(Circulation. 2000;102:2509.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Clinical and Genetic Heterogeneity of Right Bundle Branch Block and ST-Segment Elevation Syndrome
A Prospective Evaluation of 52 Families
From the Molecular Cardiology Laboratories (S.G.P., C.N., L.T., R.B.), IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; Unità operativa di Cardiologia (M.G.), Istituto Clinico Humanitas, Rozzano, Italy; Divisione di Aritmologia (C.P.), IRCCS Ospedale San Raffaele, Milan, Italy; Centro Cardiologico (P.D.B.), Fondazione Monzino IRCCS, Milan, Italy; Servizio di Cardiologia-UTIC (M.B.), Ospedale di Lavagna, Lavagna, Italy; Divisione di Cardiologia (U.G.), Ospedale Civico Di Cristina ARNAS, Palermo, Italy; Unità operativa di Cardiologia Ospedale di Prato (T.G.), Prato, Italy; Unità di Cardiologia Interventistica (C.M.), Arcispedale S. Maria Nuova, Reggio Emilia, Italy; and the Department of Cardiology (L.C., P.J.S.), IRCCS Policlinico S. Matteo and University of Pavia, Pavia, Italy.
Correspondence to Silvia G. Priori, Molecular Cardiology, Fondazione Salvatore Maugeri IRCCS, Via Ferrata 8, 27100 Pavia, Italy. E-mail spriori{at}fsm.it
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Abstract |
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Background—The ECG pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups.
Methods and Results—Sixty patients (45 males aged 40±15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33±38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%).
Conclusions—At variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management.
Key Words: heart arrest • genetics • fibrillation • arrhythmia
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Introduction |
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In 1992, Brugada and Brugada1 reported 8 patients resuscitated from cardiac arrest without demonstrable structural heart disease and exhibiting the ECG pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 originally described by Martini et al2 in survivors of cardiac arrest. The systematic collection of cases by the group of Brugada established this ECG pattern as a distinctive new syndrome associated with augmented risk of sudden death. A molecular defect in the cardiac sodium channel gene, SCN5A, has been reported as the genetic basis of the syndrome3 ; therefore, this syndrome indicates the presence of a novel cardiac ion channel disease.4
Brugada et al5 reported that the disease, now frequently called Brugada syndrome, is associated with a high incidence of sudden death, such that prompt clinical evaluation and treatment appear warranted. These conclusions have remained unchallenged. However, because most of the patients included in that study5 had survived cardiac arrest and had personal histories of recurrent syncopal events and family histories of premature sudden death, it is possible that they may represent a subgroup at especially high risk and that direct extrapolation of this prognostic information to the general population may be misleading.
In clinical practice, the diagnosis of the syndrome is frequently made in asymptomatic individuals with negative family histories. Establishing the risk of cardiac arrest at follow-up in this group is obviously important. Brugada et al6 proposed that asymptomatic patients are at high risk because the "cumulative proportion of VF [ventricular fibrillation] and cardiac arrest occurred in approximately 60% of patients within one year" and because no difference was found between the outcome of symptomatic and asymptomatic individuals.5 These views underlie the current aggressive management, including programmed electrical stimulation (PES) and implantation of a cardioverter-defibrillator (ICD) in all inducible subjects.
From a large cohort of Brugada syndrome patients, we present data at variance with the current view and propose that in analogy with the long-QT syndrome,7 the Brugada syndrome is characterized by incomplete penetrance and heterogeneous clinical phenotype (S.G.P., unpublished data, 1999). This information should be incorporated in clinical practice to redefine therapeutic strategies.
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Methods |
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Study Population and Clinical Evaluation
The study population consisted of 52 probands and 100 family members identified in 9 centers. The present study was approved by our Institutional Review Committee, and subjects gave informed consent for clinical and genetic evaluation. The clinical diagnosis of Brugada syndrome was established in 60 subjects. In all patients, the presence of structural heart disease was excluded after extensive evaluation, including blood enzymes and electrolytes (n=60), Holter monitoring (n=60), echocardiogram with careful evaluation of the right ventricle (n=60), stress test (n=45), and nuclear MRI (n=30). Invasive tests included coronary angiography (n=49), electrophysiological study with PES (n=39), and endomyocardial biopsies (n=6). Patients were treated on the basis of the attending physician’s judgment. Genetic analysis and family counseling were performed at the Molecular Cardiology Laboratories of the Maugeri Foundation in Pavia.
Follow-up data were obtained during patients’ visits. An arrhythmic event was defined as a documented episode of syncopal ventricular arrhythmia or sudden death or as an appropriate shock discharged by an ICD. Shocks were defined as "appropriate" on the basis of analysis of stored electrograms.
Mutation Analysis
DNA was extracted from peripheral blood lymphocytes
by following standard procedures. Primer pairs for the amplification of
SCN5A were used.7 SSCP analysis
was performed on amplified genomic DNA. Samples resulting in mobility
shifts were directly sequenced or subcloned into pBlueScript SK-
(Stratagene) and sequenced on both strands by use of automatic
sequencing.
Statistical Analysis
Data are presented as mean±SD. The event-free
analysis was estimated by the Kaplan-Meier method, and the
follow-up curves are shown to the point where 20% of the population at
risk was still included.
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Results |
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Demographic and Clinical Profile of Patients
Sixty individuals (45 males, mean age 40±15 years) with clinical and ECG diagnosis of Brugada syndrome5 were identified in 52 families (Table 1
). Seventeen (28%) of 60 affected
individuals (14 males, mean age 37±16 years) presented with
aborted sudden death; 14 of them (82%) had a preceding history of
syncopal episodes. Thirteen additional patients (11 males, mean age
44±18 years) had syncopal events. Overall, 30 (25 males) of the 60
patients were symptomatic (mean age 39±16 years, median 41
years), and 30 of 60 patients were asymptomatic (mean age
42±14 years, median 45 years). The Kolmogorov-Smirnov test
demonstrated normal distribution of age in both symptomatic
and asymptomatic patients. Of the symptomatic
patients, 83% were males.
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Family History
Family history revealed that 15 victims of sudden death were
present in 11 (21%) of 52 families. Victims (10, all males) died
at a mean age of 20±17 years (range 2 months to 57 years). Autopsy,
available for 7 patients, demonstrated no structural heart disease. In
one victim with negative cardiac evaluation who had died suddenly after
recurrent syncope, postmortem diagnosis of Brugada syndrome was
established by extracting genomic DNA from a cardiac tissue.
Clinical Evaluation and Treatment
Pharmacological Challenge With Sodium Channel Blockers
Flecainide (2 mg/kg IV) or ajmaline (1 mg/kg IV) was administered
as a bolus over 10 minutes in 41 individuals; the ST-segment pattern
was worsened (further elevation 
2 mm) in 17 (41.5%) of the 41
patients, and the appearance of a diagnostic ECG pattern
was induced in 18 (44%) of the 41 patients. The test was negative in 6
(14.5%) of the 41 patients (3 symptomatic and 3
asymptomatic).
The reproducibility of a positive test was assessed in 6 patients. A
concordant effect on ST-segment elevation was observed in 3 of 6
patients (Figure 1). In 3 patients with
an intermittent clinical pattern, the provocative
pharmacological test elicited an attenuated ECG pattern (Figure 2).
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Electrophysiological Study
PES was performed in 39 (65%) of 60 patients after having
obtained informed consent. Similar to the study by Brugada et
al,5 the present study evaluated patients at different
sites, and stimulation protocols were not identical: a maximum of 3
ventricular extrastimuli were delivered unless VF was
elicited at a previous step.
In 26 (67%) of 39 patients, VF or sustained polymorphic
ventricular tachycardia (VT) was induced (Table 2). Of the 26 inducible patients, 13
(50%) were asymptomatic at a mean age of 41±14 years,
whereas 7 (54%) of 13 noninducible patients were
symptomatic. Overall, in this cohort with >30 months of
follow-up, the positive predictive value of PES was 50%, and the
negative predictive value was 46% (test accuracy 49%). Two of the
noninducible patients underwent flecainide administration (2 mg/kg IV)
followed by PES. In both patients, rapid polymorphic VT was
induced.
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Treatment
The treatment of the patients was decided at each individual
center. An ICD was implanted in 26 (43%) of 60 patients. In 11, it was
implanted because of previous cardiac arrest; in 10, it was implanted
on the basis of inducibility with PES (2 with family history of
juvenile cardiac arrest); and in 5, it was implanted because of family
history of sudden death. Drugs (ß-blockers, n=1; sotalol, n=4) were
prescribed in 5 of 60 patients (in 1 patient, drugs were in addition to
the ICD). Thirty patients remained without therapy (26
asymptomatic and 4 symptomatic subjects who
refused treatment).
Clinical Follow-Up
During a mean follow-up of 33±38 months, 5 (8%) of 60 patients
experienced a cardiac arrest. All the recurrences occurred in
ICD carriers with a previous history of cardiac arrest.
Analysis of stored electrograms allowed us to define the nature
of the events triggering the shocks (Figure 3, top). None of the 30
asymptomatic patients developed symptoms (syncope,
sustained VT, or VF); in 2 of them, ICD interrogation revealed short
runs (up to 5 beats) of fast nonsustained VT.
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Standard event-free analysis during follow-up was performed
(Figure 4A), but we also constructed
Kaplan-Meier curves in consideration of the fact that in a genetic
disease, risk exposure starts at birth.8 Cases were
censored when cardiac arrest occurred in symptomatic
patients (n=17). Survival curves show that the risk of events is
relatively low before 40 years of age and that it increases
substantially thereafter (Figure 4B).
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) patient developed cardiac arrest at follow-up. B, Event-free
survival curve representing natural history of Brugada
syndrome patients. Because in genetic disease risk exposure starts at
birth, age has been used as time interval for censoring events.
Two patients experienced inappropriate discharges (Figure 3
, bottom): a 20-year-old asymptomatic man with a family
history of sudden death experienced 3 inappropriate discharges during
physical intense activity and fast sinus rhythm >190 bpm; a
45-year-old man received 32 consecutively delivered inappropriate
shocks because of detection of the repolarization wave, precipitated by
physical activity and fast rate.
Genetic Analysis
Mutations in the open reading frame of the SCN5A gene
were identified in 8 (15%) of 52 probands (5 asymptomatic
and 3 symptomatic). None of 400 controls (800 chromosomes)
and of 200 long-QT syndrome probands carried the same DNA alterations.
The 8 mutations were single residue substitutions leading to an amino
acid change and were distributed throughout the protein (Figure 5).
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Forty-four family members of 4 genotyped probands accepted
genetic screening. The ECG was negative for right bundle branch block
and ST-segment elevation in all 44 individuals, and all of them were
asymptomatic. Nonetheless, DNA analysis documented
a mutation in 20 (45%) of these 44 family members, hereafter defined
as silent gene carriers. Mutational uniformity was present among
family members; however, a large variability in clinical manifestations
was observed. Analysis of clinical manifestations and family
history reveal a highly malignant form of the disease associated with
the L567Q mutation (Figure 5).
Pharmacological Challenge in Gene Carrier Family Members
To define its accuracy, pharmacological challenge with sodium
channel blockers was offered to the 20 silent gene carriers
(gene-positive relatives) and accepted by 13. The drug challenge
unmasked the ECG pattern in only 2 (15%) of these 13 gene carriers.
Overall, the drug challenge was concordant with the genetic status only
in 6 of 17 subjects (4 of 8 probands and 2 of 13 family members),
scoring a positive predictive value of 35%.
Penetrance of Brugada Syndrome
Penetrance was assessed in the 4 genotyped families with a
positive baseline ECG in the probands. Because the baseline ECG was
negative in all 20 family-member gene carriers, the average penetrance
based on ECG analysis was 16% (4 of 24). It was 50%, 25%,
12.5%, and 12.5% in the individual families.
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Discussion |
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The current aggressive clinical management of patients affected by the Brugada syndrome is based on a single prospective study that includes a high proportion of resuscitated cardiac arrest survivors.5 The data in the present study differ from data published by Brugada et al5 and question the alleged high risk of cardiac events within 3 years from diagnosis in asymptomatic individuals and the predictive accuracy of PES. They also show that in a genotyped population, the diagnostic accuracy of pharmacological challenge is lower than previously estimated.5 This novel information should help to reshape therapeutic strategies for the individual patients affected by the Brugada syndrome when both safety and quality of life are considered.
Present Knowledge
The syndrome involving right bundle branch block and ST-segment
elevation, or Brugada syndrome, is a cardiac genetic disease manifested
by sudden death in individuals with a structurally normal heart. The
disease is inherited as an autosomal dominant trait, and mutations
cosegregating with the phenotype have been identified in the
SCN5A gene encoding for the cardiac sodium
channel.3 The natural history of the disease has been
outlined by Brugada et al5 through the prospective
evaluation of 63 patients followed for 
3 years. Their data showed
that the ECG diagnosis of Brugada syndrome is associated with a 27%
incidence of syncope or sudden death within a mean follow-up of 34
months and that the probability of sudden death in
asymptomatic individuals is not different from that of
cardiac arrest survivors. It was on this basis that the current view
fostering aggressive therapeutic management was generated.
Based on the same report,5 2 procedures have entered clinical practice for the diagnosis and management of patients with the Brugada syndrome. One is the provocative test with sodium channel blockers,6 proposed to unmask the diagnostic ECG pattern in patients with an apparently normal ECG. The other is PES, used to identify individuals at risk5 and to guide therapy.9 Both approaches still await independent validation.
Clinical Profile of Patients
We evaluated 60 consecutive patients with the diagnosis of Brugada
syndrome to define their clinical and genetic profiles. In agreement
with previous observations,1 5 10 the ECG diagnosis was
predominant among males (75%), and 80% of the cardiac arrests
occurred in males, mainly after the third decade of life. As a novel
observation, we also found that major cardiac events may occur also in
children and neonates.11
Risk of Sudden Cardiac Death
Of the patients reported by Brugada et al,5 75% had
survived cardiac arrest, and several of the remaining individuals were
their family members. This raises the possibility that the study of
Brugada et al provides prognostic information concerning a selected
subset of patients at particularly high risk, and this would justify
and explain the severity of the manifestations observed in this
population. A referral bias may be present in the initial cohort of
patients affected by any newly described disease, inasmuch as the
diagnosis is initially made only in the most severe cases. The same
phenomenon has happened with the long-QT syndrome.12
However, because the Brugada syndrome is more and more often diagnosed
in asymptomatic individuals, the need for a correct
definition of the risk of cardiac arrest in this group is now
pressing.
Despite a similar number of patients (60 versus 63) and mean
follow-up (33 versus 34 months), significant differences emerge when
the outcomes of patients in the present study and in the study of
Brugada et al5 are compared. Although the
recurrence rate in patients with history of aborted cardiac
arrest is similar (29% versus 32%), the occurrence of events in
asymptomatic individuals is strikingly different (0%
versus 27%). Overall, our data indicate a very low number of
arrhythmic events (0.007 event/y, which is based on 2449 years of
observation in 60 patients). Still, aggressive management of these
subjects may remain justifiable on the basis of the lethality of the
"few" events as shown by the persistence of a life-long risk
(Figure 4B). Importantly, if an ICD is implanted, an appropriate
therapy might be delivered after only several years. This evidence
diverges from that of the previous study,5 in which one
third of asymptomatic patients had their first event within
3 years.
Management strategies of a disease characterized by a low number of highly lethal events should be based on risk stratification algorithms to tailor treatment to the individual risk. PES is largely used to define risk even if words of caution have been raised about its prognostic value.6 We assessed the value of inducibility during PES and confirmed its limited accuracy (positive predictive value 50%, negative predictive value 46%). Remarkably, PES "missed" 7 symptomatic individuals (4 cardiac arrest survivors). Thus, there is no rationale for justifying a therapeutic decision on the basis of the outcome of PES. The difficult choice to implant or not implant an ICD in an asymptomatic patient will have to be made independently of PES and should be weighed against the cost in terms of quality of life, taking into account the risk of inappropriate shocks that may be enhanced by the abnormal repolarization. The failure of PES to correctly identify patients at high or low risk should not be surprising in a disease characterized by an intermittently abnormal repolarization, which is probably responsible for an intermittent electrical instability. In such a variable setting, the outcome of PES could simply reflect the degree of electrical stability present when the test is performed, with little bearing on future events.
Genetic Evaluation of Brugada Syndrome Patients
Most patients reported in the present study presented
as sporadic cases; only a few of them had relatives with ECG diagnosis
of the disease or with history of premature unexplained sudden death.
On the basis of our experience with the long-QT syndrome,7
we suspected that incomplete penetrance might be present in Brugada
syndrome as well and, therefore, that most of the "sporadic cases"
would in fact be members of families with nonpenetrant gene
carriers.
Genetic analysis revealed mutations in the cardiac sodium channel gene in 8 (15%) of 52 patients, suggesting that other genes are involved in the syndrome (genetic heterogeneity). In 4 of the 8 families with a cardiac sodium gene mutation, we were able to extend clinical and genetic evaluation to the family members of the proband, and we demonstrated the presence of incomplete penetrance, as low as 12.5% in 2 families. At variance with what has previously been reported,13 pharmacological challenge with flecainide or ajmaline failed to reveal the disease in most gene carriers with a normal ECG.
Clinical Management of Brugada Syndrome Patients
The present study shows that the diagnosis of Brugada syndrome
may be elusive not only because the ST-segment elevation pattern is
intermittent, as previously indicated,1 5 but also because
the pharmacological challenge with sodium channel blockers has modest
reproducibility and may be negative in nonpenetrant gene carriers.
When the diagnosis is suspected, eg, with a survivor of cardiac arrest without structural heart disease, repeated observations with a 12-lead Holter monitor and repeated provocative tests should be performed before dismissing the diagnosis. Genetic evaluation may be useful in unmasking subclinical forms.
When diagnosis is established, management strategies should be devised,
and the data in the present study call for reassessment of the
current approach6 (Figure 6A). Even if we have shown that
asymptomatic patients remain as such after a mean follow-up
of 3 years, we cannot exclude the possibility that they might develop
cardiac arrest at a later time in their life. The innovative
information of the present study is the evidence that short-term
(3-year) risk of cardiac arrest is low in asymptomatic
individuals (irrespective of the outcome of PES) and that it is
probably low enough to justify the decision to postpone implantation of
an ICD. Management strategies for asymptomatic patients
should reflect this evidence.
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Two concepts are germane to the development of a novel algorithm
for the management of Brugada syndrome patients: (1) PES is not an
adequate risk predictor, and (2) self-terminating VT episodes are
likely to be present in high-risk patients. The latter statement is
based on the evidence that 82% of cardiac arrest survivors had
histories of syncope likely to represent self-terminating VT.
Furthermore, in 2 asymptomatic patients implanted with an
ICD, nonsustained VT episodes (not perceived by the patients) were
recorded by the device. Accordingly, we are currently evaluating an
alternative strategy for the management of Brugada syndrome patients
(Figure 6B). According to the proposed algorithm,
symptomatic patients (syncope/cardiac arrest/documented VT)
and patients with a family history of premature sudden cardiac death
would receive an ICD. Asymptomatic patients without family
history of sudden death and silent gene carriers would receive an
insertable loop recorder, and family members would be trained for
providing basic life support and for using an automatic external
defibrillator. Compared with presently recommended
management5 6 (Figure 6A), this novel approach
offers a more conservative use of ICDs and a more accurate monitoring
of asymptomatic individuals (insertable loop recorders
versus periodic clinical evaluation); furthermore, it attempts to
improve the success of early resuscitation by implementing a
"domestic" chain of survival. Limitations of the proposed approach
include sudden death out of home/family surveillance and the constant
mental stress to patient and family. If our ongoing evaluation will
confirm acceptance of this approach by patients and families,
its assessment in a randomized study will become feasible.
Study Limitations
The present study has limitations. The limitations are those
commonly present in studies with patients from multiple
institutions. They include lack of uniformity in diagnostic
procedures, in therapeutic approaches, and in the length of
follow-up.
However, it is important to stress that the limitations that we mention for the present report are exactly the same present in the report5 on which current management is based. Extension of the follow-up period to at least 10 years is required before drawing safe conclusions about natural history, risk of death, and response to therapy in patients with Brugada syndrome.
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Acknowledgments |
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Supported by an educational grant from the Leducq Foundation. We thank Mirella Memmi, PhD, and Marina Cerrone, MD, who contributed to the molecular screening. Also, we are grateful to Pinuccia De Tomasi, BS, for editorial support. We would like to acknowledge the contribution to this project of the following physicians: Stefano Amidei, Valdarno, Italy; Nicola Bottoni, Reggio Emilia, Italy; Corrado Carbucicchio, Milan, Italy; Roberto Dabizzi, Prato, Italy; Attilio DelRosso, Fucecchio, Italy; Germano Gaggioli, Lavagna, Italy; Paola Galimberti, Rozzano, Italy; Gino Lolli, Reggio Emilia, Italy; Maria L. Loricchio, Milan, Italy; Massimo Mantica, Rozzano, Italy; Lucia Palmerini, Valdarno, Italy; Bernardo Piccarella, Palermo, Italy; Angelo Rolli, Reggio Emilia, Italy; and Claudio Tondo, Milan, Italy.
Received April 18, 2000; revision received June 28, 2000; accepted June 28, 2000.
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silent gene carriers mandates novel management strategies.
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K. P. Letsas, G. Gavrielatos, M. Efremidis, S. P. Kounas, G. S. Filippatos, A. Sideris, and F. Kardaras Prevalence of Brugada sign in a Greek tertiary hospital population Europace, November 1, 2007; 9(11): 1077 - 1080. [Abstract] [Full Text] [PDF]
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E. A. Stephenson and C. I. Berul Electrophysiological Interventions for Inherited Arrhythmia Syndromes Circulation, August 28, 2007; 116(9): 1062 - 1080. [Full Text] [PDF]
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M. Abello, J. L. Merino, R. Peinado, and M. Gnoatto Negative flecainide test in Brugada syndrome patients with previous positive response Europace, October 1, 2006; 8(10): 899 - 900. [Abstract] [Full Text] [PDF]
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H. Morita, D. P. Zipes, J. Lopshire, S. T. Morita, and J. Wu T wave alternans in an in vitro canine tissue model of Brugada syndrome Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H421 - H428. [Abstract] [Full Text] [PDF]
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J. Castro Hevia, C. Antzelevitch, F. Tornes Barzaga, M. Dorantes Sanchez, F. Dorticos Balea, R. Zayas Molina, M. A. Quinones Perez, and Y. Fayad Rodriguez Tpeak-Tend and Tpeak-Tend Dispersion as Risk Factors for Ventricular Tachycardia/Ventricular Fibrillation in Patients With the Brugada Syndrome J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1828 - 1834. [Abstract] [Full Text] [PDF]
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S. G. Priori and C. Napolitano Role of Genetic Analyses in Cardiology: Part I: Mendelian Diseases: Cardiac Channelopathies Circulation, February 28, 2006; 113(8): 1130 - 1135. [Abstract] [Full Text] [PDF]
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C. R. Bezzina, W. Shimizu, P. Yang, T. T. Koopmann, M. W.T. Tanck, Y. Miyamoto, S. Kamakura, D. M. Roden, and A. A.M. Wilde Common Sodium Channel Promoter Haplotype in Asian Subjects Underlies Variability in Cardiac Conduction Circulation, January 24, 2006; 113(3): 338 - 344. [Abstract] [Full Text] [PDF]
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T. Makiyama, M. Akao, K. Tsuji, T. Doi, S. Ohno, K. Takenaka, A. Kobori, T. Ninomiya, H. Yoshida, M. Takano, et al. High Risk for Bradyarrhythmic Complications in Patients With Brugada Syndrome Caused by SCN5A Gene Mutations J. Am. Coll. Cardiol., December 6, 2005; 46(11): 2100 - 2106. [Abstract] [Full Text] [PDF]
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R. Coronel, S. Casini, T. T. Koopmann, F. J.G. Wilms-Schopman, A. O. Verkerk, J. R. de Groot, Z. Bhuiyan, C. R. Bezzina, M. W. Veldkamp, A. C. Linnenbank, et al. Right Ventricular Fibrosis and Conduction Delay in a Patient With Clinical Signs of Brugada Syndrome: A Combined Electrophysiological, Genetic, Histopathologic, and Computational Study Circulation, November 1, 2005; 112(18): 2769 - 2777. [Abstract] [Full Text] [PDF]
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A. D. Krahn, M. Gollob, R. Yee, L. J. Gula, A. C. Skanes, B. D. Walker, and G. J. Klein Diagnosis of Unexplained Cardiac Arrest: Role of Adrenaline and Procainamide Infusion Circulation, October 11, 2005; 112(15): 2228 - 2234. [Abstract] [Full Text] [PDF]
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P. Brugada, R. Brugada, J. Brugada, S. G. Priori, C. Napolitano, P. Brugada, R. Brugada, J. Brugada, S. G. Priori, and C. Napolitano Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation, July 12, 2005; 112(2): 279 - 292. [Full Text] [PDF]
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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]
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L. Eckardt, V. Probst, J. P.P. Smits, E. S. Bahr, C. Wolpert, R. Schimpf, T. Wichter, P. Boisseau, A. Heinecke, G. Breithardt, et al. Long-Term Prognosis of Individuals With Right Precordial ST-Segment-Elevation Brugada Syndrome Circulation, January 25, 2005; 111(3): 257 - 263. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Cardiac repolarization. The long and short of it Europace, January 1, 2005; 7(s2): S3 - S9. [Abstract] [Full Text] [PDF]
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K. Hong, J. Brugada, A. Oliva, A. Berruezo-Sanchez, D. Potenza, G. D. Pollevick, A. Guerchicoff, K. Matsuo, E. Burashnikov, R. Dumaine, et al. Value of Electrocardiographic Parameters and Ajmaline Test in the Diagnosis of Brugada Syndrome Caused by SCN5A Mutations Circulation, November 9, 2004; 110(19): 3023 - 3027. [Abstract] [Full Text] [PDF]
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J.-S. Hermida, I. Denjoy, J. Clerc, F. Extramiana, G. Jarry, P. Milliez, P. Guicheney, S. Di Fusco, J.-L. Rey, B. Cauchemez, et al. Hydroquinidine therapy in Brugada syndrome J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1853 - 1860. [Abstract] [Full Text] [PDF]
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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]
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P. Bordachar, S. Reuter, S. Garrigue, X. Cai, M. Hocini, P. Jais, M. Haissaguerre, and J. Clementy Incidence, clinical implications and prognosis of atrial arrhythmias in brugada syndrome Eur. Heart J., May 2, 2004; 25(10): 879 - 884. [Abstract] [Full Text] [PDF]
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L J Gula, A D Krahn, A C Skanes, R Yee, and G J Klein Clinical relevance of arrhythmias during sleep: guidance for clinicians Heart, March 1, 2004; 90(3): 347 - 352. [Full Text] [PDF]
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S. G. Priori Inherited Arrhythmogenic Diseases: The Complexity Beyond Monogenic Disorders Circ. Res., February 6, 2004; 94(2): 140 - 145. [Abstract] [Full Text] [PDF]
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H. Morita, S. T. Morita, S. Nagase, K. Banba, N. Nishii, Y. Tani, A. Watanabe, K. Nakamura, K. F. Kusano, T. Emori, et al. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1624 - 1631. [Abstract] [Full Text] [PDF]
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M. V. Pitzalis, M. Anaclerio, M. Iacoviello, C. Forleo, P. Guida, R. Troccoli, F. Massari, F. Mastropasqua, S. Sorrentino, A. Manghisi, et al. QT-interval prolongation inright precordial leads: an additional electrocardiographic hallmark of Brugada syndrome J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1632 - 1637. [Abstract] [Full Text] [PDF]
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N. Phillips, M. Priestley, A. R. Denniss, and J. B. Uther Brugada-Type Electrocardiographic Pattern Induced by Epidural Bupivacaine Anesth. Analg., July 1, 2003; 97(1): 264 - 267. [Abstract] [Full Text] [PDF]
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C. R. Bezzina, A. O. Verkerk, A. Busjahn, A. Jeron, J. Erdmann, T. T. Koopmann, Z. A. Bhuiyan, R. Wilders, M. M.A.M. Mannens, H. L. Tan, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization Cardiovasc Res, July 1, 2003; 59(1): 27 - 36. [Abstract] [Full Text] [PDF]
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J Brugada, P Brugada, and R Brugada The ajmaline challenge in Brugada syndrome: A useful tool or misleading information? Eur. Heart J., June 2, 2003; 24(12): 1085 - 1086. [Full Text] [PDF]
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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]
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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]
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N. Patruno, D. Pontillo, A. Achilli, G. Ruggeri, and G. Critelli Electrocardiographic pattern of Brugada syndrome disclosed by a febrile illness: clinical and therapeutic implications Europace, January 1, 2003; 5(3): 251 - 255. [Abstract] [Full Text] [PDF]
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E. Moric, E. Herbert, M. Trusz-Gluza, A. Filipecki, U. Mazurek, and T. Wilczok The implications of genetic mutations in the sodium channel gene (SCN5A) Europace, January 1, 2003; 5(4): 325 - 334. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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L. Eckardt, P. Kirchhof, E. Schulze-Bahr, S. Rolf, M. Ribbing, P. Loh, H.-J. Bruns, A. Witte, P. Milberg, M. Borggrefe, et al. Electrophysiologic investigation in Brugada syndrome. Yield of programmed ventricular stimulation at two ventricular sites with up to three premature beats Eur. Heart J., September 1, 2002; 23(17): 1394 - 1401. [Abstract] [Full Text] [PDF]
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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]
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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]
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H.-J. Bruns, L. Eckardt, C. Vahlhaus, E. Schulze-Bahr, W. Haverkamp, M. Borggrefe, G. Breithardt, and T. Wichter Body surface potential mapping in patients with Brugada syndrome: right precordial ST segment variations and reverse changes in left precordial leads Cardiovasc Res, April 1, 2002; 54(1): 58 - 66. [Abstract] [Full Text] [PDF]
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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]
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S. G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, J. A. Camm, R. Cappato, S. M. Cobbe, C. Di Mario, et al. TASK FORCE ON SUDDEN CARDIAC DEATH, EUROPEAN SOCIETY OF CARDIOLOGY: Summary of Recommendations Europace, January 1, 2002; 4(1): 3 - 18. [Abstract] [PDF]
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J. Brugada, R. Brugada, C. Antzelevitch, J. Towbin, K. Nademanee, and P. Brugada Long-Term Follow-Up of Individuals With the Electrocardiographic Pattern of Right Bundle-Branch Block and ST-Segment Elevation in Precordial Leads V1 to V3 Circulation, January 1, 2002; 105(1): 73 - 78. [Abstract] [Full Text] [PDF]
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R. Brugada and R. Roberts Brugada Syndrome: Why Are There Multiple Answers to a Simple Question? Circulation, December 18, 2001; 104(25): 3017 - 3019. [Full Text] [PDF]
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S Sangwatanaroj, S Prechawat, B Sunsaneewitayakul, S Sitthisook, P Tosukhowong, and K Tungsanga New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives Eur. Heart J., December 2, 2001; 22(24): 2290 - 2296. [Abstract] [PDF]
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Y. Miyasaka, H. Tsuji, K. Yamada, S. Tokunaga, D. Saito, Y. Imuro, N. Matsumoto, and T. Iwasaka Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan J. Am. Coll. Cardiol., September 1, 2001; 38(3): 771 - 774. [Abstract] [Full Text] [PDF]
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B. Surawicz Brugada syndrome: manifest, concealed, "asymptomatic," suspected and simulated J. Am. Coll. Cardiol., September 1, 2001; 38(3): 775 - 777. [Full Text] [PDF]
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S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, A.J. Camm, R. Cappato, S.M. Cobbe, C. Di Mario, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology Eur. Heart J., August 2, 2001; 22(16): 1374 - 1450. [PDF]
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I. Gussak, P. Bjerregaard, and S. C. Hammill Clinical diagnosis and risk stratification in patients with brugada syndrome J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1635 - 1638. [Full Text] [PDF]
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S. G Priori, C. Napolitano, and M. Grillo Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc Res, May 1, 2001; 50(2): 218 - 223. [Abstract] [Full Text] [PDF]
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G. Baroudi, S. Acharfi, C. Larouche, and M. Chahine Expression and Intracellular Localization of an SCN5A Double Mutant R1232W/T1620M Implicated in Brugada Syndrome Circ. Res., January 11, 2002; 90 (1): e11 - e16. [Abstract] [Full Text] [PDF]
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R. Weiss, M. M. Barmada, T. Nguyen, J. S. Seibel, D. Cavlovich, C. A. Kornblit, A. Angelilli, F. Villanueva, D. M. McNamara, and B. London Clinical and Molecular Heterogeneity in the Brugada Syndrome: A Novel Gene Locus on Chromosome 3 Circulation, February 12, 2002; 105(6): 707 - 713. [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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