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 theSCN5Amutation T1620M associated with Brugada syndrome were examined for defects in intermediate inactivation (IM), 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 &bgr;1subunit 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 theIMstate. 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.