaL] and action potential duration. Ca[sup.2+] measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca[sup.2+] leak. The I[sub.NaL] was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na[sub.V]1.8. No effects on atrial APD[sub.90] were detected in any groups. Both SCN10A KO and specific blockers of Na[sub.V]1.8 led to decreased Ca[sup.2+] spark frequency and a significant reduction of arrhythmogenic Ca[sup.2+] waves. Our experiments demonstrate that Na[sub.V]1.8 contributes to I[sub.NaL] formation in human atrial CMs and that Na[sub.V]1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na[sub.V]1.8 could be a new target for antiarrhythmic strategies.

• Publisher: MDPI AG
• Subject: Anti-arrhythmia drugs / Genomics / Stem cells