Brugada Syndrome

Introduction
Background

Brugada syndrome is a disorder characterized by sudden death associated with one of several ECG patterns characterized by incomplete right bundle branch block and ST elevations in the anterior precordial leads. (See Media file 2.) In the initial description of Brugada syndrome, the heart was reported to be structurally normal, but this has been challenged.1 Moreover, subtle structural abnormalities in the right ventricular outflow tract can also be observed. The typical patient with Brugada syndrome is young, male, and otherwise healthy, with normal general medical and cardiovascular physical examinations.

Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest, or sudden cardiac death.2,3,4 Infrahisian conduction delay and atrial fibrillation may also be manifestations of the syndrome.5,6 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.7
Pathophysiology

Brugada syndrome is an example of a channelopathy; a disease caused by an alteration in the transmembrane ion currents that together constitute the cardiac action potential. Specifically, in 10-30% of cases, mutations in the SCN5A gene, which encodes the cardiac voltage-gated sodium channel Nav 1.5, have been found. These loss-of-function mutations reduce the sodium current (INa) available during the phases 0 (upstroke) and 1 (early repolarization) of the cardiac action potential. This decrease in INa is thought to affect the right ventricular endocardium differently from the epicardium, thus underlying both the Brugada ECG pattern and the clinical manifestations of the Brugada syndrome.

The mechanisms underlying the ECG alterations and arrhythmogenesis in Brugada syndrome are disputed.8 The repolarization-defect theory is based on the fact that right ventricular epicardial cells display a more prominent notch in the action potential than endocardial cells. This is thought to be due to an increased contribution of the transient outward current (Ito) to the action potential waveform in that tissue. A decrease in INa accentuates this difference, causing a voltage gradient during repolarization and the characteristic ST elevations on ECG. When the usual relative durations of repolarization are not altered, the T wave remains upright, causing a saddleback ECG pattern (Type 2 or 3). When the alteration in repolarization is sufficient enough to cause a reversal of the normal gradient of repolarization, the T wave inverts, and the coved (Type 1) ECG pattern is seen.

In a similar way, a heterogeneous alteration in cardiac repolarization may predispose to the development of reentrant arrhythmias, termed phase 2 reentry, that can clinically cause ventricular tachycardia and ventricular fibrillation.9

Human evidence for a repolarization gradient in patients with Brugada syndrome using simultaneous endocardial and epicardial unipolar recordings was recently published.10

On the other hand, the depolarization/conduction disorder hypothesis proposes that the typical ECG signs can be explained by slow conduction and activation delays in the right ventricle (in particular in the right ventricular outflow tract).8
Frequency
United States

Because of its recent identification, the incidence of Brugada syndrome is not well established. In a large university hospital on the west coast of the US, the incidence of a Brugada ECG pattern among unselected, mainly Caucasian and Hispanic adults, was 2 of 1348 patients (0.14%), both of which were type 2 EKGs.11 The prevalence in other ethnic populations may be higher.
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.12
Mortality/Morbidity

Brugada syndrome is a leading cause of death, aside from accidents, in men under 40. The true incidence is not known due to reporting biases.An estimated 4% of all sudden deaths and at least 20% of sudden death in patients with structurally normal hearts are due to the sydrome. Those with the syndrome have a mean age of sudden death of 41±15 years.13

The major manifestation of Brugada syndrome is polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden cardiac death. Patients in whom sudden death has been aborted may have neurologic sequela of prolonged ischemia. Patients in whom an automatic internal defibrillator is implanted are subject to the risks of that procedure, and may receive shocks from the device that can cause physical pain and psychological trauma.

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.14
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 therefore 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.9
Clinical
History

Syncope and cardiac arrest are the most common clinical manifestations leading to the diagnosis of Brugada syndrome. Nightmares or thrashing at night may occur. However, sometimes no symptoms have been recognized and the diagnosis of Brugada syndrome is based on a routine ECG showing ST-segment elevation in leads V1 through V3. A family history of sudden cardiac death is common, though not required, as the syndrome can occur sporadically.

The context of the cardiac event is important. In many cases, cardiac arrest occurs during sleep or rest. Cases occurring during physical activity are rare. In addition, fever is often reported to trigger or exacerbate the clinical manifestations of Brugada syndrome.
Physical

The physical examination is usually normal in patients with the Brugada syndrome. Nevertheless, physical examination is required to rule out other possible cardiac causes (eg, heart murmurs from hypertrophic cardiomyopathy or from a valvular or septal defect) that may be associated with syncope or cardiac arrest in an otherwise healthy patient.
Causes

The prototypical case of Brugada syndrome has been associated with alterations in the SCN5A gene, of which well more than 100 mutations have been found. Mutations in other genes have been proposed to cause a variant of Brugada syndrome, including the genes coding for alpha1- and beta2b-subunits of the L-type calcium channel (CACNA1C and CACNB2), which are thought to cause a syndrome of precordial ST elevation, sudden death, and short QT.15 Cases in which a mutation in the SCN5A gene cannot be demonstrated may be due to mutations of these genes, other genes that have not yet been identified, or in regions of the coding sequence or promoter region of SCN5A that are not routinely sequenced in lab tests. More recently, mutations in the genes GPD1-L16 and SCN1B17 have been identified in a few familial cases.

Many clinical situations may unmask or exacerbate the ECG pattern of Brugada syndrome. Examples are hyperkalemia, hypokalemia, hypercalcemia, alcohol or cocaine intoxication, a febrile state, and the use of sodium-channel blockers, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, heterocyclic antidepressants, and a combination of glucose and insulin.9

http://emedicine.medscape.com/article/163751-overview