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.

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.

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.