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

Wataru Shimizu, Minoru Horie, Seiko Ohno, Kotoe Takenaka, Masato Yamaguchi, Masami Shimizu, Takashi Washizuka, Yoshifusa Aizawa, Kazufumi Nakamura, Tohru Ohe, Takeshi Aiba, Yoshihiro Miyamoto, Yasunao Yoshimasa, Jeffrey Towbin, Silvia G. Priori, Shiro Kamakura

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Objectives 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.

Original languageEnglish (US)
Pages (from-to)117-125
Number of pages9
JournalJournal of the American College of Cardiology
Volume44
Issue number1
DOIs
StatePublished - Jul 7 2004

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Long QT Syndrome
Multicenter Studies
Japan
Mutation
Penetrance
Sudden Cardiac Death
Syncope
Heart Arrest

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Shimizu, Wataru; Horie, Minoru; Ohno, Seiko; Takenaka, Kotoe; Yamaguchi, Masato; Shimizu, Masami; Washizuka, Takashi; Aizawa, Yoshifusa; Nakamura, Kazufumi; Ohe, Tohru; Aiba, Takeshi; Miyamoto, Yoshihiro; Yoshimasa, Yasunao; Towbin, Jeffrey; Priori, Silvia G.; Kamakura, Shiro.

In: Journal of the American College of Cardiology, Vol. 44, No. 1, 07.07.2004, p. 117-125.

Research output: Contribution to journalArticle

Shimizu, W, Horie, M, Ohno, S, Takenaka, K, Yamaguchi, M, Shimizu, M, Washizuka, T, Aizawa, Y, Nakamura, K, Ohe, T, Aiba, T, Miyamoto, Y, Yoshimasa, Y, Towbin, J, Priori, SG & Kamakura, S 2004, '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', Journal of the American College of Cardiology, vol. 44, no. 1, pp. 117-125. https://doi.org/10.1016/j.jacc.2004.03.043
Shimizu, Wataru ; Horie, Minoru ; Ohno, Seiko ; Takenaka, Kotoe ; Yamaguchi, Masato ; Shimizu, Masami ; Washizuka, Takashi ; Aizawa, Yoshifusa ; Nakamura, Kazufumi ; Ohe, Tohru ; Aiba, Takeshi ; Miyamoto, Yoshihiro ; Yoshimasa, Yasunao ; Towbin, Jeffrey ; Priori, Silvia G. ; Kamakura, Shiro. / 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. In: Journal of the American College of Cardiology. 2004 ; Vol. 44, No. 1. pp. 117-125.
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abstract = "Objectives 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.",
author = "Wataru Shimizu and Minoru Horie and Seiko Ohno and Kotoe Takenaka and Masato Yamaguchi and Masami Shimizu and Takashi Washizuka and Yoshifusa Aizawa and Kazufumi Nakamura and Tohru Ohe and Takeshi Aiba and Yoshihiro Miyamoto and Yasunao Yoshimasa and Jeffrey Towbin and Priori, {Silvia G.} and Shiro Kamakura",
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T1 - Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome

T2 - Multicenter study in Japan

AU - Shimizu, Wataru

AU - Horie, Minoru

AU - Ohno, Seiko

AU - Takenaka, Kotoe

AU - Yamaguchi, Masato

AU - Shimizu, Masami

AU - Washizuka, Takashi

AU - Aizawa, Yoshifusa

AU - Nakamura, Kazufumi

AU - Ohe, Tohru

AU - Aiba, Takeshi

AU - Miyamoto, Yoshihiro

AU - Yoshimasa, Yasunao

AU - Towbin, Jeffrey

AU - Priori, Silvia G.

AU - Kamakura, Shiro

PY - 2004/7/7

Y1 - 2004/7/7

N2 - Objectives 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.

AB - Objectives 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.

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