Brugada Syndrome

Background
Brugada syndrome is a disorder characterized by coved or saddle-shaped ST-segment elevation in leads V1 through V3 on ECG. It is associated with complete or incomplete right bundle-branch block and T-wave inversion. In its initial description, the heart was reported to be structurally normal, but this has recently been challenged (Frustaci, 2005). Moreover, subtle structural abnormalities in the right ventricular outflow tract can also be observed. The ECG abnormality may not be evident until it is unmasked by infusion of flecainide or procainamide, or is augmented by a beta-blocker.
Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden cardiac death (Martini, 1989; Brugada, 1992; Brugada, 2001). Brugada syndrome is genetically determined and has an autosomal dominant pattern of transmission in about 50% of familial cases. About 5% of survivors of cardiac arrest have no clinically identified cardiac abnormality; about half of these cases are thought to be due to Brugada syndrome (Alings, 1999).
Pathophysiology
Dysfunction in cardiac ion channels underlies the clinical manifestations of Brugada syndrome (cardiac channelopathy). In 10-30% of patients and families, mutations in the gene SCN5A, encoding the cardiac voltage-gated sodium channel Nav1.5, have been reported. Another locus has also been reported on chromosome 3. Most SCN5A mutations lead to loss of function of the Nav1.5 channel by reducing the sodium current (INa) available during the phases 0 (upstroke) and 1 (early repolarization) of the cardiac action potential. Gain-of-function SCN5A mutations may also cause long QT syndrome type 3.
Repolarization disorder hypothesis
ECG alterations in Brugada syndrome have been proposed to be due to an imbalance between the depolarizing and repolarizing currents during phase 1 of the action potential, most particularly in cells expressing a large, transient outward Ito current, such as the epicardial cells of the right ventricle free wall. In patients with loss-of-function SCN5A mutations that result in less INa during phase 1, the large Ito current may prematurely repolarize the membrane and produce a loss of the dome (phase 2) of the action potential (see Image 1).
When such premature shortening of the action potential heterogeneously occurs in the myocardium, it may generate phase 2 reentries that can cause ventricular tachycardia and ventricular fibrillation. The large transmural voltage gradients generated by the short action potentials in the right ventricular outflow epicardium are thought to be the basis of the ECG patterns of Brugada syndrome. These specific alterations in cardiac electrical activity, which mainly affect the right ventricle, manifest at ST-segment elevation in precordial leads V1 through V3, with a QRS morphology resembling that of a right bundle-branch block (RBBB). Such a pattern may also be due to a J point elevation. This pattern is called coved-type when ST elevation is the most prominent feature, and it is called saddleback-type when J point elevation occurs without ST elevation (see Image 2).
Depolarization disorder model
An alternative hypothesis for the ECG alterations is based on conduction delay in the right ventricular outflow tract compared with the right ventricle free wall. The mechanisms underlying the Brugada syndrome ECG pattern are reviewed by Meregalli (Meregalli, 2005).
The ECG pattern in Brugada syndrome may only be intermittent. The ECG alterations may fluctuate with changes in autonomic balance or body temperature. The abnormality may only be apparent during administration of drugs that block the sodium channel (eg, flecainide, procainamide, ajmaline). The ECG abnormality may disappear with infusion of isoprenaline or with exercise, and it may increase with beta-blockers. These effects are explained by a reduced sodium current in the etiology of Brugada syndrome.

Frequency
United States
Because of its recent identification, the incidence of the Brugada syndrome is not well established. It may cause 4-10 sudden deaths per 10,000 population per year.
International
In Asia (eg, the Philippines, Thailand, Japan), Brugada syndrome seems to be the most common cause of natural death in men younger than 50 years. It is known as Lai Tai (Thailand), Bangungut (Philippines), and Pokkuri (Japan). In Northeast Thailand, the mortality rate from Lai Tai is approximately 30 per 100,000 population per year (Nademanee, 1997).
Mortality/Morbidity
Brugada syndrome may lead to polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden cardiac death.
Prolonged syncope and aborted cardiac arrest may cause nightmares, seizures, other neurologic deficits, or brain damage.

Race
Brugada syndrome is most common in people from Asia. The reason for this observation is not yet fully understood but may be due to an Asian-specific sequence in the promoter region of SCN5A (Bezzina, 2005).
Sex
Brugada syndrome is 8-10 times more prevalent in men than in women, although the probability of having a mutated gene does not differ by sex. The penetrance of the mutation appears to be much higher in men than in women.
Age
Brugada syndrome most commonly affects otherwise healthy men aged 30-50 years, but affected patients aged 0-84 years have been reported. The mean age of patients who die suddenly is 41 years (Antzelevitch, 2005).

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