TY - JOUR
T1 - Characterization of the cardiac sodium channel SCN5A mutation, N1325S, in single murine ventricular myocytes
AU - Yong, Sandro L.
AU - Ni, Ying
AU - Zhang, Teng
AU - Tester, David J.
AU - Ackerman, Michael J.
AU - Wang, Qing K.
N1 - Funding Information:
We thank Dr. G. Kirsch for critical reading of the manuscript. This work was supported by the NIH Grant R01 HL66251 (to Q.W.), an AHA Established Investigator Award (to Q.W.), and an AHA-Ohio-Affiliate Postdoctoral Fellowship (to S.Y.).
PY - 2007/1/12
Y1 - 2007/1/12
N2 - 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 (INa,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.
AB - 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 (INa,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.
KW - APD
KW - Intracellular Ca
KW - Late persistent sodium current
KW - Sodium channel gene SCN5A
KW - Sudden death
KW - Type 3 long-QT syndrome (LQTS)
KW - Ventricular arrhythmias
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U2 - 10.1016/j.bbrc.2006.11.019
DO - 10.1016/j.bbrc.2006.11.019
M3 - Article
C2 - 17118339
AN - SCOPUS:33751540669
SN - 0006-291X
VL - 352
SP - 378
EP - 383
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -