Inhibition of NaV1.8 prevents atrial arrhythmogenesis in human and mice

• Published in: Basic research in cardiology Vol. 115; no. 2; p. 20
• Main Authors: Pabel, Steffen, Ahmad, Shakil, Tirilomis, Petros, Stehle, Thea, Mustroph, Julian, Knierim, Maria, Dybkova, Nataliya, Bengel, Philipp, Holzamer, Andreas, Hilker, Michael, Streckfuss-Bömeke, Katrin, Hasenfuss, Gerd, Maier, Lars S., Sossalla, Samuel
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2020; Springer Nature B.V
• Subjects: Ablation; Action potential; Arrhythmia; Atria; Calcium (reticular); Calcium ions; Cardiac arrhythmia; Cardiology; Cardiomyocytes; Electrocardiography; Electrophysiology; Fibrillation; Genomes; Isoproterenol; Leak channels; Medicine; Medicine & Public Health; mRNA; Myocardium; Original Contribution; Patients; Pharmacology; Rhythm; Sarcoplasmic reticulum; Side effects; Sodium; Sodium channels (voltage-gated); Target recognition; Therapeutic applications; Ventricle; channel; Antiarrhythmic drugs; Atrial arrhythmias; Late sodium current; Na
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-020-0780-8

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 V 1.8) in atrial electrophysiology. This study investigated the role and involvement of Na V 1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking Na V 1.8. Na V 1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of Na V 1.8 and Na V 1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of Na V 1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of Na V 1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that Na V 1.8 significantly contributes to late Na + current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca 2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of Na V 1.8 potently reduced late Na + current, proarrhythmic diastolic Ca 2+ 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 V 1.8). Pharmacological Na V 1.8 inhibition showed no effects in SCN10A −/− mice. Importantly, in vivo experiments in SCN10A −/− mice showed that genetic ablation of Na V 1.8 protects against atrial fibrillation induction. This study demonstrates that Na V 1.8 is expressed in the murine and human atria and contributes to late Na + current generation and cellular arrhythmogenesis. Blocking Na V 1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias.