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 (I-NaL) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na(V)1.8 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 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 mu M) 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. Conclusions 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

Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart

Aims In heart failure (HF), enhanced persistent Na+ current (I-NaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel Na(V)1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy Methods and results By western blot, we found that Na(V)1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform Na(V)1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of Na(V)1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of Na(V)1.8 on I-NaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. Na(V)1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased I-NaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of Na(V)1.8 (SCN10A(-/-)), were associated with reduced I-NaL and abbreviated APD Conclusion We provide first evidence of differential regulation of Na(V)1.8 and Na(V)1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of I-NaL. We propose inhibition of Na(V)1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF