Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo.
OBJECTIVE
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.


METHODS
We engineered selective cardiac expression of a long QT syndrome (LQTS) mutation (N1325S) in human SCN5A and generated a transgenic mouse model, TGM(NS31).


RESULTS
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.


CONCLUSIONS
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.
Tian
Xiao-Li
XL
Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
Yong
Sandro L
SL
Wan
Xiaoping
X
Wu
Ling
L
Chung
Mina K
MK
Tchou
Patrick J
PJ
Rosenbaum
David S
DS
Van Wagoner
David R
DR
Kirsch
Glenn E
GE
Wang
Qing
Q
D000200:Action Potentials; D000818:Animals; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D015716:Electrocardiography, Ambulatory; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*; D013686:Telemetry
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels