Na1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model.

The sodium channel Na1.8, encoded by the gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that Na1.8 contributes to arrhythmogenesis by inducing a persistent Na current (late Na current, I) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of Na1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that I was significantly reduced in ventricular -KO iPSC-CM and in control CM after a specific pharmacological inhibition of Na1.8. In contrast, we did not find any effects on ventricular APD. The frequency of spontaneous sarcoplasmic reticulum Ca sparks and waves were reduced in KO iPSC-CM and control cells following the pharmacological inhibition of Na1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in KO iPSC-CM and after the specific inhibition of Na1.8 in control cells. In conclusion, we show that Na1.8-induced I primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca release. The inhibition or knockout of Na1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms Na1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy.