Detrimental proarrhythmogenic interaction of Ca(2+)/calmodulin-dependent protein kinase II and Na(V)1.8 in heart failure

An interplay between Ca(2+)/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na(+) current (I(NaL)) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na(V)1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na(V)1.8, we demonstrate that Na(V)1.8 contributes to I(NaL) formation. In addition, we reveal a direct interaction between Na(V)1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na(V)1.8 and CaMKIIδc, we show that Na(V)1.8-driven I(NaL) is CaMKIIδc-dependent and that Na(V)1.8-inhibtion reduces diastolic SR-Ca(2+) leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na(V)1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy.