Na V 1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model.

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