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CLINICAL RESEARCH: CARDIAC RHYTHM DISORDER

High Risk for Bradyarrhythmic Complications in Patients With Brugada Syndrome Caused by SCN5A Gene Mutations

Takeru Makiyama, MD^_*, Masaharu Akao, MD, PhD^_*, Keiko Tsuji, BS^_*, Takahiro Doi, MD^_*, Seiko Ohno, MD^_*, Kotoe Takenaka, MD, PhD^_*, Atsushi Kobori, MD, PhD^_*, Tomonori Ninomiya, MD, PhD^_*, Hidetada Yoshida, MD, PhD^_*, Makoto Takano, MD, PhD, Naomasa Makita, MD, PhD, Fumiko Yanagisawa, MD, Yukei Higashi, MD, PhD, Youichi Takeyama, MD, PhD, Toru Kita, MD, PhD^_* and Minoru Horie, MD, PhD^||,_*

^_* Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
Division of Biophysics, Department of Physiology, Jichii Medical School, Tochigi, Japan
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan
^|| Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.

Manuscript received February 23, 2005; revised manuscript received July 29, 2005, accepted August 1, 2005.

^_* Reprint requests and correspondence: Dr. Minoru Horie, Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan. (Email: horie{at}belle.shiga-med.ac.jp).

OBJECTIVES: We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship.

BACKGROUND: The gene SCN5A encodes the pore-forming -subunit of voltage-gated cardiac sodium (Na) channel, which plays an important role in heart excitation/contraction. Mutations of SCN5A have been identified in 15% of patients with Brugada syndrome.

METHODS: In 38 unrelated patients with clinically diagnosed Brugada syndrome, we screened for SCN5A gene mutations using denaturing high-performance liquid chromatography and direct sequencing, and conducted a functional assay for identified mutations using whole-cell patch-clamp in heterologous expression system.

RESULTS: Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic complications: three with sick sinus syndrome (SSS) and the other (D356N) with paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were associated with a higher incidence of bradyarrhythmia (4 of 4) than non–SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had been diagnosed as having familial SSS without any clinical signs of Brugada syndrome, showed a Brugada-type ST-segment elevation after intravenous administration of pilsicainide and programmed electrical stimulation-induced ventricular tachycardia. All of the mutations encoded non-functional Na channels, and thus were suggested to cause impulse propagation defect underlying bradyarrhythmias.

CONCLUSIONS: Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.

Abbreviations and Acronyms   AVB = atrioventricular block   DHPLC = denaturing high-performance liquid chromatography   hß1 = human ß1-subunit   PCCD = progressive cardiac conduction defect   SSS = sick sinus syndrome   VF = ventricular fibrillation   VT = ventricular tachycardia

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