DEFINITION
The Brugada syndrome is a genetic disease that is characterised by abnormal electrocardiogram (ECG) findings and an increased risk of sudden cardiac death.
It is named by the Spanish cardiologists Pedro Brugada and Josep Brugada. It is the major cause of Sudden Unexpected Death Syndrome (SUDS), and is the most common cause of sudden death in young men without known underlying cardiac disease in Thailand and Laos.
Although the ECG findings of Brugada syndrome were first reported among survivors of cardiac arrest in 1989, it was only in 1992 that the Brugada brothers recognized it as a distinct clinical entity, causing sudden death by causing ventricular fibrillation (a lethal arrhythmia) in the heart.
EPIDEMIOLOGY
Although the genetic mutation responsible for the Brugada syndrome is equally distributed between the sexes, the clinical phenotype is 8 to 10 times more prevalent in males than in females.
The basis for this sex-related distinction has been shown to be due to a more prominent Ito-mediated AP notch in the RV epicardium of males versus females.
The more prominent Ito causes the end of phase 1 of the RV epicardial AP to repolarize to more negative potentials in tissue and arterially perfused wedge preparations from males, facilitating loss of the AP dome and the development of phase 2 reentry and polymorphic VT.
Terfenadine induces Brugada phenotype more readily in male than female RV wedge preparations. Each panel shows action potentials recorded from 2 epicardial sites and 1 endocardial site, together with a transmural ECG. Control recordings were obtained at a BCL of 2,000 ms, whereas terfenadine data were recorded at a BCL of 800 ms after a brief period of pacing at a BCL of 400 ms. (A) Terfenadine (5 µM)-induced, heterogeneous loss of action potential dome, ST-segment elevation, and phase 2 reentry (arrow) in a male RV wedge preparation. (B) Terfenadine fails to induce Brugada phenotype in a female RV wedge preparation. © Polymorphic VT triggered by spontaneous phase 2 reentry in a male preparation. (D) Incidence of phase 2 reentry in male (6 of 7) versus female (2 of 7) RV wedge preparations when perfused with 5 µM terfenadine for up to 2 hours.
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.
SYMPTOMS
The main difficulty to act promptly on the Brugada syndrome has to do with being a asymptomatic disease that mainly affects people during sleep or at rest. In these cases the only element that could serve as an alert is a cardiac arrest.
PATOGENESIS
Approximately 20% of the cases of Brugada syndrome have been shown to be associated with mutation(s) in the gene that encodes for the sodium ion channel in the cell membranes of the muscle cells of the heart (the myocytes). The gene, named SCN5A, is located on the short arm of the third chromosome (3p21). Loss-of-function mutations in this gene lead to a loss of the action potential dome of some epicardial areas of the right ventricle. This results in transmural and epicardial dispersion of repolarization. The transmural dispersion underlies ST-segment elevation and the development of a vulnerable window across the ventricular wall, whereas the epicardial dispersion of repolarization facilitates the development of phase 2 reentry, which generates a phase 2 reentrant extrasystole that captures the vulnerable window to precipitate ventricular tachycardia and/or fibrillation that often results in sudden cardiac death. At present time however, all the reported patients who died because of the disease and were submitted to detailed autopsy study have shown a structural right ventricular pathology underlying the syndrome.
Over 160 mutations in the SCN5A gene have been discovered to date, each having varying mechanisms and effects on function, thereby explaining the varying degrees of penetration and expression of this disorder.
Recently Antzelevitch has identified mutations in the L-type calcium channel subunits (CACNA1C (A39V and G490R) and CACNB2 (S481L)) leading to ST elevation and a relatively short QT interval (below 360 msec).
This condition is inherited in an autosomal dominant pattern and is more common in males. In addition it has a higher prevalence in most Asian populations.
The table below shows the genetic alterations that cause Brugada syndrome:
DIAGNOSIS
The disease can be detected by observing characteristic patterns on an electrocardiogram, which may be present all the time, or might be elicited by the administration of particular drugs (e.g., Class IA (ajmaline) or class 1C (flecainide) antiarrhythmic drugs that blocks sodium channels and causing appearance of ECG abnormalities) or resurface spontaneously due to as yet unclarified triggers.
Brugada syndrome has 3 different ECG patterns:
# Type 1 has a coved type ST elevation with at least 2 mm (0.2 mV) J-point elevation a gradually descending ST segment followed by a negative T-wave.
- Type 2 has a saddle back pattern with a least 2 mm J-point elevation and at least 1 mm ST elevation with a positive or biphasic T-wave. Type 2 pattern can occasionally be seen in healthy subjects.
- Type 3 has either a coved (type 1 like) or a saddle back (type 2 like) pattern with less than 2 mm J-point elevation and less than 1 mm ST elevation. Type 3 pattern is not uncommon in healthy subjects.
The pattern seen on the ECG is persistent ST elevations in the electrocardiographic leadsV1-V3 with a right bundle branch block (RBBB) appearance with or without the terminal S waves in the lateral leads that are associated with a typical RBBB. A prolongation of the PR interval (a conduction disturbance in the heart) is also frequently seen.The electrocardiogram can fluctuate over time, depending on the autonomic balance and the administration of antiarrhythmic drugs. Adrenergic stimulation decreases the ST segment elevation, while vagal stimulation worsens it. (There is a case report of a patient who died while shaving, presumed due to the vagal stimulation of the carotid sinus massage) The administration of class Ia, Ic and III drugs increases the ST segment elevation, and also fever. Exercise decreases ST segment elevation in some patients but increases it in others (after exercise when the body temperature has risen). The changes in heart rate induced by atrial pacing are accompanied by changes in the degree of ST segment elevation. When the heart rate decreases, the ST segment elevation increases and when the heart rate increases the ST segment elevation decreases. However, the contrary can also be observed.
TREATMENT AND PREVENTION
At present, implantation of an automatic implantable cardiac defibrillator (ICD) is the only treatment proven effective in treating ventricular tachycardia and fibrillation and preventing sudden death in patients with Brugada syndrome. No pharmacologic therapy has been proven to reduce the occurrence of ventricular arrhythmias or sudden death.
Patients with Brugada syndrome and a history of cardiac arrest must be treated with an ICD. In contrast, asymptomatic patients with no family history of sudden cardiac death can be managed conservatively with close follow-up, and ICD implantation is not recommended.
Because regular physical activity may increase vagal tone, sport may eventually enhance the propensity of athletes with Brugada syndrome to have ventricular fibrillation and sudden cardiac death at rest or during recovery after exercise.
Therefore patients with a definite diagnosis of Brugada syndrome should be restricted from competitive sports.
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