The functional consequences of sodium channel Na_V 1.8 in human left ventricular hypertrophy

In hypertrophy and heart failure, the proarrhythmic persistent Na⁺ current (I_NaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na_V 1.8 in human hypertrophied myocardium.

Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of Na_V 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na_V 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I_NaL was significantly reduced after addition of novel Na_V 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na_V 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca²⁺ leak and SR-Ca²⁺ spark frequency after exposure to both Na_V 1.8 inhibitors.

We show for the first time that the neuronal sodium channel Na_V 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na_V 1.8 reduced augmented I_NaL , abbreviated the action potential duration, and decreased the SR-Ca²⁺ leak. The findings of our study suggest that Na_V 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.