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


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.
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan.
Hideki
H
Itoh
Tomoko
T
Sakaguchi
Wei-Guang
WG
Ding
Eiichi
E
Watanabe
Ichiro
I
Watanabe
Yukiko
Y
Nishio
Takeru
T
Makiyama
Seiko
S
Ohno
Masaharu
M
Akao
Yukei
Y
Higashi
Naoko
N
Zenda
Tomoki
T
Kubota
Chikara
C
Mori
Katsunori
K
Okajima
Tetsuya
T
Haruna
Akashi
A
Miyamoto
Mihoko
M
Kawamura
Katsuya
K
Ishida
Iori
I
Nagaoka
Yuko
Y
Oka
Yuko
Y
Nakazawa
Takenori
T
Yao
Hikari
H
Jo
Yoshihisa
Y
Sugimoto
Takashi
T
Ashihara
Hideki
H
Hayashi
Makoto
M
Ito
Keiji
K
Imoto
Hiroshi
H
Matsuura
Minoru
M
Horie
D000328:Adult; D000368:Aged; D000818:Animals; D003198:Computer Simulation; D006224:Cricetinae; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels