on August 2, 2009
Published online before print August 2, 2009, doi: 10.1161/CIRCEP.109.862649
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Original Article |
Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-induced Long QT Syndrome
1 Shiga University of Medical Science, Shiga, Japan;
2 Fujita Health University School of Medicine, Toyoake, Japan;
3 Nihon University School of Medicine, Tokyo, Japan;
4 Kyoto University Graduate School of Medicine, Kyoto, Japan;
5 Showa University Fujigaoka Hospital, Yokohama, Japan;
6 Gifu University Graduate School of Medicine, Gifu, Japan;
7 Jikei University School of Medicine, Daisan Hospital, Tokyo, Japan;
8 Hyogo Brain and Heart Center, Himeji, Japan;
9 Kitano Hospital, Osaka, Japan;
10 National Institute for Physiological Sciences, Okazaki, Japan
* Corresponding author; email: horie{at}belle.shiga-med.ac.jp
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 (CHO) cells together with a computer simulation model. The positive-mutation rate in dLQTS was similar to cLQTS (dLQTS vs. cLQTS, 8 of 20 [40%] vs. 91 of 176 [52%] subjects, p=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by non-antiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic vs. others, 3 of 14 [21%] vs. 5 of 6 [83%] subjects, p<0.05). When reconstituted in CHO 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 (WT). With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of WT and cLQTS.
Conclusions—dLQTS had a similar positive-mutation rate compared to cLQTS while 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.
Key Words: drugs • electrophysiology • ion channels • long-QT syndrome • secondary