AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Brugada syndrome is a disorder characterized by coved or saddle-shaped ST-segment elevation in leads V₁ through V₃ on ECG. It is associated with complete or incomplete right bundle-branch block and T-wave inversion. In its initial description, the heart was reported to be structurally normal, but this has recently been challenged (Frustaci, 2005). Moreover, subtle structural abnormalities in the right ventricular outflow tract can also be observed. The ECG abnormality may not be evident until it is unmasked by infusion of flecainide or procainamide, or is augmented by a beta-blocker.

Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden cardiac death (Martini, 1989; Brugada, 1992; Brugada, 2001). 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 (Alings, 1999).

Pathophysiology

Dysfunction in cardiac ion channels underlies the clinical manifestations of Brugada syndrome (cardiac channelopathy). In 10-30% of patients and families, mutations in the gene SCN5A, encoding the cardiac voltage-gated sodium channel Na_v1.5, have been reported. Another locus has also been reported on chromosome 3. Most SCN5A mutations lead to loss of function of the Na_v1.5 channel by reducing the sodium current (I_Na) available during the phases 0 (upstroke) and 1 (early repolarization) of the cardiac action potential. Gain-of-function SCN5A mutations may also cause long QT syndrome type 3.

Repolarization disorder hypothesis

ECG alterations in Brugada syndrome have been proposed to be due to an imbalance between the depolarizing and repolarizing currents during phase 1 of the action potential, most particularly in cells expressing a large, transient outward I_to current, such as the epicardial cells of the right ventricle free wall. In patients with loss-of-function SCN5A mutations that result in less I_Na during phase 1, the large I_to current may prematurely repolarize the membrane and produce a loss of the dome (phase 2) of the action potential (see Image 1).

When such premature shortening of the action potential heterogeneously occurs in the myocardium, it may generate phase 2 reentries that can cause ventricular tachycardia and ventricular fibrillation. The large transmural voltage gradients generated by the short action potentials in the right ventricular outflow epicardium are thought to be the basis of the ECG patterns of Brugada syndrome. These specific alterations in cardiac electrical activity, which mainly affect the right ventricle, manifest at ST-segment elevation in precordial leads V₁ through V₃, with a QRS morphology resembling that of a right bundle-branch block (RBBB). Such a pattern may also be due to a J point elevation. This pattern is called coved-type when ST elevation is the most prominent feature, and it is called saddleback-type when J point elevation occurs without ST elevation (see Image 2).

Depolarization disorder model

An alternative hypothesis for the ECG alterations is based on conduction delay in the right ventricular outflow tract compared with the right ventricle free wall. The mechanisms underlying the Brugada syndrome ECG pattern are reviewed by Meregalli (Meregalli, 2005).

The ECG pattern in Brugada syndrome may only be intermittent. The ECG alterations may fluctuate with changes in autonomic balance or body temperature. The abnormality may only be apparent during administration of drugs that block the sodium channel (eg, flecainide, procainamide, ajmaline). The ECG abnormality may disappear with infusion of isoprenaline or with exercise, and it may increase with beta-blockers. These effects are explained by a reduced sodium current in the etiology of Brugada syndrome.

Frequency

United States

Because of its recent identification, the incidence of the Brugada syndrome is not well established. It may cause 4-10 sudden deaths per 10,000 population per year.

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 (Nademanee, 1997).

Mortality/Morbidity

• Brugada syndrome may lead to polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden cardiac death.
• Prolonged syncope and aborted cardiac arrest may cause nightmares, seizures, other neurologic deficits, or brain damage.

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 (Bezzina, 2005).

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 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 (Antzelevitch, 2005).

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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. Positive family history is not required, as it 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

Physical examination does not reveal any indicator of 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

In 20-30% of cases, a loss-of-function mutation in the SCN5A gene is found. Another locus on chromosome 3 has been reported, but thus far the gene is still unknown. The genetic cause or causes of the remaining cases of Brugada syndrome are still under investigation.

Many clinical situations may unmask or exacerbate the ECG pattern of Brugada syndrome. Examples are use of sodium-channel blockers, a febrile state, use of vagotonic agents, use of alpha-adrenergic agonists, use of beta-adrenergic blockers, use of heterocyclic antidepressants, use of a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and alcohol or cocaine intoxication (Antzelevitch, 2005).

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Acute cardiac ischemia
Other causes of syncope, cardiac arrest, or sudden death in an otherwise healthy subject - Hypertrophic cardiomyopathy, congenital long QT syndrome, aberrant coronary origins, and arrhythmogenic right ventricular dysplasia (ARVD)

Differential diagnosis for the ECG pattern (ie, ST-segment elevation in the right precordial leads) (Antzelevitch, 2005; Wilde, 2002)

Atypical RBBB
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

Section 5 of 11  

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Lab 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.
• 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 Na_v1.5 of the cardiac sodium channel.
• • The results of this test support the clinical diagnosis and are important for the early identification of family members at potential risk.
  • 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 dysplasia 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 syndrome (Wilde, 2002) (see Image 2).

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

• Signal-averaged ECG: Arrhythmogenic right ventricular dysplasia (ARVD) 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 ARVD.
• Challenge with sodium channel blockers: In some patients, the intravenous administration of drugs that block sodium channels may unmask or modify the ECG pattern.
• • 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.
  • The sensitivity and specificity of this test is not yet confirmed.
  • This challenge should be performed with continuous cardiac monitoring and in a setting equipped for resuscitation.
  • 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.
  • 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.
  • In patients with the type 2 or 3 patterns, the drug challenge is recommended to clarify the diagnosis (Antzelevitch, 2005).
  • 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.
  • Isoproterenol and sodium lactate may be effective as antidotes if the sodium channel blocker induces an arrhythmia.
• Electrophysiological (EP) study: This test may be performed to determine the inducibility of arrhythmias in Brugada syndrome. The predictive value of the EP study is still debated. In 2002, Priori reported poor predictive value, whereas in 2001, Brugada showed that inducibility may be a good predictor of outcome.

TREATMENT

Section 6 of 11  

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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 (Antzelevitch, 2005). 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. For details about risk stratification and indications for implanting an ICD, readers are referred to the consensus report (Antzelevitch, 2005).

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 (Pelliccia, 2005). Regarding the asymptomatic carriers of SCN5A mutations, at the present time, whether they should also be restricted from participation in sports is uncertain.

MEDICATION

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Thus far, no drug treatment for Brugada syndrome is recommended.

FOLLOW-UP

Section 8 of 11  

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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

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

Deterrence/Prevention

• When indicated, use of an ICD may prevent sudden cardiac death (Antzelevitch, 2005).
• The patient's relatives and coworkers should be educated about Brugada syndrome and the basics of cardiopulmonary resuscitation (CPR).

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 (Brugada, 2003).

Patient Education

• Educating the patient and his or her family members and coworkers about basic CPR is important.

MISCELLANEOUS

Section 9 of 11  

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• Miscellaneous
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Medical/Legal Pitfalls

• Many patients with Brugada syndrome are young and otherwise healthy and may present with syncope.
• • Patients with syncope should not be assumed to have a benign condition, and 12-lead ECG should be performed.
  • A drug challenge with a sodium channel blocker should be considered in each patient with syncope in whom no obvious cause is found.
  • An experienced physician should read the ECGs, and, if possible, an electrophysiologist should review them.
  • Consider the full differential diagnosis.

Special Concerns

• Asymptomatic patients with a type 1 ECG pattern on routine ECG represent a difficult case.
• • According to the latest consensus guidelines (Antzelevitch, 2005), a clinical electrophysiologist should examine patients in this situation.
  • The guidelines advise the implantation of an ICD if programmed electrical stimulation induces ventricular tachycardia or fibrillation.

MULTIMEDIA

Section 10 of 11  

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Media file 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. Adapted from Antzelevitch, 2005.
	View Full Size Image
Media type:  Graph

Media file 2:  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. Modified from Wilde, 2002.
	View Full Size Image
Media type:  Rhythm Strip

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Follow-up
• Miscellaneous
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• References

• Alings M, Wilde A. "Brugada" syndrome: clinical data and suggested pathophysiological mechanism. Circulation. Feb 9 1999;99(5):666-73. [Medline].
• 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. Circulation. Feb 8 2005;111(5):659-70. [Medline].
• Antzelevitch C, Brugada P, Brugada J, Brugada R. Brugada syndrome: from cell to bedside. Curr Probl Cardiol. Jan 2005;30(1):9-54.
• Bezzina CR, Shimizu W, Yang P, et al. Common sodium channel promoter haplotype in asian subjects underlies variability in cardiac conduction. Circulation. Jan 24 2006;113(3):338-44.
• Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation. Dec 23 2003;108(25):3092-6.
• Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. Nov 15 1992;20(6):1391-6. [Medline].
• Brugada P, Geelen P, Brugada R, et al. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol. Sep 2001;12(9):1004-7.
• Frustaci A, Priori SG, Pieroni M, et al. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. Dec 13 2005;112(24):3680-7.
• Martini B, Nava A, Thiene G, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J. Dec 1989;118(6):1203-9.
• Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more?. Cardiovasc Res. Aug 15 2005;67(3):367-78.
• Nademanee K, Veerakul G, Nimmannit S, et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation. Oct 21 1997;96(8):2595-600.
• Pelliccia A, Fagard R, Bjornstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of M. Eur Heart J. Jul 2005;26(14):1422-45.
• Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. Mar 19 2002;105(11):1342-7.
• Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. Nov 5 2002;106(19):2514-9. [Medline].

Article Last Updated: Nov 10, 2006