The N1325S mutation in the cardiac sodium channel gene SMA 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,I-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 nonbradycardic 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. (c) 2006 Elsevier Inc. All rights reserved.