Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome

被引:29
作者
Kobori, A
Sarai, N
Shimizu, W
Nakamura, Y
Murakami, Y
Makiyama, T
Ohno, S
Takenaka, K
Ninomiya, T
Fujiwara, Y
Matsuoka, S
Takano, M
Noma, A
Kita, T
Horie, M
机构
[1] Shiga Univ Med Sci, Dept Cardiovasc & Resp Med, Otsu, Shiga 5202192, Japan
[2] Tokyo Med & Dent Univ, Dept Physiol, Tokyo, Japan
[3] Osaka City Gen Hosp, Dept Pediat Cardiol, Osaka, Japan
[4] Wakayama Med Ctr, Japanese Red Cross Soc, Dept Pediat, Wakayama, Japan
[5] Natl Cardiovasc Ctr, Dept Internal Med, Div Cardiol, Osaka, Japan
[6] Kyoto Univ, Grad Sch Med, Dept Physiol & Biophys, Kyoto, Japan
[7] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Kyoto, Japan
关键词
long QT syndrome; beta-blocker; KCNQ1; KCNH2; KCNJ2; computer simulation;
D O I
10.1046/j.1540-8167.2004.03212.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Additional Mutations in LQT1. Introduction: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. Methods and Results: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. Conclusion: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.
引用
收藏
页码:190 / 199
页数:10
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