Journal Article

Nasub.V1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model

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

2024

Overview

The sodium channel Na[sub.V]1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na[sub.V]1.8 contributes to arrhythmogenesis by inducing a persistent Na[sup.+] current (late Na[sup.+] current, I[sub.NaL]) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of Na[sub.V]1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that I[sub.NaL] was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of Na[sub.V]1.8. In contrast, we did not find any effects on ventricular APD[sub.90]. The frequency of spontaneous sarcoplasmic reticulum Ca[sup.2+] sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of Na[sub.V]1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of Na[sub.V]1.8 in control cells. In conclusion, we show that Na[sub.V]1.8-induced I[sub.NaL] primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca[sup.2+] release. The inhibition or knockout of Na[sub.V]1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms Na[sub.V]1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.

• Publisher: MDPI AG
• Subject: Stem cells