Andersen-Tawil syndrome (ATS1)-associated ventricular tachycardias (VTs) are initiated by frequent, hypokalemia-exacerbated, premature ventricular activity (PVA). We previously demonstrated that a guinea pig model of drug-induced ATS1 (DI-ATS1) evidenced increased arrhythmias from regions with high Na⁺/Ca²⁺-exchange expression.

Therefore, we hypothesize that reduced cytosolic Na⁺ entry through either cardiac isoform of or tetrodotoxin (TTX)-sensitive Na⁺ channels during DI-ATS1 can ameliorate arrhythmia burden.

DI-ATS1 was induced with 10 μM BaCl₂ and 2 mM extracellular K⁺. Ca²⁺ transients and conduction velocity (CV) were optically mapped with indo-1 and di-4-ANEPPS, respectively, from Langendorff-perfused guinea pig ventricles.

Nonselective Na⁺ channel blockade with 1 μM flecainide reduced amplitude (Ca_A), slowed left ventricular CV, reduced tissue excitability, and abolished the incidence of VT while decreasing the incidence of PVA relative to DI-ATS1. Selective, TTX-sensitive Na⁺ channel blockade with TTX (100 nM) during DI-ATS1 decreased Ca_A and decreased the inducibility of VTs and PVA relative to DI-ATS1 without slowing CV. Ranolazine altered Ca_A, left ventricular CV, tissue excitability, and reduced inducibility of VT and PVA in a concentration-dependent manner. None of the aforementioned interventions altered diastolic Ca²⁺ levels or Ca²⁺ transient decay time constant.

These data suggest that cytosolic Na⁺ entry and its modulation of Ca²⁺ handling are necessary for arrhythmogenesis. During the loss of inward-rectifier K⁺ current function, not only Na⁺/Ca²⁺-exchange dominance but Na⁺ flux may determine arrhythmia burden. Therefore, selective inhibition of TTX-sensitive Na⁺ channels may offer a potential therapeutic target to alleviate arrhythmias during states of Ca²⁺ overload secondary to loss of inward-rectifier K⁺ current function without compromising the excitability reserve.