Why the study?
Although interplay between CaMKIIδc and late Na+ current induces arrhythmias in the failing heart, the role of sodium channel isoform NaV1.8 in CaMKIIδc-dependent proarrhythmia remained to be elucidated.
Does NaV1.8 inhibition or knockout reduce CaMKIIδc-dependent proarrhythmia and improve survival in heart failure models?
Does NaV1.8 inhibition or knockout reduce CaMKIIδc-dependent proarrhythmia and improve survival in heart failure models?
Effect estimate: HR 0.6
Absolute Event Rate: 98% vs 72%
Knockout or pharmacological inhibition of NaV1.8 reduces CaMKIIδc-driven late sodium current and cellular arrhythmias, translating to decreased ventricular tachycardia and improved survival in a heart failure mouse model.
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.
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Bengel et al. (2021) studied Heart failure. NaV1.8 knockout vs. CaMKIIδc+/T (wildtype for NaV1.8) was evaluated on Median survival (days) (HR 0.6).
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