Characterization of the cardiac sodium channel SCN5A mutation, N₁₃₂₅S, in single murine ventricular myocytes

The N₁₃₂₅S mutation in the cardiac sodium channel gene SCN5A causes the type-3 long-QT syndrome but the arrhythmogenic trigger associated with N₁₃₂₅S has not been characterized. In this study, we investigated the triggers for cardiac events in the expanded N₁₃₂₅S family. Among 11 symptomatic patients with document triggers, six died suddenly during sleep or while sitting (bradycardia-induced trigger), three died suddenly, and two developed syncope due to stress and excitement (non-bradycardia-induced). Patch-clamping studies revealed that the late sodium current (I_Na,L) generated by mutation N₁₃₂₅S in ventricular myocytes from TG-NS/LQT3 mice was reduced with increased pacing, which explains bradycardia-induced mortalities in the family. The non-bradycardic triggers are related to the finding that APD became prolonged and unstable at increasing rates, often with alternating repolarization phases which was corrected with verapamil. This implies that Ca²⁺ influx and intracellular Ca²⁺ ([Ca²⁺]_i) ions are involved and that [Ca²⁺]_i inhomogeneity may be the underlying mechanisms behind non-bradycardia LQT3 arrhythmogenesis associated with mutation N₁₃₂₅S.