窦性心律
心房颤动
后去极化
电生理学
内科学
舒张去极化
心房动作电位
舒张期
赫尔格
心脏电生理学
内分泌学
医学
化学
心脏病学
中庭(建筑)
窦房结
心率
钾通道
复极
血压
作者
Steffen Pabel,Shakil Ahmad,Petros Tirilomis,Thea Stehle,Julian Mustroph,M Knierim,Nataliya Dybkova,Philipp Bengel,Andreas Holzamer,Michael Hilker,Katrin Streckfuß‐Bömeke,Gerd Hasenfuß,Lars S. Maier,Samuel Sossalla
标识
DOI:10.1007/s00395-020-0780-8
摘要
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 (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.
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