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Brugada Syndrome (BS) is a genetic cause of sudden cardiac
arrest (SCA) which occurs due to the development of either
polymorphic ventricular tachycardia (VT) or ventricular
fibrillation (VF). These are lethal arrhythmias that prevent the
ventricle from contracting effectively. Without prompt
defibrillation (electrical shock), death ensues within a few
minutes due to lack of blood flow to the body’s vital organs.
In approximately 30% of patients, SCA is the initial clinical
manifestation of BS. When VT or VF occurs, it tends to be in the
evening hours. This
is thought to be due to increased nocturnal parasympathetic
activity as part of the body’s natural circadian rhythm.
Patients with BS do not have structural heart disease on
conventional cardiac tests such as an echocardiogram, a stress
test, or cardiac catheterization. However, a standard
electrocardiogram (ECG) usually shows the characteristic
abnormality: right bundle branch block type morphology of the
QRS complex with ST segment elevation in the right precordial
leads (V1 – V3; Figure1). The differential
diagnosis for the ECG pattern seen in BS is extensive (Table 1)
so not all patients with this sort of ECG abnormality actually
have the BS and thus will not be at risk for SCA. The risk of
SCA in asymptomatic patients with “true” Brugada type ECG
pattern ranges from 0.5 to 14 percent. Because of this risk, it
is important to identify and appropriately manage BS patients at
high risk according to best available evidence.
BS typically presents during adulthood.
Although most patients are in their 30’s to 40’s, BS has been
reported in patients as young as 2 years of age and as old as 84
years. Men are affected more commonly than women with a ratio of
8 - 9:1. The reason for this male preponderance is possibly
related to underlying differences in hormonal status. It is
estimated that BS is responsible for at least 4% of all sudden
deaths and at least 20% of all sudden deaths
occurring in patients without structural heart disease. The
syndrome occurs more commonly in Southeast Asians, with the
highest incidence occurring in the peoples of
BS is a genetic disorder. In the inherited form, the mutant
genes are passed down from parents to offspring and the syndrome
runs in families. Since BS is an autosomal dominant disorder,
offspring of people with the mutant gene have a 50% chance of
inheriting it from their affected parent. A sporadic form is
also seen due to spontaneous mutations in the germ cells (ova or
sperm) of the patient’s parents affecting the segments of DNA
that code for the specific Brugada proteins.
To date, the only gene linked with this condition, SCN5A,
occurs on chromosome 3. It codes for the α subunit of the
cardiac sodium channel. Only 18 to 30 percent of families with
BS have been found to have this mutant gene, making it likely
that additional genes, yet to be identified, are responsible for
this syndrome. In patients with BS, we know that there is
altered depolarization of the right ventricle making a person
vulnerable to fatal ventricular arrhythmias. Genetic counseling
about BS is available through our center, as is the commercially
available test for SCN5A.
The mutant sodium channel leads to decrease in the
sodium (INA) current due to either failure
of expression of the sodium channel, accelerated inactivation,
or prolonged recovery from inactivation. This causes a
shortening of the action potential duration by blunting phase 0
depolarization. Furthermore, in the right ventricular (RV)
epicardium, there is an increased number of transient outward
potassium current channels, Ito. This mismatch in
potassium and sodium currents leads to decreased activation of
the L-type calcium channels that maintain the depolarized state
during phase 2 of the action potential. The net effect is loss
of the action potential dome causing a short refractory period
of the RV epicardium and heterogeneity of refractory periods
between the RV endo- and epicardium (Figure 2).
Since these mutant sodium channels fail to activate
properly there is unidirectional block. The unidirectional block
coupled with the short refractory period makes this substrate
ideal for reentry; the reentrant circuit leads to continuous
depolarization of the ventricular myocardium causing ventricular
tachycardia and fibrillation. This form of reentry tends to
occur in phase 2 of the action potential, thus is termed phase 2
Patients with BS are also at increased risk for developing
atrial fibrillation, an irregularly irregular rhythm originating
from the upper chambers of the heart. Atrial fibrillation is
observed clinically in up to 20% of these patients. Other
arrhythmias include AV nodal reentrant tachycardia and
Wolf-Parkinson-White syndrome. The increased incidence of these
arrhythmias may reflect the diffuse nature of the sodium channel
abnormality. These arrhythmias may lead to inappropriate firing
from implanted cardioverter-defibrillator (ICD) highlighting the
importance of appropriate device programming in the management
of supraventricular arrhythmias in BS.
The ECG manifestations of Brugada syndrome are often
concealed, but can be unmasked by various clinical conditions,
such as being febrile, or administration of certain drugs,
sodium channel blockers. These precipitating factors and lead to
changes in ion currents that occur in the myocardial cells
during depolarization, leading to the abnormal ECG pattern
typical of BS (Figure 3).
Antzelevitch C. Brugada P. Borggrefe M. et al:
Brugada syndrome: report of the second consensus conference:
endorsed by the Heart Rhythm Society and the European Heart
Rhythm Association. Circulation111;659-670, 2005.
Three ECG patterns in the right precordial (chest) leads
are recognized as being associated with BS (Figure 2.1).
Type 1 is diagnostic of Brugada pattern and is
characterized by a coved ST-segment elevation
mm followed by a negative T wave. A definitive diagnoses of BS
can be made when a type 1 ST-segment elevation pattern
is observed in >1 right precordial lead (V1 to
V3) along with one of the following: documented
polymorphic VT or VF; a family history of sudden cardiac death
at < 45 years of age; similar type ECGs in family
members, inducibility of VT/VF during an electrophysiology
study; unexplained syncope; or history of nocturnal agonal
The type 2 ST-segment elevation pattern has a saddleback
appearance with a ST-segment elevation of
2 mm, a trough displaying >1
mm ST elevation, and then either a positive or biphasic T
wave. The type 3 pattern has either a saddleback or coved
appearance with an ST-segment elevation of <1 mm.
Unlike the type 1 pattern, type 2 and 3 pattern ECGs are not
diagnostic of the Brugada pattern.
In order for a diagnosis of BS to be made in patients
with either a type 2 or 3 pattern, conversion to a more
diagnostic type 1 pattern must be observed
either spontaneously or after administration
of a sodium channel blocker e.g. procainamide. (ST-segment
elevation should be >2
mm) in conjunction with one or more of the clinical criteria
described above. Placement of the right precordial
leads in a superior position (up to the second
intercostal space above normal) can increase the
sensitivity of the ECG for detecting the BS.
The pharmacological approach to therapy is based on rebalancing
of currents during the action potential. Antiarrhythmic drugs,
that affect the transient outward potassium current (Ito),
have shown promise because they reestablish the action potential
dome. Unfortunately medications that specifically target Ito
are not available.
Instead, quinidine, which has some Ito
blocking properties, is used most commonly. Quinidine has been
used in some patients to reestablish a normal contour to the
action potential and normalize the ECG pattern in patients with
BS. The recommended dosing of quinidine is 1200 to 1500 mg/ day
given in divided doses.
However, clinical trials demonstrating the long-term
efficacy of quinidine are limited; thus quinidine cannot be
recommended as sole first-line therapy for patients with BS.
Other agents that boost the L-type calcium current,
such as isoproterenol, may be also useful
in patients with BS. The phosphodiesterase III
inhibitor, cilostazol, normalizes the ST segment by
augmenting the calcium current (ICa), as well
as by reducing Ito secondary to an
increase in heart rate. Tedisamil, an experimental
antiarrhythmic agent, with Ito blocking properties
may be more potent than quinidine because it lacks
the relatively strong inward Na current–blocking
actions of quinidine. Nevertheless, appropriate clinical trials
are needed to establish the effectiveness of all of
the above pharmacological agents. Currently, these medications
are reserved for controlling "electrical storms"
(incessant episodes of VT/VF) in BS.
Currently, ICDs are the only proven treatment for
BS. Furthermore, since SCA may be the initial
manifestation of the disease, it is critically important to
identify patients who many benefit from ICD implantation (Figure
4). These patients
include those with the type 1 ECG pattern (either spontaneous or
induced by administration of a sodium channel blocker) who have
been successfully resuscitated from SCA or have had unexplained
syncope, seizures, or nocturnal agonal respirations.
The indications for ICD become less clear in asymptomatic
patients with the Brugada pattern on ECG, and unfortunately,
there is no consensus among physicians. One method for risk
stratifying asymptomatic patients is with an electrophysiology
study. Patients in whom a sustained ventricular arrhythmia (ventricular
fibrillation, polymorphic ventricular tachycardia, or
monomorphic ventricular tachycardia lasting >30
seconds ) is inducible
are felt to be at high risk and may warrant ICD implantation.
However, the specificity of this test in this patient population
has been questioned. Thus, the management of asymptomatic
patients still remains to be definitively defined.