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Titolo:
Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias
Autore:
Napolitano, C; Schwartz, PJ; Brown, AM; Ronchetti, E; Bianchi, L; Pinnavaia, A; Acquaro, G; Priori, SG;
Indirizzi:
Fdn S Maugeri IRCCS, Mol Cardiol Lab, I-27100 Pavia, Italy Fdn S Maugeri IRCCS Pavia Italy I-27100 ardiol Lab, I-27100 Pavia, Italy Fdn S Maugeri IRCCS, Electrophysiol Lab, I-27100 Pavia, Italy Fdn S Maugeri IRCCS Pavia Italy I-27100 hysiol Lab, I-27100 Pavia, Italy Univ Milan, Ctr Fisiol Clin & Ipertens, Milan, Italy Univ Milan Milan Italy Milan, Ctr Fisiol Clin & Ipertens, Milan, Italy Policlin San Matteo, IRCCS, Dept Cardiol, I-27100 Pavia, Italy Policlin San Matteo Pavia Italy I-27100 pt Cardiol, I-27100 Pavia, Italy Univ Pavia, I-27100 Pavia, Italy Univ Pavia Pavia Italy I-27100Univ Pavia, I-27100 Pavia, Italy Case Western Reserve Univ, Rammellkamp Res Ctr, Cleveland, OH 44106 USA Case Western Reserve Univ Cleveland OH USA 44106 Cleveland, OH 44106 USA Osped Ivrea, Div Cardiol, Ivrea, Italy Osped Ivrea Ivrea ItalyOsped Ivrea, Div Cardiol, Ivrea, Italy
Titolo Testata:
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY
fascicolo: 6, volume: 11, anno: 2000,
pagine: 691 - 696
SICI:
1045-3873(200006)11:6<691:EFACIC>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
TORSADES-DE-POINTES; POTASSIUM CHANNEL; MOLECULAR-BASIS; CISAPRIDE; HERG; TERFENADINE; GENE; ERYTHROMYCIN; INTERVALS; RISK;
Keywords:
acquired long QT syndrome; drug-induced arrhythmias; genetics; sudden cardiac death;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Priori, SG Fdn S Maugeri IRCCS, Mol Cardiol Lab, Via Ferrata 8, I-27100 Pavia, Italy Fdn S Maugeri IRCCS Via Ferrata 8 Pavia Italy I-27100 a, Italy
Citazione:
C. Napolitano et al., "Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias", J CARD ELEC, 11(6), 2000, pp. 691-696

Abstract

The aim of this study was to test the hypothesis that some cases of drug-induced arrhythmias depend on genetic predisposition, Excessive prolongationof 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 LOTS 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 LOTS-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 patientwith 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,vith 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 mag lead to rapidscreening for mutations of candidate genes that cause drug-induced life-threatening arrhythmias and allow early identification of individuals at risk.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 14:01:55