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(Circulation. 1999;99:666-673.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
"Brugada" Syndrome
Clinical Data and Suggested Pathophysiological Mechanism
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 |
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 Top Introduction Historical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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 1
) 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.
|
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.
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Historical Overview |
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TopIntroductionHistorical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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
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Clinical Data |
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TopIntroductionHistorical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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 1
). In 11 patients, some form of RV
cardiomyopathy accounted for the ECG
abnormalities.7 8 16 These patients are included in Table 1 but are excluded from further analysis. Thus, 163
patients meet the criteria described by Brugada and
Brugada.4
|
Epidemiology
Males (n=150) outnumber females (n=13) by far (Table 1
), 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 2).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 1).
|
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 1). 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 1).
Abnormal left and/or right ventriculography was reported for 2 of 80
patients (Table 1). 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 1).
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 1), 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 2). 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.
|
In 58 patients, arrhythmic events were readily inducible. VF was
induced in 50 patients and nonsustained polymorphic VT in 8 (Table 2). 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
-adrenergic receptor agonist in another.13
Signal-Averaged ECG
Late potentials were shown in 22 of 27 patients (Table 2).
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
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Pathophysiological Background |
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TopIntroductionHistorical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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 3), 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
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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 3).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 4).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
|
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 -adrenergic and muscarinic
stimulation.13 15 The effect of -adrenergic agonists
was mitigated by -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.
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Clinical Course and Therapy |
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TopIntroductionHistorical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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 2
).
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 -blockade (n=1). Arrhythmic events
recurred in 9 patients (30%), causing 7 deaths (Table 2).
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.
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Molecular Biological Background |
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TopIntroductionHistorical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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 -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.
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Synopsis |
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TopIntroductionHistorical OverviewClinical DataPathophysiological BackgroundClinical Course and TherapyMolecular Biological BackgroundSynopsisReferences |
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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.
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Acknowledgments |
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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.
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Footnotes |
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(Circulation. 1999;99:666-673.)
Received June 19, 1998; revision received October 6, 1998; accepted October 22, 1998.
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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