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Circulation: Arrhythmia and Electrophysiology

Year: 2009  |  Volume: 2  |  Issue: 5  |  Page No.: 511 - 523

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome

H Itoh, T Sakaguchi, W. G Ding, E Watanabe, I Watanabe, Y Nishio, T Makiyama, S Ohno, M Akao, Y Higashi, N Zenda, T Kubota, C Mori, K Okajima, T Haruna, A Miyamoto, M Kawamura, K Ishida, I Nagaoka, Y Oka, Y Nakazawa, T Yao, H Jo, Y Sugimoto, T Ashihara, H Hayashi, M Ito, K Imoto, H Matsuura and M. Horie

Abstract

Background— Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown.

Methods and Results— Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.

Conclusions— dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

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