Brugada Syndrome

Author: Jose M Dizon, MD, Associate Professor of Medicine and Surgery, Clinical
Electrophysiology Laboratory, Division of Cardiology, Columbia University; Consulting Staff,
Department of Medicine, New York-Presbyterian Hospital, Columbia University Medical Center
Coauthor(s): Deepak Saluja, MD, Fellow in Clinical Cardiac Electrophysiology, New York
Presbyterian Hospital, Columbia Campus; Hugues Abriel, MD, PhD, Director, Department of
Clinical Research, University of Bern, Switzerland
Updated: Aug 24, 2009

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.)

1
Schematics show the 3 types of action potentials in the right ventricle: endocardial (End), mid
myocardial (M), and epicardial (Epi). A, Normal situation on V2 ECG generated by transmural
voltage gradients during the depolarization and repolarization phases of the action potentials. B-
E, Different alterations of the epicardial action potential that produce the ECGs changes
observed in patients with Brugada syndrome.

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

3
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

4
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

5
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.

6
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.

Differential Diagnoses

Arrhythmogenic Right Ventricular Dysplasia (ARVD)

Hypothermia
Pericarditis, Acute
Pulmonary Embolism

Other Problems to Be Considered

The differential diagnosis of sudden cardiac death in an otherwise presumably healthy subject is
varied, but includes such entities as acute cardiac ischemia due to atherosclerosis or coronary
anomaly, hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia,
long QT syndrome, and arrhythmogenic right ventricular cardiomyopathy (ARVC). Many of
these entities can be differentiated on the basis of history and physical examination.
Occasionally, however, there is overlap that requires special consideration.

7
The differential diagnosis of right precordial ST-segment elevation is as follows.9,18

Atypical right bundle branch block

Left ventricular hypertrophy
Early repolarization
Acute pericarditis
Acute myocardial ischemia or infarction
Prinzmetal angina
Pulmonary embolism
Dissecting aortic aneurysm
Mediastinal tumor or hemopericardium compressing the right ventricular outflow tract (RVOT)
Arrhythmogenic right ventricular dysplasia and/or cardiomyopathy
Various abnormalities of the central and autonomic nervous systems
Overdose of a heterocyclic antidepressant
Cocaine intoxication
Duchenne muscular dystrophy
Friedreich ataxia
Thiamine deficiency
Hypercalcemia
Hyperkalemia
Hypothermia
Pectus excavatum
Effects of athletic training

Workup

Laboratory Studies

• Check serum potassium and calcium levels in patients presenting with ST-segment
elevation in the right precordial leads because both hypercalcemia and hyperkalemia
may generate an ECG pattern similar to that of Brugada syndrome.

8
 • Laboratory markers, such as creatine kinase-MB (CK-MB) and troponin, should be
checked in patients who have acute symptoms compatible with a coronary artery
syndrome.
• Patients with high likelihood of the disease may be genetically tested for a mutation
in SCN5A, which codes for the alpha subunit Nav 1.5 of the cardiac sodium channel.
o The results of this test support the clinical diagnosis and are important for the
early identification of family members at potential risk.
o Mutations in SCN5A are found in only about 20-30% of index cases.

Imaging Studies

Echocardiography and/or MRI should be performed mainly to exclude arrhythmogenic right

ventricular cardiomyopathy and also to assess for other potential causes of arrhythmias, such as
hypertrophic cardiomyopathy, unsuspected myocardial injury, myocarditis, or aberrant coronary
origins.

Other Tests

• Exercise stress testing may suppress ECG changes and arrhythmias.

• ECG: Three ECG patterns have been described in Brugada syndrome18 (see Media file
2).

9
Three types of ST-segment elevation in Brugada syndrome, as shown in the precordial
leads on ECG in the same patient at different times.
Left panel shows a type 1 ECG pattern with pronounced elevation of the J point (arrow),
a coved-type ST segment, and an inverted T wave in V1 and V2.
The middle panel illustrates a type 2 pattern with a saddleback ST-segment elevated by
>1 mm.
The right panel shows a type 3 pattern in which the ST segment is elevated <1 mm.
According to a consensus report (Antzelevitch, 2005), the type 1 ECG pattern is
diagnostic of Brugada syndrome.

10
 ECG Patterns in Brugada Syndrome
Characteristic Type 1 Type 2 Type 3
J wave amplitude (mm) >2 mm >2 mm >2 mm

T wave Negative Positive or biphasic Positive

ST-T configuration Coved-type Saddleback Saddleback

Elevated by Elevated by
ST segment, terminal portion Gradually descending
>1 mm <1 mm

• Recently, the QRS duration on 12-lead ECG has been suggested as a risk marker for
vulnerability to dangerous arrhythmias.19,20
• Signal-averaged ECG: Arrhythmogenic right ventricular cardiomyopathy (ARVC)
and Brugada syndrome may be difficult to differentiate in some cases. Late potentials
on signal-averaged ECG may reveal the fibrofatty degeneration of the right ventricle
seen in ARVC.
• Challenge with sodium channel blockers: In some patients, the intravenous
administration of drugs that block sodium channels may unmask or modify the ECG
pattern, aiding in diagnosis and/or risk stratification in some individuals.
o Flecainide 2 mg/kg (maximum 150 mg) over 10 minutes, procainamide 10
mg/kg over 10 minutes, ajmaline 1 mg/kg over 5 minutes, or pilsicainide 1
mg/kg over 10 minutes may unmask or exaggerate the ST-segment elevation.
o The sensitivity and specificity of this test is not yet confirmed.
o This challenge should be performed with continuous cardiac monitoring and
in a setting equipped for resuscitation.
o In patients with a normal baseline ECG, the results are positive when the drug
generates a J wave with an absolute amplitude of 2 mm or more in leads V1,
V2, and/or V3 with or without an RBBB.
o This drug test should not be performed in patients with a type 1 ECG pattern
(see Table above) because it adds no information to that obtained with other
tests.

11
 o In patients with the type 2 or 3 patterns, the drug challenge is recommended to
clarify the diagnosis.9
o Administration of the drug should be stopped when the result is positive,
when ventricular arrhythmia occurs, or when QRS widening of greater than
30% is observed.
o Isoproterenol and sodium lactate may be effective as antidotes if the sodium
channel blocker induces an arrhythmia.

Procedures

Some investigators use electrophysiologic study (EPS) to determine the inducibility of

arrhythmias in an effort to risk-stratify patients with Brugada syndrome. However, the
predictive value of this approach is debated. In 2002, Priori21 reported poor predictive value,
whereas in 2001, Brugada22 showed that inducibility may be a good predictor of outcome. A
study by Gehi concluded that EPS was not of use in guiding the management of patients with
Brugada syndrome.23

Treatment

Medical Care

At present, implantation of an implantable cardiac defibrillator (ICD) is the only treatment that
has been proven effective for Brugada syndrome. No proven pharmacologic approach reduces
the occurrence of ventricular tachycardia or ventricular fibrillation, and no approach prevents
sudden death in a prospective manner.

Indications for ICD implantation were published in the report of the Second Consensus
Conference on Brugada syndrome.13 For patients at the 2 extremes of risk stratification, the
decision to implant or not to implant an ICD is clear. Patients with Brugada syndrome with a
history of cardiac arrest must be given an ICD. In contrast, close follow-up is recommended for
asymptomatic patients with no family history of sudden cardiac death. Patients with intermediate
clinical characteristics present a greater challenge. For details about risk stratification and
indications for implanting an ICD, readers are referred to the consensus report.13

12
Surgical Care

Surgery (other than ICD placement) is not indicated.

Consultations

A board-certified cardiologist who specializes in cardiac arrhythmic disorders (ie, a clinical

electrophysiologist) should examine patients with suspected Brugada syndrome. Consultation
with a genetic counselor is also indicated for genetic screening and counseling of patients and
their relatives.

Diet

No data from controlled studies support the need for a special diet for patients with Brugada
syndrome.

Activity

Because regular physical activity may increase the 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, Pelliccia et al recommend that patients
with a definite diagnosis of Brugada syndrome should be restricted from competitive sports.24
Regarding the asymptomatic carriers of SCN5A mutations, at the present time, whether they
should also be restricted from participation in sports is uncertain.

Medication

Thus far, no drug treatment for Brugada syndrome is recommended

Follow-up

Further Inpatient Care

Patients with syncope or cardiac arrest and suspected or diagnosed Brugada syndrome must be
hospitalized with continuous cardiac monitoring until definitive treatment (ie, ICD placement) is
given.

Further Outpatient Care

13
A board-certified cardiologist should closely follow up with patients with Brugada syndrome.

Deterrence/Prevention

• When indicated, use of an ICD may prevent sudden cardiac death.9

• The patient's relatives and coworkers should be educated about Brugada syndrome
and the basics of cardiopulmonary resuscitation (CPR).
• Genetic counseling is recommended.

Complications

Hypoxia during cardiac arrest may cause neurologic deficits.

Prognosis

During a mean follow-up of 24 months, sudden cardiac death or ventricular fibrillation occurred
in 8.2% of patients with Brugada syndrome. A history of syncope, a spontaneously abnormal
ECG, and inducibility during programmed electrical stimulation significantly increased this risk.3

Patient Education

Educating the patient and his or her family members and coworkers about basic CPR is
important. Genetic counseling is reasonable although genetic testing may not be diagnostic
because not all mutations may be detected.

Special Concerns

Asymptomatic patients with a type 1 ECG pattern on routine ECG represent a difficult case.
According to the latest consensus guidelines, a clinical electrophysiologist should examine
patients in this situation.9 Patients in this situation can be risk-stratified using the techniques
described above, and a decision on ICD implantation should be made accordingly.

14