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CLINICAL RESEARCH: ELECTROPHYSIOLOGY

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, MD, PhD^*,*, Minoru Horie, MD, PhD, Seiko Ohno, MD, Kotoe Takenaka, MD, Masato Yamaguchi, MD, PhD^||, Masami Shimizu, MD, PhD^||, Takashi Washizuka, MD, PhD^¶, Yoshifusa Aizawa, MD, PhD^¶, Kazufumi Nakamura, MD, PhD^#, Tohru Ohe, MD, PhD^#, Takeshi Aiba, MD, PhD^**, Yoshihiro Miyamoto, MD, PhD, Yasunao Yoshimasa, MD, PhD, Jeffrey A. Towbin, MD, Silvia G. Priori, MD, PhD and Shiro Kamakura, MD, PhD^*

^* Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Japan
Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Japan
Department of Cardiopulmonary Medicine, Shiga University of Medical Science, Ohtsu, Japan
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
^|| Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
^¶ Division of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan
^# Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
^** Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Suita, Japan
Department of Pediatrics (Cardiology), Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Molecular Cardiology, Salvatore Maugeri Foundation, IRCCS, Pavia, Italy

Manuscript received February 9, 2004; revised manuscript received March 4, 2004, accepted March 11, 2004.

^* Reprint requests and correspondence: Dr. Wataru Shimizu, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565 Japan.
wshimizu{at}hsp.ncvc.go.jp

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.

Abbreviations and Acronyms   APD = action potential duration   DNA = deoxyribonucleic acid   ICl(Ca) = Ca2+-activated chloride current   IKr = fast component of the delayed rectifier potassium current   IKs = slow component of the delayed rectifier potassium current   INa-Ca = Na+/Ca2+ exchange current   LQTS = long QT syndrome   LZ = leucine zipper   PCR = polymerase chain reaction   TdP = torsade de pointes   Tpeak-end = interval between Tpeak and Tend

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