Cellular and ionic mechanisms responsible for the Brugada syndrome

Abstract

The Brugada syndrome is characterized by ST-segment elevation in the right precordial leads, V1-V3 (unrelated to ischemia or structural disease), normal QT intervals, RBBB pattern, and sudden cardiac death, particularly in men of Asian origin. An autosomal dominant mode of inheritance with variable penetrance is generally observed. The only gene mutations thus far linked to the Brugada Syndrome appear in the alpha subunit of the gene that encodes for the cardiac sodium channel, SCN5A. An outward shift in the balance of currents contributing to phase 1 of the right ventricular action potential is thought to underline to electrocardiographic manifestation of the syndrome. Strong sodium channel block, among other modalities, can accentuate the action potential notch in right ventricular epicardial cells, eventually leading to loss of the action potential dome. This results in the development of a large dispersion of repolarization within epicardium as well as between epicardium and endocardium, providing the substrate for the development of phase 2 and cirus movement reentry, which underline VT/VF. Therapy is directed at restoring the balance of current via inhibition of the transient outward current, Ito, and/or stimulation of inward calcium using beta adrenergic agonists, among several strategies.