Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure

In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na(V)1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model. An interplay between Ca2+/calmodulin-dependent protein kinase II delta c (CaMKII delta c) 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 CaMKII delta c-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 CaMKII delta c in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na(V)1.8 and CaMKII delta c, we show that Na(V)1.8-driven I-NaL is CaMKII delta c-dependent and that Na(V)1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKII delta c-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 CaMKII delta c downstream target which may constitute a prognostic and antiarrhythmic strategy.