A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease

doi:10.1016/S0008-6363(01)00494-1

Cardiovascular Research 2002 53(2):348-354; doi:10.1016/S0008-6363(01)00494-1
© 2002 by European Society of Cardiology

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A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease

Nobumasa Shirai^a, Naomasa Makita^a^,*, Koji Sasaki^a, Hisataka Yokoi^a, Ichiro Sakuma^a, Harumizu Sakurada^b, Jun Akai^c, Akinori Kimura^c, Masayasu Hiraoka^d and Akira Kitabatake^a

^aDepartment of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-8638, Japan
^bDepartment of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan
^cEtiology and Pathogenesis Research Unit, and Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
^dEtiology and Pathogenesis Research Unit, and Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

^* Corresponding author. Tel.: +81-11-716-1161; fax: +81-11-706-7874 makitan{at}med.hokudai.ac.jp

Objective: Loss of Na⁺ channel function has been implicatedin idiopathic ventricular fibrillation (IVF) and Brugada syndrome.We have studied the biophysical properties of an IVF mutation(S1710L) that exhibited an unusual clinical phenotype: rate-dependentbundle branch block without manifestation of Brugada-type ECGpattern. Methods: The mutant S1710L channels were expressedin mammalian cells and their gating properties, studied usingwhole-cell patch clamp techniques, were compared with wild-type(WT) and a Brugada syndrome mutant channel T1620M. Results:The S1710L channel exhibited significantly faster macroscopiccurrent decay than WT or T1620M. In addition, S1710L showeda negative shift in the voltage-dependence of fast inactivationand slower recovery from fast inactivation than in WT or T1620M.In addition to the alterations in fast inactivation most commonlyobserved in Brugada syndrome mutations, S1710L exhibited markedenhancement in slow inactivation and a large positive shiftof activation that potentially decreases conduction velocity.Conclusions: These functional abnormalities may be responsiblefor the overlapping clinical phenotypes associated with Brugadasyndrome and the cardiac conduction defect, a novel cardiacNa⁺ channelopathy.

KEYWORDS Arrhythmia (mechanisms); Conduction (block); Na-channel; Sudden death; Ventricular arrhythmias

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