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.) 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 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
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
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.
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.9
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| Follow-up: Brugada Syndrome |
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| References |
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References
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. [Medline].
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. [Medline].
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. [Medline].
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].
Vorobiof G, Kroening D, Hall B, et al. Brugada syndrome with marked conduction disease: dual implications of a SCN5A mutation. Pacing Clin Electrophysiol. May 2008;31(5):630-4. [Medline].
Kusano KF, Taniyama M, Nakamura K, Miura D, Banba K, Nagase S, et al. Atrial fibrillation in patients with Brugada syndrome relationships of gene mutation, electrophysiology, and clinical backgrounds. J Am Coll Cardiol. Mar 25 2008;51(12):1169-75. [Medline].
Alings M, Wilde A. "Brugada" syndrome: clinical data and suggested pathophysiological mechanism. Circulation. Feb 9 1999;99(5):666-73. [Medline].
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. [Medline].
Antzelevitch C, Brugada P, Brugada J, et al. Brugada syndrome: from cell to bedside. Curr Probl Cardiol. Jan 2005;30(1):9-54. [Medline].
Nagase S, Kusano KF, Morita H, et al. Longer repolarization in the epicardium at the right ventricular outflow tract causes type 1 electrocardiogram in patients with Brugada syndrome. J Am Coll Cardiol. Mar 25 2008;51(12):1154-61. [Medline].
Donohue D, Tehrani F, Jamehdor R, et al. The prevalence of Brugada ECG in adult patients in a large university hospital in the western United States. Am Heart Hosp J. Winter 2008;6(1):48-50. [Medline].
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. [Medline].
[Guideline] 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].
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. [Medline].
Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. Jan 30 2007;115(4):442-9. [Medline].
London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation. Nov 13 2007;116(20):2260-8. [Medline].
Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR, Schott JJ. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. Jun 2008;118(6):2260-8. [Medline].
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].
Takagi M, Yokoyama Y, Aonuma K, Aihara N, Hiraoka M. Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with brugada syndrome: multicenter study in Japan. J Cardiovasc Electrophysiol. Dec 2007;18(12):1244-51. [Medline].
Junttila MJ, Brugada P, Hong K, et al. Differences in 12-lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients. J Cardiovasc Electrophysiol. Apr 2008;19(4):380-3. [Medline].
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. [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. [Medline].
Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. Jun 2006;17(6):577-83. [Medline].
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 Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J. Jul 2005;26(14):1422-45. [Medline].
Márquez MF, Salica G, Hermosillo AG, Pastelín G, Gómez-Flores J, Nava S, et al. Ionic basis of pharmacological therapy in Brugada syndrome. J Cardiovasc Electrophysiol. Feb 2007;18(2):234-40. [Medline].
Márquez MF, Salica G, Hermosillo AG, Pastelín G, Cárdenas M. Drug therapy in Brugada syndrome. Curr Drug Targets Cardiovasc Haematol Disord. Oct 2005;5(5):409-17. [Medline].
Yang F, Hanon S, Lam P, Schweitzer P. Quinidine revisited. Am J Med. Apr 2009;122(4):317-21. [Medline].
Further Reading
Keywords
Brugada syndrome, idiopathic ventricular fibrillation, idiopathic VFib, ventricular tachyarrhythmias, syncope, cardiac arrest, sudden death, sudden unexpected nocturnal death syndrome, SUNDS, SCN5A mutation, sodium channel blockers, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, heterocyclic antidepressants, glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, alcohol intoxication, cocaine intoxication
