Enhanced Na + Channel Intermediate Inactivation in Brugada Syndrome

Abstract

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 β 1 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.