Brugada syndrome (BrS) is a genetic disease that is characterised by

abnormal electrocardiogram (ECG) findings and an increased risk of sudden cardiac

death. It is named for the Spanish cardiologists Pedro Brugada and Josep Brugada. It
is the major cause of sudden unexplained death syndrome (SUDS), also known as
sudden adult death syndrome (SADS), 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
causingventricular fibrillation (a potentially lethal arrhythmia) in the heart.
Genetics
Approximately 20% of the cases of Brugada syndrome have been shown to be
associated with mutations in a gene that encodes for a sodium ion channel in
the cellmembranes of the muscle cells of the heart (the myocytes); this is often
referred to as a sodium channelopathy. The majority of patients affected by
Brugada syndrome are not found to have known genetic mutations to explain the
disease, as of 2015. 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 ventricular 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 likelihood of the genetic mutation leading to the disease ( that is to
say, penetrance) and expression of this disorder.
An example of one of the mechanisms in which a loss of function of the sodium
channel occurs is a mutation in the gene that disrupts the sodium channel's ability
to bind properly to ankyrin-G, an important protein mediating interaction between
ion channels and cytoskeletal elements. Very recently a mutation in a second gene,
Glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L) has been shown to result
in Brugada syndrome in a large multigenerational family (London, 2006). This gene
acts as an ion channel modulator in the heart, although the exact mechanism is not
yet understood.

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 ms. For a comprehensive list
of all mutations see In 2013, Bezzina et al. showed that common variants at SCN5ASCN10A and HEY2 are associated with Brugada syndrome.
This condition is inherited in an autosomal dominant pattern and manifests itself
more commonly in males, due to a higher penetrance. In addition it has a higher
prevalence in most Asian populations.
Prevalence
The prevalence of Brugada ECG is indeed higher in Asia than in the United States
and Europe. Specifically, Brugada Type 1 ECG appears more frequently in Asia (0%
0.36% of the population) and Europe (0%0.25%) than in the United States (0.03%).
Type 2 and Type 3 ECG is more prevalent in Asia (0.12%2.23%) than in Europe
(0.0%0.6%) or the United States (0.02%).
Diagnosis
Genetic testing for Brugada syndrome is clinically available and may help confirm a
diagnosis as well as differentiate between relatives who are at risk for the disease
and those who are not. Some symptoms when pinpointing this disease include
fainting, irregular heartbeats, and chaotic heartbeats. However, just detecting the
irregular heartbeat may be a sign of another disease so the doctor must detect
another symptom as well.
Electrocardiography

ECG pattern in Brugada syndrome. According to a recent consensus document, type

1 ST segment elevation either spontaneously present or induced with the sodiumchannel blocker challenge test is considered diagnostic. Type 2 and 3 may lead to

suspicion but the drug challenge is required for diagnosis. The ECGs in the right and
left panels are from the same patient before (right panel, type 3) and after (left
panel, type 1) endovenous administration of 1 mg/kg of Ajmaline during 10 minutes.
In some cases, the disease can be detected by observing characteristic patterns on
anelectrocardiogram, which may be present all the time or might be elicited by the
administration of particular drugs (e.g., Class IA (ajmaline, procainamide) or class
1C (flecainide, pilsicainide) antiarrhythmic drugs that block sodium channels and
cause appearance of ECG abnormalities) or resurface spontaneously due to as yet
unclarified triggers.
Brugada syndrome has three 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 rare in healthy subjects.

The pattern seen on the ECG is persistent ST elevations in the electrocardiographic

leads V1-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 ECG 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,
as does 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
The cause of sudden death in Brugada syndrome is ventricular fibrillation (VF). The
average age of death is 41. According to clinical reports, sudden death in people
with Brugada syndrome most often happens during sleep.The episodes of syncope
(fainting) and sudden death (aborted or not) are caused by fast polymorphic

ventricular tachycardias or ventricular fibrillation. These arrhythmias appear with no

warning. While there is no exact treatment modality that reliably and totally
prevents ventricular fibrillation from occurring in this syndrome, treatment lies in
termination of this lethal arrhythmia before it causes death. This is done via
insertion of an implantable cardioverter-defibrillator (ICD), which continuously
monitors the heart rhythm and will shock the wearer if ventricular fibrillation is
sensed.

Labelled sketch of an already-implanted cardioverter-defibrillator

Recent studies have evaluated the role of quinidine, a Class Ia antiarrhythmic drug,
for decreasing VF episodes occurring in this syndrome. Quinidine has been found to
both decrease the number of VF episodes and correct spontaneous ECG changes,
possibly via inhibiting Ito channels.Some drugs have been reported to induce the
type-1 ECG and/or (fatal) arrhythmias in Brugada syndrome patients. Patients with
Brugada syndrome can prevent arrhythmias by avoiding these drugs or using them
only in controlled conditions. Those with risk factors for coronary artery disease may
require anangiogram before ICD implantation.