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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.

View larger version (22K): [in a new window]   Figure 1 Topology of the voltage-gated sodium (Na) channel. Scheme of the transmembrane topology of the cardiac Na channel illustrating the location of four mutations found in our study. The cardiac Na channel -subunit consists of four domains (DI through DIV), each containing six transmembrane-spanning segments.

View larger version (40K): [in a new window]   Figure 2 Denaturing high-performance liquid chromatography (DHPLC) analysis and deoxyribonucleic acid (DNA) sequencing. (Top panels of A through D) DHPLC confirms abnormal migration patterns in the affected individuals. (Bottom panels of A through D) Automated DNA sequencing electropherograms demonstrate mutations in each proband.

View larger version (65K): [in a new window]   Figure 3 Electrocardiogram (ECG) recordings. (A through D) ECG recordings (V1 through V3) obtained from the probands. (Bottom panel of C) Programmed electrical stimulation (S1-S1/S1-S2/S2-S3/S3-S4 = 600/280/260/240 [ms]) at the right ventricular outflow tract induced monomorphic ventricular tachycardia.

View larger version (29K): [in a new window]   Figure 4 (A through D) Pedigrees are shown. Circles represent female subjects and squares represent male subjects. The arrowhead indicates the proband. Diagonal bars indicate deceased family members. Members carrying the mutation are represented by solid circles or solid squares. Further explanation is given in the figure. AVB = atrioventricular block; BS = Brugada syndrome; PM = patients with a pacemaker; SSS = sick sinus syndrome.

View larger version (32K): [in a new window]   Figure 5 Biophysical assay. (A) Whole-cell current recordings of wild-type (WT) and mutant sodium (Na) channels. Sodium channels were expressed with transient transfection in HEK293 cells in the presence of hß1. Currents were recorded at various membrane potentials from –90 to +90 mV in 10-mV increments from a holding potential of –120 mV. No currents were detected in cells expressing each mutant. (B) Voltage dependence of steady-state inactivation and activation of mutant Na channels cotransfected with WT (mutant-hH1 [or pRcCMV as a control to adjust the total amount of DNA]: WT-hH1: hß1 = 1:1:1). The curve was fit with the Boltzmann equation: I/Imax = [1+exp((V-V1/2)/k)–1]. (C) Current densities of mutant Na channels. Na currents were elicited at –30 mV from a holding potential of –120 mV. hH1 = human cardiac Na channel -subunit.