Abstract
Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involvement of NaV1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking NaV1.8. NaV1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of NaV1.8 and NaV1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of NaV1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of NaV1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that NaV1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of NaV1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A−/− mice (genetic ablation of NaV1.8). Pharmacological NaV1.8 inhibition showed no effects in SCN10A−/− mice. Importantly, in vivo experiments in SCN10A−/− mice showed that genetic ablation of NaV1.8 protects against atrial fibrillation induction. This study demonstrates that NaV1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking NaV1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.
Highlights
Atrial arrhythmias, in particular atrial fibrillation (AF), contribute to the morbidity and mortality of western societies [4]
Using Quantitative real‐time PCR (qPCR), we detected the expression of N aV1.8 mRNA in human atrial tissue, which was 3.0 ± 0.9-fold higher in the human atrium as compared to ventricular non-failing myocardium
To evaluate whether NaV1.8 or the major cardiac sodium channel isoform NaV1.5 might be differentially regulated in atrial fibrillation (AF) compared to sinus rhythm (SR), we investigated atrial myocardium from patients with sarcoplasmic reticulum (SR) or with AF
Summary
In particular atrial fibrillation (AF), contribute to the morbidity and mortality of western societies [4]. The mechanisms for atrial arrhythmogenesis include electrical remodelling and disturbances in ion homeostasis [16]. Both can cause focal triggered activity, which might evoke atrial arrhythmias or promote re-entry mechanisms. One potent substrate in promoting electrical disturbances and focal triggered activity in the atria is an increased late N a+ current (INaL), which is a persistent N a+ influx throughout the action potential [3, 16, 22, 33]. Increasing diastolic Ca2+ levels may promote a depolarizing inward current (Iti), resulting in delayed afterdepolarizations (DADs), which serve as a trigger for irregular action potentials and focal arrhythmias [32]. The mechanisms involved in INaL generation in the atria are not fully understood
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