title: 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.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan. wshimizu@hsp.ncvc.go.jp
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Kotoe
authors.initials: K
authors.lastname: Takenaka
authors.forename: Masato
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Washizuka
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
mesh_terms: 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
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated