Genotype-phenotype correlations in Brugada syndrome

Abstract

Brugada syndrome was described as a new clinical entity by Pedro and Josep Brugada in 1992, and characterized by ST-segment elevation in the right precordial leads (V 1 -V 3 ) and an episode of ventricular fibrillation (VF). The first and the only gene mutation linked to Brugada syndrome was identified in SCN5A , the gene encoding the α subunit of the sodium channel. Therefore, data about genotype-phenotype correlations in clinical studies are limited. On the other hand, genotype-phenotype correlations in experimental studies using arterially perfused right ventricular wedge preparations have greatly advanced our knowledge of the cellular, ionic, and molecular mechanisms for Brugada phenotype, providing a suitable strategy for managing and treating patients with the Brugada syndrome. Experimental data suggest that a prominent transient outward current ( I to )–mediated action potential (AP) notch and a loss of the AP 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 VF because of phase 2 reentry mechanism. Because maintenance of the AP dome is determined by the balance of currents at the end of phase 1 of the AP, any therapeutic agents or interventions which decrease net outward currents (↓ I to or I K , ↑ I Ca-L or fast I Na ) may normalize the Brugada phenotype, and, thus, are therapeutic candidates in patients with the Brugada syndrome. Several agents may be used as adjunctive pharmacologic treatment to reduce the incidence of VF episodes in symptomatic patients with Brugada syndrome only under a backup with implantable cardioverter defibrillator therapy. Oral quinidine has been reported to be of therapeutic value because of its relatively strong I to blocking effect. Oral denopamine (an adrenergic stimulant), atropine (an anticholinergic agent), or cilostazol (a phosphodiesterase III inhibitor) increases I Ca-L and may be another choice for pharmaceutical therapy. At the electrical storm of VF, continuous infusion of isoproterenol attenuates ST-segment elevation and prevents VF by strongly augmenting I Ca-L and heart rate. Further genotype-phenotype correlations in clinical studies will be required to develop more effective strategies for managing and treating patients with Brugada syndrome.