The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities

PHYSIOLOGY IN MEDICINE In collaboration with The American Physiological Society, Thomas E. Andreoli, MD, Editor

The Brugada Syndrome: Clinical, Genetic, Cellular, and Molecular Abnormalities Gerald V. Naccarelli, MD, and Charles Antzelevitch, PhD The Brugada syndrome is an arrhythmic syndrome characterized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these patients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on

chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator. Am J Med. 2001;110:573–581. 䉷2001 by Excerpta Medica, Inc.

A

MOLECULAR GENETICS OF BRUGADA SYNDROME

pproximately 5% of patients who experience sudden cardiac death have no demonstrable structural heart disease or obvious cause and are classified as having idiopathic ventricular fibrillation (1– 4). A subgroup of these patients has been shown to manifest a right bundle branch block (RBBB) pattern, ST segment elevation in leads V1 to V3 (Figure 1), and a high incidence of sudden death. Such patients die suddenly, commonly in their sleep, secondary to ventricular fibrillation (5–26). This combination has been labeled the Brugada syndrome (5,18). This disorder is often inherited with an autosomal dominant mode of transmission; the only mutations thus far linked to the syndrome appear in the gene that encodes for the alpha subunit of the sodium channel, SCN5A (5–26). This article reviews the clinical presentation, the cellular and ionic bases for the syndrome, and the impact that our understanding of the molecular biology and genetics of this syndrome has had on rendering appropriate treatment to these patients.

From the Division of Cardiology (GVN), Cardiovascular Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Masonic Medical Research Laboratory (CA), Utica, New York. Requests for reprints should be addressed to Gerald V. Naccarelli, MD, Department of Medicine, Division of Cardiology, Cardiovascular Center, Pennsylvania State University College of Medicine, 500 University Drive, H047, Hershey, Pennsylvania 17033. 䉷2001 by Excerpta Medica, Inc. All rights reserved.

Genetic abnormalities have been discovered in several arrhythmic disorders, including the long QT (LQT) syndrome, arrhythmogenic right ventricular dysplasia, conduction system disease (Lenegre’s disease), and the Brugada syndrome (7,14,27) (Table). About 20% of patients with Brugada syndrome have documented SCN5A mutations (Figure 2) (17). Genetic studies have demonstrated that some cases of Brugada syndrome and chromosome 3–linked long-QT syndrome (LQT3) are allelic disorders of the cardiac sodium channel gene (SCN5A, 3p21). Three types of SCN5A mutations have been identified in the Brugada syndrome: splice-donor, frameshift, and missense (6,17). All of these lead to a reduction in the fast sodium channel current. In LQT3 the defect in the sodium channel causes a persistent late sodium current. An autosomal dominant SCN5A gene abnormality has also been shown to underlie a progressive cardiac conduction system disease (Lev’s or Lenegre’s disease) in two European families (27). In 1998, Chen et al (6) reported on six families and several sporadic cases of the Brugada syndrome. Linkage to known arrhythmogenic right ventricular dysplasia (ARVD) chromosomal loci was excluded at the outset. In three families, mutations in SCN5A were identified (6), including 1) a missense mutation (C-to-T base substitution) causing a substitution of a highly conserved threonine by methionine at codon 1620 (T1620 M) in the ex0002-9343/01/$–see front matter 573 PII S0002-9343(01)00625-8

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

Figure 1. Twelve-lead electrocardiogram demonstrating right bundle branch block and ST segment elevation in the right precordial leads in a patient with Brugada syndrome. Reprinted with permission from Circulation (41).

of the Brugada mutations, was initially shown to shift the inactivation curve in the depolarizing direction and to accelerate the recovery of the channel from inactivation when coexpressed with the R1232W polymorphism (6). Makita et al (7) subsequently showed that when expressed alone, T1620 M shifts steady-state inactivation to more positive potentials but does not accelerate recovery from inactivation. Coexpression of the ␤1 subunit (hB1) was found to shift the steady-state inactivation to still more positive potentials and to accelerate recovery from inactivation. These changes in the function of the channel could not adequately explain the phenotype of the Brugada syndrome. Dumaine et al (24) expressed the T1620 M mutation in a mammalian cell line (HEK293) and

tracellular loop between transmembrane segments S3 and S4 of domain IV (DIVS3–DIVS4), an area important for coupling of channel activation to fast inactivation; 2) a two nucleotide insertion (AA), which disrupts the splice-donor sequence of intron 7 of SCN5A; and 3) a single nucleotide deletion (A) at codon 1397, which results in an in-frame stop codon that eliminates DIIIS6, DIVS1–DIVS6, and the carboxy-terminus of SCN5A. Biophysical analysis of the mutants in Xenopus oocytes demonstrated a reduction in the number of functional sodium channels in both the splicing mutation and onenucleotide deletion mutation, which would be expected to result in a marked reduction of sodium channel current. The T1620 M missense mutation, the most studied Table. Genetic Defects in Arrhythmic Syndromes

Brugada syndrome 1 Brugada syndrome 2 Long QT syndrome 1 Long QT syndrome 2 Long QT syndrome 3 Long QT syndrome 5 Long QT syndrome 6 Conduction system disease Familial atrial fibrillation Arrhythmogenic right ventricular dysplasia/cardiomyopathy

574

May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110

Gene or Chromosomal Locus

Ion Channel Dysfunction

SCN5A 3p22-25 KVLQT1 HERG SCN5A KCNE1 KCNE2 SCN5A 10q22–q24 1q42–q43 2q32.1–q32.3 3p23 14q12–q22 14q23–q24 17q21 (Naxos)

Decreased INa Unknown Decreased IKs Decreased IKr Increased INa Decreased IKs Decreased IKr Decreased INa Unknown Unknown Unknown Unknown Unknown Unknown Plakoglobin

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

caused a defect in inactivation of the channel, leading to augmentation of late sodium channel current. The effect of the mutation to reduce the early sodium current but augment late sodium current is consistent with the presentation of both Brugada and LQT3 syndrome features in patients with this mutation.

CELLULAR BASIS FOR THE BRUGADA SYNDROME

Figure 2. Mutations in the cardiac sodium gene SCN5A from different arrhythmic syndromes. In the Brugada syndrome, a splicing error at the donor site of intron 7 affects the first transmembrane segment of domain I (6). In Lenegre’s disease, a splicing error at exon 22 is associated with the disease (17). In long QT3, there is a delta KPQ deletion at position 1505–1507 in the intercellular linker between domains III and IV (27). Reprinted with permission from J Cardiovasc Electrophysiol (66).

showed that at more physiological temperatures (32 to 40⬚ C) the sodium channel inactivates prematurely and recovers from inactivation more slowly. The accelerated decay of sodium channel current is temperature sensitive and can be missed if studied at room temperature (24,25). The authors suggested that this temperature dependence might predispose patients with this mutation to the development of ventricular tachycardia/fibrillation during a febrile state. Subsequent experiments by Wang et al (25) coexpressed T1620 M with the ␤1 subunit and showed that the mutation causes the channel to enter an intermediate inactivation state from which it recovers more slowly. Wan et al (28) further demonstrated that when T1620 M, R1232W, and the ␤1 subunit are coexpressed in HEK cells, sodium channel density is dramatically reduced because of failure of much of the channel protein to reach the cell membrane. These reports served to highlight the fact that the results of such studies are a sensitive function of the expression system, incubation temperature of the cell culture, recording temperature, as well as the presence or absence of the ␤1 subunit. The common denominator of the findings obtained from the studies performed in the HEK cells is that the T1620 M mutation importantly reduces sodium channel current density. Veldkamp et al (20) demonstrated that the insertion of an amino acid (aspartic acid) at codon 1795 of SCN5A (1795insD) leads to a reduction of sodium channel current. This change is the result of a positive shift of the activation curve and negative shift of the inactivation curve coupled with a slowing of recovery of the sodium channel from inactivation. The insertion mutation also

Under normal conditions, the presence of an Ito-mediated action potential notch or spike and dome morphology in ventricular epicardium, but not endocardium, creates a transmural voltage gradient responsible for the electrocardiographic J wave or J point elevation (29). A reduction in the density of the sodium channel current, as occurs with the inherited mutations discussed above, is known to accentuate the epicardial action potential notch leading to ST segment elevation secondary to the accentuation of the transmural voltage gradients normally responsible for inscription of the J wave. If the epicardial repolarization precedes repolarization of the cells in M and endocardial regions, the T wave will remain positive and the result will be a saddleback form of ST segment elevation (Figure 3B). Further accentuation of the notch as a consequence of additional reduction of INa may be accompanied by a prolongation of the epicardial action potential such that the direction of the transmural voltage gradient is reversed, thus leading to the development of a coved-type of ST segment elevation and inversion of the T wave (Figure 3C), typically observed in the electrocardiograms (ECG) of patients with Brugada syndrome. A delay in epicardial activation can also contribute to inversion of the T wave. Although the typical Brugada morphology is present at this juncture, the substrate for reentry is not. A further shift in the balance of currents leads to loss of the action potential dome at some epicardial sites, which manifests in the ECG as a further ST segment elevation (Figure 3D). Loss of the action potential dome in epicardium but not endocardium results in the development of a marked transmural dispersion of repolarization, which is responsible for the development of a vulnerable window during which a premature impulse or extrasystole can induce a reentrant arrhythmia. Moreover, loss of the epicardial action potential dome at some sites but not others creates a dispersion of repolarization within epicardium (Figure 3D) (30). Propagation of the action potential dome from sites at which it is maintained to sites at which it is lost causes local re-excitation by means of a phase 2–reentry mechanism. This causes the development of a very closely coupled extrasystole, which is capable of initiating circus movement reentry (Figures 3E and 4) (30,31). The phase 2 reentrant beat coincides with the negative T wave of the basic response causing May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110 575

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

Figure 3. Schematic showing right ventricular epicardial action potential changes thought to underlie the electrocardiographic manifestation of the Brugada syndrome. Modified from Eur Heart J (67), with permission.

fusion of the QRS of the extrasystole with the T wave of the preceding beat.

CLASS I AGENTS EXPRESSING BRUGADA SYNDROME ELECTROCARDIOGRAPHIC ABNORMALITY The use of sodium channel blockers in an already diseased sodium channel can facilitate loss of the epicardial action potential dome and slowing conduction. These antiarrhythmics can cause the appearance of a RBBB pattern and ST elevation, and may even provoke spontaneous premature ventricular contractions, ventricular

Figure 4. Cellular mechanisms proposed to underlie arrhythmogenesis in the Brugada syndrome. 576

May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110

tachycardia, and/or ventricular fibrillation (Figure 5). The mechanism responsible for class I antiarrhythmic agents expressing the ECG abnormalities associated with the Brugada syndrome has been studied extensively (8,9,20,32–34). Recently, Priori et al (21) reported that there was an overlap between the LQT3 and the Brugada syndromes. In 12 of 13 patients with LQT3 syndrome, flecainide shortened the QT interval. In 6 of these 13 patients, flecainide produced ST segment elevation in V1 through V3. Sodium channel blockade appears to facilitate the loss of the right ventricular epicardial action dome by shifting the balance of current at the end of phase I of the action potential from inward to outward. Sodium channel blockers further diminish INa already reduced by Brugada mutations that speed up inactivation of INa. Some LQT3 mutations, including delta KPQ, accelerate inactivation of the early sodium current in addition to slowing inactivation of late INa. In both situations, the premature inactivation of the early current can leave Ito unopposed in the epicardium of the right ventricle, which has a denser Ito current than the left ventricular myocardium (29). This will cause a transmural voltage gradient that manifests itself as ST segment elevation in the right precordial leads (Figure 3) (35,36). Pharmacological and/or pathophysiological changes in other currents can contribute to loss of the action potential dome in the right ventricle and thus precipitate the Brugada syndrome (Figure 4).

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

Figure 5. Antiarrhythmic provocation of right bundle branch block and ST segment elevation in the right precordial leads by intravenous ajmaline in a patient with Brugada syndrome whose baseline electrocardiogram (left panel) demonstrated no electrocardiographic abnormalities. Panels 2 through 8 are changes noted over 5 minutes after intravenous ajmaline. The last panel on the right shows resolution of changes 10 minutes after administration of the drug. Modified from Am J Cardiol (64), with permission.

Because of the pivotal role of the transient outward current, agents that block Ito, including 4-aminopyridine and quinidine, have been shown to restore the action potential dome and electrical homogeneity, thus suppressing all arrhythmic activity in experimental models (30,37). Agents that potently block INa, but not Ito (flecainide, ajmaline, and procainamide), exacerbate or unmask the Brugada syndrome, whereas those with actions to block both INa and Ito (eg, quinidine and disopyramide) may exert a therapeutic effect (30). The anticholinergic effects of quinidine may also contribute to its effectiveness. In patients with the Brugada syndrome and various forms of idiopathic ventricular fibrillation, anecdotal evidence exists for an ameliorative effect of quinidine, an agent with Ito blocking actions (38 – 40).

CLINICAL GENETICS OF BRUGADA SYNDROME Patients are usually male, Caucasian, and Asian with no reported cases in black Africans. In 25% of patients the genetics are unclear, and in 15% there is no family history; these cases may represent sporadic mutations. In the Brugada syndrome, 25% of families have apparent autosomal dominant inheritance with variable expression of the abnormal gene (41). Approximately 50% of offspring of affected patients develop the disease. Family members should be screened for the disease.

CLINICAL ASPECTS OF BRUGADA SYNDROME Osher and Wolff (42) first identified the ECG pattern of RBBB with ST elevation in leads V1 to V3 (Figure 1). Shortly thereafter, Edeiken (43) identified persistent ST elevation without RBBB in 10 asymptomatic males and Levine et al (44) described ST elevation in the right chest leads and conduction block in the right ventricle in patients with severe hyperkalemia. Several authors described the association of this ECG pattern with sudden death (45,46). In 1992, Josep and Pedro Brugada (5) de-

scribed 8 patients with a history of aborted sudden death and a distinct ECG pattern of RBBB, ST segment elevations in the right precordial leads, and a normal QT interval in the absence of any structural heart disease. In 4 of the 8 patients, a family history was suggested. The finding of ST-elevation in the right chest leads has been observed in a variety of clinical and experimental settings and is not unique or diagnostic of Brugada syndrome itself. Situations in which these ECG findings occur include electrolyte or metabolic disorders, pulmonary or inflammatory diseases, and abnormalities of the central or peripheral nervous system. In the absence of these abnormalities, the term idiopathic ST elevation is often used. The above ECG findings and associated sudden and unexpected death had been reported as a common problem in Japan and Southeast Asia where it most commonly affects men during sleep (47–53). This disorder has been labeled as sudden and unexpected death syndrome (SUDS) or sudden unexpected nocturnal death syndrome (SUNDS). General characteristics of SUDS include young, healthy men in whom death occurs suddenly with a groan, usually during sleep late at night. No precipitating factors are identified, and autopsy findings are generally negative (8). Life-threatening ventricular tachyarrhythmias as a primary cause of SUDS has been demonstrated, with ventricular fibrillation occurring in most cases. This syndrome probably is the same as Brugada syndrome, because the ECG in these patients typically displays a RBBB morphology and a precordial injury pattern in V1 through V3. Typically, medical histories and physical examinations are unremarkable. In a review of 163 cases reported in the literature up to 1998, men (n ⫽ 150) far outnumbered women (n ⫽ 13) (41). In this same review, 58% of patients were of Asian ancestry. A family history of syncope, documented ventricular fibrillation, or sudden death was reported in 22% of the population. Among the 104 patients who presented with symptoms, 76 had ventricular fibrillation and 28 had syncope. The remaining patients in this series had the typical electrocardiographic findings noted during screening of family members of the proband. Of 21 patients whose activity was reported at the May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110 577

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

time of their arrhythmic event, 17 events occurred at rest or during sleep.

ELECTROCARDIOGRAPHIC FINDINGS The typical ECG findings (5,8,18) of the Brugada syndrome suggest premature repolarization and/or conduction delay in the right ventricle as noted by the ST segment elevation in the right precordial leads and in some cases other leads (Figure 1). The ST segment elevation is typically down sloping and followed by a negative T wave, which differentiates it from early repolarization syndrome (ERS). ST segment elevation in leads V2 to V4 with upward concavity and a positive T wave characterize ERS. No reciprocal ST segment depression is noted in most cases of the Brugada syndrome. Widened S waves in the lateral leads are usually absent, suggesting the absence of true right bundle branch block. The presence of a right bundle branch block pattern in the right precordial leads was present in 12 of 22,027 subjects (.05%) in one study (54) and in 0.1% in another study of 3,585 asymptomatic subjects (55). The ECG can normalize transiently in up to 40% of cases, and this intermittent nature can make diagnosis difficult. Sodium channel blocking agents, such as ajmaline, procainamide, flecainide, and propafenone, can accentuate the changes and be used as a diagnostic test (Figure 5) (8,9,20,32–34). Class IB sodium channel blockers have no effect on the ST segment elevation. Class IA or IC sodium channel blocker challenge can cause spontaneous ventricular fibrillation. Therefore, this testing should be done in a laboratory with cardiopulmonary resuscitation facilities. Stress testing and isoproterenol may normalize the abnormal ECG findings noted above (8,32).

BRUGADA SYNDROME AND ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA (ARVD) Controversy exists concerning the possible association of Brugada syndrome and ARVD, with some investigators arguing that these are the same disorder or at least one is a forme-fruste of the other (6,16,56 – 61). Although both syndromes exhibit autosomal dominant inheritance with incomplete expression, the Brugada gene abnormalities do not appear to be related to the mutations reported in ARVD. However, the classic echocardiographic, angiographic, and magnetic resonance imaging findings of ARVD (54) are not seen in Brugada syndrome patients (Table). In addition, patients with Brugada syndrome typically are without the histopathologic findings of ARVD (57). 578

May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110

EVALUATION A detailed family history is critical (41,56). A history of unexplained syncope or rapid palpitations with presyncope is concerning. Because 50% of cases are familial, a resting ECG can be diagnostic, because it can demonstrate the classic RSR and ST segment elevation in the precordial leads. However, because 50% of cases are concealed, the resting ECG may not be diagnostic. Ruling out left ventricular dysfunction and arrhythmogenic right ventricular dysplasia by noninvasive imaging (56) or obstructive coronary artery disease in older patients is important. Holter and stress testing may depict frequent premature ventricular complexes or nonsustained polymorphic ventricular tachycardia. In the Brugada syndrome, polymorphic ventricular tachycardia is often very rapid and the precipitating extrasystole is short-coupled, which may differentiate this syndrome from torsades de pointes. About 10% of patients with Brugada syndrome have concomitant atrial fibrillation. Electrophysiologic testing often reveals easily inducible sustained polymorphic ventricular tachycardia or ventricular fibrillation using programmed ventricular stimulation techniques. Inducible patients appear to have more recurrences and mortality than do noninducible patients. The HV interval is usually prolonged (41). Signal averaged electrocardiograms were reported to be abnormal in 22 of 27 cases in one study (41). Molecular biologic analysis can document SCN5A gene mutations in 15% of patients (62).

DIAGNOSIS The classic Brugada syndrome is characterized by: a familial history of sudden cardiac death; polymorphic ventricular tachycardia; typical right ventricular conduction delay and ST segment elevation in V1 to V3; no evidence of structural heart disease by cardiac catheterization, echocardiography, magnetic resonance imaging, or myocardial biopsy; worsening of ST segment elevation by class IA or IC drugs; and demonstration of a genetic defects secondary to a mutation of SCN5A on chromosome 3. Patients with Brugada syndrome may include symptomatic patients with overt or transient ECG abnormalities; asymptomatic patients with abnormal or provoked ECG findings; and asymptomatic family members. The Brugada syndrome should be differentiated from arrhythmogenic right ventricular dysplasia, idiopathic ventricular fibrillation, polymorphic ventricular tachycardia secondary to an inherited or acquired prolonged QT syndrome or asymptomatic and normal variants, such as patients with an RSR pattern. Other causes of ST segment elevation, including epicardial injury, pericarditis, early repolarization, and electrolyte abnormalities, should also be ruled out.

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

Idiopathic ventricular fibrillation may account for up to 9% of unexpected sudden cardiac deaths and up to 50% of sudden deaths occurring in patients with no demonstrable heart disease (2– 4,63). The onset of ventricular tachycardia/fibrillation in Brugada syndrome is typically not pause dependent and may help differentiate these patients from patients with other forms of idiopathic ventricular fibrillation or prolonged QT syndrome.

PROGNOSIS AND TREATMENT The prognosis is poor, whether the patient is symptomatic or asymptomatic, with a 10% per year mortality. Antiarrhythmic drugs, such as beta blockers and amiodarone, appear to be of little use in prolonging survival. Use of beta blockers is still associated with a 10% per year death rate. Beta blockade worsens whereas beta stimulation usually reduces ST segment elevation. Class IC agents can be used to express the ST segment elevation in latent cases. During a 37-month follow-up, Brugada et al (18) noted no differences in the incidence of ventricular tachycardia or fibrillation in 34 patients demonstrating transient abnormalities exposed by antiarrhythmic agents versus 24 patients with persistent overt ECG abnormalities. The treatment of choice is implantation of an implantable cardioverter-defibrillator (ICD). Compared with no therapy, beta blockers, or amiodarone, ICDs statistically (P ⫽ 0.0009) prevent sudden cardiac death (personal communication, Josep and Pedro Brugada). Asymptomatic patients appear to have a better prognosis than symptomatic patients and possibly should not be treated as aggressively (62,64). In one study, 19 patients with Brugada syndrome were treated with an ICD (65). During a follow-up of 34.7 ⫾ 19.4 months, 46 episodes of ventricular fibrillation attacks were documented in 7 of 19 patients (37%). The role of electrophysiologic studies in managing patients with Brugada syndrome remains controversial. In Ailing and Wilde’s review (41), electrophysiologic studies were reported in 76 patients. In 50 patients ventricular fibrillation was induced by programmed electrical stimulation, and in 8 patients nonsustained polymorphic ventricular tachycardia was induced. The predictive accuracy of these findings was not reported. In Priori et al’s study (62), programmed electrical stimulation had limited value in identifying patients at risk for sudden death. They reported a 50% positive predictive accuracy and a 46% negative predictive value. Patients with inducible sustained ventricular tachycardia/fibrillation have a markedly worse prognosis than patients in whom ventricular tachycardia cannot be induced (personal communication, Pedro Brugada). Whether ICDs should be

implanted in noninducible patients remains controversial at this time.

CONCLUSION This review outlined the clinical, electrocardiographic, cellular, and molecular biological abnormalities associated with the Brugada syndrome. Proper recognition can be made only after a detailed history and review of the electrocardiographic abnormalities. Avoidance of sodium channel blockers is critical. Patients should be referred to an arrhythmia center with capabilities of performing programmed stimulation and inserting ICDs. Further investigation into the molecular biology and genetics will improve our understanding of this syndrome. At this time only 15% of patients have a documented genetic abnormality (62). It is difficult to make recommendations for managing the care of carriers of the disease, because asymptomatic carriers outnumber clinically affected gene carriers (66). Until there is commercial availability of molecular biologic analysis, the diagnosis should be made on clinical grounds.

REFERENCES 1. Wever EFD, Hauer RNS, Oomen A, et al. Unfavorable outcome in patients with primary electrical disease who survived an episode of ventricular fibrillation. Circulation. 1993;88:1021–1029. 2. Tung RT, Shen WK, Hammill SC, Gersh BJ. Idiopathic ventricular fibrillation in out-of-hospital cardiac arrest survivors. Pacing Clin Electrophysiol. 1994;17:1405–1412. 3. Belhassen B, Viskin S. Idiopathic ventricular tachycardia and fibrillation. J Cardiovasc Electrophysiol. 1993;4:356 –368. 4. Myerburg RJ. Sudden cardiac death in persons with normal (or near normal) hearts. Am J Cardiol. 1997;79:3–9. 5. 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. 6. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature. 1998; 392:293–296. 7. Makita N, Shirai N, Wang DW, et al. Cardiac Na(⫹) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit. Circulation. 2000;101:54 – 60. 8. Gussak I, Antzelevitch C, Bjerregaard P, et al. The Brugada syndrome: clinical, electrophysiological and genetic aspects. J Am Coll Cardiol. 1999;33:5–15. 9. Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol. 1998;9:513–516. 10. Alshinawi C, Mannens M, Wilde AAM. Mutations in the human cardiac sodium channel gene (SCN5A) in patients with Brugada syndrome [abstract]. Eur Heart J. 1998;19:78. 11. Rook MB, Alshinawi CB, Groenewegen WA, et al. Human SCN5A gene mutations alter cardiac sodium channel kinetics, and are associated with the Brugada syndrome. Cardiovasc Res. 1999;44:507– 517. 12. Brugada R, Roberts R. The molecular genetics of arrhythmias and sudden death. Clin Cardiol. 1998;21:553–560. 13. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechaMay 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110 579

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch

14. 15. 16.

17.

18.

19.

20.

21.

22. 23.

24.

25.

26.

27. 28.

29. 30.

31.

32.

33.

34.

580

nism for an inherited cardiac arrhythmia. Nature. 1995;376:683– 685. Towbin JA. Cardiac arrhythmias: the genetic connection. J Cardiovasc Electrophysiol. 2000;11:601– 602. Towbin JA, Vatta M. The genetics of cardiac arrhythmias. Pacing Clin Electrophysiol. 2000; 23:106 –119. Brugada R, Brugada J, Antzelevitch C, et al. 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. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80: 805– 811. Brugada J, Brugada R, Brugada P. Right bundle-branch block and ST-segment elevation in leads V1 through V3. A marker for sudden death in patients without demonstrable structural heart disease. Circulation. 1998;97:457– 460. 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. Veldkamp MW, Viswanathan PC, Bezzina C, et al. Two distinct congenital arrhythmias evoked by a multidysfunctional Na(⫹) channel. Circ Res. 2000;86:E91–E97. Priori SG, Napolitano C, Schwartz PJ, et al. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000; 102:945–947. Priori SG. Long QT and Brugada syndromes: from genetics to clinical management. J Cardiovasc Electrophysiol. 2000;11:1174 –1178. Bezzina C, Veldkamp MW, van Den Berg MP, et al. A single Na(⫹) channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999;85:1206 –1213. Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999;85:803– 809. Wang DW, Makita N, Kitabatake A, et al. Enhanced Na(⫹) channel intermediate inactivation in Brugada syndrome. Circ Res. 2000;87: E37–E43. Moss AJ. Phenotype (ECG)-genotype considerations in long QT syndrome, and Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:1055–1057. Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associated with mutations in SCN5A. Nat Genet. 1999;23:20 –21. Wan X, Wang Q, Kirsch GE. Functional suppression of sodium channels by beta(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation. J Mol Cell Cardiol. 2000; 32:1873– 1884. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996;93:372–379. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST segment elevation. Circulation. 1999;100:1660 –1666. Lukas A, Antzelevitch C. Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. The antiarrhythmic effects of 4-aminopyridine. Cardiovasc Res. 1996;32:593– 603. Miyazaki T, Mitamura H, Miyoshi S, et al. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27:1061–1070. Matsuo K, Shimizu W, Kurita T, et al. Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 1998;9:508 –512. Chinushi M, Aizawa Y, Ogawa Y, et al. Discrepant drug action of disopyramide on ECG abnormalities and induction of ventricular arrhythmias in a patient with Brugada syndrome. J Electrocardiol. 1997;30:133–136. May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110

35. Di Diego JM, Sun ZQ, Antzelevitch C. Ito and action potential notch are smaller in left versus right canine ventricular epicardium. Am J Physiol. 1996;271:H548 –H561. 36. Litovsky SH, Antzelevitch C. Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: the role of the transient outward current. J Am Coll Cardiol. 1989;14:1053–1066. 37. Antzelevitch C. Ion channels and ventricular arrhythmias. Cellular and ionic mechanisms underlying the Brugada syndrome. Curr Opin Cardiol. 1999;14:274 –279. 38. Garg A, Finneran W, Feld GK. Familial sudden cardiac death associated with a terminal QRS abnormality on surface 12-lead electrocardiogram in the index case. J Cardiovasc Electrophysiol. 1998;9: 642– 647. 39. Belhassen B, Viskin S, Fish R, et al. Effects of electrophysiologicguided therapy with class IA antiarrhythmic drugs on the long-term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol. 1999; 10:1301–1312. 40. Suzuki H, Torigoe K, Numata O, Yazaki S. Infant case with a malignant form of Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:1277–1280. 41. Alings M, Wilde A. “Brugada” syndrome: clinical data and suggested pathophysiological mechanism. Circulation. 1999;99:666 – 673. 42. Osher HL, Wolff L. Electrocardiographic pattern simulating acute myocardial injury. Am J Med Sci. 1953;226:541–545. 43. Edeiken J. Elevation of the RS-T segment, apparent or real in right precordial leads as probably normal variant. Am Heart J. 1954;48: 331–339. 44. Levine HD, Wanzer SH, Merrill JP. Dialyzable currents of injury in potassium intoxication resembling acute myocardial infarction or pericarditis. Circulation. 1956;13:29 –36. 45. Martini B, Nava A, Thiene G, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J. 1989; 118:1203–1209. 46. Aihara N, Ohe T, Kamakura S, et al. Clinical and electrophysiologic characteristics of idiopathic ventricular fibrillation. Shinzo. 1990; 22:80 – 86. 47. Nademanee K, Veerakul G, Nimmannit S, et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation. 1997;96:2595–2600. 48. Otto CM, Tauxe RV, Cobb LA, et al. Ventricular fibrillation causes sudden death in Southeast Asian immigrants. Ann Intern Med. 1984;101:45– 47. 49. Namiki T, Ogura T, Kuwabara Y, et al. Five-year mortality and clinical characteristics of adult subjects with right bundle branch block and ST elevation [abstract]. Circulation. 2000;92:I-334. 50. Atarashi H, Ogawa S, Harumi K, et al. 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. 51. Kobayashi T, Shintani U, Yamamoto T, et al. Familial occurrence of electrocardiographic abnormalities of the Brugada-type. Intern Med. 1996;35:637– 640. 52. Shimada M, Miyazaki T, Miyoshi S, et al. Sustained monomorphic ventricular tachycardia in a patient with Brugada syndrome. Jpn Circ J. 1996;60:364 –370. 53. Sumiyoshi M, Nakata Y, Hisaoka T, et al. A case of idiopathic ventricular fibrillation with incomplete right bundle branch block and persistent ST segment elevation. Jpn Heart J. 1993;34:661– 666. 54. Tohyou Y, Nakazawa K, Ozawa A, 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.

Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch 55. 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. 56. Naccarella F, Lepera G, Iachetti F, et al. Accurate noninvasive evaluation and genetic screening could help in differentiating congenital Brugada’s syndrome from the acquired one, secondary to right ventricular dysplasia cardiomyopathy. J Ital Cardiol. 1999;29:374 – 379. 57. Corrado D, Nava A, Buja G, et al. Familial cardiomyopathy underlies syndrome of right bundle branch block, ST segment elevation and sudden death. J Am Coll Cardiol. 1996;27:443– 448. 58. Naccarella F. Malignant ventricular arrhythmias in patients with a right bundle-branch block and persistent ST segment elevation in V1–V3: a probable arrhythmogenic cardiomyopathy of the right ventricle. G Ital Cardiol. 1993;23:1219 –1222. 59. Fontaine G, Piot O, Sohal P, et al. Right precordial leads and sudden death. Relation with arrhythmogenic right ventricular dysplasia. Arch Mal Coeur Vaiss. 1996;89:1323–1329. 60. Proclemer A, Facchin D, Feruglio GA, Nucifora R. Recurrent ventricular fibrillation, right bundle-branch block and persistent ST

61. 62.

63.

64. 65.

66. 67.

segment elevation in V1–V3: a new arrhythmia syndrome? A clinical case report. G Ital Cardiol. 1993;23:1211–1218. Scheinman MM. Is the Brugada syndrome a distinct clinical entity? J Cardiovasc Electrophysiol. 1997;8:332–336. Priori SG, Napolitano C, Gasparini M, et al. 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. Antzelevitch C, Sicouri S, Litovsky SH, et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res. 1991;69:1427–1449. Brugada P, Brugada R, Brugada P. Sudden death in high-risk family members: Brugada syndrome. Am J Cardiol. 2000;86:40K– 43K. Kakishita M, Kurita T, Matsuo K, et al. Mode of onset of ventricular fibrillation in patients with Brugada syndrome detected by implantable cardioverter defibrillator therapy. J Am Coll Cardiol. 2000;36:1646 –1653. Priori SG. Long QT and Brugada syndromes: from genetics to clinical management. J Cardiovasc Electrophysiol. 2000;11:1174 –1178. Antzelevitch C. The Brugada syndrome. Diagnostic criteria and cellular mechanisms. Eur Heart J. 2000; in press.

May 2001

THE AMERICAN JOURNAL OF MEDICINE威

Volume 110 581