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.
Itoh
Hideki
H
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan.
Sakaguchi
Tomoko
T
Ding
Wei-Guang
WG
Watanabe
Eiichi
E
Watanabe
Ichiro
I
Nishio
Yukiko
Y
Makiyama
Takeru
T
Ohno
Seiko
S
Akao
Masaharu
M
Higashi
Yukei
Y
Zenda
Naoko
N
Kubota
Tomoki
T
Mori
Chikara
C
Okajima
Katsunori
K
Haruna
Tetsuya
T
Miyamoto
Akashi
A
Kawamura
Mihoko
M
Ishida
Katsuya
K
Nagaoka
Iori
I
Oka
Yuko
Y
Nakazawa
Yuko
Y
Yao
Takenori
T
Jo
Hikari
H
Sugimoto
Yoshihisa
Y
Ashihara
Takashi
T
Hayashi
Hideki
H
Ito
Makoto
M
Imoto
Keiji
K
Matsuura
Hiroshi
H
Horie
Minoru
M
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