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

ABSTRACT: 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 (nNa_v) 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 nNa_v 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 nNa_v 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 nNa_Vs mediate Na⁺-Ca²⁺ crosstalk within nanodomains containing Ca²⁺ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa_v inhibition can effectively prevent AF arising from diverse causes.

SUBMITTER: Munger MA 

PROVIDER: S-EPMC7429002 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature