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The Brugada Syndrome

Drifmeyer, Erin B. MD; Batts, Kenneth B. DO

Current Sports Medicine Reports: April 2005 - Volume 4 - Issue 2 - p 83–87
doi: 10.1097/01.CSMR.0000306078.67322.a0

Brugada syndrome is a recognized cause of sudden cardiac death worldwide. An inherited ion channel abnormality produces abnormal repolarization leading to characteristic ST-segment elevation in precordial leads V1 to V3 and a pseudo right bundle branch block on electrocardiogram. Only recently has medical therapy and management been defined to allow for athletes to lead healthy lifestyles. This article provides a concise review of the clinical manifestations, pathophysiology, and therapeutic options for the sports medicine team.

Address Tripler Army Medical Center, Department of Family Medicine and Emergency Medicine Services, 1 Jarrett White Road, Honolulu, HI 96859, USA. E-mail:

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The antithetical thought of sudden cardiac death (SCD) and exercise in professional sport and collegiate athletics has captured the public's awareness and garnered the attention of the medical community worldwide. Over the past decade our gifted, young athletes and sports heroes have unexpectedly died leaving us to wonder, could this happen to me or one of my athletes? In the United States, an estimated 450,000 cases of SCD occur annually. Fortunately, SCD is rare in young athletes and the majority of cases are due to structural abnormalities of the heart or congenital cardiovascular disease. About 2% of these events occur in people with no known external cause or evidence of structural heart disease, often termed idiopathic ventricular fibrillation (VF) [1]. A recent study found that 40% to 60% of idiopathic VF occurred in patients with an electrocardiogram (ECG) demonstrating right precordial ST-segment elevations and an incomplete right bundle branch block (RBBB) with a normal QT interval, characteristic of the Brugada syndrome [2].

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First reported by the Brugada brothers in 1992, the syndrome has an autosomal dominant transmission with variable penetrance clinically manifesting as an electrical cardiac abnormality varying in magnitude from presyncope to ventricular arrhythmias and sudden death. Brugada syndrome patients are frequently male, and often of Southeast Asian descent, although cases have been documented worldwide. The condition has been described in the Philippines as Bangugnut (“moaning and dying during sleep”), in northeast Thailand as Lai Tai (“died during sleep”), and Pokkuri (“sudden unexpected death at night”) in Japan [3]. By 1997 research showed that 16 of 27 Thai men with aborted sudden death had Brugada syndrome patterns on their ECG. A literature review in 1999 showed that 58% of patients meeting criteria for Brugada syndrome were of Asian descent [4•]. The syndrome was first considered by the Brugada brothers in 1986 after they investigated the case of a 3-year-old Polish boy and his family [4•]. They have since conducted studies involving patients in their native Italy.

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The exact pathophysiology of this autosomal dominant disorder has not been elucidated. Initially thought to be a structural defect, this idea has fallen out of favor. Echocardiograms and endomyocardial biopsies have failed to find structural abnormalities [5••]. The ECG pattern suggests against a structural problem due to individual patients have varying ECGs over time along with certain drugs and autonomic tone altering the Brugada ECG wave forms. If a structural cause were the explanation, the ECG could be expected to be relatively constant [5••].

Recently 30% of Brugada syndrome patients were discovered to have a mutation in the SCN5A gene on chromosome 3, which encodes the pore-forming alpha subunit of the cardiac sodium channel [6]. The abnormal sodium channel creates an abnormal repolarization in the epicardium. This leads to a voltage gradient between the epicardium and endocardium. The transmural difference in repolarization and subsequent difference in refractory periods provides a window of time in which early impulses or extrasystolic beats are conducted, leading to reentry circuits and ultimately VF [4•].

When patients with Brugada syndrome are given Class Ia sodium channel blockers, this further inhibits the already faulty ion channel, and provides more hindrance to repolarization. The ST-segment elevation increases, and may change shape from saddleback to coved, indicating more unstable repolarization and predisposition toward reentry. This augmentation of ECG findings suggests that an already abnormal sodium channel system is made worse by pharmacologically blocking the channels [6]. People with normal baseline ECGs but a family history of Brugada syndrome have been shown to have ST-segment elevation with sodium channel blockers and are thus predisposed to similar arrhythmias.

Additional clinical features may also be explained in terms of ion channels. It is well known that Brugada syndrome patients frequently go into VT while sleeping, or during periods of rest. It is thought that increased vagal tone allows predisposed patients to suddenly convert to VT. Indeed, when given β-blockers or muscarinic stimulators, ST-segment elevation increased, whereas β-agonists reduced ST-segment elevation. These findings are explained by the slow (L type) calcium channels being augmented with β-agonists, which allows normal repolarization and restores the shape of the epicardial action potential, eliminating the transmural gradient and the potential for reentry phenomena [5••]. The calcium channels are inhibited by acetylcholine and β-blockers, preventing normal repolarization, and allowing the possibility of reentry phenomena to occur.

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Clinical Features

The Brugada syndrome is characterized primarily in terms of ECG findings, with commonly associated symptoms and demographic trends completing the clinical picture. The typical ECG involves a pseudo RBBB with ST-segment elevation in the right precordial leads (V1–V3) [7••]. Three specific types of repolarization patterns have been described based on the shape of the ST segment and degree of J-wave elevation (Fig. 1). These categories are important for prognosis, with Type I having triangular (coved) shaped ST-segment elevation in V1 to V3. There may or may not be inverted T waves in V1 to V3 with a right ventricular conduction delay. This pattern carries the highest risk of sudden death. Types II and III feature saddleback ST-segment changes. The downward displacement of the ST segment in Type II dips between the two elevations but does not return to the baseline (Fig. 2). In Type III the downward segment is displaced all the way to the baseline. Each may or may not have inverted T waves and right ventricular conduction delay. These forms are associated with less risk of sudden death than Type I [8]. An individual may demonstrate each pattern at different points in time.

Figure 2

Figure 2

Figure 1

Figure 1

The RBBB is referred to as “pseudo” because true RBBB has a widened S wave in the lateral leads. In Brugada syndrome, there is early high takeoff of the ST segment in the right precordial leads (actually the J wave), which looks like an RBBB pattern [5••]. The other key features of the Brugada syndrome ECG are extrasystoles, and when the patient is symptomatic, rapid polymorphic ventricular tachycardia (VT) may be indistinguishable from VF [4•].

Electrocardiographic findings are recognized prior to manifestation of symptoms because frequently there are no symptoms other than sudden death in a patient with Brugada syndrome. Often, a patient is sleeping and dies suddenly in the early morning, after having gone into polymorphic VT [9••]. Patients may present with syncope, or presyncope and palpitations. Nocturnal agonal respirations have also been described. Patients may report a family history of sudden death or VF. In fact, often the family history is the most important part of the encounter with a patient with suspected Brugada syndrome, as the past medical history and physical examination are unremarkable [10]. Onset of arrhythmias range from age 22 to 65, with a peak in the fourth decade [5•].

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A key feature in the diagnosis of Brugada syndrome is the inducibility of ECG changes with a drug challenge. This type of evaluation is useful, for example, in the patient who presents with syncope and a family history of sudden death. The patient is placed on continuous blood pressure and ECG monitoring, with defibrillator and advanced cardiac life support facilities immediately available. A Class Ia sodium channel blocker (ajmaline, flecanide, or procainamide) is administered and ECG changes in the precordial leads are observed. The test is positive when a normal baseline ECG develops a J-wave amplitude of 2 mm in two of leads V1 to V3, or when a person with saddleback ST-segment elevation (Types II and III) converts to coved-type ST-segment elevation (Type I) [7••]. The patient is then monitored until the ECG normalizes.

Current recommendations for the diagnosis of Brugada syndrome require a patient to have the following: 1) a baseline ECG with saddleback ST-segment elevation in more than one precordial lead, which converts to a coved Type I after sodium channel blocker challenge, and one of either documented VF, polymorphic VT, family history of SCD before age 45, family history of coved-type ST elevation, inducible changes on an electrophysiologic study, history of syncope, or history of agonal respirations; or 2) coved (Type I) ST-segment elevation in more than one precordial lead and one of the above list [9••].

Although the diagnostic criteria for Brugada syndrome are fairly specific, other conditions should be considered in the differential diagnosis. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is similar to Brugada syndrome and should be excluded. Although both conditions may produce syncope, cardiac arrest, and sudden death from VT, ARVC has characteristic inverted T waves precordially, does not have the same effects from sodium channel blockers and β-agonists, and will usually show fibrofatty involvement histologically [9••]. Other conditions which can lead to V1 to V3 ST-segment elevation include cocaine intoxication, hypercalcemia, hyperkalemia, tricyclic antidepressant overdose, right and left bundle branch block, left ventricular hypertrophy, acute myocardial infarction, myocarditis, pulmonary embolism, aortic aneurism, and Duchenne muscular dystrophy [9••].

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Previous treatment options for asymptomatic Brugada syndrome patients included no intervention, pharmacologic antiarrhythmics (β-blockers or amiodarone), or an implantable cardiac defibrillator (ICD). The ICD is the present treatment of choice, as studies have proven it effective in terminating VF episodes [11]. One study showed a 10% annual mortality with β-blockers, which is not acceptable given the demonstrated effectiveness of the ICD [12]. The most pressing question currently, revolves around who is an appropriate candidate for ICD placement due to a significant number of Brugada syndrome patients being asymptomatic. The 2002 American College of Cardiology/American Heart Association/North American Society for Pacing and Electrophysiology Committee on Pacemaker Implantation recommends ICD placement in Brugada syndrome patients who have experienced syncope or have a family history of SCD due to the high incidence of VF [13]. The committee did not recommend ICD placement in Brugada syndrome individuals who only exhibit ECG findings.

Brugada syndrome patients can be broken down into three risk groups: high (history of syncope and baseline ST elevation), intermediate (no history of syncope and only baseline ST elevation), and low (SCN5A mutation carrier or ECG change induced with drug challenge).

High-risk patients are ICD candidates, intermediate-risk patients have undetermined treatment recommendations, and low-risk patients should be advised to avoid tricyclic antidepressants and sodium channel blockers and to seek care if presyncope or syncope develops [14].

Another study based prognosis on an individual's symptom and ECG findings [15]. One must consider whether the ECG showed a Brugada pattern spontaneously or only after induction with a sodium channel blocker. These two groups of patients were further broken down based on whether or not VF could be induced with programmed ventricular stimulation. Patients diagnosed with Brugada syndrome based on a spontaneously abnormal ECG, with no history of syncope, have a 1.8% risk of sudden death in 2 years if no arrhythmia could be induced, compared with a 14.0% risk if arrhythmia could be induced. Those with an abnormal ECG, history of syncope, and inducible arrhythmia on ECG are at the most risk, with a 27% risk of dying within 2 years. Patients with only an abnormal ECG after drug challenge and no history of syncope or arrhythmia after ventricular stimulation, are at the least risk, 0.5% [14].

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Sports Medicine

A sports medicine physician is often expected to screen potential athletes for medical conditions that may predispose them to injury or illness preventing their participation. The goal of cardiovascular screening in young athletes is early recognition of congenital heart disease to reduce the risk and prevent adverse arrhythmic events leading to sudden nontraumatic cardiac death. In the past, the medical community has focused on structural cardiac anomalies in the young and coronary artery disease in the elderly. Along with hypertrophic cardiomyopathy, anomalous coronary artery origin, right ventricular dysplasia, Wolff-Parkinson-White syndrome, and long QT syndrome, Brugada syndrome is one of the indolent conditions that should be considered during cardiovascular screening.

History and physical examination are the first steps in screening and a history of syncope, palpitations, nocturnal agonal respirations, and family history of sudden death all should prompt consideration of the Brugada syndrome. Although the physical examination will be unrevealing, the ECG findings are classic. Echocardiogram is not recommended in routine sports screening and would not be helpful in the case of Brugada syndrome [15].

What is a sports medicine physician to tell an athlete with Brugada syndrome? Brugada syndrome is unique among cardiovascular risks in that the associated arrhythmias occur at rest and may be inhibited by the increased adrenergic tone produced during exercise. The American Heart Association recommends safe guidelines for athletic participation of young athletes diagnosed with genetic cardiovascular diseases. Although little empiric data is available for making recommendations regarding athletes diagnosed with Brugada syndrome, they draw on what data they find as well as on personal and collective experience [16].

Patients with Brugada syndrome are strongly discouraged from body building, windsurfing, hockey, lifting free weights, rock climbing, underwater (SCUBA) diving, and downhill skiing. There are uncertain recommendations for participation in basketball, singles tennis, racquetball, flag football, sprinting, motorcycling, soccer, and horseback riding. Brugada syndrome patients are likely safe to participate in cross country skiing, doubles tennis, baseball, bowling, biking, golf, hiking, skating, jogging, snorkeling, sailing, using weight machines, swimming, and walking.

Brugada syndrome patients are advised to be wary of overheating, as temperature-dependent dysfunction of the SCN5A gene has been observed. Patients with an ICD should be prohibited from contact sports due in part to disruption of leads. Sinus tachycardia from exercise may trigger inappropriate ICD shock and therefore well programmed dual chamber ICD cardioverters should be utilized [16].

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Sudden cardiac death due to Brugada syndrome most often occurs in young, otherwise healthy individuals. This is the very population that seeks to participate in sports. Therefore, the sports medicine physician must be astutely aware of this condition when screening patients for athletic participation. Should the characteristic ECG changes be discovered, it is the role of the sports medicine physician to work with the athlete in designing an exercise prescription. This depends largely on the physician-patient relationship and an understanding of the specific needs of the athlete. Recommendations must be used in combination with considerations of the sports environment, patient medications, and even emotional/social context of sports participation for the individual. The relatively recent discovery of Brugada syndrome and the active field of research surrounding it suggest that there is much more information forthcoming regarding management of this unique group of athletes.

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The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Army Medical Department or the Army Service at large.

The authors would like to acknowledge three physicians: Colonel Francis G. O'Connor, MD, Colonel Thomas P. Dove, MD, and Captain John E. Thomas, MD in helping prepare the paper.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

1. Maron B: Sudden death in young athletes. N Engl J Med 2003, 349:1064–1075.
2. Remme C, Wever E, Wilde A, et al.: Diagnosis and long-term follow up of the Brugada syndrome in patient with idiopathic ventricular fibrillation. Eur Heart J 2001, 22:400–409.
3. Nademanee K, Veerakul G, Nimmannit S, et al.: Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation 1997, 96:2595–2600.
4.• Antezelevich C, Brugada P, Brugada J, Brugada R, et al.: Brugada syndrome: a decade of progress. Circ Res 2002, 91:1114–1118.

A review of the genetic and ionic mechanisms along with ECG changes in the Brugada syndrome.

5.•• Alings M, Wilde A: Brugada syndrome: clinical data and suggested pathophysiological mechanism. Circulation 1999, 99:666–673.

Excellent review of ionic pathways and clinical determinants corresponding with therapeutic outcomes.

6. Tukkie R, Sogaard P, Vleugels J, et al.: Delay in right ventricular activation contributes to Brugada syndrome. Circulation 2004, 109:1272–1277.
7.•• Gussak I, Antzelevitch C, Bjerregaard P, et al.: The Brugada syndrome: clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol 1999, 33:5–15.

Excellent review identifying the full spectrum of the Brugada syndrome.

8. Ahn J, Hurst J: Worrisome thoughts about the diagnosis and treatment of patient with Brugada waves and the brugada syndrome. Circulation 2004, 12:1463–1467.
9.•• Wilde A, Antezelevich C, Borggrefe M, et al.: Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002, 106:2514–2519.

A consensus statement proposing diagnostic criteria for the Brugada syndrome.

10. Beckerman J, Wang P, Hlatky M: Cardiovascular screening of athletes. Clin J Sports Med 2004, 14:127–133.
11. Naccarelli G, Antezelevich C, Wolbrette D, Luck J: The Brugada syndrome. Curr Opin Cardiol 2002, 17:19–23.
12. Nademanee K, Veerakul G, Mower M, et al.: Defibrillator Versus Beta Blockers for Unexplained Death in Thailand (DEBUT): a randomized clinical trial. Circulation 2003, 107:2221–2226.
13. Gregoratos G, Abrams J, Epstein AE, et al.: ACC/AHA/NASPE 2002 guideline update for implantation of pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee on Pacemaker Implantation). 2002 .
14. Priori S, Napolitano C, Gasparini M, Pappone C, et al.: Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002, 105:1342–1347.
15. 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 2003, 108:3092–3096.
16. Maron B, Chaitman B, Ackerman M, et al.: Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation 2004, 109:2807–2816.
© 2005 American College of Sports Medicine