Are women with severely symptomatic brugada syndrome different from men?
ABSTRACT Women with Brugada Syndrome.
Spontaneous type-1 ECG has been recognized as a risk factor for sudden cardiac death (SCD) in Brugada syndrome (BrS), but studied populations predominantly consisted of men. We sought to investigate whether a spontaneous type-1 ECG pattern was also associated in women with severely symptomatic BrS. Other known risk factors were also examined for gender specificity.
Patients with severely symptomatic BrS, defined as resuscitated SCD and/or appropriate implantable cardioverter-defibrillator (ICD) shock, were included from 11 European centers. Clinical data, investigation of family history, 12-lead ECG, and results of electrophysiological study (EPS) were collected. The average follow-up was 4 +/- 3 years.
Fifty-eight patients fulfilled the inclusion criteria (mean age 47 +/- 11 years, 8 women). Thirty-six men (72%) but only two women (25%) had a spontaneous type-1 ECG at baseline (P = 0.02). Maximal ST elevation before or after drug challenge was 3.7 +/- 1.3 mm in men versus 2.4 +/- 0.7 mm in women (P = 0.007). The proportion of patients with a family history of SCD or an SCN5A mutation was not significantly different between both groups. Of those patients with high-risk BrS who underwent EPS, 76%(12/25) of men and 50%(2/4) of women had a positive study.
In contrast to men, most women with BrS and resuscitated SCD or appropriate ICD shock do not have a spontaneous type-1 ECG pattern. In addition, the degree of ST elevation is less pronounced in women than men. While women represent a lower-risk group overall, risk factors established from a predominantly male population may not be helpful in identifying high-risk females.
- SourceAvailable from: Yanmin Zhang[Show abstract] [Hide abstract]
ABSTRACT: Both Brugada Syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated respectively with diffuse and discrete alterations in conduction pathways affected by ageing and sex. This study assessed for contributions of such processes to the mechanism of conduction changes in Scn5a(+/-) and WT hearts stratified by age (3 and 12 months) and sex. In vivo electrocardiographic chest-lead assessment demonstrated greater incidences of bundle branch block in all Scn5a(+/-) mice compared to WT. Frequency analysis of right ventricular (RV) epicardial activation obtained from a 64-channel multi-electrode array demonstrated greater prominence of late conducting components in Scn5a(+/-) compared to WT male, and in male compared to female Scn5a(+/-) following stratification by genotype and sex. Similar differences were observed between old male Scn5a(+/-) and young male Scn5a(+/-), old female Scn5a(+/-), and old male WT, following stratification by genotype, age and sex. These findings directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls preferentially involving the RV. We demonstrate complex alterations in conduction distributions suggesting a conversion of normal to slow-conducting tissue, modulated by ageing and sex, coupled with fibrosis in Scn5a(+/-) hearts. These features suggest an overlap between pathophysiological processes related to BrS and PCCD in Scn5a(+/-) hearts.Mechanisms of ageing and development 08/2012; 133(9-10):591-9. · 4.18 Impact Factor
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ABSTRACT: Sudden cardiac death (SCD) following ventricular tachyarrhythmias constitutes an important clinical cause of mortality; 4% of cases may involve ion channel-mediated cellular excitation in structurally normal hearts. Alterations in such processes could disturb action potential conduction, depolarization/ repolarization gradients, or Ca(2+) homeostasis with potential arrhythmogenic consequences. Although SCD may be the first presentation of arrhythmic syndromes, patients may present to the general physician with symptoms of palpitations or hemodynamic compromise, including dizziness, seizure, or syncope, particularly following exertion. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other, pharmacological, treatments being developed. Furthermore, as the genetic basis of these diseases becomes established, genetic testing will form an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation. This article bridges the gap between molecular medicine and clinical practice by reviewing recent developments in the pathophysiological understanding of SCD, and their implications for the management of patients with these complex diseases.Annals of Medicine 05/2013; · 4.73 Impact Factor
- Acta Physiologica 04/2013; 207(4):584-7. · 4.25 Impact Factor
Different from Men?
Are Women with Severely
Symptomatic Brugada Syndrome
Frédéric Sacher, Paola G. Meregalli, Christian Veltmann,
Michael E. Field, Aude Solnon, Paul Bru, Sélim Abbey,
Pierre Jaïs, Hanno L. Tan, Christian Wolpert, Gilles Lande,
Valérie Bertault, Nicolas Derval, Dominique Babuty,
Dominique Lacroix, Serge Boveda, Philippe Maury,
Mélèze Hocini, Jacques Clémenty, Philippe Mabo,
Hervé Le Marec, Jacques Mansourati, Martin Borggrefe,
Arthur A.M. Wilde, Michel Haïssaguerre and Vincent Probst
Journal of Cardiovascular Electrophysiology 2008; 19:1181-5
Introduction: Spontaneous type I ECG has been recognized as a risk factor for
sudden cardiac death (SCD) in Brugada syndrome, but studied populations
predominantly consisted of men. We sought to investigate whether a spontaneous
type I ECG pattern was also associated with SCD in women with symptomatic
Brugada syndrome. Other known risk factors were also examined for gender-
Methods: Patients with severely symptomatic Brugada syndrome, defined as
resuscitated SCD and/or appropriate implantable cardioverter-defibrillator (ICD)
shock were included from 11 European centers. Clinical data, investigation of
family history, twelve-lead ECG and results of electrophysiological study (EPS)
were collected. The average follow-up was 4±3 years.
Results: Fifty-eight patients fulfilled the inclusion criteria (mean age 47±11 years, 8
women). Thirty-six men (72%) but only two women (25%) had a spontaneous type
I ECG at baseline (p=0.02). Maximal ST elevation before or after drug challenge
was 3.7±1.3 in men vs 2.4±0.7 mm in women (p=0.007). The proportion of patients
with a family history of SCD or a SCN5A mutation was not significantly different
between men and women. Of those patients with high-risk Brugada syndrome
who underwent EPS, 76% (12/25) of men and 50% (2/4) of women had a positive
Conclusion: In contrast to men, most women with Brugada syndrome and
resuscitated SCD or appropriate ICD shock do not have a spontaneous type I ECG
pattern. In addition, the degree of ST elevation is less pronounced in women than
in men. While women represent a lower risk group overall, risk factors established
from a predominantly male population may not be helpful in identifying high risk
Manifestation of Brugada Syndrome in Women
Mutations in the SCN5A gene, which encodes the α subunit of the sodium channel
protein, are responsible for a subset of patients with Brugada syndrome. This gene
displays an autosomal dominant mode of transmission. While men and women
are expected to inherit the defective gene equally, disease manifestation is clearly
predominant in males. Up to now, Brugada syndrome population studies that
evaluated risk factors for sudden cardiac death (SCD)1-3 were mainly composed
of men. Whether women with severely symptomatic Brugada syndrome share the
same characteristics and risk factors, such as a spontaneous type I ECG pattern is
not known. We sought to investigate whether a spontaneous type I ECG pattern
was also prevalent in women with severely symptomatic Brugada syndrome.
Other known risk factors were also examined for gender-specificity.
Consecutive patients with Brugada syndrome were enrolled in a multicenter registry
from 11 participating centers in Europe. Patients were included in the present study
only if they had a type I ECG pattern on at least one baseline ECG spontaneously,
or after provocation with a class I anti-arrhythmic drug. A type I ECG was defined
as a prominent coved ST-segment elevation displaying J-point amplitude or ST-
segment elevation 2 mm at its peak in lead V1 through V3 4. The choice of class I
drug was determined by its availability in the participating hospitals: intravenous
ajmaline (1 mg/kg body weight at a rate of 10 mg/min) or flecainide (2 mg/kg
body weight over 10 minutes with a maximum of 150 mg). In addition, treadmill
exercise testing, biochemical analysis, and, in some cases, coronary angiography
excluded acute ischemia and metabolic or electrolyte disturbances. The total
Brugada syndrome population followed in these centres numbered 739, with 211
women (29%). These centers were the “reference arrhythmic department” for their
geographical area and included all patients with Brugada syndrome whether or
not they were symptomatic. The following clinical data were collected in all 11
participating centers: gender, age and circumstances at diagnosis, indication for
implantable cardioverter-defibrillator (ICD) implantation (when appropriate),
family history of SCD (< 45 years of age). Patients with resuscitated SCD and/or
appropriate ICD shock in the context of Brugada syndrome were considered as
“severely symptomatic” Brugada syndrome and included in the current analysis.
All patients included in this study had at least three baseline ECGs and/or 24
hours continuous 12-lead ECG reviewed. When invasive electrophysiological
testing (EPS) was performed, the protocol consisted of ventricular stimulation
from 2 sites at 2 drive cycle lengths with up to 3 extrastimuli until 200 ms. All
these severely symptomatic patients were prospectively followed for 4 ± 3 years.
Values are expressed as mean ± standard deviation. Comparison of categorical
values was performed using a Fisher’s exact test. Continuous parameters were
compared using the non-parametric Mann-Whitney test. A p-value < 0.05 was
Fifty-eight patients (mean age 47±11 years; 8 women (14%); 8% of all Brugada
syndrome patients followed in the 11 centers) met preset criteria for severely
symptomatic Brugada syndrome in this international registry (n= 739). Clinical
and electrocardiographic characteristics are summarized in the table (see below).
The proportion of men with severely symptomatic Brugada syndrome was
significantly higher than the proportion of women (9.5% vs. 3.8%, p=0.009). The 8
women were not significantly older than the men at the time of onset of symptoms
(50 ±13 vs. 45 ±11, p=0.22). Diagnosis was made because of aborted-SCD (33 men
and 3 women), syncope (11 men and 4 women), and a VT in 1 woman. Six men
were asymptomatic, but experienced ICD shocks during follow-up. All patients
underwent ICD implantation (the six asymptomatic men because of a positive
EPS). A higher proportion of men had a spontaneous type I ECG at baseline (72%
of men vs. 25% of women, p=0.02). In the remaining individuals, a type I ECG
Manifestation of Brugada Syndrome in Women
pattern was present only after drug challenge (14 men and 6 women). Maximal
ST segment elevation, measured either before or after drug challenge, was 3.7 ±1.3
mm in men vs. 2.4 ±0.7 mm in women (p= 0.007). In patients without spontaneous
type I ECG pattern (n=20), 12 of 14 men and 4 of 6 women underwent flecainide
challenge, the remaining patients had ajmaline. Figure 1 shows the ECGs of the
eight women. The onset of ventricular tachyarrhythmia in a female patient was
not preceded by ST segment elevation (Figure 2). There was no difference between
men and women with regard to the duration of PR and QTc intervals. The
proportion of patients with a family history of SCD was not significantly different
between both groups, nor was the presence of a SCN5A mutation (Table).
Appropriate shocks occurred in 25 men (8 with prior aborted-SCD, 12 implanted
for syncope and 5 previously asymptomatic patients) after a mean follow-up of 24
± 35 months and in 6 women (1 with prior aborted-SCD, 4 implanted for syncope
and 1 implanted for sustained monomorphic ventricular tachycardia (VT) after a
mean follow-up of 25 ± 33 months.
Ventricular arrhythmias in women were polymorphic ventricular tachycardia or
ventricular fibrillation (VF) in 7 cases and monomorphic VT in 1 (case reported
by Boersma et al 5). Arrhythmic storm was the clinical presentation in 2 women.
Isolated ventricular arrhythmias at night or during periods of high vagal tone
were observed in 2 female patients with ICD shocks. There was no identifiable
arrhythmic trigger in 4 cases. None of the arrhythmic events was related to exertion.
Concerning men, 23 had a polymorphic VT or VF and 2 monomorphic VT. Eight
men experienced arrhythmic storms. Of the 17 remaining men, 10 experienced
shocks at night, 6 during the daytime and 1 during both.
EPS was performed in 29 (50%) patients of our study (n=58). Of these severely
symptomatic patients, 19/25 (76%) men and 2/4 (50%) women had inducible
ventricular tachyarrhythmia (p=ns).
Table: Clinical and electrocardiographic characteristics of patients with severely
symptomatic Brugada syndrome according to gender.
Age, years p=0.22
Prior resuscitated SCD33 (66%) 3 (38%) p=0.03*
Appropriate shock 25 (50%) 6 (75%)p=0.26
Family history of SCD15 (30%)2 (25%) p=0.99
Spontaneous type I ECG36 (72%)
3.7 ± 1.3
2.4 ± 0.7
QTc, ms p=0.08
Maximal ST elevation, mm p=0.007*
Mean ST elevation
in pts with spontaneous type I ECG,
2.8 ± 1
2.3 ± 0.9
Positive EPS19/25 (76%)2/4 (50%) p=0.25
SCN5A mutation carriers 13/42 (31%)3/7 (43%) p=0.79
* indicates statistical significance
Manifestation of Brugada Syndrome in Women
Figure 1: ECGs with maximal degree of ST elevation in the eight women with severe symptoms. The
first three ECGs belong to women who received an ICD because of aborted-SCD.
Women with Brugada syndrome have a lower prevalence (3.8%) of life-threatening
arrhythmias compared to men (9.5%) in this non selected international Brigade
population (739 pts). The subgroup of women with severely symptomatic Brugada
syndrome displayed a spontaneous type 1 ECG pattern less frequently than men.
Also, the amount of ST segment elevation in the right precordial ECG leads is less
accentuated compared to the severely symptomatic men.
Despite equal genetic transmission of the affected gene, the clinical phenotype is
much more severe in men than in women. The basis for this intriguing sex-related
difference in disease penetrance is not completely understood. It seems that the
presence of a more prominent Ito in the right ventricular epicardium in males
contributes to their predisposition to develop the Brugada syndrome phenotype 6.
However hormonal, environmental or genetic factors other than SCN5A mutations
may alter the function of Ito or of other yet unknown factors that explain the gender
difference in disease penetrance. In families with a particular SCN5A mutation,
Kyndt et al.7 reported a classical Brugada syndrome phenotype in males but an
isolated cardiac conduction defect in females. Hong et al. 8, however, described
another specific SCN5A gene defect with predominantly female phenotypic
expression (characterized by ST segment elevation). It is also well established
that sex hormones impact on cardiac cellular electrophysiology, in particular
on cardiac repolarization 9. Matsuo et al. 10 reported two cases of asymptomatic
Brugada syndrome in which typical coved type ST segment elevation disappeared
following orchiectomy, as therapy for prostate cancer. More recently, Shimizu et al.
11 found no correlation between testosterone level and clinical presentation, degree
of ST elevation, the presence of a SCN5A mutation or events during follow-up, but
males with Brugada syndrome men have higher testosterone levels than males
without Brugada syndrome.
Regarding the gender difference in relation to the risk of developing ventricular
arrhythmia, a previous meta-analysis 12 combining 788 patients from three studies
found a 3.47-fold increase in risk of event (syncope, SCD or ICD shock) in men vs.
women with Brugada syndrome. In our study, the relative risk of aborted-SCD
Manifestation of Brugada Syndrome in Women
or appropriate ICD shock is increased by a factor 2.5 in men vs. women over a
follow-up period exceeding 3 years.
Spontaneous type I ECG is a risk factor for arrhythmic events in several large
studies 2, 3, which included mainly men. However, no studies focused on women.
In our population, only 25 % of the women had a spontaneous type I ECG pattern,
despite the occurrence of ventricular arrhythmias. Figure 2 contains tracings from
a 33 year old woman with arrhythmic storm not controlled with either β-blocker
or intravenous amiodarone infusion. Despite VF episodes, there was no ST
elevation on 12 lead ECG. Brugada syndrome diagnosis was made 2 weeks later
with flecainide challenge (Figure 3).
Based on these data, the absence of a spontaneous type I ECG in women may
not be reassuring as suggested in the literature 1, 2. Right ventricular transmural
epicardial or endocardial voltage gradients leading to ST elevation in the right
precordial leads is one of the proposed mechanisms leading to the development
of phase 2 reentry 13, followed by ventricular arrhythmia. It is intriguing, given
the mechanism proposed, that patients may develop ventricular arrhythmia in
the context of Brugada syndrome without concomitant ST elevation. Alternative
explanations have, however, been proposed 14, such as structural cardiac disorders
or the presence of slow-conducting tissue in the right ventricular outflow tract.
Figure 2: ECG during arrhythmic storm in a 33 year-old woman (patient 1). She was unsuccessfully
treated with beta-blocker and amiodarone infusion and was then referred for polymorphic VT
ablation. Panel (a) shows VF during monitoring and panel (b) non-sustained VT on 12 lead ECG 3
days later. Note the absence of ST elevation in the acute period as well as the T wave inversion and
QT interval prolongation due to the combination of amiodarone and multiple shocks.
Manifestation of Brugada Syndrome in Women
Figure 3: This is the same patient presented in Figure 2. Intravenous flecainide unmasked the
Brugada phenotype two weeks after the end of the arrhythmic storm. Note the normalization of the
QT interval. Genetic testing did not find any mutation in SCN5A, HERG and KVLQT1 genes.
Although this is a large international multicenter cohort, there is still a relatively
small number of female patients with severely symptomatic Brugada syndrome,
limiting the statistical power. However this is the largest study so far comparing
the clinical characteristics of men and women with severely symptomatic Brugada
Women with Brugada syndrome have a lower risk (3.8%) of life-threatening
arrhythmias than men (9.5%). Risk stratification in Brugada syndrome remains
limited, but the female sub-population may be a particularly challenging group
Neither the presence of a spontaneous type I ECG nor the total magnitude of ST
elevation seemed to correlate with severe symptoms in female Brugada syndrome
patients. The role of EP study remains unclear both in symptomatic female and
male Brugada syndrome patients.
Further investigations are needed to identify better methods for risk
Manifestation of Brugada Syndrome in Women
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