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

Aims In hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV1.8 in human hypertrophied myocardium. Methods and results 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 NaV1.8 mRNA (2.34‐fold) and protein expression (1.96‐fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV1.5 protein expression was significantly reduced in parallel (0.60‐fold). Using whole‐cell patch‐clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV1.8‐specific blockers either A‐803467 (30 nM) or PF‐01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV1.8 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 NaV1.8 inhibitors. Conclusions We show for the first time that the neuronal sodium channel NaV1.8 is up‐regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of NaV1.8 reduced augmented INaL, abbreviated the action potential duration, and decreased the SR‐Ca2+ leak. The findings of our study suggest that NaV1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation