Napolitano C, Schwartz P J, Brown A M, Ronchetti E, Bianchi L, Pinnavaia A, Acquaro G, Priori S G
Molecular Cardiology and Electrophysiology Laboratories, Fondazione S. Maugeri IRCCS, Pavia, Italy.
J Cardiovasc Electrophysiol. 2000 Jun;11(6):691-6. doi: 10.1111/j.1540-8167.2000.tb00033.x.
The aim of this study was to test the hypothesis that some cases of drug-induced arrhythmias depend on genetic predisposition. Excessive prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some drug-induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of drug-induced QT prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause drug-induced life-threatening arrhythmias and allow early identification of individuals at risk.
本研究的目的是检验药物性心律失常的某些病例取决于遗传易感性这一假说。QT间期过度延长和危及生命的心律失常（尖端扭转型室速或室颤）可能由多种心脏和非心脏药物引起，对患者安全和制药行业的投资都会产生不利影响。莫斯和施瓦茨推测，一些药物性心律失常可能是先天性长QT综合征（LQTS）的“顿挫型”病例。LQTS基因分子筛查技术的出现使我们能够检验这一假说。一名老年女性患者有记录显示因西沙必利（一种阻断I(Kr)并短暂延长QT间期的促胃肠动力药）导致心脏骤停，对其进行了已知LQTS相关基因的突变分析，采用单链构象多态性和DNA测序方法。以非洲爪蟾卵母细胞作为表达系统的双电极电压钳用于研究与野生型（WT）基因共表达时遗传缺陷所导致的体外细胞表型。分子分析显示存在一个杂合突变，导致KvLQT1孔区一个高度保守的氨基酸被替代。这种突变不仅存在于发生室颤的患者中，还存在于她的两个QT间期正常的成年无症状儿子中。突变的KvLQT1蛋白的体外表达显示电流严重丧失，对WT-KvLQT1通道有显性负性作用。我们的研究结果表明，某些药物性QT间期延长病例可能取决于遗传底物。分子筛查可能有助于在家族成员中识别出如果接受I(Kr)阻滞剂治疗可能有风险的基因携带者。不断发展的技术可能会导致对引起药物性危及生命心律失常的候选基因突变进行快速筛查，并能早期识别有风险的个体。
