The functional consequences of sodium channel Na_V1.8 in human left ventricular hypertrophy

Abstract

AimsIn 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 resultsMyocardial 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.ConclusionsWe 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.

Absence of Functional Nav1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes

“…While our findings indicate a lack of functional relevance for Na V 1.8 in CMs under physiological conditions, they do not rule out a potential function during pathophysiological situations. Recently, increased SCN10A/Na V 1.8 expression in human ventricular tissue isolated from heart failure and hypertrophic patients as compared to non-failing and healthy myocardium, has been demonstrated [39,40]. Na V 1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased late I Na magnitude, abbreviated APD and reduced cellular-spontaneous Ca 2+− release and proarrhythmic events in human failing and hypertrophic CMs [39,40].…”

The Role of Nav1.8 in Cardiac Electrophysiology—a Matter of the Heart or the Nerve?

“…In contrast to these findings in healthy, structurally normal hearts and cardiomyocytes, in disease states-such as heart failure and cardiac hypertrophy-a significant and relevant upregulation of SCN10A/Nav1.8 mRNA and protein expression has been observed both in cardiac tissue and in cardiomyocytes and its functional relevance has been verified by blocking experiments (13,14), suggesting that in the diseased, remodeled heart, the neural form Nav1.8 may indeed directly affect the cardiomyocyte's electrical function.…”

“…SCN10A/Nav1.8 mutations have been identified in Brugada syndrome (11,12). Moreover, recently, it has been demonstrated that SCN10A/Nav1.8 is upregulated in heart failure (13) and cardiac hypertrophy (14), thus contributing to electrical remodeling in diseased hearts. All these studies suggest that SCN10A/Nav1.8 may play a role in arrhythmogenic cardiac diseases.…”

Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents

“…The enhanced CaMKII-mediated Na v 1.5 phosphorylation, therefore, certainly takes part in increasing I Na,late under oxidative stress. Recent studies have found that Na v 1.8 expression is significantly up-regulated, while Na v 1.5 is reduced in human left ventricular hypertrophy (Ahmad et al, 2019) and HF (Dybkova et al, 2018). The Vicious Circle of CaMKII-I Na,late -…”

“…Targeting Na v 1.8 with specific inhibitors might provide a potential novel approach in the future in antiarrhythmic drug therapy, because recent studies have found that Na v 1.8 expression is significantly up-regulated in human left ventricular hypertrophy (Ahmad et al, 2019) and HF (Dybkova et al, 2018). By using Na v 1.8-specific blockers [either A-803467 (30 nM) or PF-01247324 (1 mM)] the authors managed to reduce I Na,late and APD in these experiments.…”