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】

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