GENETICS AND PATHOGENESIS

The initial observation linking the Brugada syndrome to a specific genetic abnormality was reported by Chen et al in 1998 (3). These studies showed 3 families with a mutation in the SCN5A gene, which is the same gene known to be responsible for the LQT3 form of the long QT syndrome. Of note is the fact that the SCN5A abnormality in the long QT syndrome results in enhanced sodium current, prolonging the action potential. The opposite effect is seen in the Brugada syndrome; the SCN5A abnormality is at a different location and results in either more rapid recovery of the sodium channel (missense mutation) or nonfunctional sodium channels (deletion mutations).

The pioneering research of Antzelevitch and coworkers has greatly elucidated possible explanations for both the abnormal electrocardiographic pattern as well as the genesis of the arrhythmias (4). In higher mammals, the ST segment (phase 2 of the action potential) is isoelectric. The normal plateau phase is due to the balance of currents operative during phase 2. At the end of phase 1, strong calcium and sodium currents tend to maintain the plateau and overwhelm concomitant outward currents (i.e., Ito). A number of situations such as severe ischemia or use of sodium or calcium channel blockers may cause loss of the action potential dome because of predominance of the Ito current. This situation results in unbalanced current flowing from endocardium to epicardium and explains the typical electrocardiographic contour. In addition, the inhomogeneity of SCN5A expression has been hypothesized to lead to development of both premature ventricular contractions (PVCs) and serious ventricular arrhythmias.

ELECTROCARDIOGRAPHIC MANIFESTATIONS

The electrocardiographic manifestations of Brugada syndrome have been divided into 2 subgroups. One is manifested by coved ST segmental elevation terminated by inverted T waves. The second involves a notched or camelback deformity of the ST segment. Both are associated with an atypical RBBB pattern manifested by a terminal J wave in V1 and V2 (5). Representative samples of these patterns are shown in Figures 1 and 2, and rapid ventricular tachycardia in a patient with this disorder is displayed in Figure 3. The classic electrocardiographic pattern may come and go, and thus serial electrocardiograms are desirable. In addition, enhancement or induction of the characteristic electrocardiographic abnormalities is possible by administering agents that have strong sodium channel blockade. Antiarrhythmic agents such as intravenous procainamide, ajmaline, or flecainide may unmask or intensify the electrocardiographic pattern (6). These maneuvers, as well as the use of the signal-averaged electrocardiogram, are very helpful in making the diagnosis. The characteristic electrocardiographic abnormality may be difficult to distinguish from that of the early repolarization syndrome, a benign condition that usually shows an elevated ST segment in V2 through V4 associated with upward concavity of the ST segment and upright T wave. The Brugada pattern is best seen 1 or 2 interspaces above the V1 position, is downsloping, and is followed by a negative T wave (7).

A host of other conditions may mimic the Brugada pattern. More common causes include acute myocardial ischemia or infarction, hypothermia, tricyclic antidepressants, and electrolyte abnormalities (8). These conditions must be excluded prior to making the diagnosis.

OTHER INVASIVE EXAMINATIONS

In view of the malignant potential of this condition, precise diagnosis is very important. Invasive electrophysiologic studies may be confirmatory when the patient is shown to have infranodal conduction disease. In the original report by Brugada et al (1), 8 patients showed a prolonged atrioventricular interval. In addition, the authors emphasized initiation of polymorphous ventricular tachycardia (VT) or ventricular fibrillation (VF) with single or double ventricular extrastimuli in these patients. The other important feature of this syndrome is absence of structural cardiac disease, especially arrhythmogenic right ventricular dysplasia (9).

CLINICAL MANIFESTATIONS AND COURSE

The onset of symptoms of syncope or sudden cardiac death in Brugada syndrome usually occurs in adults aged 40 years or older. In the majority of cases, particularly those described in Japan and Southeast Asia, malignant arrhythmia or death occurs during sleep (2, 9). Initial observations of asymptomatic patients with the Brugada pattern (whether the pattern was present spontaneously or induced by drugs) showed a prognosis that was poor and essentially similar to that of patients who had experienced aborted sudden death (10). For example, those with a transiently concealed pattern had a 35% incidence of VF or sudden death over a follow-up period of 43 ? 32 months (11).

A recent study by Priori et al challenged these findings (12). They found that asymptomatic individuals with the Brugada pattern were at very low risk for sudden cardiac death. In symptomatic individuals (i.e., those who had experienced aborted sudden death), the incidence of sudden death on follow-up was similar to that reported by Brugada (i.e., 23% mortality rate during a mean follow-up interval of 33 ? 38 months). In addition, they found that the abnormality in SCN5A was demonstrable in only 15% of affected individuals. A positive electrophysiologic study (i.e., one in which VT or VF was induced) had a positive predictive accuracy of 50%; pharmacologic challenge with sodium channel blockers failed to unmask most silent gene carriers (positive predictive accuracy, 35%).

TREATMENT

Proper treatment strategies are urgently needed in view of the prevalence of this electrocardiographic finding. In Japan, the prevalence of this finding is 0.05% (13), and in Europe, 0.1% (14). Initial reports suggested that both symptomatic as well as asymptomatic individuals were at risk and that automatic defibrillator therapy was superior to drug therapy for prevention of sudden cardiac death (11). More recent studies have shown that asymptomatic individuals are at low risk (0% over a follow-up of 3 years) (12). It is generally agreed that symptomatic patients (i.e., syncope, VF, aborted sudden death) should be treated with a defibrillator. Asymptomatic individuals with no family history of sudden death appear to be at low risk, and the suggestion has been made that these patients be monitored by an implanted loop recorder (12).

1. 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 1992;20:1391-1396.
2. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, Tunsanga K, Kuasirikul S, Malasit P, Tansupasawadikul S, Tatsanavivat P. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation 1997;96:2595-2600.
3. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293-296.
4. Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:513-516.
5. Atarashi H, Ogawa S, Harumi K, Hayakawa H, Sugimoto T, Okada R, Murayama M, Toyama J. Characteristics of patients with right bundle branch block and ST-segment elevation in right precordial leads. Idiopathic Ventricular Fibrillation Investigators. Am J Cardiol 1996;78:581-583.
6. Brugada J, Brugada P, Brugada R. Ajmaline unmasks right bundle branch block-like and ST segment elevation in V1-V3 in patients with idiopathic ventricular fibrillation [abstract]. PACE Pacing Clin Electrophysiol 1996;19(Part II):599, no. 134.
7. Ferracci A, Fromer M, Schlapfer J, Pruvot E, Kappenberger L. [Primary ventricular fibrillation and early recurrence: apropos of a case of association of right bundle branch block and persistent ST segment elevation]. Arch Mal Coeur Vaiss 1994;87:1359-1362.
8. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol 1999;33:5-15.
9. Martini B, Nava A, Canciani B, Thiene G. Right bundle branch block, persistent ST segment elevation and sudden cardiac death. J Am Coll Cardiol 1993;22:633.
10. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101:510-515.
11. Brugada J, Brugada P. Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death. J Cardiovasc Electrophysiol 1997;8:325-331.
12. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Brignole M, Giordano U, Giovannini T, Menozzi C, Bloise R, Crotti L, Terreni L, Schwartz PJ. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: a prospective evaluation of 52 families. Circulation 2000;102:2509-2515.
13. Tohyou Y, Nakazawa K, Takenobu H, et al. A survey in the incidence of right bundle branch block with ST elevation among normal population. Jpn J Electrocardiol 1995;15:223-226.
14. Hermida JS, Lemoine JL, Aoun FB, Jarry G, Rey JL, Quiret JC. Prevalence of the Brugada syndrome in an apparently healthy population. Am J Cardiol 2000;86:91-94.