Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan.
OBJECTIVE
We sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1 channel in the LQT1 form of congenital long QT syndrome (LQTS).


BACKGROUND
The LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms.


METHODS
Sixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes.


RESULTS
Patients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005).


CONCLUSIONS
In this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations.
Shimizu
Wataru
W
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan. wshimizu@hsp.ncvc.go.jp
Horie
Minoru
M
Ohno
Seiko
S
Takenaka
Kotoe
K
Yamaguchi
Masato
M
Shimizu
Masami
M
Washizuka
Takashi
T
Aizawa
Yoshifusa
Y
Nakamura
Kazufumi
K
Ohe
Tohru
T
Aiba
Takeshi
T
Miyamoto
Yoshihiro
Y
Yoshimasa
Yasunao
Y
Towbin
Jeffrey A
JA
Priori
Silvia G
SG
Kamakura
Shiro
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001145:Arrhythmias, Cardiac / Q000151:congenital / Q000453:epidemiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005080:Exercise Test; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006329:Heart Conduction System / Q000473:pathology; D006801:Humans; D007564:Japan / Q000453:epidemiology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D017354:Point Mutation / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D016016:Proportional Hazards Models; D012307:Risk Factors; D012680:Sensitivity and Specificity
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated