Tetrodotoxin‐Sensitive Neuronal‐Type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Cynthia A. Carnes¹  Silvia G. Priori¹  Heather L. Struckman²  Przemysław B. Radwański²  Héctor H. Valdivia³  Roberto Ramos Mondragon⁴  Joseph Biskupiak⁴  Jessica Mandrioli⁵  Kibum Kim⁶  Rengasayee Veeraraghavan⁶  Mark A. Munger⁷  Yusuf Olğar⁸  Megan L. Koleske⁸  Sándor Györke⁸  Ingrid Bonila⁸  Qing Lou⁸  Pompeo Volpe⁹ 

[1] Integrative Physiology University of Michigan Ann Arbor MI;Department of Biomedical Engineering College of Engineering The Ohio State University Columbus OH;Department of Biomedical Sciences University of Padova Italy;;Department of Internal Medicine and of Molecular &Department of Neuroscience St. Agostino Estense Hospital Azienda Ospedaliero Universitaria di Modena Italy;Department of Pharmacotherapy University of Utah Health Sciences Center Salt Lake City UT;Departments of Pharmacotherapy and Internal Medicine University of Utah Health Sciences Center Salt Lake City UT;Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH;Molecular Cardiology Istituti Clinici Scientifici Maugeri IRCCS University of Pavia Italy;

关键词: atrial arrhythmias;    atrial fibrillation;    cardiac arrhythmias;    neuronal‐type Na+ channel blockade;   

DOI  :  10.1161/JAHA.119.015119

来源: DOAJ

【 摘 要 】

Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca2+‐dependent nature of both of these pathologies, AF often responds to Na+ channel blockers. We investigated how targeting interdependent Na+/Ca2+ dysregulation might prevent focal activity and control AF. Methods and Results We studied AF in 2 models of Ca2+‐dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing‐induced heart failure. Imaging studies revealed close association of neuronal‐type Na+ channels (nNav) with ryanodine receptors and Na+/Ca2+ exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild‐type mice only during pharmacological augmentation of nNav activity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNav inhibition (tetrodotoxin or riluzole) implicating Na+/Ca2+ dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole‐treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new‐onset AF, supporting the preclinical results. Conclusions These data suggest that nNaVs mediate Na+‐Ca2+ crosstalk within nanodomains containing Ca2+ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNav inhibition can effectively prevent AF arising from diverse causes.

【 授权许可】

Unknown