Neuronal Na+ Channels as a Novel Cardiac Antiarrhythmic Target

Abstract

Listen

Translate article

BackgroundCertain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum. Surprisingly, CPVT patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains elusive.MethodsConfocal microscopy and patch‐clamp recordings ofventricular myocytes isolated from CPVT mouse model with genetic ablation of cardiac calsequestrinwere used to assess Ca2+ handling and Na+ current density during various pharmacological interventions, while surface electrocardiograms were performed during catecholamine challenge.ResultsA subpopulation of Na+ channels (neuronal‐ and not cardiac‐type Na+ channels) colocalize with RyR2. Disruption of the cross‐talk between these by neuronal Na+ channel blockade abolished persistent Na+ current and reduced DCR in cells (Fig a).imageSuch reduction of DCR on cellular level translated in decreased arrhythmias in vivo (Fig b). On the other hand, augmentation of the neuronal Na+ channel activity with β‐Pompilidotoxin (β‐PMTX) increased DCR and caused frequent arrhythmias.ConclusionThese data suggest that neuronal Na+ channels can potentially serve as an antiarrhythmic target. As current antiarrhythmic drugs are all cardiac‐type Na+ channel blockers, this is a major conceptual shift in cellular arrhythmogenesis.