Inhibition of Na_V1.8 prevents atrial arrhythmogenesis in human and mice

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 (Na_V1.8) in atrial electrophysiology. This study investigated the role and involvement of Na_V1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking Na_V1.8. Na_V1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of Na_V1.8 and Na_V1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of Na_V1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of Na_V1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that Na_V1.8 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 Na_V1.8 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 Na_V1.8). Pharmacological Na_V1.8 inhibition showed no effects in SCN10A^-/- mice. Importantly, in vivo experiments in SCN10A^-/- mice showed that genetic ablation of Na_V1.8 protects against atrial fibrillation induction. This study demonstrates that Na_V1.8 is expressed in the murine and human atria and contributes to late Na⁺ current generation and cellular arrhythmogenesis. Blocking Na_V1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.