Enhanced Na+ channel intermediate inactivation in Brugada syndrome

Brugada syndrome is an inherited cardiac disease that causes sudden death r elated to idiopathic ventricular fibrillation in a structurally normal hear t. The disease is characterized by ST-segment elevation in the right precor dial ECG leads and is frequently accompanied by an apparent right bundle-br anch block. The biophysical properties of the SCN5A mutation T1620M associa ted with Brugada syndrome were examined for defects in intermediate inactiv ation (I-M) a gating process in Na+ channels with kinetic features intermed iate between fast and slow inactivation. Cultured mammalian cells expressin g T1620M Na+ channels in the presence of the human beta (1) subunit exhibit enhanced intermediate inactivation at both 22 degreesC and 32 degreesC com pared with wild-type recombinant human heart Na+ channels (WT-hH1). Our fin dings support the hypothesis that Brugada syndrome is caused, in part, by f unctionally reduced Na+ current in the myocardium due to an increased propo rtion of Na+ channels that enter the I-M state. This phenomenon may contrib ute significantly to arrhythmogenesis in patients with Brugada syndrome. Th e full text of this article is available at http://www.circresaha.org.