Drug-induced Long-QT syndrome associated with a subclinical SCN5A mutation | |
Article | |
关键词: INHERITED CARDIAC-ARRHYTHMIA; TORSADE-DE-POINTES; NA+ CHANNEL; BRUGADA-SYNDROME; SODIUM-CHANNEL; VENTRICULAR-FIBRILLATION; MOLECULAR MECHANISM; LQT3 MODELS; REPOLARIZATION; PROLONGATION; | |
DOI : 10.1161/01.CIR.0000027139.42087.B6 | |
来源: SCIE |
【 摘 要 】
Background-Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K+ channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na+ channel mutation in an individual who exhibited drug-induced LQTS. Methods and Results-An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na+ channel (SCN5A). The L1825P channel heterologously expressed in tsA-201 cells showed Na+ cur-rent with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A-associated congenital LQTS (LQT3). In addition, L1825P exhibited loss of function Na+ channel features characteristic of Brugada syndrome. Peak Na+ current density observed in cells expressing L1825P was significantly diminished, and the voltage dependence of activation and inactivation was shifted toward more positive and negative potentials, respectively. Conclusions-This study demonstrates that subclinical mutations in the LQTS-related gene SCN5A may predispose certain individuals to drug-induced cardiac arrhythmias.
【 授权许可】
Free