Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias

The aim of this study was to test the hypothesis that some cases of drug-in duced 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 an d noncardiac drugs, with detrimental effects on patient safety and the inve stments 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 s creening techniques for LOTS genes allowed us to test this hypothesis. An e lderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I-Kr, and transiently prolonged QT interval u nderwent mutational analysis of the known LOTS-related genes performed by s ingle-strand conformational polymorphism and DNA sequencing, Double-electro de voltage clamp in Xenopus oocytes as the expression system was used to st udy the in vitro cellular phenotype caused by the genetic defect in coexpre ssion with the wild-type (WT) gene, Molecular analysis revealed a heterozyg ous mutation leading to substitution of a highly conserved amino acid in th e pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons w ho have a normal QT interval, In vitro expression of the mutated KvLQT1 pro tein showed a severe loss of current,vith a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of drug-induce d QT prolongation may depend on a genetic substrate. Molecular screening ma y allow identification among family members of gene carriers potentially at risk if treated with I-Kr blockers, Evolving technology mag lead to rapid screening for mutations of candidate genes that cause drug-induced life-thr eatening arrhythmias and allow early identification of individuals at risk.