Kenichiro Yamagata1, Minoru Horie1, Takeshi Aiba1, Satoshi Ogawa1, Yoshifusa Aizawa1, Tohru Ohe1, Masakazu Yamagishi1, Naomasa Makita1, Harumizu Sakurada1, Toshihiro Tanaka1, Akihiko Shimizu1, Nobuhisa Hagiwara1, Ryoji Kishi1, Yukiko Nakano1, Masahiko Takagi1, Takeru Makiyama1, Seiko Ohno1, Keiichi Fukuda1, Hiroshi Watanabe1, Hiroshi Morita1, Kenshi Hayashi1, Kengo Kusano1, Shiro Kamakura1, Satoshi Yasuda1, Hisao Ogawa1, Yoshihiro Miyamoto1, Jamie D Kapplinger1, Michael J Ackerman1, Wataru Shimizu2. 1. From Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.Y., T.A., K.K., S.K. S.Y., H.O., W.S.); Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Japan (M.H., S. Ohno); Department of Cardiovascular Medicine, University of Tokyo, Japan (K.Y.); Department of Cardiopulmonary Medicine, Keio University, Tokyo, Japan (S. Ogawa, K.F.); Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan (Y.A., H.W.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan (T.O., H.M.); Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Ishikawa, Japan (M.Y., K.H.); Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Japan (N.M.); Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Japan (H.S.); Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan (T.T.); Division of Cardiology, Yamaguchi University Graduate School of Medicine, Japan (A.S.); Department of Cardiology, Tokyo Women's Medical University, Japan (N.H.); Department of Cardiology, St Marianna University of Medicine, Kanagawa, Japan (R.K.); Department of Cardiovascular Medicine, Hiroshima University, Japan (Y.N.); Department of Cardiovascular Medicine, Osaka City University, Japan (M.T.); Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.M.); Laboratory of Molecular Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.M.); Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (J.D.K., M.J.A.); and Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). 2. From Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.Y., T.A., K.K., S.K. S.Y., H.O., W.S.); Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Japan (M.H., S. Ohno); Department of Cardiovascular Medicine, University of Tokyo, Japan (K.Y.); Department of Cardiopulmonary Medicine, Keio University, Tokyo, Japan (S. Ogawa, K.F.); Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan (Y.A., H.W.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan (T.O., H.M.); Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Ishikawa, Japan (M.Y., K.H.); Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Japan (N.M.); Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Japan (H.S.); Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan (T.T.); Division of Cardiology, Yamaguchi University Graduate School of Medicine, Japan (A.S.); Department of Cardiology, Tokyo Women's Medical University, Japan (N.H.); Department of Cardiology, St Marianna University of Medicine, Kanagawa, Japan (R.K.); Department of Cardiovascular Medicine, Hiroshima University, Japan (Y.N.); Department of Cardiovascular Medicine, Osaka City University, Japan (M.T.); Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.M.); Laboratory of Molecular Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.M.); Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (J.D.K., M.J.A.); and Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). wshimizu@nms.ac.jp.
Abstract
BACKGROUND: The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. METHODS: This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations. RESULTS: During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations (SCN5A (-), n=355), probands with SCN5A mutations (SCN5A (+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years, P=0.013), had a higher positive rate of late potentials (89% versus 73%, P=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (P=0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events (SCN5A (+) versus SCN5A (-): hazard ratio, 2.0 and P=0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and P<0.001). CONCLUSIONS: Brugada syndrome patients with SCN5A mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events.
BACKGROUND: The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. METHODS: This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations. RESULTS: During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations (SCN5A (-), n=355), probands with SCN5A mutations (SCN5A (+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years, P=0.013), had a higher positive rate of late potentials (89% versus 73%, P=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (P=0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events (SCN5A (+) versus SCN5A (-): hazard ratio, 2.0 and P=0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and P<0.001). CONCLUSIONS:Brugada syndromepatients with SCN5A mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events.
Authors: Marta Pérez-Hernández; Marcos Matamoros; Silvia Alfayate; Paloma Nieto-Marín; Raquel G Utrilla; David Tinaquero; Raquel de Andrés; Teresa Crespo; Daniela Ponce-Balbuena; B Cicero Willis; Eric N Jiménez-Vazquez; Guadalupe Guerrero-Serna; Andre M da Rocha; Katherine Campbell; Todd J Herron; F Javier Díez-Guerra; Juan Tamargo; José Jalife; Ricardo Caballero; Eva Delpón Journal: JCI Insight Date: 2018-09-20
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