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Original Articles

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

Hideki Itoh, MD; Tomoko Sakaguchi, MD; Wei-Guang Ding, MD; Eiichi Watanabe, MD; Ichiro Watanabe, MD; Yukiko Nishio, MD; Takeru Makiyama, MD; Seiko Ohno, MD; Masaharu Akao, MD; Yukei Higashi, MD; Naoko Zenda, MD; Tomoki Kubota, MD; Chikara Mori, MD; Katsunori Okajima, MD; Tetsuya Haruna, MD; Akashi Miyamoto, MD; Mihoko Kawamura, MD; Katsuya Ishida, MD; Iori Nagaoka, MD; Yuko Oka, MD; Yuko Nakazawa, MD; Takenori Yao, MD; Hikari Jo, MD; Yoshihisa Sugimoto, MD; Takashi Ashihara, MD; Hideki Hayashi, MD; Makoto Ito, MD; Keiji Imoto, MD; Hiroshi Matsuura, MD and Minoru Horie, MD

From the Department of Cardiovascular and Respiratory Medicine (H.I., T.S., A.M., M.K., K.I., I.N., Y.O., Y.N., T.Y., H.J., Y.S., T.A., H.H., M.I., M.H.) and the Department of Physiology (W.-G.D., H.M.), Shiga University of Medical Science, Shiga, Japan; the Department of Laboratory Medicine (E.W.), Fujita Health University School of Medicine, Toyoake, Japan; the Division of Cardiology (I.W.), Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; the Department of Cardiovascular Medicine (Y.N., T.M., S.O., M.A.), Kyoto University Graduate School of Medicine, Kyoto, Japan; the Cardiovascular Division (Y.H., N.Z.), Showa University Fujigaoka Hospital, Yokohama, Japan; the Division of Cardiology (T.K.), Gifu University Graduate School of Medicine, Gifu, Japan; the Division of Cardiology (C.M.), Department of Internal Medicine, Jikei University School of Medicine, Daisan Hospital, Tokyo, Japan; the Department of Cardiology (K.O.), Hyogo Brain and Heart Center, Himeji, Japan; the Department of Cardiology (T.H.), Kitano Hospital, Osaka, Japan; and the Department of Information Physiology (K.I.), National Institute for Physiological Sciences, Okazaki, Japan.

Correspondence to Minoru Horie, MD, Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, Japan 520-2192. E-mail horie{at}belle.shiga-med.ac.jp

Received February 29, 2008; accepted July 6, 2009.

Background— Drugs with I_Kr-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 I_Kr-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.

Key Words: long-QT syndrome • secondary • drug • electrophysiology • ion channel

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