Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo
Copyright policy )Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo
Mutations in the cardiac sodium channel gene SCN5A are responsible for type-3 long QT disease (LQT3). The genesis of cardiac arrhythmias in LQT3 is multifaceted, and the aim of this study was to further explore mechanisms by which SCN5A mutations lead to arrhythmogenesis in vivo.We engineered selective cardiac expression of a long QT syndrome (LQTS) mutation (N1325S) in human SCN5A and generated a transgenic mouse model, TGM(NS31).Conscious and unrestrained TGM(NS31)L12 mice demonstrated a significant prolongation of the QT-interval and a high incidence of spontaneous polymorphic ventricular tachycardia (VT) and fibrillation (VF), often resulting in sudden cardiac death (n=52:156). Arrhythmias were suppressed by mexiletine, a sodium channel blocker for the late persistent sodium current. Action potentials (APs) from TGM(NS31)L12 ventricular myocytes exhibited early afterdepolarizations and longer 90% AP durations (APD90=69 +/- 5.9 ms) than control (APD90=46.7 +/- 4.8 ms). Voltage-clamp experiments in transgenic myocytes revealed a peak inward sodium current (INa) followed by a slow recovery from inactivation. After mexiletine application, transgenic ventricular APDs were shortened, and recovery from inactivation of INa was enhanced. These suggest that the N1325S transgene is responsible for the abnormal signals present in transgenic cells as well as the genesis of lethal arrhythmias in mice. Interestingly, transgenic but not wild-type myocytes displayed longer APDs with a shortening of CLs.Our findings show that a new model for LQTS has been established, and we report on an arrhythmogenic mechanism that, unlike other SCN5A mutations, results in poor restitution of APD with increasing rate as a possible substrate for arrhythmogenesis.
- Cleveland Clinic United States
- University System of Ohio United States
- Cleveland State University United States
- Cleveland Clinic Lerner College of Medicine United States
- Case Western Reserve University United States
Long QT Syndrome, Mice, Death, Sudden, Cardiac, Models, Animal, Mutation, Electrocardiography, Ambulatory, Action Potentials, Animals, Telemetry, Mice, Transgenic, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel
Long QT Syndrome, Mice, Death, Sudden, Cardiac, Models, Animal, Mutation, Electrocardiography, Ambulatory, Action Potentials, Animals, Telemetry, Mice, Transgenic, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel
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