Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects

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Abstract

Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy.

Section snippets

Clinical Characteristics and Diagnostic Criteria

Brugada syndrome (BrS) typically manifests in the third or fourth decade of life (average age of 41 ± 15 years), although patients have been diagnosed with the syndrome at an age as young as 2 days and as old as 84 years. Prevalence of BrS electrocardiograph (ECG) in the general population varies significantly among continents, countries, and ethnic groups.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 The prevalence of the disease is the highest in Southeast

Genetic Basis

Inheritance of BrS is via an autosomal dominant mode of transmission. Mutations in 19 genes have been identified as associated with the Brugada phenotype (Table 1). These mutations cause either a decrease in inward sodium or calcium current or an increase in outward potassium currents, resulting in an outward shift in the balance of current active during the early phases of the AP.

Indrajit Choudhuri, MD: At the time of printing, this review provides a complete and up-to-date list of currently

Cellular and Ionic Basis

An outward shift in the balance of currents active during phases 1 and 2 of the epicardial AP via either a reduction of inward current (INa or ICa) or increase in outward current (IKr or IK-ATP) allows the already prominent Ito to accentuate phase 1 repolarization (FIG 2, FIG 3). When phase 1 is repolarized beyond the voltage range in which L-type Ca2+ channels activate, the Ca2+ channels fail to activate, resulting in loss of the AP plateau, predominantly in the RV subepicardial cells, where I

Approach to Therapy

Table 3 lists device and pharmacologic therapies suggested on the basis of clinical experience or experimental studies.

Funding Sources

This study was supported by grant HL47678 from NHLBI (CA), NYSTEM grant no. C026424 (CA), and the Masons of New York, Florida, Massachusetts, Connecticut, Maryland, Delaware, New Hampshire, and Wisconsin.

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    Dr Antzelevith is a consultant to Gilead Sciences in Foster City, CA, and has received research support from Gilead Sciences and the Buchang Group in Xi’an, China.

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