Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca²⁺ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca²⁺ cycling, the incidence of refractory cases is still significant. Surprisingly, these 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 poorly understood and is the object of this study.

We performed optical Ca²⁺ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na⁺ channels (neuronal Na⁺ channels; nNa_v) colocalize with ryanodine receptor Ca²⁺ release channels (RyR2). Disruption of the crosstalk between nNa_v and RyR2 by nNa_v blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice.

Thus, our study offers the first evidence that nNa_v contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy.