Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome

Minoru Horie, Hideki Itoh, Tomoko Sakaguchi, Wei Guang Ding, Eiichi Watanabe, Ichiro Watanabe, Yukiko Nishio, Takeru Makiyama, Seiko Ohno, Masaharu Akao, Yukei Higashi, Naoko Zenda, Tomoki Kubota, Chikara Mori, Katsunori Okajima, Tetsuya Haruna, Akashi Miyamoto, Mihoko Kawamura, Katsuya Ishida, Iori Nagaoka & 10 others Yuko Oka, Yuko Nakazawa, Takenori Yao, Hikari Jo, Yoshihisa Sugimoto, Takashi Ashihara, Hideki Hayashi, Makoto Ito, Keiji Imoto, Hiroshi Matsuura

Research output: Contribution to journalArticle

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Abstract

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); lectrophysiological 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 r-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. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)

Original languageEnglish
Pages (from-to)511-523
Number of pages13
JournalCirculation: Arrhythmia and Electrophysiology
Volume2
Issue number5
DOIs
Publication statusPublished - 01-10-2009
Externally publishedYes

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Long QT Syndrome
Pharmaceutical Preparations
Genetic Background
Mutation
Mutation Rate
Cricetulus
Computer Simulation
Action Potentials
Ovary
Torsades de Pointes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Horie, Minoru ; Itoh, Hideki ; Sakaguchi, Tomoko ; Ding, Wei Guang ; Watanabe, Eiichi ; Watanabe, Ichiro ; Nishio, Yukiko ; Makiyama, Takeru ; Ohno, Seiko ; Akao, Masaharu ; Higashi, Yukei ; Zenda, Naoko ; Kubota, Tomoki ; Mori, Chikara ; Okajima, Katsunori ; Haruna, Tetsuya ; Miyamoto, Akashi ; Kawamura, Mihoko ; Ishida, Katsuya ; Nagaoka, Iori ; Oka, Yuko ; Nakazawa, Yuko ; Yao, Takenori ; Jo, Hikari ; Sugimoto, Yoshihisa ; Ashihara, Takashi ; Hayashi, Hideki ; Ito, Makoto ; Imoto, Keiji ; Matsuura, Hiroshi. / Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. In: Circulation: Arrhythmia and Electrophysiology. 2009 ; Vol. 2, No. 5. pp. 511-523.
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abstract = "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); lectrophysiological 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 r-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. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)",
author = "Minoru Horie and Hideki Itoh and Tomoko Sakaguchi and Ding, {Wei Guang} and Eiichi Watanabe and Ichiro Watanabe and Yukiko Nishio and Takeru Makiyama and Seiko Ohno and Masaharu Akao and Yukei Higashi and Naoko Zenda and Tomoki Kubota and Chikara Mori and Katsunori Okajima and Tetsuya Haruna and Akashi Miyamoto and Mihoko Kawamura and Katsuya Ishida and Iori Nagaoka and Yuko Oka and Yuko Nakazawa and Takenori Yao and Hikari Jo and Yoshihisa Sugimoto and Takashi Ashihara and Hideki Hayashi and Makoto Ito and Keiji Imoto and Hiroshi Matsuura",
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Horie, M, Itoh, H, Sakaguchi, T, Ding, WG, Watanabe, E, Watanabe, I, Nishio, Y, Makiyama, T, Ohno, S, Akao, M, Higashi, Y, Zenda, N, Kubota, T, Mori, C, Okajima, K, Haruna, T, Miyamoto, A, Kawamura, M, Ishida, K, Nagaoka, I, Oka, Y, Nakazawa, Y, Yao, T, Jo, H, Sugimoto, Y, Ashihara, T, Hayashi, H, Ito, M, Imoto, K & Matsuura, H 2009, 'Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome', Circulation: Arrhythmia and Electrophysiology, vol. 2, no. 5, pp. 511-523. https://doi.org/10.1161/CIRCEP.109.862649

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

In: Circulation: Arrhythmia and Electrophysiology, Vol. 2, No. 5, 01.10.2009, p. 511-523.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome

AU - Horie, Minoru

AU - Itoh, Hideki

AU - Sakaguchi, Tomoko

AU - Ding, Wei Guang

AU - Watanabe, Eiichi

AU - Watanabe, Ichiro

AU - Nishio, Yukiko

AU - Makiyama, Takeru

AU - Ohno, Seiko

AU - Akao, Masaharu

AU - Higashi, Yukei

AU - Zenda, Naoko

AU - Kubota, Tomoki

AU - Mori, Chikara

AU - Okajima, Katsunori

AU - Haruna, Tetsuya

AU - Miyamoto, Akashi

AU - Kawamura, Mihoko

AU - Ishida, Katsuya

AU - Nagaoka, Iori

AU - Oka, Yuko

AU - Nakazawa, Yuko

AU - Yao, Takenori

AU - Jo, Hikari

AU - Sugimoto, Yoshihisa

AU - Ashihara, Takashi

AU - Hayashi, Hideki

AU - Ito, Makoto

AU - Imoto, Keiji

AU - Matsuura, Hiroshi

PY - 2009/10/1

Y1 - 2009/10/1

N2 - 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); lectrophysiological 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 r-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. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)

AB - 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); lectrophysiological 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 r-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. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)

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