Detrimental proarrhythmogenic interaction of Ca²⁺/calmodulin-dependent protein kinase II and Na_V1.8 in heart failure.

Abstract

An interplay between Ca²⁺/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_V1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na_V1.8, we demonstrate that Na_V1.8 contributes to I_NaL formation. In addition, we reveal a direct interaction between Na_V1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na_V1.8 and CaMKIIδc, we show that Na_V1.8-driven I_NaL is CaMKIIδc-dependent and that Na_V1.8-inhibtion reduces diastolic SR-Ca²⁺ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na_V1.8 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.