Mechanisms of disease: current understanding and future challenges in Brugada syndrome.
Brugada syndrome is a clinical entity characterized by ST-segment elevation in the right precordial leads (V1-V3) and an episode of ventricular fibrillation in the absence of structural heart disease. Data regarding genotype-phenotype relationships are limited, since SCN5A, the gene encoding the a subunit of the sodium channel, is as yet the only gene linked to Brugada syndrome. Studies of SCN5A mutations responsible for the Brugada phenotype have shown the presence of functional defects in the sodium-channel current. Experimental studies employing arterially perfused right-ventricular wedge preparations have elucidated cellular mechanisms for this phenotype. Data indicate that an accentuated action-potential notch, mediated by a prominent transient outward current and loss of the action-potential dome in the epicardium (but not in the endocardium) of the right ventricle give rise to a transmural voltage gradient, resulting in ST-segment elevation and the induction of ventricular fibrillation. On the basis of cellular mechanisms, it might be possible to normalize the Brugada phenotype by use of therapeutic agents or interventions that decrease net outward currents by decreasing the transient outward current or outward potassium currents, or increasing the L-type inward calcium current or fast sodium current. Interventions that increase net outward currents through raising the transient outward current or outward potassium currents or decreasing the L-type inward calcium current or fast sodium current might aggravate or unmask the Brugada phenotype, resulting in an acquired form of this syndrome. In this review, we discuss future challenges relating to risk stratification, genetic heterogeneity, sex and ethnic differences in Brugada syndrome.
Shimizu
Wataru
W
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. wshimizu@hsp.ncvc.go.jp
Aiba
Takeshi
T
Kamakura
Shiro
S
D002037:Bundle-Branch Block / Q000175:diagnosis / Q000235:genetics; D004562:Electrocardiography; D005838:Genotype; D006801:Humans; D009154:Mutation; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics; D013577:Syndrome; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics*; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics*
D015222:Sodium Channels