Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
Circulation. 1999;99:666-673

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alings, M.
Right arrow Articles by Wilde, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alings, M.
Right arrow Articles by Wilde, A.
Right arrowPubmed/NCBI databases
*OMIM
Medline Plus Health Information
*Cardiac Arrest
Related Collections
Right arrow Clinical genetics
Right arrow Arrhythmias, clinical electrophysiology, drugs

(Circulation. 1999;99:666-673.)
© 1999 American Heart Association, Inc.


Clinical Investigation and Reports

"Brugada" Syndrome

Clinical Data and Suggested Pathophysiological Mechanism

Marco Alings, MD, PhD; Arthur Wilde, MD, PhD

From the Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam (M.A., A.W.), and the Department of Cardiology, Heart Lung Institute, Utrecht University Hospital (A.W.), Netherlands.

Correspondence to Dr Marco Alings, AMC, Department of Cardiology, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail a.m.alings{at}amc.uva.nl


Key Words: Brugada syndrome • antiarrhythmia agents • arrhythmia • death, sudden • tachyarrhythmias


*    Introduction
up arrowTop
*Introduction
down arrowHistorical Overview
down arrowClinical Data
down arrowPathophysiological Background
down arrowClinical Course and Therapy
down arrowMolecular Biological Background
down arrowSynopsis
down arrowReferences
 
The occurrence of ventricular fibrillation (VF) in the absence of any structural heart disease is classified as "primary electrical disease" or (in the absence of any relevant findings) "idiopathic VF." This diagnosis implies that the arrhythmogenic substrate is inherent to the excitable and conducting properties of the heart. With the exception of a positive family history, demographic variables are, as a rule, not very helpful in establishing the diagnosis of primary electrical disease.1 The paradigm of primary electrical disease is the long-QT syndrome (LQTS), in which altered ionic channel function secondary to mutations in genes encoding ion channels has been shown to underlie QT-interval prolongation.2 3

In 1992, Brugada and Brugada4 described 8 patients with a history of aborted sudden death and a distinct ECG pattern, consisting of right bundle-branch block (RBBB) with ST-segment elevation in the right precordial leads (V1, V2, and V3, Figure 1Down) and normal QT interval in the absence of any structural heart disease (as determined by routine clinical, biochemical, echocardiographic, and angiographic examinations). In 4 of the reported patients, a family history was suspected.



View larger version (64K):
[in this window]
[in a new window]
 
Figure 1. ECG tracings of 1 patient originally described by Brugada and Brugada.4 Tracings show RBBB with ST-segment elevation in right precordial leads. There is marked left axis deviation, suggesting presence of left anterior hemiblock. In presence of RBBB, QTc is prolonged (482 ms).

Patients with these unique ECG abnormalities have been recognized as a distinct subgroup in male Thai patients presenting with cardiac arrest due to VF.5 In northeastern Thailand, sudden unexpected death, typically occurring during sleep, is a leading cause of death in young men, and 40% of these patients have a family history of sudden death.6

The suspected inherited occurrence of the entity strongly suggested possible involvement of defective ion channels, as in LQTS. However, others have reported forms of right ventricular (RV) cardiomyopathy associated with the syndrome.7 8 The clinical data of the patients are crucial to the question of whether this syndrome is another "ion channelopathy" or a subclinical form of a more diffuse cardiomyopathy. This review aims to (1) summarize these clinical data and (2) speculate on the underlying pathophysiological mechanism. Finally, diagnostic guidelines will be proposed.


*    Historical Overview
up arrowTop
up arrowIntroduction
*Historical Overview
down arrowClinical Data
down arrowPathophysiological Background
down arrowClinical Course and Therapy
down arrowMolecular Biological Background
down arrowSynopsis
down arrowReferences
 
Patients with (aborted) sudden cardiac death and the "Brugada" ECG were described in the late 1980s.8 In a series of 6 patients successfully resuscitated from VF and without apparent structural heart disease, the typical ECG was recognized in 3 patients. In these patients, subclinical RV cardiomyopathy was postulated on the basis of results of RV biopsy in 1 patient and echocardiography in 2.8 In this and later reports, the authors consistently concluded that structural abnormalities underlie the syndrome.7 8 9 10

Brugada and Brugada4 were the first to speculate on a functional cardiac disorder. It was suggested that "Marked dispersion of refractoriness of cardiac tissue or extreme anisotropic conduction properties of the conduction system and the ventricular muscle" represented the underlying pathophysiological abnormality.4 The notion that the syndrome represents a "functional" disorder was further substantiated by the recognition that ECG abnormalities were inconsistently present11 12 13 and that altered autonomic tone5 13 and antiarrhythmic drugs modulated the extent of ST-segment elevation.11 13

The entity is increasingly recognized. In 1997, Brugada and Brugada11 reported on 47 patients, and the series has been extended to 63 patients in 1998.12 In a Japanese multicenter study, a further 63 patients were recognized, of whom 17 had a documented episode of VF.14 Kasanuki et al15 recognized the abnormal ECG pattern in 6 of 11 idiopathic VF subjects, and Nademanee et al5 recognized it in 16 of 27 Thai men resuscitated from VF. On the basis of pharmacological tests, it has been speculated that 40% to 60% of patients diagnosed with idiopathic VF might actually suffer the syndrome under discussion.16


*    Clinical Data
up arrowTop
up arrowIntroduction
up arrowHistorical Overview
*Clinical Data
down arrowPathophysiological Background
down arrowClinical Course and Therapy
down arrowMolecular Biological Background
down arrowSynopsis
down arrowReferences
 
To date, 108 symptomatic and 66 asymptomatic patients with the characteristic ECG consisting of right precordial ST-segment elevation with or without an RBBB pattern have been described (Table 1Down). In 11 patients, some form of RV cardiomyopathy accounted for the ECG abnormalities.7 8 16 These patients are included in Table 1Down but are excluded from further analysis. Thus, 163 patients meet the criteria described by Brugada and Brugada.4


View this table:
[in this window]
[in a new window]
 
Table 1. Clinical Data of Patients With Right Precordial ST-Segment Elevation

Epidemiology
Males (n=150) outnumber females (n=13) by far (Table 1Up), in contrast to the female preponderance of symptomatic LQTS. At least 95 patients (58%) were of Asian origin. Mean age at first arrhythmic event varied from 22 to 65 years. Age distribution reveals a peak around the fourth decade (range, 2 to 77 years).12 14 A family history of syncope, documented VF, or sudden death of suspected cardiac origin was reported for 36 patients (22%). In general, the patients' medical histories were unremarkable.

Electrocardiogram
By definition, the ECG was abnormal, displaying an RBBB pattern with right precordial ST-segment elevation (>=0.1 mV in leads V1 to V2 and V3). In most patients, however, the typical widened S wave in the left lateral leads is absent, suggesting that this is not true RBBB. Early high takeoff of the ST segment in the right precordial leads (the "J wave") can mimic RBBB (Figure 2Down).23 As can be derived from published tracings, in many patients, left axis deviation was present simultaneously, suggesting the presence of left anterior hemiblock as well (Figure 1Up).



View larger version (123K):
[in this window]
[in a new window]
 
Figure 2. ECG characteristics as seen in most patients with Brugada syndrome, displaying RBBB pattern with right precordial ST-segment elevation (>=0.1 mV in leads V1 and V2). Absence of widened S wave in left lateral leads suggests this is not true RBBB but early high takeoff of ST segment in leads V1 and V2 ("J wave").23

Descriptive or quantitative QTc data are reported as normal for all but 2 patients. In a 46-year-old man with a positive family history for sudden death, QTc was 488 ms,4 and in a 22-year-old man with an unremarkable family history, QTc was 500 ms.22

Two ST-segment morphologies have been described in leads V1, V2, and V3: convex curved or "coved" and "saddle shaped"–type ST-segment elevation.14 15 18 In individual patients, both morphologies may subsequently be present. The presence of coved ST-segment elevation has been suggested to have a stronger arrhythmogenic potential,14 18 but this relation could not be confirmed by others.15

Persistence of the abnormal ECG findings can last up to 40 years.27 Transient normalization seems to be common during follow-up; it may last up to 4 months and is unrelated to heart rate.11 With increasing heart rate, both ECG normalization5 15 18 and increasing J-wave amplitude have been reported.23

It is not clear whether the magnitude of the ST-segment shift relates to the occurrence of arrhythmias. In individual patients, the onset of polymorphic ventricular tachycardia (VT)/VF was preceded by ST-segment shifts,13 15 18 whereas in others it was not.23 24

Arrhythmia onset seems to be unlike that seen in LQTS. The coupling interval of the first ectopic beat to the preceding sinus beat is usually short ("R on T," or in the terminal part of the T wave), and arrhythmia episodes are not preceded by particular R-R sequences.4 23 24

Arrhythmic Events
Among the 104 patients who presented with symptoms, VF was present in 76 (73%) and syncope in 28 (27%) (Table 1Up). In the remaining 59 patients, the abnormal ECG was noted during routine ECG or screening because of sudden death of a family member. At presentation, none of the symptomatic patients were taking antiarrhythmic drugs or had electrolyte imbalances.

The activity at the moment of the arrhythmic event was reported for 21 patients. In at least 17 patients, it occurred while they were at rest or asleep; all of these patients were of Asian origin,5 13 15 18 20 21 26 and 9 were Thai men.5 In 4 patients, alcohol ingestion induced an arrhythmic event.

Echocardiography, Ventriculography, and Endomyocardial Biopsies
No echocardiographic evidence for structural cardiac abnormalities was found in 157 patients (Table 1Up). Abnormal left and/or right ventriculography was reported for 2 of 80 patients (Table 1Up). Nonspecific mild thickening of the moderator band was seen in 1,25 and hypokinesis of the left ventricular (LV) anterior wall was seen in the other.26 Endomyocardial biopsies were taken from 32 patients and were normal in all cases (Table 1Up).

Magnetic Resonance Imaging
Normal echocardiographic findings and even normal ventricular endocardial biopsy findings do not exclude arrhythmic RV dysplasia (ARVD), because minor and/or localized forms may remain undiagnosed. In 1 of 35 patients in whom routine diagnostic methods showed no abnormalities, MRI demonstrated fatty replacement in the RV infundibulum, consistent with ARVD.17 This shows that MRI may be an important supplemental tool in the evaluation of these patients.17 28

Ischemia
To exclude ischemia as a causal arrhythmogenic factor, coronary angiography was performed in 82 patients (Table 1Up), with normal results in all cases. In 65 of them, coronary spasm could not be induced by intracoronary ergonovine or acetylcholine injection. In 1 case, coronary artery spasm was induced, causing ST-segment elevation but not VF. Exclusion of ischemia by thallium scintigraphy has been reported in 3 patients only.4

Results of treadmill testing are available for 43 patients only.4 5 13 15 20 22 24 Exercise-induced ventricular arrhythmias did not occur, except in 1 patient, in whom a self-terminating monomorphic VT with LBBB configuration occurred at peak exercise.

Electrophysiological Studies
Programmed electrical stimulation was performed in 76 patients (Table 2Down). The HV interval was measured in 21 patients and was prolonged in 20. This observation is not typical for RBBB, and in conjunction with the left axis, in most published ECGs, it reflects a more general conduction defect in the His-Purkinje system.


View this table:
[in this window]
[in a new window]
 
Table 2. Programmed Electrical Stimulation (PES), Therapy, and Clinical Course

In 58 patients, arrhythmic events were readily inducible. VF was induced in 50 patients and nonsustained polymorphic VT in 8 (Table 2Up). Occasionally, VF was not inducible.12 13 18 24 In 2 patients, VF could not be induced in the baseline state but was inducible during administration of edrophonium in 1 patient15 and during administration of edrophonium and an {alpha}-adrenergic receptor agonist in another.13

Signal-Averaged ECG
Late potentials were shown in 22 of 27 patients (Table 2Up). In 4 patients, late potentials, representative for the presence of a J wave, were present even in the absence of r' waves in the right precordial leads.15


*    Pathophysiological Background
up arrowTop
up arrowIntroduction
up arrowHistorical Overview
up arrowClinical Data
*Pathophysiological Background
down arrowClinical Course and Therapy
down arrowMolecular Biological Background
down arrowSynopsis
down arrowReferences
 
Both theoretical considerations and in vivo experiments support the idea that heterogeneity of repolarization across the wall of the RV outflow tract (RVOT) contribute to the ECG patterns and the genesis of arrhythmias in the Brugada syndrome.

In contrast to endocardial cells, action potentials (APs) of epicardial cells display a pronounced phase 1 (Figure 3Down), referred to as "spike-and-dome morphology." The transient outward current, Ito, present in epicardial cells and virtually absent in endocardial cells, underlies the difference between the AP configurations.29



View larger version (16K):
[in this window]
[in a new window]
 
Figure 3. Difference between epicardial and endocardial AP morphology. Top tracings show epicardial and endocardial APs; bottom, surface ECG. Epicardial AP is characterized by a pronounced phase 1 (top left), which coincides with J wave in surface ECG (bottom left).29 Loss of epicardial AP dome (top right) shortens epicardial AP duration. This causes transmural heterogeneity and ST-segment elevation in surface ECG (bottom right).30

The spike-and-dome morphology is the result of at least 3 different currents: INa, Ito, and L-type calcium current, ICa. The magnitude and duration of sodium current, INa, during phase 0 determines the voltage level at which phase 1 begins. This will have an impact on activation/inactivation characteristics of Ito directly and of L-type ICa indirectly. Perturbations in these (or perhaps other, eg, ICl) currents can lead to striking abbreviation of the epicardial AP, with the resultant potential for reexcitation based on epicardial-endocardial heterogeneity of repolarization.

In an experimental model, the spike-and-dome configuration of APs coincides with J waves in the surface ECG. Loss of AP dome in epicardial cells but not endocardial cells may cause transmural heterogeneity and ST-segment elevation as a result of transmural current flow from endocardium to epicardium (Figure 3Up).30 It can be hypothesized that, because of the thinness of the RV wall, the relative contribution of epicardial APs to the surface ECG is more prominent in right than left precordial leads. In addition, it has been demonstrated in dogs that the Ito-mediated phase 1 is more pronounced in RV than LV epicardium.31 Hence, the impact of changes in epicardial AP morphology will be most pronounced in precordial leads V1 and V2 facing the RVOT.

Theoretically, a reduction in INa or L-type ICa or an increase in Ito and/or addition of any other time-independent potassium current may cause the above-described changes. Experiments in canine heart lend further support to the idea that epicardial-endocardial heterogeneity causes the arrhythmias. Sodium channel blockers reduce phase 0 amplitude. The presence of Ito will subsequently depress phase 1 nadir and availability of L-type ICa will be diminished, leading to instantaneous all-or-non repolarization.32 Indeed, flecainide causes marked abbreviation of canine epicardial but not endocardial AP duration due to loss of AP dome. Thereby, flecainide causes electrical heterogeneity and phase 2 reexcitation.32

These findings are consistent with the reported effects of sodium channel blocking drugs in patients with the Brugada syndrome. Treatment with class Ia activated-state blockers (disopyramide, procainamide, flecainide, and ajmaline) increased ST-segment elevation (Figure 4Down).5 11 13 Treatment with class Ib antiarrhythmic drugs (mexiletine and lidocaine) had no effect on ST-segment elevation.13 Administration of the class Ia antiarrhythmic drugs ajmaline and procainamide reproduced the abnormal ECG both in patients with transient normalized ECGs and in family members of affected individuals with a normal ECG.11



View larger version (157K):
[in this window]
[in a new window]
 
Figure 4. A, ECG tracings showing transient normalization of ST segments (same patient as in Figure 2Up, baseline state). B, In same patient, abnormal Brugada ECG with ST-segment elevation of >=0.1 mV in leads V1 through V3 is reproduced after treatment with flecainide (therapeutic blood levels).

There are also profound effects of autonomic stimulation or suppression in these patients.13 33 ß-Adrenergic stimulation might be expected to reduce electrical heterogeneity by augmenting L-type ICa, which restores epicardial AP dome. Indeed, both physiological and pharmacological ß-adrenergic stimulation consistently reduced and ß-adrenergic receptor blockade increased right precordial ST-segment elevation.5 13 15 Enhanced ST-segment elevation was also observed after {alpha}-adrenergic and muscarinic stimulation.13 15 The effect of {alpha}-adrenergic agonists was mitigated by {alpha}-adrenergic antagonists.13 The way in which these latter interventions modulate the amplitude of Ito, INa, or L-type ICa in epicardial versus endocardial cells is still being worked out.

An alternative hypothesis for the genesis of the arrhythmia is based on data from signal-averaged ECG and body-surface mapping. These data show conduction delay in the area between the anterior wall and the septal region of the RVOT, which is aggravated by accelerated vagal activity.15 Independent of the presence of a spike-and-dome morphology, significant epicardial conduction delay may give rise to the J wave as well. To explain ST-segment elevation, however, substantial shortening of the epicardial AP is needed. This alternative explanation for the ECG abnormalities may help to explain the preferential occurrence of nocturnal VF episodes.


*    Clinical Course and Therapy
up arrowTop
up arrowIntroduction
up arrowHistorical Overview
up arrowClinical Data
up arrowPathophysiological Background
*Clinical Course and Therapy
down arrowMolecular Biological Background
down arrowSynopsis
down arrowReferences
 
Therapy is documented in 105 patients. Seventy-five patients did not receive pharmacological treatment. In 54 of them, an implantable cardioverter-defibrillator (ICD) was implanted; 21 patients did not receive any form of therapy. In 31 of these patients (40%), arrhythmic events recurred during follow-up. In all 23 events occurring in patients with an ICD implanted, the device effectively terminated VF. However, in the 21 patients who did not receive any form of therapy, 8 arrhythmic events resulted in 7 deaths (Table 2Up).

Treatment with antiarrhythmic drugs did not effectively prevent new events. Thirty patients were treated with either ß-adrenergic receptor blockade (n=9), amiodarone (n=4), sodium channel blockade (n=1), a combination of ß-adrenergic receptor blockade with amiodarone (n=15), or {alpha}-blockade (n=1). Arrhythmic events recurred in 9 patients (30%), causing 7 deaths (Table 2Up).

Thus, irrespective of the underlying mechanism, RBBB with right precordial ST-segment elevation identifies patients at risk for VF. From the reviewed data, no particular antiarrhythmic drug emerges that seems useful in preventing new episodes of VF. ß-Adrenergic receptor blockade even seems to be contraindicated.15 On a theoretical basis, quinidine, a vagolytic drug that blocks Ito, among other potassium currents, may prove to be of benefit. Interestingly, quinidine has been demonstrated to exert antiarrhythmic potency in patients with idiopathic VF, of whom some may actually suffer from Brugada's syndrome.34

Only an ICD effectively prevents sudden death.5 12 Transient normalization of the ECG abnormalities does not decrease the need for therapy. Based on the preferential occurrence of nocturnal arrhythmic events and enhanced vagal activity during sleep, pacemaker implantation might be prudent.


*    Molecular Biological Background
up arrowTop
up arrowIntroduction
up arrowHistorical Overview
up arrowClinical Data
up arrowPathophysiological Background
up arrowClinical Course and Therapy
*Molecular Biological Background
down arrowSynopsis
down arrowReferences
 
The proposed underlying mechanisms of the syndrome suggest that mutations in the genes encoding the cardiac sodium channels, the transient outward channels, and/or calcium channels are candidates to explain the hereditary transmission of the disease.

Mutations have been identified in the cardiac sodium channel gene (SCN5A) in 3 small families and individual patients with a history of VF in the presence of the described ECG abnormalities.16 35 Although these initial data have not yet provided a complete explanation for the manifestations of the disease and lack genetic linkage, they form a very encouraging first step for future research.

The cardiac sodium channel {alpha}-subunit consists of 4 domains (D-I through D-IV), each containing 6 transmembrane-spanning segments (S1 through S6). In 1 family, 2 single nucleotide missense mutations were identified (R1232W and T1620M) in the extracellular loops of DIII (S1-S2) and DIV (S3-S4), respectively.16 Unlike the SCN5A mutations associated with LQTS,36 expression of T1620M showed no persistent inactivation-resistant currents but faster recovery from inactivation. R1232W behaves like normal channels and probably constitutes a rare polymorphism.

In a second family, insertion of 2 nucleotides disrupted a splice-donor site within the intracellular loop between S2 and S3 of D-I. Functional consequences of this splicing mutation have not been studied.16

In a third family, a single nucleotide deletion introduced a premature in-frame stop codon in DIII S6. Mutant mRNA failed to express INa in Xenopus oocytes.16 This finding suggests that affected patients would have a 50% reduction of sodium channels. However, this is a huge decrease, so preferential expression of the normal allele seems possible.

In individual patients, we report missense mutations (R1512W in the highly conserved DIII-IV cytoplasmic linker and A1924T in the C-terminal cytoplasmic domain).35 Preliminary data demonstrate that both mutations affect channel function, most notably causing a negative voltage shift of the steady-state activation curve.37

A loss of functional sodium channels, which is suggested to result from the disrupted splice-donor site,16 results in less INa. Pharmacological inhibition of INa has been shown to cause less AP dome and phase 2 reexcitation.32 In contrast, the mentioned alterations in sodium channel characteristics will enhance availability of sodium channels and/or INa and is therefore difficult to reconcile with the discussed underlying electrophysiological basis of the syndrome.


*    Synopsis
up arrowTop
up arrowIntroduction
up arrowHistorical Overview
up arrowClinical Data
up arrowPathophysiological Background
up arrowClinical Course and Therapy
up arrowMolecular Biological Background
*Synopsis
down arrowReferences
 
Brugada and Brugada4 are to be credited for recognizing a distinct subgroup of patients with idiopathic VF. These patients are electrocardiographically characterized by the presence of an RBBB pattern or J wave and right precordial ST-segment elevation >=0.1 mV. Absence of organic heart disease is demonstrated by echocardiography, ventriculography, MRI, and RV endomyocardial biopsies and can be inferred from the occurrence of transient ECG normalization. Administration of the class I antiarrhythmic drugs ajmaline or procainamide reproduces the abnormal ECG in patients with transient normalized ECGs and in family members of affected individuals with normal ECGs.11 Patients are mostly male and have a first arrhythmic event around their fourth decade. The recurrence rate of new arrhythmic events is as high as 40%. Pharmacological treatment does not protect effectively against recurrent events, and currently, implantation of an ICD is the only effective therapy to prevent sudden death.

Therefore, not least because of cost-effectiveness, an unequivocal diagnostic definition of this life-threatening syndrome is needed. In our opinion, at least the following diagnostic criteria should be met: (1) >=0.1-mV ST-segment elevation in leads V1, V2, and V34 ; (2) absence of organic heart disease4 ; (3) dynamic nature of the ST segment, both spontaneously in time and under the influence of pharmacological agents (sodium channel blockers and autonomic modulators); and (4) malignant family history in the case of an asymptomatic individual.

Given the occurrence of transient ECG normalization, we recommend challenge with sodium channel blockers (procainamide, ajmaline, or flecainide in therapeutic dosages) in asymptomatic family members. The occurrence of >=0.1-mV ST-segment elevation in leads V1, V2, and V3 is regarded as a positive response. Current data do not allow us to define the prevalence of asymptomatic syndrome carriers or to draw conclusions about their treatment. However, we would suggest that additional studies be performed, including programmed electrical stimulation, in asymptomatic young to middle-aged (especially male) individuals without a malignant family history. In the case of inducible VF, an ICD should be implanted. In asymptomatic individuals with a malignant family history, the threshold for ICD implantation should be low, regardless of electrophysiology results. In general, the role of quinidine remains to be established.

There is little doubt that major advances in further unraveling the molecular mechanism of this syndrome will occur in the near future.


*    Acknowledgments
 
Dr Alings is the recipient of an Interuniversity Cardiology Institute Netherlands fellowship. Dr Wilde is a Clinical Investigator for the Netherlands Heart Foundation (grant D95/014). Dr Dan Roden (Vanderbilt University, Nashville, Tenn) is gratefully acknowledged for his critical reading of the manuscript.


*    Footnotes
 
(Circulation. 1999;99:666-673.)

Received June 19, 1998; revision received October 6, 1998; accepted October 22, 1998.


*    References
up arrowTop
up arrowIntroduction
up arrowHistorical Overview
up arrowClinical Data
up arrowPathophysiological Background
up arrowClinical Course and Therapy
up arrowMolecular Biological Background
up arrowSynopsis
*References
 
1. Belhassen B, Viskin S. Idiopathic ventricular tachycardia and fibrillation. J Cardiovasc Electrophysiol. 1993;4:356–368.[Medline] [Order article via Infotrieve]

2. Kass RS, Davies MP. The roles of ion channels in an inherited heart disease: molecular genetics of the long QT syndrome. Cardiovasc Res. 1996;32:443–454.[Medline] [Order article via Infotrieve]

3. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM. Multiple mechanisms in the long QT syndrome: current knowledge, gaps, and future directions. Circulation. 1996;94:1996–2012.[Abstract/Free Full Text]

4. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol. 1992;20:1391–1396.[Abstract]

5. 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.[Abstract/Free Full Text]

6. Tatsanavivat P, Chiravatkul A, Klungboonkrong V, Chaisiri S, Jarerntanyaruk L, Munger RG, Saowakontha S. Sudden and unexplained deaths in sleep (Laitai) of young men in rural northeastern Thailand. Int J Epidemiol. 1992;21:904–910.[Abstract/Free Full Text]

7. Corrado D, Nava A, Buja G, Martini B, Fasoli G, Oselladore L, Turrini P, Thiene G. Familial cardiomyopathy underlies syndrome of right bundle branch block, ST segment elevation and sudden death. J Am Coll Cardiol. 1996;27:443–448.[Abstract]

8. Martini B, Nava A, Thiene G, Buja GF, Canciani B, Scognamiglio R, Daliento L, Dalla Volta S. Ventricular fibrillation without apparent heart disease: description of 6 cases. Am Heart J. 1989;118:1203–1209.[Medline] [Order article via Infotrieve]

9. Martini B, Nava A, Canciani B, Thiene G. Right bundle branch block, persistent segment elevation and sudden cardiac death. J Am Coll Cardiol. 1993;22:633. Letter.[Medline] [Order article via Infotrieve]

10. Corrado D, Basso C, Nava A, Buja G, Thiene G. Right bundle branch block, persistent right precordial ST segment elevation and sudden arrhythmic death in young people. Pacing Clin Electrophysiol. 1996;19:669. Abstract.

11. Brugada J, Brugada P. Further characterization of the syndrome of right bundle branch block, persistent ST-segment elevation, and sudden cardiac death. J Cardiovasc Electrophysiol. 1997;8:325–331.[Medline] [Order article via Infotrieve]

12. 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.[Abstract/Free Full Text]

13. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27:1061–1070.[Abstract]

14. 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. Am J Cardiol. 1996;78:581–583.[Medline] [Order article via Infotrieve]

15. Kasanuki H, Ohnishi S, Ohtuka M, Matsuda N, Nirei T, Isogai R, Shoda M, Toyoshima Y, Hosoda S. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation. 1997;95:2277–2285.[Abstract/Free Full Text]

16. 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.[Medline] [Order article via Infotrieve]

17. d'Onofrio A, Cuomo S, Musto B, Boccalatte A. Right bundle branch block, persistent ST-segment elevation in V1–V3 and sudden cardiac death: always a distinct syndrome? G Ital Cardiol. 1995;25:1171–1175.[Medline] [Order article via Infotrieve]

18. Matsuo K, Shimizu W, Kurita T, Inagaki M, Aihara N, Kamakura S. Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 1998;9:508–512.[Medline] [Order article via Infotrieve]

19. Marcus FI. Idiopathic ventricular fibrillation. J Cardiovasc Electrophysiol. 1997;8:1075–1083. See Reply to the Editor. J Cardiovasc Electrophysiol. 1998;9:111.[Medline] [Order article via Infotrieve]

20. Kobayashi T, Shintani U, Yamamoto T, Shida S, Isshiki N, Tanaka T, Ohmoto Y, Kitamura M, Kato S, Misaki M. Familial occurrence of electrocardiographic abnormalities of the Brugada-type. Intern Med. 1996;35:637–640.[Medline] [Order article via Infotrieve]

21. Shimada M, Miyazaki T, Miyoshi S, Soejima K, Hori S, Mitamura H, Ogawa S. Sustained monomorphic ventricular tachycardia in a patient with Brugada syndrome. Jpn Circ J. 1996;60:364–370.[Medline] [Order article via Infotrieve]

22. Viskin S, Belhassen B. Clinical problem-solving: when you only live twice. N Engl J Med. 1995;332:1221–1225.[Free Full Text]

23. Bjerregaard P, Gussak I, Kotar SL, Gessler JE, Janosik D. Recurrent syncope in a patient with prominent J wave. Am Heart J. 1994;127:1426–1430.[Medline] [Order article via Infotrieve]

24. Ferraci A, Fromer M, Schläpfer J, Pruvot E, Kappenberger L. Fibrillation ventriculaire primitive et récidive précoce: à propos d'un cas associant bloc de branche droit et sus-décalage persistant du segment ST. Arch Mal Coeur. 1994;87:1359–1362.

25. Proclemer A, Facchin D, Feruglio GA, Nucifora R. Fibrillazione ventriculare recidivante, blocco di branca destra, persistente sopraslivellamento del tratto ST in V1–V3: una nuova sindrome aritmica? Descrizione di un caso clinico. G Ital Cardiol. 1993;23:1211–1218.[Medline] [Order article via Infotrieve]

26. Sumiyoshi M, Nakata Y, Hisaoka T, Ogura S, Nakazato Y, Kawai S, Okada R, Yamaguchi H. A case of idiopathic ventricular fibrillation with incomplete right bundle branch block and persistent ST segment elevation. Jpn Heart J. 1993;34:661–666.[Medline] [Order article via Infotrieve]

27. Wilde AAM, Düren DR. Sudden cardiac death, RBBB, and right precordial ST-segment elevation. Circulation. 1999;99:722. Letter.[Free Full Text]

28. Naccarella F. Aritmie ventricolari maligne in pazienti con blocco di branca destra e persistente sopraslivellamento di ST in V1-V3: probabile cardiomiopatia aritmogena del ventricolo destro. G Ital Cardiol. 1993;23:1219–1222.[Medline] [Order article via Infotrieve]

29. Litovsky SH, Antzelevitch C. Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: role of the transient outward current. J Am Coll Cardiol. 1989;14:1053–1066.[Abstract]

30. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996;93:372–379.[Abstract/Free Full Text]

31. DiDiego JM, Sun ZQ, Antzelevitch C. Ito and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol. 1996;271:H548–H561.[Abstract/Free Full Text]

32. Krishnan SC, Antzelevitch C. Flecainide-induced arrhythmia in canine epicardium: phase 2 reentry? Circulation. 1993;87:562–572.[Abstract/Free Full Text]

33. Scheinman MM. Is the Brugada syndrome a distinct clinical entity? J Cardiovasc Electrophysiol. 1997;8:332–336.[Medline] [Order article via Infotrieve]

34. Otto CM, Tauxe RV, Cobb LA, Greene HL, Gross BW, Werner JA, Burroughs RW, Samson WE, Weaver WD, Trobaugh GB. Ventricular fibrillation causes sudden death in Southeast Asian immigrants. Ann Intern Med. 1984;101:45–47.

35. Alshinawi C, Mannens M, Wilde A. Mutations in the human cardiac sodium channel gene (SCN5A) in patients with Brugada syndrome. Eur Heart J. 1998;19:78. Abstract.

36. Bennett PB, Yazawa K, Makita N, George AL. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376:683–685.[Medline] [Order article via Infotrieve]

37. Rook MB, Alshinawi C, Groenewegen WA, van Ginneken ACG, Jongsma HJ, van Gelder IC, Mannens MMAM, Wilde AAM. Human SCN5A gene mutations alter Na-current kinetics and associate with VF in patients without structural heart disease. Circulation. 1998;98(suppl):I-468. Abstract.




This article has been cited by other articles:


Home page
J Am Coll CardiolHome page
R. J. Myerburg, V. Reddy, and A. Castellanos
Indications for implantable cardioverter-defibrillators based on evidence and judgment.
J. Am. Coll. Cardiol., August 25, 2009; 54(9): 747 - 763.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
B. Surawicz, R. Childers, B. J. Deal, and L. S. Gettes
AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram: Part III: Intraventricular Conduction Disturbances A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society Endorsed by the International Society for Computerized Electrocardiology
J. Am. Coll. Cardiol., March 17, 2009; 53(11): 976 - 981.
[Full Text] [PDF]


Home page
CirculationHome page
B. Surawicz, R. Childers, B. J. Deal, and L. S. Gettes
AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram: Part III: Intraventricular Conduction Disturbances: A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: Endorsed by the International Society for Computerized Electrocardiology
Circulation, March 17, 2009; 119(10): e235 - e240.
[Full Text] [PDF]


Home page
PNHome page
E. Marsh, P. O'Callaghan, and P. Smith
The humble electrocardiogram
Practical Neurology, January 1, 2008; 8(1): 46 - 59.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al.
Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function
Circulation, November 13, 2007; 116(20): 2325 - 2345.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
K. S. Stokoe, R. Balasubramaniam, C. A. Goddard, W. H. Colledge, A. A. Grace, and C. L.-H. Huang
Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/ murine hearts modelling the Brugada syndrome
J. Physiol., May 15, 2007; 581(1): 255 - 275.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
K. S. Stokoe, G. Thomas, C. A. Goddard, W. H. Colledge, A. A. Grace, and C. L.-H. Huang
Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/{Delta} murine hearts modelling long QT syndrome 3
J. Physiol., January 1, 2007; 578(1): 69 - 84.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
H. Hallaq, Z. Yang, P. C. Viswanathan, K. Fukuda, W. Shen, D. W. Wang, K. S. Wells, J. Zhou, J. Yi, and K. T. Murray
Quantitation of protein kinase A-mediated trafficking of cardiac sodium channels in living cells
Cardiovasc Res, November 1, 2006; 72(2): 250 - 261.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al.
ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death)
J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346.
[Full Text] [PDF]


Home page
EuropaceHome page
Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al.
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society
Europace, September 1, 2006; 8(9): 746 - 837.
[Full Text] [PDF]


Home page
EuropaceHome page
B. Sassone, S. Sacca, and M. Donateo
Paradoxical effect of ajmaline in a patient with Brugada syndrome.
Europace, April 1, 2006; 8(4): 251 - 254.
[Abstract] [Full Text] [PDF]


Home page
Postgrad. Med. J.Home page
M C S Hall and D M Todd
Modern management of arrhythmias
Postgrad. Med. J., February 1, 2006; 82(964): 117 - 125.
[Abstract] [Full Text] [PDF]


Home page
J Clin PharmacolHome page
R. Ogawa, R. Kishi, K. Mihara, H. Takahashi, A. Takagi, N. Matsumoto, K. Masuhara, K. Nakazawa, F. Miyake, S. Kobayashi, et al.
Population Pharmacokinetic and Pharmacodynamic Analysis of a Class IC Antiarrhythmic, Pilsicainide, in Patients With Cardiac Arrhythmias
J. Clin. Pharmacol., January 1, 2006; 46(1): 59 - 68.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
A. O. Verkerk, R. Wilders, E. Schulze-Bahr, L. Beekman, Z. A. Bhuiyan, J. Bertrand, L. Eckardt, D. Lin, M. Borggrefe, G. Breithardt, et al.
Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome
Cardiovasc Res, December 1, 2005; 68(3): 441 - 453.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
M. Shah, F. G. Akar, and G. F. Tomaselli
Molecular Basis of Arrhythmias
Circulation, October 18, 2005; 112(16): 2517 - 2529.
[Abstract] [Full Text] [PDF]


Home page
Emerg. Med. J.Home page
E Aksay, T Okan, and S Yanturali
Brugada syndrome, manifested by propafenone induced ST segment elevation
Emerg. Med. J., October 1, 2005; 22(10): 748 - 750.
[Abstract] [Full Text] [PDF]


Home page
Asian Cardiovasc. Thorac. Ann.Home page
M. Haghjoo, A. Arya, Z. Emkanjoo, and M. A. Sadr-Ameli
Clinical and Electrophysiologic Profile of Brugada Syndrome in Iranian Patients
Asian Cardiovasc Thorac Ann, September 1, 2005; 13(3): 241 - 246.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
C. R. Bezzina, A. A.M. Wilde, and D. M. Roden
The molecular genetics of arrhythmias
Cardiovasc Res, August 15, 2005; 67(3): 343 - 346.
[Full Text] [PDF]


Home page
Cardiovasc ResHome page
P. G. Meregalli, A. A.M. Wilde, and H. L. Tan
Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more?
Cardiovasc Res, August 15, 2005; 67(3): 367 - 378.
[Abstract] [Full Text] [PDF]


Home page
Emerg. Med. J.Home page
A T D Mills, S Dasan, and A Wan
Brugada syndrome: syncope in the younger patient and the risk of sudden cardiac death
Emerg. Med. J., August 1, 2005; 22(8): 604 - 606.
[Full Text] [PDF]


Home page
J Am Coll CardiolHome page
G. C.M. Beaufort-Krol, M. P. van den Berg, A. A.M. Wilde, J. P. van Tintelen, J. W. Viersma, C. R. Bezzina, and M. Th.E. Bink-Boelkens
Developmental Aspects of Long QT Syndrome Type 3 and Brugada Syndrome on the Basis of a Single SCN5A Mutation in Childhood
J. Am. Coll. Cardiol., July 19, 2005; 46(2): 331 - 337.
[Abstract] [Full Text] [PDF]


Home page
Biol Res NursHome page
T. T. Beery
The Genetics of Cardiac Arrhythmias
Biol Res Nurs, April 1, 2005; 6(4): 249 - 261.
[Abstract] [PDF]


Home page
CirculationHome page
C. Antzelevitch, P. Brugada, M. Borggrefe, J. Brugada, R. Brugada, D. Corrado, I. Gussak, H. LeMarec, K. Nademanee, A. R. Perez Riera, et al.
Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association
Circulation, February 8, 2005; 111(5): 659 - 670.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
Task Force members, M. Brignole, P. Alboni, D. G. Benditt, L. Bergfeldt, J.-J. Blanc, P. E. B. Thomsen, J. G. van Dijk, A. Fitzpatrick, S. Hohnloser, et al.
Guidelines on management (diagnosis and treatment) of syncope - Update 2004: The task force on Syncope, European Society of Cardiology
Eur. Heart J., November 2, 2004; 25(22): 2054 - 2072.
[Full Text] [PDF]


Home page
CirculationHome page
B. Martini, H. L. Tan, R. Tukkie, J. Vleugels, I. K.L.M. de Groot, A. A.M. Wilde, and P. Sogaard
Further Confirmation That a Conduction Disturbance Underlies the Electrocardiographic Pattern of the So-Called Brugada Syndrome * Response
Circulation, August 3, 2004; 110(5): e53 - e53.
[Full Text] [PDF]


Home page
Eur Heart JHome page
J. H van Berlo, D. Duboc, and Y. M Pinto
Often seen but rarely recognised: cardiac complications of lamin A/C mutations
Eur. Heart J., May 2, 2004; 25(10): 812 - 814.
[Full Text] [PDF]


Home page
Eur Heart JHome page
M.J Junttila, M.J.P Raatikainen, J Karjalainen, H Kauma, Y.A Kesaniemi, and H.V Huikuri
Prevalence and prognosis of subjects with Brugada-type ECG pattern in a young and middle-aged Finnish population
Eur. Heart J., May 2, 2004; 25(10): 874 - 878.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
E. F. D. Wever and E. O. Robles de Medina
Sudden death in patients without structural heart disease
J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1137 - 1144.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
R. Tukkie, P. Sogaard, J. Vleugels, I. K.L.M. de Groot, A. A.M. Wilde, and H. L. Tan
Delay in Right Ventricular Activation Contributes to Brugada Syndrome
Circulation, March 16, 2004; 109(10): 1272 - 1277.
[Abstract] [Full Text] [PDF]


Home page
Mayo Clin Proc.Home page
J. M. Sanchez and A. M. Kates
Brugada-type Electrocardiographic Pattern Unmasked by Fever
Mayo Clin. Proc., February 1, 2004; 79(2): 273 - 274.
[PDF]


Home page
EuropaceHome page
P. Maury, P. Couderc, M. Delay, S. Boveda, and J. Brugada
Electrical storm in Brugada syndrome successfully treated using isoprenaline
Europace, January 1, 2004; 6(2): 130 - 133.
[Abstract] [Full Text] [PDF]


Home page
EuropaceHome page
N. Colman, W. Wieling, and A.A.M. Wilde
A patient with recurrent syncope and ST-elevation on the electrocardiogram
Europace, January 1, 2004; 6(4): 296 - 300.
[Abstract] [Full Text] [PDF]


Home page
EuropaceHome page
Guidelines on Management (diagnosis and treatment) of syncope - update 2004: The Task Force on Syncope, European Society of Cardiology
Europace, January 1, 2004; 6(6): 467 - 537.
[Full Text] [PDF]


Home page
NEJMHome page
K. Wang, R. W. Asinger, and H. J.L. Marriott
ST-Segment Elevation in Conditions Other Than Acute Myocardial Infarction
N. Engl. J. Med., November 27, 2003; 349(22): 2128 - 2135.
[Full Text] [PDF]


Home page
Adv. Psychiatr. Treat.Home page
P. O'Brien and F. Oyebode
Psychotropic medication and the heart
Adv. Psychiatr. Treat., November 1, 2003; 9(6): 414 - 423.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
S. Rolf, H.-J. Bruns, T. Wichter, P. Kirchhof, M. Ribbing, K. Wasmer, M. Paul, G. Breithardt, W. Haverkamp, and L. Eckardt
The ajmaline challenge in Brugada syndrome: Diagnostic impact, safety, and recommended protocol
Eur. Heart J., June 2, 2003; 24(12): 1104 - 1112.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada, J. A. Towbin, and K. Nademanee
Brugada syndrome: 1992-2002: A historical perspective
J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1665 - 1671.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde
Genetic control of sodium channel function
Cardiovasc Res, March 15, 2003; 57(4): 961 - 973.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
C. R. Bezzina, M. B. Rook, W.A. Groenewegen, L. J. Herfst, A. C. van der Wal, J. Lam, H. J. Jongsma, A. A.M. Wilde, and M. M.A.M. Mannens
Compound Heterozygosity for Mutations (W156X and R225W) in SCN5A Associated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System
Circ. Res., February 7, 2003; 92(2): 159 - 168.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada, W. Shimizu, I. Gussak, and A.R. Perez Riera
Brugada Syndrome: A Decade of Progress
Circ. Res., December 13, 2002; 91(12): 1114 - 1118.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
T. Noda, W. Shimizu, A. Taguchi, K. Satomi, K. Suyama, T. Kurita, N. Aihara, and S. Kamakura
ST-segment elevation and ventricular fibrillation without coronary spasm by intracoronary injection of acetylcholine and/or ergonovine maleate in patients with Brugada syndrome
J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1841 - 1847.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
A. A.M. Wilde, C. Antzelevitch, M. Borggrefe, J. Brugada, R. Brugada, P. Brugada, D. Corrado, R. N.W. Hauer, R. S. Kass, K. Nademanee, et al.
Proposed Diagnostic Criteria for the Brugada Syndrome: Consensus Report
Circulation, November 5, 2002; 106(19): 2514 - 2519.
[Full Text] [PDF]


Home page
Eur Heart JHome page
A.A.M. Wilde, C. Antzelevitch, M. Borggrefe, J. Brugada, R. Brugada, P. Brugada, D. Corrado, R.N.W. Hauer, R.S. Kass, K. Nademanee, et al.
Proposed Diagnostic Criteria for the Brugada Syndrome
Eur. Heart J., November 1, 2002; 23(21): 1648 - 1654.
[Full Text] [PDF]


Home page
Cardiovasc ResHome page
C. R Bezzina and H. L Tan
Pharmacological rescue of mutant ion channels
Cardiovasc Res, August 1, 2002; 55(2): 229 - 232.
[Full Text] [PDF]


Home page
J Am Coll CardiolHome page
T. Kurita, W. Shimizu, M. Inagaki, K. Suyama, A. Taguchi, K. Satomi, N. Aihara, S. Kamakura, J. Kobayashi, and Y. Kosakai
The electrophysiologic mechanism of ST-segment elevation in Brugada syndrome
J. Am. Coll. Cardiol., July 17, 2002; 40(2): 330 - 334.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
J. P. P. Smits, L. Eckardt, V. Probst, C. R. Bezzina, J. J. Schott, C. A. Remme, W. Haverkamp, G.u. Breithardt, D. Escande, E. Schulze-Bahr, et al.
Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients
J. Am. Coll. Cardiol., July 17, 2002; 40(2): 350 - 356.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
D. M. Roden
The problem, challenge and opportunity of genetic heterogeneity in monogenic diseases predisposing to sudden death
J. Am. Coll. Cardiol., July 17, 2002; 40(2): 357 - 359.
[Full Text] [PDF]


Home page
J Am Coll CardiolHome page
M. Kanda, W. Shimizu, K. Matsuo, N. Nagaya, A. Taguchi, K. Suyama, T. Kurita, N. Aihara, and S. Kamakura
Electrophysiologic characteristics andimplications of induced ventricular fibrillationin symptomatic patients with brugada syndrome
J. Am. Coll. Cardiol., June 5, 2002; 39(11): 1799 - 1805.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
G. A. Papadatos, P. M. R. Wallerstein, C. E. G. Head, R. Ratcliff, P. A. Brady, K. Benndorf, R. C. Saumarez, A. E. O. Trezise, C. L.-H. Huang, J. I. Vandenberg, et al.
Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a
PNAS, April 18, 2002; (2002) 82121299.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
A.A.M. Wilde, C.A. Remme, R. Derksen, E.F.D. Wever, and R.N.W. Hauer
Brugada syndrome
Eur. Heart J., April 2, 2002; 23(8): 675 - 676.
[Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. R. Balser
Inherited sodium channelopathies: models for acquired arrhythmias?
Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1175 - H1180.
[Full Text] [PDF]


Home page
CirculationHome page
S. G. Priori, C. Napolitano, M. Gasparini, C. Pappone, P. D. Bella, U. Giordano, R. Bloise, C. Giustetto, R. De Nardis, M. Grillo, et al.
Natural History of Brugada Syndrome: Insights for Risk Stratification and Management
Circulation, March 19, 2002; 105(11): 1342 - 1347.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
N. Shirai, N. Makita, K. Sasaki, H. Yokoi, I. Sakuma, H. Sakurada, J. Akai, A. Kimura, M. Hiraoka, and A. Kitabatake
A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease
Cardiovasc Res, February 1, 2002; 53(2): 348 - 354.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
F. Kyndt, V. Probst, F. Potet, S. Demolombe, J.-C. Chevallier, I. Baro, J.-P. Moisan, P. Boisseau, J.-J. Schott, D. Escande, et al.
Novel SCN5A Mutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family
Circulation, December 18, 2001; 104(25): 3081 - 3086.
[Abstract] [Full Text] [PDF]


Home page
HeartHome page
S H Wong, N T Mulvihill, M Norton, and R. HALL
Assessing the risk of sudden cardiac death
Heart, December 1, 2001; 86(6): 624 - 625.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
B. Martini, S. Cannas, and A. Nava
Brugada by any other name?
Eur. Heart J., October 1, 2001; 22(19): 1835 - 1836.
[PDF]


Home page
CirculationHome page
P. C. Viswanathan, C. R. Bezzina, A. L. George Jr., D. M. Roden, A. A.M. Wilde, and J. R. Balser
Gating-Dependent Mechanisms for Flecainide Action in SCN5A-Linked Arrhythmia Syndromes
Circulation, September 4, 2001; 104(10): 1200 - 1205.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
K. Matsuo, M. Akahoshi, E. Nakashima, A. Suyama, S. Seto, M. Hayano, and K. Yano
The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram: A population-based study of four decades
J. Am. Coll. Cardiol., September 1, 2001; 38(3): 765 - 770.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
Task Force on Syncope, European Society of Cardiol, M Brignole, P Alboni, D Benditt, L Bergfeldt, J.J Blanc, P.E Bloch Thomsen, J.G van Dijk, A Fitzpatrick, S Hohnloser, et al.
Guidelines on management (diagnosis and treatment) of syncope
Eur. Heart J., August 1, 2001; 22(15): 1256 - 1306.
[Abstract] [PDF]


Home page
HeartHome page
M Furuhashi, K Uno, K Tsuchihashi, D Nagahara, M Hyakukoku, T Ohtomo, S Satoh, T Nishimiya, and K Shimamoto
Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugada-type ST shift) among the general Japanese population
Heart, August 1, 2001; 86(2): 161 - 166.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
T. Ikeda, H. Sakurada, K. Sakabe, T. Sakata, M. Takami, N. Tezuka, T. Nakae, M. Noro, Y. Enjoji, T. Tejima, et al.
Assessment of noninvasive markers in identifying patients at risk in the brugada syndrome: insight into risk stratification
J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1628 - 1634.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
D. M. Roden
Pharmacogenetics and drug-induced arrhythmias
Cardiovasc Res, May 1, 2001; 50(2): 224 - 231.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
M Bianco, S Bria, A Gianfelici, N Sanna, V Palmieri, and P Zeppilli
Does early repolarization in the athlete have analogies with the Brugada syndrome?
Eur. Heart J., March 2, 2001; 22(6): 504 - 510.
[Abstract] [PDF]


Home page
Eur Heart JHome page
C Antzelevitch
The Brugada syndrome: diagnostic criteria and cellular mechanisms
Eur. Heart J., March 1, 2001; 22(5): 356 - 363.
[PDF]


Home page
Eur Heart JHome page
C.A Remme, E.F.D Wever, A.A.M Wilde, R Derksen, and R.N.W Hauer
Diagnosis and long-term follow-up of the Brugada syndrome in patients with idiopathic ventricular fibrillation
Eur. Heart J., March 1, 2001; 22(5): 400 - 409.
[Abstract] [PDF]


Home page
Cardiovasc ResHome page
D. J. Huelsing, A. E. Pollard, and K. W. Spitzer
Transient outward current modulates discontinuous conduction in rabbit ventricular cell pairs
Cardiovasc Res, March 1, 2001; 49(4): 779 - 789.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
C. R Bezzina, M. B Rook, and A. A.M Wilde
Cardiac sodium channel and inherited arrhythmia syndromes
Cardiovasc Res, February 1, 2001; 49(2): 257 - 271.
[Full Text] [PDF]


Home page
Emerg. Med. J.Home page
J M Butler
Brugada syndrome--the missed epidemic
Emerg. Med. J., November 1, 2000; 17(6): 426 - 428.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
D. W. Wang, N. Makita, A. Kitabatake, J. R. Balser, and A. L. George Jr
Enhanced Na+ Channel Intermediate Inactivation in Brugada Syndrome
Circ. Res., October 13, 2000; 87 (8): e37 - e43.
[Abstract] [Full Text] [PDF]


Home page
HeartHome page
S Viskin, R Fish, M Eldar, D Zeltser, M D Lesh, A Glick, and B Belhassen
Prevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controls
Heart, July 1, 2000; 84(1): 31 - 36.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
M. W. Veldkamp, P. C. Viswanathan, C. Bezzina, A. Baartscheer, A. A. M. Wilde, and J. R. Balser
Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na+ Channel
Circ. Res., May 12, 2000; 86 (9): e91 - e97.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
B. Martini, A. Nava, D. Corrado, G. Thiene, A. Wilde, and M. Alings
Right Bundle-Branch Block, ST-Segment Elevation, and Sudden Death Response
Circulation, April 25, 2000; 101 (16): e176 - e176.
[Full Text] [PDF]


Home page
Cardiovasc ResHome page
A. A.M. Wilde and M. W. Veldkamp
What we can learn from individual resuscitated patients
Cardiovasc Res, April 1, 2000; 46(1): 14 - 16.
[Full Text] [PDF]


Home page
Cardiovasc ResHome page
I. Deschenes, G. Baroudi, M. Berthet, I. Barde, T. Chalvidan, I. Denjoy, P. Guicheney, and M. Chahine
Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes
Cardiovasc Res, April 1, 2000; 46(1): 55 - 65.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
P Brugada, R Brugada, and J Brugada
Sudden death in patients and relatives with the syndrome of right bundle branch block, ST segment elevation in the precordial leads V1to V3and sudden death
Eur. Heart J., February 2, 2000; 21(4): 321 - 326.
[Abstract] [PDF]


Home page
CirculationHome page
N. Makita, N. Shirai, D. W. Wang, K. Sasaki, A. L. George Jr, M. Kanno, and A. Kitabatake
Cardiac Na+ Channel Dysfunction in Brugada Syndrome Is Aggravated by {beta}1-Subunit
Circulation, January 4, 2000; 101(1): 54 - 60.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
C. Bezzina, M. W. Veldkamp, M. P. van den Berg, A. V. Postma, M. B. Rook, J.-W. Viersma, I. M. van Langen, G. Tan-Sindhunata, M. Th. E. Bink-Boelkens, A. H. van der Hout, et al.
A Single Na+ Channel Mutation Causing Both Long-QT and Brugada Syndromes
Circ. Res., December 3, 1999; 85(12): 1206 - 1213.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
M. B. Rook, C. Bezzina Alshinawi, W.A. Groenewegen, I. C. van Gelder, A. C.G. van Ginneken, H. J. Jongsma, M. M.A.M. Mannens, and A. A.M. Wilde
Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome
Cardiovasc Res, December 1, 1999; 44(3): 507 - 517.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
R. Dumaine, J. A. Towbin, P. Brugada, M. Vatta, D. V. Nesterenko, V. V. Nesterenko, J. Brugada, R. Brugada, and C. Antzelevitch
Ionic Mechanisms Responsible for the Electrocardiographic Phenotype of the Brugada Syndrome Are Temperature Dependent
Circ. Res., October 29, 1999; 85(9): 803 - 809.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
J. R. Balser
Sodium "Channelopathies" and Sudden Death : Must You Be So Sensitive?
Circ. Res., October 29, 1999; 85(9): 872 - 874.
[Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
G. A. Papadatos, P. M. R. Wallerstein, C. E. G. Head, R. Ratcliff, P. A. Brady, K. Benndorf, R. C. Saumarez, A. E. O. Trezise, C. L.-H. Huang, J. I. Vandenberg, et al.
From the Cover: Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a
PNAS, April 30, 2002; 99(9): 6210 - 6215.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
T. Wichter, P. Matheja, L. Eckardt, P. Kies, K. Schafers, E. Schulze-Bahr, W. Haverkamp, M. Borggrefe, O. Schober, G. Breithardt, et al.
Cardiac Autonomic Dysfunction in Brugada Syndrome
Circulation, February 12, 2002; 105(6): 702 - 706.
[Abstract] [Full Text] [PDF]


This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alings, M.
Right arrow Articles by Wilde, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alings, M.
Right arrow Articles by Wilde, A.
Right arrowPubmed/NCBI databases
*OMIM
Medline Plus Health Information
*Cardiac Arrest
Related Collections
Right arrow Clinical genetics
Right arrow Arrhythmias, clinical electrophysiology, drugs