Brugada syndrome: From cell to bedside

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Abstract

Since its introduction as a new clinical entity in 1992, the Brugada syndrome has attracted great interest because of its high incidence in many parts of the world and its association with high risk for sudden death in infants, children, and young adults. Recent years have witnessed an exponential rise in the number of reported cases and a striking proliferation of articles serving to define the clinical, genetic, cellular, ionic, and molecular aspects of the disease. A consensus report published in 2002 delineated diagnostic criteria for the syndrome. A second consensus conference was held in September 2003. This review provides an in-depth overview of the clinical, genetic, molecular, and cellular aspects of the Brugada syndrome, incorporating the results of the two consensus conferences, and the numerous clinical and basic publications on the subject. The proposed terminology, diagnostic criteria, risk stratification schemes, and device and pharmacologic approach to therapy discussed are based on available clinical and basic studies and should be considered a work-in-progress that will without doubt require fine-tuning as confirmatory data from molecular studies and prospective trials become available.

Section snippets

Clinical characteristics

The Brugada syndrome is characterized by ST segment elevation in the right precordial ECG leads and a high incidence of sudden death in patients with structurally normal hearts. The syndrome manifests primarily during adulthood, with a mean age of sudden death of approximately 40 years. The youngest patient diagnosed with the syndrome was 2 days of age, and the oldest was 84. The syndrome is thought to be responsible for 4–12% of all sudden deaths and at least 20% of deaths in patients with

Relationship with structural heart disease

A subpopulation of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have been found to display an ST-segment elevation and polymorphic VT characteristic of the Brugada syndrome.25 In addition one case has been reported in which a patient with a Brugada phenotype required heart transplantation due to untreatable arrhythmias26 and in whom severe fibrosis of the right ventricle was subsequently reported.

These facts notwithstanding, the vast majority of Brugada patients possess a

Factors that precipitate and modulate the ECG and arrhythmic manifestations of the Brugada syndrome

ST segment elevation in the Brugada syndrome can be very dynamic. The Brugada ECG is often concealed, but may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, first-generation antihistaminics (dimenhydrinate), a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and alcohol and cocaine toxicity (Fig 16).6, 7, 8, 83, 84, 85, 86, 87, 88, 89

Therapy of congenital Brugada syndrome

Despite impressive strides in the identification and characterization of Brugada syndrome over the past decade, progress relative to therapy has been less noteworthy. The various device and pharmacologic therapies tested clinically or suggested based on experimental evidence are listed in Table 7. Currently, an implantable cardioverter defibrillator (ICD) is the only proven effective treatment for the disease.99, 100 In a multicenter trial of 690 patients with Brugada syndrome, in which 258

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    Supported by Grants HL47678 and HL066169 from NHLBI (C.A., R.B.), American Heart Association (R.B., C.A.), and NYS and Florida Grand Lodges F.&A.M.

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