Abstract

Aims

Brugada syndrome (BrS) is an inherited channelopathy that predisposes to malignant ventricular arrhythmias and thereby syncope and sudden cardiac death. Prior studies characterizing BrS patients have used highly selected referral populations from tertiary centres and prevalence estimates have been carried out using electrocardiogram (ECG) surveys only. We aimed to identify and characterize all diagnosed BrS patients in Denmark (population 5.4 million).

Methods and results

Brugada syndrome patients were identified using several modalities including identification in all Danish tertiary referral centres, search in public health registries, contact to all cardiology departments in Denmark, and searching in a pedigree database for inherited heart disease used nationwide in Denmark. We identified 43 definite diagnosed BrS patients and 25 possible BrS patients, corresponding to a prevalence of 1.1 definite BrS cases per 100 000 inhabitants. Most definite BrS patients were men (86%) and the median age at diagnosis was 48 years. A total of 35 definite BrS patients (81%) had an implantable cardioverter defibrillator (ICD) implanted and of these 9 (26%) experienced appropriate shocks and 3 (8%) experienced inappropriate shocks during a median follow-up of 47 months. No patient died or experienced aborted sudden cardiac death during follow-up.

Conclusions

We report the first nationwide study of BrS patients. We found a low incidence of diagnosed definite BrS compared with estimates from ECG surveys. Follow-up data show a lower rate of inappropriate therapies in ICD carriers than that reported in previous studies.

Introduction

Brugada syndrome (BrS) (OMIM ID 601144) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias often during rest or sleep and characteristic electrocardiogram (ECG) changes in the right precordial leads (V1–V3).1 Brugada syndrome patients are typically males diagnosed in their 40s and many are and seem to remain asymptomatic during follow-up.2–4 Brugada syndrome is regarded as an autosomal-dominant disorder, although many cases seem to be sporadic.2 Brugada syndrome was first described as a separate entity in 1992,5 and has since been associated with mutations affecting mainly the cardiac sodium (Ina) current but also the calcium (ICaL) and potassium (Ito) currents.6–9 However, some of the associations with regard to the calcium and potassium currents are based on single-mutation findings in families with weak genotype phenotype co-segregation and may thus be false associations.10 Furthermore in only 20–30% of cases a likely genetic cause is found.

In general, two kinds of epidemiologic studies have been carried out in the field of BrS: (i) studies trying to estimate the population prevalence and (ii) studies trying to characterize the prognosis and risk factors in BrS patients.

The first type of studies typically uses ECGs from population studies,11 or from screening efforts,12 and BrS patterns are identified from the ECGs. These studies thereby aim to estimate the population prevalence of BrS using the ECG pattern as a proxy. However, the diagnosis of BrS requires more than just a BrS type 1 ECG pattern,1 and the studies suffer from not being able to identify BrS but only BrS type 1 ECG patterns, resulting in low specificity. Furthermore, as the presence of a type 1 ECG pattern fluctuates significantly over time even in definitely diagnosed BrS patients they also suffer from reduced sensitivity.13 The second type of studies has mainly included patients from tertiary centres and covered ‘opportunistic’ geographical areas. This could lead to bias in the form of mainly including very symptomatic and/or resourceful patients, as both these categories of patients are more likely to be referred to tertiary centres.

We aimed to do a nationwide study of BrS patients using four different modalities to identify all diagnosed patients in Denmark (population 5.4 million) and characterize the population.

Methods

Identification of subjects

Different modalities were used in the attempt to identify all diagnosed BrS patients in Denmark: (i) all tertiary referral centres (n= 5) participated in this study and identified all their BrS patients; (ii) a letter was sent to all cardiology departments in Denmark asking them to report any BrS patients; (iii) a search for international classification of diseases (ICD)-10 codes DI472L (Brugada ECG pattern, unspecified), DI472LA (Brugada ECG pattern, type 1), DI472LB (Brugada ECG pattern, type 2), DI472LC (Brugada ECG pattern, type 3), and DI472M (Brugada syndrome) was conducted in the Danish National Patient Registry, a registry with complete nationwide coverage, covering all hospital visits with ICD-10 diagnostic codes since 1994; and (iv) a search was conducted in a nationwide database used by all the tertiary referral centres in Denmark for recording pedigree data for families with inherited heart diseases (Progeny Clinical, Progeny Software LLC, USA).

Collection of data

Data were entered into an online web-based registry. All data were validated by one of the authors (A.G.H.) by reviewing the original patient records. Data on ICD therapies were validated by going through the ICD records for all patients with an ICD.

Definitions

The presence of BrS type 1–3 ECG patterns was defined as noted in the second BrS consensus report.1 Patients were divided into definite and possible BrS patients. Definite BrS patients were patients fulfilling the diagnostic criteria according to the consensus report.1 Possible BrS patients were patients with a BrS type 1 ECG pattern but without fulfilling other diagnostic criteria.

Date of diagnosis was defined as the date on which a definite diagnosis of BrS was established.

Statistical analyses

Values were reported as mean (standard deviation) when normally distributed and median [interquartile range (IQR)] when not. Differences between groups were tested using Student's t-test for continuous variables. All analyses were done using Stata 11 (StataCorp LP).

The study was approved by the Danish Data Protection Agency.

Results

Identification

Sixty-two patients were primarily identified through tertiary centres, four additional patients were identified through the Danish National Patient Registry, two additional patients (both of them family members) were identified through the nationwide pedigree database, and finally no additional patients were identified through the contact to all cardiology departments (all had been referred to tertiary centres).

Characteristics

Follow-up and inclusion ended on 1 June 2011. A total of 43 definite BrS patients and 25 possible BrS patients were identified. Characteristics for the group of BrS patients are shown in Table 1. Most definite BrS patients were men (86%) and the median age at diagnosis was 48 years (see Figure 1). No patient died or experienced aborted sudden cardiac death (ASCD) during follow-up, but 26% experienced ASCD before baseline.

Table 1

Clinical characteristics for Danish Brugada syndrome patients

 Definite patients Possible patients 
Cases, n 43 25 
Probands, n 33 22 
Male gender 37 (86%) 16 (64%) 
Median age (IQR), years 52 (36–62) 47 (39–58) 
Median age at diagnosis (IQR), years 48 (32–61) – 
Median follow-up time (IQR), months 43 (14–83) 35 (9–52) 
Reason for initial contact 
 Aborted sudden death 10 (23%) 4 (16%) 
 Chest pain (typical and atypical) 5 (12%) 6 (24%) 
 Syncope 10 (23%) 2 (8%) 
 Near syncope 2 (5%) 2 (8%) 
 Palpitations 2 (5%) 4 (16%) 
 Family examination 11 (26%) 3 (12%) 
 Other 3 (7%) 4 (16%) 
Spontaneous ECG pattern 
 Type 1 29 (67%) 13 (52%) 
 Type 2 3 (7%) 3 (12%) 
 Type 3 7 (16%) 7 (28%) 
 Not Brugada 4 (9%) 2 (8%) 
Provoked type 1 ECG pattern 20 (47%) 5 (20%) 
EPS result 
 Not tested 18 (42%) 19 (76%) 
 Not inducible 6 (14%) 2 (8%) 
 Ventricular tachycardia 8 (19%) 2 (8%) 
 Ventricular fibrillation 11 (26%) 2 (8%) 
Pre-baseline syncope 19 (44%) 3 (12%) 
Pre-baseline ASCD 11 (26%) 4 (16%) 
Nocturnal agonal respiration 6 (14%) 0 (0%) 
Atrial fibrillation, n 8 (19%) 3 (12%) 
Family history/genetics (probands only) 
 Familial type 1 ECG, n 4 (12%) 2 (9%) 
 Familial sudden death <45 years, n 3 (9%) 1 (5%) 
 Familial SIDS, n 0 (0%) 0 (0%) 
 SCN5A mutation, positive/tested 7/27 (26%) 0/0 (0%) 
 Definite patients Possible patients 
Cases, n 43 25 
Probands, n 33 22 
Male gender 37 (86%) 16 (64%) 
Median age (IQR), years 52 (36–62) 47 (39–58) 
Median age at diagnosis (IQR), years 48 (32–61) – 
Median follow-up time (IQR), months 43 (14–83) 35 (9–52) 
Reason for initial contact 
 Aborted sudden death 10 (23%) 4 (16%) 
 Chest pain (typical and atypical) 5 (12%) 6 (24%) 
 Syncope 10 (23%) 2 (8%) 
 Near syncope 2 (5%) 2 (8%) 
 Palpitations 2 (5%) 4 (16%) 
 Family examination 11 (26%) 3 (12%) 
 Other 3 (7%) 4 (16%) 
Spontaneous ECG pattern 
 Type 1 29 (67%) 13 (52%) 
 Type 2 3 (7%) 3 (12%) 
 Type 3 7 (16%) 7 (28%) 
 Not Brugada 4 (9%) 2 (8%) 
Provoked type 1 ECG pattern 20 (47%) 5 (20%) 
EPS result 
 Not tested 18 (42%) 19 (76%) 
 Not inducible 6 (14%) 2 (8%) 
 Ventricular tachycardia 8 (19%) 2 (8%) 
 Ventricular fibrillation 11 (26%) 2 (8%) 
Pre-baseline syncope 19 (44%) 3 (12%) 
Pre-baseline ASCD 11 (26%) 4 (16%) 
Nocturnal agonal respiration 6 (14%) 0 (0%) 
Atrial fibrillation, n 8 (19%) 3 (12%) 
Family history/genetics (probands only) 
 Familial type 1 ECG, n 4 (12%) 2 (9%) 
 Familial sudden death <45 years, n 3 (9%) 1 (5%) 
 Familial SIDS, n 0 (0%) 0 (0%) 
 SCN5A mutation, positive/tested 7/27 (26%) 0/0 (0%) 

Data reported as n (%) unless otherwise indicated. IQR, interquartile range.

Figure 1

Age at diagnosis for definite Brugada syndrome patients in Denmark.

Figure 1

Age at diagnosis for definite Brugada syndrome patients in Denmark.

Prevalence

We identified 43 definite BrS patients in Denmark and with a population of 4 056 152 in the corresponding age group (21–82 years) this translates into a prevalence of 1.1 per 100 000.

Electrocardiogram parameters

Electrocardiogram parameters divided into groups with and without SCN5A mutation are shown in Table 2. The group with SCN5A mutation was found to have a significantly prolonged PR interval (P = 0.01) on the ECG compared with the group without SCN5A mutation.

Table 2

Electrocardiogram parameters in Danish definite Brugada syndrome patients with and without SCN5A mutation

Parameter All patients (n = 44) SCN5A mutation (n= 7) No SCN5A mutation (n = 17) P value 
PR interval, ms 191 (35) 225 (46) 178 (19) 0.01 
QRS duration, ms 113 (19) 127 (27) 110 (15) 0.09 
Max ST-elevation, mV 4.5 (2.9) 3.3 (3.3) 4.8 (2.4) 0.07 
Parameter All patients (n = 44) SCN5A mutation (n= 7) No SCN5A mutation (n = 17) P value 
PR interval, ms 191 (35) 225 (46) 178 (19) 0.01 
QRS duration, ms 113 (19) 127 (27) 110 (15) 0.09 
Max ST-elevation, mV 4.5 (2.9) 3.3 (3.3) 4.8 (2.4) 0.07 

Data reported as mean (standard deviation). P values derived from testing for differences between groups with and without SCN5A mutation.

Medication

Only one patient was treated medically for recurrent ventricular tachycardia or fibrillation. The patient experienced >20 episodes of ventricular fibrillation over a period of ∼18 months. All episodes were terminated by ICD shocks. After initiation of quinidine shocks to reduce the number of ICD shocks, 2 years have passed without any arrhythmias.

Electrophysiological study and implantable cardioverter defibrillator

A total of 25 definite BrS patients underwent electrophysiological study (EPS) and of these, 19 were inducible to either sustained poly- or monomorphic ventricular tachycardia or ventricular fibrillation. Data on ICD shocks are shown in Table 3. A total of 35 definite BrS patients had an ICD implanted and of these 9 (26%) experienced appropriate shocks and 3 (8%) experienced inappropriate shocks during follow-up. No patient experienced both appropriate and inappropriate shocks.

Table 3

Characteristics and follow-up data for Danish definite Brugada syndrome patients with implantable cardioverter defibrillator

Patients with ICD 35 
Median FU time with ICD (IQR), months 47 (14–94) 
Risk factor in ICD patients 
 ASCD 9 (26%) 
 Syncope 16 (46%) 
 Spontaneous type 1 ECG pattern 26 (74%) 
ICD events 
 Appropriate shocks, patients 9 (26%) 
 Inappropriate shocks, patients 3 (8%) 
 Lead change, patients 5 (14%) 
 Battery change, patients 8 (23%) 
Patients with ICD 35 
Median FU time with ICD (IQR), months 47 (14–94) 
Risk factor in ICD patients 
 ASCD 9 (26%) 
 Syncope 16 (46%) 
 Spontaneous type 1 ECG pattern 26 (74%) 
ICD events 
 Appropriate shocks, patients 9 (26%) 
 Inappropriate shocks, patients 3 (8%) 
 Lead change, patients 5 (14%) 
 Battery change, patients 8 (23%) 

Data reported as n (%) unless otherwise indicated. ICD, implantable cardioverter defibrillator; FU, follow-up.

Discussion

We report the first nationwide study of diagnosed Brugada patients. Other studies of BrS populations have mainly enrolled patients from tertiary centres, thus being sensitive for referral bias.

We found a prevalence of definite BrS of 1.1 per 100 000 persons. As noted in the introduction other studies have tried to estimate the prevalence of BrS by identifying ECGs with BrS patterns. When looking at studies performed in populations of mainly European ethnicity a recent study using data from the Copenhagen City Heart Study reviewed 42 560 ECGs from 18 974 participants and found that no ECGs are exhibiting a type 1 pattern.11 Another study using data from the German KORA study studied 4149 participants and also found no type 1 patterns.14 Other surveys found 2 out of 12 012 (Italy),15 1 out of 1000 (France),16 and finally 2 out of 11 488 (Greece) participants with a type 1 pattern.17 This corresponds to a prevalence of 10 per 100 000 persons with type 1 ECG patterns in these European populations and is 10 times higher than our prevalence of diagnosed BrS cases. Multiple explanations are likely for this discrepancy: First and foremost a type 1 pattern is not enough to meet the BrS diagnostic criteria, and it is well established that many patients with a type 1 pattern remain asymptomatic and are without family history of sudden death.2–4,12 The only way that these patients can become definite BrS patients is to demonstrate inducibility during EPS, something that is not done routinely in most Danish centres. Secondly, maybe the true prevalence rate of type 1 patterns in the Danish population is much lower than10 per 100 000. This is supported by the aforementioned ECG surveys performed in Denmark and Germany, which found no type 1 patterns, maybe reflecting a true difference in prevalence between northern and southern Europe. The often-cited prevalence in the range of 50 per 100 000 persons1,18 is thus maybe a gross overestimation of the true prevalence of definite BrS at least in northern Europe.

We found 25 possible BrS cases, but this was a very heterogenous group and, as can be seen from Table 1, not all of them displayed the type 1 ECG pattern either spontaneously or during provocation testing. As such, this group probably encompasses other phenotypes as well, and will not be discussed further.

The demographics of our definite population were comparable with what was found in the FINGER registry with 86 vs. 72% men and a median age at diagnosis of 52 vs. 45 years, respectively.2 We also found comparable rates of SCN5A mutations carriers when compared with the FINGER registry (26 vs. 22%),2 and we found the PR interval to be significantly prolonged in SCN5A mutation carriers as reported previously.19–21

With regard to ICD therapies we found that during a median follow-up of 47 months 26% of ICD recipients received appropriate shocks and only 8% received inappropriate shocks. Sacher et al.22 studied 220 BrS ICD patients with a mean follow-up of 38 months and found that 8% received appropriate and 20% received inappropriate shocks. Sarkozy et al.4 studied 47 patients during a median follow-up of 48 months and found that 15% received appropriate and 36% received inappropriate shocks. Rosso et al.23 studied 59 patients and during a mean follow-up of 45 months found that 8% received appropriate and 27% received inappropriate shocks. Our ratio between appropriate and inappropriate shocks thereby differs significantly from others. This could be due to a different severity of disease in our ICD population compared to others. As such we found a high proportion of ICD carriers with a spontaneous type 1 pattern (74%), syncope (46%), and ASCD (26%), the three only factors that have been consistently associated with a poor prognosis in multivariate analyses.2,24,25 Sacher et al. found a lower proportion of ASCD (8%), comparable proportion of syncope (40%) and type 1 ECG (62%). Sarkozy et al. excluded cases with ASCD, and found a lower proportion of type 1 ECGs (49%) and syncope (55%). Rosso et al. found a somewhat lower proportion of ASCD (18%) and comparable proportions of syncope (53%) and type 1 ECG (63%). Thus, some of the differences with regard to ICD shocks can be explained by disease severity differences between the studies, but most must stem from other factors such as better discrimination algorithms in newer ICDs as well as better programming of these. An alternative explanation could be avoidance of triggers such as certain drugs (www.brugadadrugs.org) or treatment of fever.26

Although the rate of inappropriate therapies was low, a significant number (14%) of patients underwent lead replacements, indicating that the overall ICD complication rate in this population was still fairly high.

Of note no deaths occurred, either in ICD carriers or in non-carriers during follow-up, indicating good risk stratification.

Limitations

Our study design has some clear limitations. First and foremost we only identified diagnosed BrS patients and a large number of individuals with BrS, without doubt, remain undiagnosed, in some of the cases the first symptom being sudden cardiac death/aborted cardiac arrest, as recently shown by Raju et al.27 Our group has recently found an incidence rate of sudden unexplained death (sudden death with a negative autopsy) in the young (aged 1–35 years) in Denmark of 0.8 per 100 000 person-years.28 Studies examining the diagnostic yield of screening relatives to victims of sudden unexplained death find that 9–15% of cases, on the basis of findings in relatives, is assumed to be due to BrS.29,30 This implies that each year up to five cases of sudden unexplained death in Denmark could be due to undiagnosed BrS.

Secondly, we cannot exclude the possibility that we have missed even some diagnosed BrS patients. But as the health care system in Denmark (a public single-payer system) is highly integrated, homogenous and health care data are universally accessible we believe we were able to identify most if not all patients.

Unfortunately, we had no data on ICD complications such as infection and pneumothorax and thus could not report this.

Conclusions

In conclusion, we report the first nationwide study of diagnosed BrS patients. We found a low incidence of diagnosed definite BrS compared with estimates from European ECG surveys. Follow-up data show a lower rate of inappropriate therapies in ICD recipients than previous studies.

Conflict of interest: none declared.

Funding

This work was funded by The Foundation of 17-12-1981, The John and Birthe Meyer Foundation, and the Danish National Research Foundation.

References

1
Antzelevitch
C
Brugada
P
Borggrefe
M
Brugada
J
Brugada
R
Corrado
D
, et al.  . 
Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association
Circulation
 , 
2005
, vol. 
111
 (pg. 
659
-
70
)
2
Probst
V
Veltmann
C
Eckardt
L
Meregalli
PG
Gaita
F
Tan
HL
, et al.  . 
Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada syndrome registry
Circulation
 , 
2010
, vol. 
121
 (pg. 
635
-
43
)
3
Brugada
J
Brugada
R
Antzelevitch
C
Towbin
J
Nademanee
K
Brugada
P
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
 , 
2002
, vol. 
105
 (pg. 
73
-
8
)
4
Sarkozy
A
Boussy
T
Kourgiannides
G
Chierchia
G-B
Richter
S
De Potter
T
, et al.  . 
Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy in Brugada syndrome
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
334
-
44
)
5
Brugada
P
Brugada
J
Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report
J Am Coll Cardiol
 , 
1992
, vol. 
20
 (pg. 
1391
-
6
)
6
Hu
D
Barajas-Martinez
H
Burashnikov
E
Springer
M
Wu
Y
Varro
A
, et al.  . 
A Mutation in the {beta}3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype
Circ Cardiovasc Genet
 , 
2009
, vol. 
2
 (pg. 
270
-
8
)
7
Antzelevitch
C
Genetic basis of Brugada syndrome
Heart Rhythm
 , 
2007
, vol. 
4
 (pg. 
756
-
7
)
8
Burashnikov
E
Pfeiffer
R
Barajas-Martinez
H
Delpón
E
Hu
D
Desai
M
, et al.  . 
Mutations in the cardiac L-type calcium channel associated with inherited j wave syndromes and sudden cardiac death
Heart Rhythm
 , 
2010
, vol. 
7
 (pg. 
1872
-
82
)
9
Giudicessi
JR
Ye
D
Tester
DJ
Crotti
L
Mugione
A
Nesterenko
VV
, et al.  . 
Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome
Heart Rhythm
 , 
2011
, vol. 
8
 (pg. 
1024
-
32
)
10
Wilde
AAM
Ackerman
MJ
Exercise extreme caution when calling rare genetic variants novel arrhythmia syndrome susceptibility mutations
Heart Rhythm
 , 
2010
, vol. 
7
 (pg. 
1883
-
5
)
11
Pecini
R
Cedergreen
P
Theilade
S
Haunsø
S
Theilade
J
Jensen
GB
The prevalence and relevance of the Brugada-type electrocardiogram in the Danish general population: data from the Copenhagen City Heart Study
Europace
 , 
2010
, vol. 
12
 (pg. 
982
-
6
)
12
Tsuji
H
Sato
T
Morisaki
K
Iwasaka
T
Prognosis of subjects with Brugada-type electrocardiogram in a population of middle-aged Japanese diagnosed during a health examination
Am J Cardiol
 , 
2008
, vol. 
102
 (pg. 
584
-
7
)
13
Veltmann
C
Schimpf
R
Echternach
C
Eckardt
L
Kuschyk
J
Streitner
F
, et al.  . 
A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification
Eur Heart J
 , 
2006
, vol. 
27
 (pg. 
2544
-
52
)
14
Sinner
MF
Pfeufer
A
Perz
S
Schulze-Bahr
E
Monnig
G
Eckardt
L
, et al.  . 
Spontaneous Brugada electrocardiogram patterns are rare in the German general population: results from the KORA study
Europace
 , 
2009
, vol. 
11
 (pg. 
1338
-
44
)
15
Gallagher
MM
Forleo
GB
Behr
ER
Magliano
G
De Luca
L
Morgia
V
, et al.  . 
Prevalence and significance of Brugada-type ECG in 12,012 apparently healthy European subjects
Int J Cardiol
 , 
2008
, vol. 
130
 (pg. 
44
-
8
)
16
Hermida
J-S
Lemoine
J-L
Aoun
FB
Jarry
G
Rey
J-L
Quiret
J-C
Prevalence of the Brugada syndrome in an apparently healthy population
Am J Cardiol
 , 
2000
, vol. 
86
 (pg. 
91
-
4
)
17
Letsas
KP
Gavrielatos
G
Efremidis
M
Kounas
SP
Filippatos
GS
Sideris
A
, et al.  . 
Prevalence of Brugada sign in a Greek tertiary hospital population
Europace
 , 
2007
, vol. 
9
 (pg. 
1077
-
80
)
18
Benito
B
Brugada
R
Brugada
J
Brugada
P
Brugada Syndrome
Prog Cardiovasc Dis
 , 
2008
, vol. 
51
 (pg. 
1
-
22
)
19
Yokokawa
M
Noda
T
Okamura
H
Satomi
K
Suyama
K
Kurita
T
, et al.  . 
Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands
Am J Cardiol
 , 
2007
, vol. 
100
 (pg. 
649
-
55
)
20
Hong
K
Brugada
J
Oliva
A
Berruezo-Sanchez
A
Potenza
D
Pollevick
GD
, et al.  . 
Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations
Circulation
 , 
2004
, vol. 
110
 (pg. 
3023
-
7
)
21
Smits
JPP
Eckardt
L
Probst
V
Bezzina
CR
Schott
JJ
Remme
CA
, et al.  . 
Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients
J Am Coll Cardiol
 , 
2002
, vol. 
40
 (pg. 
350
-
6
)
22
Sacher
F
Probst
V
Iesaka
Y
Jacon
P
Laborderie
J
Mizon-Gerard
F
, et al.  . 
Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study
Circulation
 , 
2006
, vol. 
114
 (pg. 
2317
-
24
)
23
Rosso
R
Glick
A
Glikson
M
Wagshal
A
Swissa
M
Rosenhek
S
, et al.  . 
Outcome after implantation of cardioverter defribrillator in patients with Brugada syndrome: a multicenter Israeli study (ISRABRU)
Isr Med Assoc J
 , 
2008
, vol. 
10
 (pg. 
435
-
9
)
24
Giustetto
C
Drago
S
Demarchi
PG
Dalmasso
P
Bianchi
F
Masi
AS
, et al.  . 
Risk stratification of the patients with Brugada type electrocardiogram: a community-based prospective study
Europace
 , 
2009
, vol. 
11
 (pg. 
507
-
13
)
25
Gehi
AK
Duong
TD
Metz
LD
Gomes
JA
Mehta
D
Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis
J Cardiovasc Electrophysiol
 , 
2006
, vol. 
17
 (pg. 
577
-
83
)
26
Postema
PG
Wolpert
C
Amin
AS
Probst
V
Borggrefe
M
Roden
DM
, et al.  . 
Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org)
Heart Rhythm
 , 
2009
, vol. 
6
 (pg. 
1335
-
41
)
27
Raju
H
Papadakis
M
Govindan
M
Bastiaenen
R
Chandra
N
O'Sullivan
A
, et al.  . 
Low prevalence of risk markers in cases of sudden death due to Brugada syndrome: relevance to risk stratification in Brugada syndrome
J Am Coll Cardiol
 , 
2011
, vol. 
57
 (pg. 
2340
-
5
)
28
Winkel
BG
Holst
AG
Theilade
J
Kristensen
IB
Thomsen
JL
Ottesen
GL
, et al.  . 
Nationwide study of sudden cardiac death in persons aged 1–35 years
Eur Heart J
 , 
2011
, vol. 
32
 (pg. 
983
-
90
)
29
van der Werf
C
Hofman
N
Tan
HL
van Dessel
PF
Alders
M
van der Wal
AC
, et al.  . 
Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands
Heart Rhythm
 , 
2010
, vol. 
7
 (pg. 
1383
-
9
)
30
Behr
ER
Dalageorgou
C
Christiansen
M
Syrris
P
Hughes
S
Tome Esteban
MT
, et al.  . 
Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
1670
-
80
)