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(Circulation Research. 2000;87:e37.)
© 2000 American Heart Association, Inc.

UltraRapid Communication

Enhanced Na⁺ Channel Intermediate Inactivation in Brugada Syndrome

Dao W. Wang, Naomasa Makita, Akira Kitabatake, Jeffrey R. Balser, Alfred L. George, Jr

From the Departments of Pharmacology (D.W.W., J.R.B., A.L.G.), Anesthesiology (J.R.B.), and Medicine (A.L.G.), Vanderbilt University School of Medicine, Nashville, Tenn, and the Department of Cardiovascular Medicine (N.M., A.K.), Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to Alfred L. George, Jr, Division of Genetic Medicine, 451 MRB-II, Vanderbilt University Medical Center, Nashville, TN 37232-6304. E-mail al.george{at}vanderbilt.edu

Abstract—Brugada syndrome is an inherited cardiac disease that causes sudden death related to idiopathic ventricular fibrillation in a structurally normal heart. The disease is characterized by ST-segment elevation in the right precordial ECG leads and is frequently accompanied by an apparent right bundle-branch block. The biophysical properties of the SCN5A mutation T1620M associated with Brugada syndrome were examined for defects in intermediate inactivation (I_M), a gating process in Na⁺ channels with kinetic features intermediate between fast and slow inactivation. Cultured mammalian cells expressing T1620M Na⁺ channels in the presence of the human ß₁ subunit exhibit enhanced intermediate inactivation at both 22°C and 32°C compared with wild-type recombinant human heart Na⁺ channels (WT-hH1). Our findings support the hypothesis that Brugada syndrome is caused, in part, by functionally reduced Na⁺ current in the myocardium due to an increased proportion of Na⁺ channels that enter the I_M state. This phenomenon may contribute significantly to arrhythmogenesis in patients with Brugada syndrome. The full text of this article is available at http://www.circresaha.org.

Key Words: Brugada syndrome • Na⁺ channel • SCN5A • slow inactivation

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