Age of First Arrhythmic Event in Brugada Syndrome
Abstract
Background
Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE.
Methods and Results
A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter–defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27–84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years).
Conclusions
SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE.
Introduction
WHAT IS KNOWN?
Data collected from limited series of Brugada syndrome patients with aborted cardiac arrest found that their first arrhythmic event (AE) typically occurs in men aged 40 to 50 years.
WHAT THE STUDY ADDS?
It describes the largest multicenter international survey of patients with Brugada syndrome and their first AE documented either at the time of aborted cardiac arrest (n=426) or after prophylactic implantable cardioverter–defibrillator implantation (n=252).
Although the marked male predominance (91.3%) is confirmed, the involvement of the pediatric (4.3%) and elderly population (1.5%) is scarce, and the peak AE occurs at ≈42 years of age. Two age cutoffs (16 and 70 years) are suggested for decision-making.
Age at time of AE markedly differs according to the mode of presentation of the arrhythmia and sex but not according to patient ethnicity.
An estimated AE rate for each age group has been calculated by sex, mode of AE documentation, and ethnicity using data provided by a large registry of patients with Brugada syndrome from the main SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) centers.
Brugada syndrome (BrS) is an inherited arrhythmic disorder that may result in sudden cardiac death (SCD).1 BrS is estimated to account for 4% of all SCDs and for 20% of all SCDs in patients with apparently normal hearts.2 BrS is more prevalent in Asia than in Europe and in the United States.1 Despite its autosomal-dominant mode of transmission, there is a men predominance among patients with aborted cardiac arrest (CA), even more so in those originating from Southeast Asia.3,4 Malignant ventricular arrhythmic events (AE) are documented either at patient presentation because of aborted CA or after prophylactic implantable cardioverter–defibrillator (ICD) implantation. The first AE typically occurs in male patients aged 40 to 50 years5–8 and rarely during childhood9,10 or in the elderly.11,12
However, these data are from limited patient cohorts, the largest in Europe being the FINGER (France, Italy, Netherlands, Germany BrS registry)5 that gathered 62 patients with aborted CA from 4 European countries.
To clarify the issue of AE in BrS, we have recently organized a multicenter international survey SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) that enabled data collection on a large cohort of 678 patients with BrS with AE from multiple Western and Asian countries.
The present study has 2 objectives: (1) to define the age at first AE in a large cohort of patients with BrS originating from Western and Asian countries, and (2) to assess the influence of the mode of AE documentation, sex, and ethnic origin on the age at first AE.
Methods
The data that support the findings of this study are available from the corresponding author or the first author ([email protected]) on reasonable request.
Data Source and Center Selection
A Medline search was used to locate academic electrophysiology centers involved in BrS. The search, limited to English language articles published between 1992—year of the principle publication of the syndrome13—and April 2016, included all clinical publications with no limitation to patient age. All major electrophysiology centers with publications reporting AE in BrS were eligible for inclusion.
Meta-analyses and case reports were excluded. When data from multicenter studies were provided, the data origin of each center was specifically requested and carefully checked to prevent any duplication in data collection.
Center Recruitment
Twenty-three (85%) of the 27 contacted centers agreed to participate. Sixteen (69.5%) centers provided data from their institution only, whereas the remaining 7 (31.5%) provided data from multiple institutions from their countries. The French center that coordinated the FINGER registry5 provided data from multiple (n=20) French centers only. The number of patients provided by each of the 23 centers ranged from 7 to 105. All 23 centers but 2 attested that there was no limitation of age in the recruitment of patients.
The survey gathered 678 patients in total: 415 (61.2%) from 10 Western countries and 263 (38.8%) from 4 Asian countries. The countries of origin of the patients are listed in Table I in the Data Supplement.
Data Acquisition
The study was approved by the Tel-Aviv Medical Center Institutional Review Board committee. Study inclusion criteria consisted of (1) a typical Brugada type-1 ECG either spontaneously or after the intravenous administration of a sodium channel blocker and (2) a first documented AE. Participating centers were sent a questionnaire and were asked to provide anonymous information on clinical, ECG, electrophysiology, and genetic findings for each of their patients, including (1) mode of AE documentation (group A or group B, see below), (2) patients' age at the time of their first AE, (3) patient’s sex, (4) patient’s proband status, and (5) patient’s ethnicity (white, Asian, other, or unknown). Only patients for whom the entire questionnaire was completed were included.
The patients were classified in 2 groups according to the mode of AE documentation: group A, patients with documented aborted CA in whom the BrS diagnosis was made during workup performed after CA; group B, patients with a BrS diagnosis in whom prophylactic ICD implantation was performed for any reason and in whom an AE requiring appropriate ICD shock therapy was documented during follow-up by ICD interrogation.
In addition, 22 of the 23 centers were able to provide the age and sex distribution of the entire BrS population followed at their own center (with or without prior AE). The centers from Western and Asian countries were assumed to include white and Asian patients, respectively (see Results section below). The number of AEs collected in SABRUS by these same centers was also determined. An estimated AE rate for each age group by sex, mode of AE documentation, and ethnicity was calculated by dividing the number of patients with AE collected in SABRUS by the number of patients collected in the BrS registry from the same centers.
Definitions
Proband Status
Proband was defined as the first patient of a family who has been diagnosed with the type-1 Brugada ECG (spontaneous or drug induced). A nonproband was defined as a family member of a known BrS patient.
Age Cutoffs
We defined an upper age cutoff of 16 years for the pediatric patient group based on the exclusion of patients aged <16 years in the FINGER registry5 and the fact that 70% of AEs occurred before the age of 15 years in the largest pediatric series.10 Taking into account the results of 2 studies showing the rarity of AE in patients with BrS >70 years,11,12 we also defined an upper age cutoff of 70 years for the elderly. Patients’ age at time of AE was allocated to 5 bins of 11 years between these 2 age cutoffs.
Statistical Analysis
Assumptions of normality of the general age distribution and the age distribution among patient subgroups were assessed by Kolmogorov–Smirnov test and Q-Q plots. Differences in means of normally distributed ages were assessed using a Welch t test. Differences between non-normally distributed ages were assessed using a Mann–Whitney U test. Ratio differences were examined by a χ2 test or a Fisher exact test as appropriate. Significance of differences between curves of cumulative event occurrence by age was assessed using a Mantel–Cox test. Statistical significance was defined as P<0.05. Numeric data are presented as mean±SD for normally distributed variables or as median (interquartile range) for not normally distributed variables. All calculations were performed using SPSS, version 24 (IBM, Armonk, NY).
Results
Study Patient Cohort
Complete information was provided for 678 patients, 619 (91.3%) men and 59 (8.7%) women aged 41.9±14.8 years at the time of their first AE (Table). Most patients (n=426; 62.8%) belonged to group A, whereas the remaining 252 (37.2%) belonged to group B. Of the 678 patients, 364 (53.7%) were whites, 270 (39.8%) patients were Asians, and 14 (2.1%) were of other ethnic origin. Ethnicity was unavailable for 30 (4.4%) patients. Seven (1.7%) of the 415 patients from Western countries had an Asian origin, whereas no patient from Asian countries was white.
| No. of Patients | SABRUS | |
|---|---|---|
| 678 | ||
| Age at AE, y | Range | 0.27–84 |
| Mean±SD | 41.9±14.8 | |
| Age distribution, y | <16 | 29 (4.3) |
| 16≥y≤70 | 639 (94.2) | |
| >70 | 10 (1.5) | |
| Group | A | 426 (62.8) |
| B | 252 (37.2) | |
| Sex | Men | 619 (91.3) |
| Women | 59 (8.7) | |
| Country of origin | Western | 415 (61.2) |
| Eastern | 263 (38.8) | |
| Ethnicity | Whites | 364 (53.7) |
| Asian | 270 (39.8) | |
| Unknown | 30 (4.4) | |
| Other | 14 (2.1) | |
| Proband | Yes | 542 (79.9) |
| No | 88 (13) | |
| Unknown | 48 (7.1) | |
| Family history of SCD | Yes | 145 (21.4) |
| No | 468 (69) | |
| Unknown | 65 (9.6) | |
| Prior syncope | Yes | 265 (39.1) |
| No | 413 (60.9) | |
| Spontaneous type-1 ECG | Yes | 451 (66.5) |
| No | 227 (33.5) | |
| EPS | Performed | 400 (58.9) |
| Inducible arrhythmia | Yes | 253 (63.2) |
| No | 147 (36.8) | |
| Genetic testing | Performed | 485 (71.5) |
| SCN5A mutation | Yes | 143 (29.5) |
| No | 342 (70.5) |
The great majority (79.9%) of the survey patients were probands, 13% of patients were diagnosed during family member screening, whereas no information on the proband status was available for the remaining 7.1%. Distribution of proband status by age group is shown in Figure I in the Data Supplement.
Age at First AE
The age of first AE was not normally distributed, with a left tail representing a higher occurrence in the pediatric group. Exclusion of pediatric patients resulted in a normally distributed age with a mean age of 43.5±12.9 years. Ages in the entire cohort ranged from 0.27 to 84 years. The vast majority of patients (n=639; 94.2%) were 16 to 70 years old, 29 patients (4.3%) belonged to the pediatric group (age, <16 years) and 10 patients (1.5%) to the elderly group (age, >70 years; Figure 1A). Peak AE rate occurred in the 38- to 48-year age group (n=204 patients; 30.1% of all study patients). The AE rate more than doubled from 4.3% (n=29; 86.2% from group A) before 16 years of age to 9.7% between ages 16 and 26 years (n=66; 78.8% from group A). In the pediatric group, the median age was 4 (1.6–10.4) years, and 17 (58.6%) of the 29 AEs occurred in children aged ≤5 years. In the elderly group, the 2 oldest patients were 84 years old.
Figure 1. Age distribution of arrhythmic event (AE) in the 678 SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) patients (A) and in the 6441 patients of the registry (B). In both instances, the age of first AE is normally distributed with a single peak in the 38- to 48-year age group. Note that the age distribution is similar in both patient groups.
Mode of AE Documentation
The mean age at first AE was significantly lower in group A than in group B (39.4±15.0 versus 46.1±13.2 years; P<0.001; Figure 2A). The majority of pediatric patients (86.2%) and two thirds of the elderly patients belonged to group A. Overall, group A maintained a significant earlier occurrence of AE (P<0.001; Figure 2B).
Figure 2. Age distribution by mode of arrhythmic event (AE) documentation in SABRUS (Survey on Arrhythmic Events in Brugada Syndrome).A, The mean age at first AE is significantly lower in group A than in group B. B, The occurrence of AE is significantly earlier in group A, which is maintained in older age groups.
Sex Distribution
Age was normally distributed in men, whereas the female distribution was abnormal because of a high prevalence of AE in women in the pediatric group. Women exhibited their AE at a similar median age as men (46 [28–58] versus 42 [33–52]; P=0.255; Figure 3A). After filtering out pediatric patients from the entire cohort, both sex groups were normally distributed, and age at onset of AE was significantly higher in women (mean, 49.5±14.4 versus 43.0±12.7; P=0.003). In the pediatric group (age, <16; n=29), the male predominance was significantly lower than in the rest of the cohort (65.5% versus 92.4%; P<0.001). Above the age of 49 years, male predominance was also lower (87.7% versus 92.8%; P=0.029). Figure 3B highlights how the occurrence of AE at an earlier age depends on sex and age group (ie, AE occurs earlier in women ≤38–48 years of age, and then this trend reverses afterward).
Figure 3. Age distribution by sex in SABRUS (Survey on Arrhythmic Events in Brugada Syndrome).A, Age is normally distributed in men, whereas the female distribution is abnormal because of a high prevalence of arrhythmic event (AE) in women of prepubescent age. Women exhibit their AE at a significantly older age than men. B, AE occurs earlier in women ≤38 to 48 years of age. Then this trend reverses, and men experience more AEs.
Ethnic Distribution
Because of the small number of patients of other ethnicity, only comparisons between whites and Asians were performed. Whites and Asians exhibited their AE at the same median age (43 [31–53] and 43 [34.8–51.2] years, respectively; P=0.285; Figure 4A). Only 1 of 26 patients with known ethnicity in the pediatric group and 2 of 9 patients in the elderly group were Asian (Figure 4A), but overall, there was no ethnical difference in the age at onset of AE (Figure 4B).
Figure 4. Arrhythmic event (AE) distribution by ethnicity in SABRUS (Survey on Arrhythmic Events in Brugada Syndrome).A, Whites and Asians exhibit their AE at similar mean ages. Note that only 1 of the 26 patients with known ethnicity in the pediatric group and 2 of the 9 patients of the elderly group are Asians. B, Cumulative incidence of AE by age in white and Asian patients. Overall, there is no difference in the age of AE.
Patients from Japan (n=119), South Korea (n=79), and Taiwan (n=40) exhibited their AE at similar ages (45.0±12.3 versus 43.2±12.3 versus 42.4±14.1 years, respectively; P=0.442). However, patients from China (n=25) exhibited their AE at a younger age than patients from the other Asian countries (37.0±7.0 versus 43.9±12.6 years; P<0.001).
Multifactorial Analysis
The age of onset at AE was similar in men and women from both group A and group B (Table IIA in the Data Supplement). The age of onset of AE in both groups was not affected by patient ethnicity (Table IIA in the Data Supplement).
The age of onset of AE in both women and men was higher in group B patients (P<0.05) and not affected by ethnicity (Table IIB in the Data Supplement). The age of onset at AE in both white and Asian patients was higher for group B (P<0.001) and not affected by sex (Table IIB in the Data Supplement).
BrS Registry and Estimated AE Rate
Data on patient sex and age distribution were provided by 22 SABRUS centers and included as the BrS registry. The registry comprised 6441 patients (73.4% men). The vast majority (92.5%) of patients were 16 to 70 years old, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.7% and 2.8%, respectively (Figure 1B). Age distribution of the 6441 registry patients showed a single peak in the 38- to 48-year age group in men (28.2% of the male patients) and a single peak in the 49- to 59-year age group in women (26.8% of the female patients; Figure 5A). There were significantly less patients of Asian ethnicity before age 26 (5.6%) than after age 27 (12.7%) (P<0.0001) (Figure 5B).
Figure 5. Data from the 6441 patients of the Registry according to sex(A) and ethnicity (B). Peak incidence for Brugada syndrome diagnosis for men is observed in the 38- to 48-year age group and in the 49- to 59-year age group in women (A). Ethnicity distribution does not differ between whites and Asians, with a similar peak incidence in the 38- to 48-year age group (B).
The estimated total AE rates, based on the 500 AEs documented in these 22 centers, ranged from 6.6% to 7.8% up to 70 years of age before dropping to 3.9% thereafter (mean, 7.1%; Figure 6A). The mean estimated rates of AE presenting as aborted CA (group A) or after a prophylactic ICD implantation (group B) were 4.8% and 2.9%, respectively (P<0.001; Figure 6B). The mean estimated AE rates were significantly higher in men (8.6%) as compared with women (2.9%; P<0.001; Figure 6C). The estimated AE rate in Asian patients (25.5%) was significantly greater than that in whites (4.7%; P<0.001; Figure 6D).
Figure 6. Estimated arrhythmic event (AE) rates.A, In all age groups. The AE rate is similar throughout all age groups with the exception of the elderly group (P=0.088 vs the nonelderly group). B, According to mode of AE documentation. The AE rate is higher in group A than group B up to the age of 49, thereafter there is no difference. *P<0.01; †P<0.001. C. According to sex. The AE rate is higher in men than women except for the pediatric and elderly patients. *P<0.01; †P<0.001. D, According to ethnicity. The estimated AE rate is significantly higher in Asians than whites in all age groups except for the pediatric and elderly group (P<0.001). Note that there are no Asians who experienced an AE in the pediatric population. †P<0.001.
Discussion
SABRUS includes the largest cohort of patients with BrS with documented AE ever reported. The results gathered from 678 patients with BrS confirm those previously reported on the male prevalence (91.3%) and the mean age of AE between the fourth and fifth decades. The survey highlights 5 main findings: (1) the distribution of the age at AE occurrence in patients with BrS and the paucity of AE in the pediatric and elderly population (4.3% and 1.5%, respectively); (2) the absence of male predominance in pediatric and elderly patients; (3) an earlier age at onset of AE (by a mean of 6.7 years) in patients who presented with aborted CA, compared with those who experienced an AE documented after prophylactic ICD implantation; (4) a later presentation (by a mean of 6.5 years) of first AE in female adults; and (5) no difference between the age at onset of AE in white and Asian patients.
Age at First AE in BrS
Information on the age of onset of AE in BrS is limited to relatively small series mainly involving CA survivors. FINGER—the largest European multicenter study—included 62 CA survivors.5 The age of patients at AE ranged from 35 to 54 (mean, 43) years; however, this study did not include patients aged <16 years. Makarawate et al3 from Thailand reported 65 patients with aborted CA aged 44.2±8.8 years. Kawata et al6 reported on 49 patients with BrS and ventricular fibrillation from 2 Japanese institutes; the age of patients at AE ranged from 22 to 73 (mean, 46±13) years. In a Japanese multicenter study involving 33 patients, ventricular fibrillation occurred at a mean age of 49±14 years.7 The report of the 20-year experience of the Pedro Brugada group by Conte et al8 identified 25 CA survivors with a mean age of 39.5±15.6 years (range, 6 days to 61 years) at the time of CA. The results of SABRUS in a large cohort of patients with AE documented during aborted CA or after prophylactic ICD implantation that were obtained from 23 centers (21 of them with no age limitation at recruitment) revealed a wide range of ages from 0.27 to 84 years. The vast majority (94.2%) of AEs occurred between 16 and 70 years of age, whereas AEs were rare (4.3%) in patients aged <16 years and even more so (1.5%) in those aged >70 years. The latter 2 findings are consistent with the paucity of publications dealing with these 2 patient populations.9–12
SABRUS showed that 98.9% of men and 94.9% of women exhibited their AE at ≤70 years of age. Sarkozy et al14 excluded patients aged >65 years in their assessment of the possible predictive role of familial SCD in future AE. The present study suggests that a positive family history of SCD might still be clinically relevant up to 70 years of age in the affected family member although the risk of AE resulting from coronary heart disease is higher in this patient population.
Age of AE and the Mode of AE Documentation
In SABRUS, most (62.8%) patients exhibited their initial AE at the time of their CA without an ICD (group A), whereas the remainder (37.2%) experienced their AE after prophylactic ICD implantation (group B). In group A, the AE occurred 6.5 years earlier. This confirms previous results by Priori et al15,16 who also found a significant age difference (14 years) between patients presenting with aborted CA (33±13 years)15 compared with those who had AE documented after prophylactic ICD implantation (47±12 years).16
More importantly, our results showed an inverse relationship over time between the number of AEs presenting as aborted CA and the number documented by appropriate ICD therapy, with a 1:1 ratio achieved in the 38- to 48-year age group. These findings may suggest a more malignant character of AEs that strikes patients at a younger age in group A.
Age of AE and Sex Distribution
Previous studies have shown a male predominance of patients experiencing AEs in Western countries (64%–94%),5,8,17 which is further exaggerated in southeastern Asian countries (94%–100%).3,4,6,7 The electrophysiological mechanism underlying this male predominance and the role of testosterone in the development of Brugada ECG pattern and ventricular fibrillation have been studied previously.18–20 Also, steroid hormone-responsive elements, particularly sensitive to testosterone in genes involved in BrS, such as SCN5A (which encodes the cardiac sodium channel) and CACNA1C (which encodes the L-type calcium channel), have been identified.21 The SABRUS cohort also showed a strong male predominance (91.3%). However, this predominance disappeared in 2 age groups: (1) the pediatric group (<16 years) and (2) the group aged >49 years (Figure 3A). These data raise the possible involvement of female hormones, such as estrogens. Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels and in terms of estrogenic activity. In contrast, its level is lowest in the pediatric population and after menopause. Song et al22 showed that estrogen may regulate the expression of Ito channels by diminishing the transcription of Kv4.3. This protective nature of a smaller Ito density in the right ventricular epicardium of women may decrease the propensity for arrhythmias although this is still debated. One may speculate, however, that in the setting of low estrogenic activity in the pediatric population and after menopause, the propensity for arrhythmias increases. In addition, adult women exhibited their AE much later than men, which might also be explained, in part, by the relative protective effect of estradiol.
Age of AE and Ethnicity
A similar age at first AE was observed in white and Asian patients in our survey. In Southeast Asia, there is an endemic syndrome of sudden unexpected nocturnal death occurring in young and middle-aged male patients that has been assumed to be mainly caused by BrS.23–28 However, the vast majority of decedents in Asians with sudden unexpected nocturnal death are aged 20 to 40 years,29 that is, much younger than the Asian patients’ age at onset of AE in SABRUS (42.3±14.9 years). Furthermore, a series of 50 British autopsy-negative sudden deaths (in the setting of sudden arrhythmic death syndrome) of mainly white origin (Elijah Behr, MD, Personal Communication, 2016) and with a familial diagnosis of BrS demonstrated a mean age at death of 29.1±10.6 years.30 A possible explanation for the difference in age at AE between sudden unexpected nocturnal death and sudden arrhythmic death syndrome patients and those of our survey could be that these 2 patient populations are a different part of the disease spectrum, failing to survive CA or being less likely to present with prior warning symptoms than SABRUS cases.
Interestingly, we found a significant difference of age at onset of AE between Japan, Taiwan, and South Korea versus China. Because the Chinese cohort was small, this point should be interpreted with caution. However, it is possible that this difference could be related to genetic variation between these countries28 and represent the spectrum of the disease in Asian countries. Another important aspect of ethnicity is found in the extreme age groups of SABRUS, which comprised little if any Asian patients (Figure 4A). The reason for this finding is unclear.
BrS Registry and Estimated AE Rate
Data provided from 22 main SABRUS centers allowed to establish a registry of 6441 patients that comprises ≈6-fold and 12-fold more patients than the FINGER5 and the Pedro Brugada31 registries, respectively, which are the largest available BrS registries to date. A male predominance (73.3%) was found that was similar to that observed in FINGER (72%)5 but higher to that of the Pedro Brugada group (58%).31 In addition, men had a peak age at diagnosis in the 38- to 48-year age group, whereas women were diagnosed later in the 49- to 59-year age group, in agreement with the FINGER results,5 showing median ages of 45 and 49 years for men and women, respectively (P=0.03). Of note, our registry included 4.6% of pediatric patients as opposed to FINGER that did not include any patients aged <16 years. In addition, the proportion of probands in our survey (79.9%) was similar to that found in FINGER (78%),5 whereas nonprobands predominated in the Pedro Brugada series (67%) assumedly because of an exhaustive familial screening program established at their institution.31
The estimated AE rates obtained from 22 centers that provided registry data deserve further discussion. The estimated mean AE rate for the entire cohort was 7.1%. However, a lower rate (3.9%) was found in the elderly population (P=0.088)—a finding that is consistent with the paucity of AEs found in the SABRUS population as well (Figure 1A). Interestingly, the pediatric group had an estimated AE rate (8%) similar to adult patients suggesting that although BrS is rarely diagnosed in the pediatric population, the arrhythmic risk is not negligible once the diagnosis of BrS is made. However, we cannot exclude that this result could merely be because of detection bias. In addition, our analysis of the estimated total AE rate after excluding pediatric patients showed a figure (7.75%) similar to that of the FINGER registry (6%), which did not include pediatric patients. Finally, it confirmed the considerable higher arrhythmic risk in men as compared with women and in Asians as compared with whites.
Clinical Relevance
The results of SABRUS highlight 2 special populations:
Pediatric Population
Because the vast majority of our pediatric population presented with aborted CA (86%) and were probands (74% of patients with known proband status), prevention of SCD seems to be a difficult task in children, especially in whites who constituted the vast majority of this age group. In addition, the ideal timing of screening asymptomatic first-degree relatives of patients with BrS is unknown. Taking into account the marked increase of AE rate in patients aged 16 to 26 years (9.7%) compared with that in patients <16 years (4.3%) observed in our survey, it would seem advisable to recommend screening before the age of 16 years. However, performing ECG screening and provocative drug testing during childhood has been shown to carry a low yield for predicting future AEs9,10 and has been associated with serious complications in some patients.9 In addition, Conte et al32 found that in 23% of children (aged 11.4±2.5 years) with a negative Ajmaline challenge test, BrS will be unmasked when the test is repeated several years later (age, 20.9±4.2 years). Therefore, in asymptomatic patients with periodical normal ECG, adopting a cutoff of 16 years for sodium channel blocker challenge would seem reasonable and in agreement with the cutoff of 15 years suggested previously by Andorin et al.10 This does not preclude periodical ECG and clinical assessment in the under-16 group and careful genetic counseling of the parents if a clear pathogenic variant is present in a family member.9,10
Elderly Population
At present, there are no guidelines for an age limit at which ICD should not be replaced on battery depletion except for patients with terminal illnesses and projected life expectancy ≤6 months. Thus, ICD should be theoretically replaced until patient’s natural death. The results of SABRUS showing the extreme rarity of AE in patients with BrS after the age of 70 years (especially those of Asian ethnicity), along with the relatively low estimated AE rate in the elderly population, would support careful consideration and discussion of withholding ICD replacement for those patients who have received a prophylactic ICD and reached the age of 70 years without having AE.
Study Limitations
This is not a multicenter prospective study but rather a retrospective cumulative analysis of results from the largest electrophysiology centers that have experience with BrS. Despite our repeated efforts, we could not recruit more centers from other Asian countries (such as from Thailand). Nevertheless, it is noteworthy that the number of patients provided per Asian center was much higher than that provided per center from Western countries. We cannot exclude that the low reported AE rate in the pediatric and the elderly population may be related, in part, to misdiagnosis of the pathogenesis of the AE at these ages.
Conclusions
SABRUS is a retrospective analysis of multicenter data from 23 well-recognized centers in the management of BrS worldwide. This survey confirms the male predominance and the peak age of AE at the early fourth decade of life. It also presents for the first time the age distribution of AE in BrS, suggesting 2 age cutoffs (16 and 70 years) that may be important for decision-making. Finally, it allows an analysis of the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age of onset of AE in a large BrS population. Hopefully this will ultimately result in both a significant decrease in SCD rate of patients with BrS and in a decrease of the number of unnecessarily treated patients.
Acknowledgments
We thank Jaime Hernandez, MD (Hospital Clínic de Barcelona, Spain); Sergi Cesar, MD (Hospital Sant Joan de Déu, Spain); Giuseppe Allocca, MD (Hospital of Conegliano, Italy); Camilla Helene Bang Jespersen, MD (Copenhagen University Hospital, Denmark); and Rami Fogelman, MD (Schneider Medical Center, Israel) for their cooperation in collecting the data.
Disclosures
None.
Footnotes
References
- 1.
Mizusawa Y, Wilde AA . Brugada syndrome.Circ Arrhythm Electrophysiol. 2012; 5:606–616. doi: 10.1161/CIRCEP.111.964577.LinkGoogle Scholar - 2.
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde AA . Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.Circulation. 2005; 111:659–670.LinkGoogle Scholar - 3.
Makarawate P, Chaosuwannakit N, Vannaprasaht S, Tassaneeyakul W, Sawanyawisuth K . Clinical characteristics and treatment outcomes of patients with Brugada syndrome in northeastern Thailand.Singapore Med J. 2014; 55:217–220.CrossrefMedlineGoogle Scholar - 4.
Kim JY, Kim SH, Kim SS, Lee KH, Park HW, Cho JG, Uhm JS, Joung B, Pak HN, Lee MH, Park SJ, On YK, Kim JS, Lim HE, Shim J, Choi JI, Park SW, Kim YH, Lee WS, Kim J, Nam GB, Choi KJ, Kim YH, Oh YS, Lee MY, Rho TH . Benefit of implantable cardioverter-defibrillator therapy after generator replacement in patients with Brugada syndrome.Int J Cardiol. 2015; 187:340–344. doi: 10.1016/j.ijcard.2015.03.262.CrossrefMedlineGoogle Scholar - 5.
Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty D, Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre M, Mabo P, Le Marec H, Wolpert C, Wilde AA . Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada syndrome registry.Circulation. 2010; 121:635–643. doi: 10.1161/CIRCULATIONAHA.109.887026.LinkGoogle Scholar - 6.
Kawata H, Morita H, Yamada Y, Noda T, Satomi K, Aiba T, Isobe M, Nagase S, Nakamura K, Fukushima Kusano K, Ito H, Kamakura S, Shimizu W . Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: a novel risk factor for Brugada syndrome with ventricular fibrillation.Heart Rhythm. 2013; 10:1161–1168. doi: 10.1016/j.hrthm.2013.04.009.CrossrefMedlineGoogle Scholar - 7.
Takagi M, Yokoyama Y, Aonuma K, Aihara N, Hiraoka M ; Japan Idiopathic Ventricular Fibrillation Study (J-IVFS) Investigators. Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with brugada syndrome: multicenter study in Japan.J Cardiovasc Electrophysiol. 2007; 18:1244–1251. doi: 10.1111/j.1540-8167.2007.00971.x.CrossrefMedlineGoogle Scholar - 8.
Conte G, Sieira J, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, Di Giovanni G, La Meir M, Wellens F, Czapla J, Wauters K, Levinstein M, Saitoh Y, Irfan G, Julià J, Pappaert G, Brugada P . Implantable cardioverter-defibrillator therapy in Brugada syndrome: a 20-year single-center experience.J Am Coll Cardiol. 2015; 65:879–888. doi: 10.1016/j.jacc.2014.12.031.CrossrefMedlineGoogle Scholar - 9.
Conte G, Dewals W, Sieira J, de Asmundis C, Ciconte G, Chierchia GB, Di Giovanni G, Baltogiannis G, Saitoh Y, Levinstein M, La Meir M, Wellens F, Pappaert G, Brugada P . Drug-induced Brugada syndrome in children: clinical features, device-based management, and long-term follow-up.J Am Coll Cardiol. 2014; 63:2272–2279. doi: 10.1016/j.jacc.2014.02.574.CrossrefMedlineGoogle Scholar - 10.
Andorin A, Behr ER, Denjoy I, Crotti L, Dagradi F, Jesel L, Sacher F, Petit B, Mabo P, Maltret A, Wong LC, Degand B, Bertaux G, Maury P, Dulac Y, Delasalle B, Gourraud JB, Babuty D, Blom NA, Schwartz PJ, Wilde AA, Probst V . Impact of clinical and genetic findings on the management of young patients with Brugada syndrome.Heart Rhythm. 2016; 13:1274–1282. doi: 10.1016/j.hrthm.2016.02.013.CrossrefMedlineGoogle Scholar - 11.
Conte G, DE Asmundis C, Sieira J, Levinstein M, Chierchia GB, DI Giovanni G, Baltogiannis G, Ciconte G, Saitoh Y, Casado-Arroyo R, Pappaert G, Brugada P . Clinical characteristics, management, and prognosis of elderly patients with Brugada syndrome.J Cardiovasc Electrophysiol. 2014; 25:514–519. doi: 10.1111/jce.12359.CrossrefMedlineGoogle Scholar - 12.
Kamakura T, Wada M, Nakajima I, Ishibashi K, Miyamoto K, Okamura H, Noda T, Aiba T, Takaki H, Yasuda S, Ogawa H, Shimizu W, Makiyama T, Kimura T, Kamakura S, Kusano K . Evaluation of the necessity for cardioverter-defibrillator implantation in elderly patients with Brugada syndrome.Circ Arrhythm Electrophysiol. 2015; 8:785–791. doi: 10.1161/CIRCEP.114.002705.LinkGoogle Scholar - 13.
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; 20:1391–1396.CrossrefMedlineGoogle Scholar - 14.
Sarkozy A, Sorgente A, Boussy T, Casado R, Paparella G, Capulzini L, Chierchia GB, Yazaki Y, De Asmundis C, Coomans D, Brugada J, Brugada P . The value of a family history of sudden death in patients with diagnostic type I Brugada ECG pattern.Eur Heart J. 2011; 32:2153–2160. doi: 10.1093/eurheartj/ehr129.CrossrefMedlineGoogle Scholar - 15.
Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J . Natural history of Brugada syndrome: insights for risk stratification and management.Circulation. 2002; 105:1342–1347.CrossrefMedlineGoogle Scholar - 16.
Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M . Risk stratification in Brugada syndrome: results of the PRELUDE (Programmed Electrical Stimulation Predictive Value) registry.J Am Coll Cardiol. 2012; 59:37–45. doi: 10.1016/j.jacc.2011.08.064.CrossrefMedlineGoogle Scholar - 17.
Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y, Marquie C, Rosa A, Diallo A, Cassagneau R, Loizeau C, Martins R, Field ME, Derval N, Miyazaki S, Denis A, Nogami A, Ritter P, Gourraud JB, Ploux S, Rollin A, Zemmoura A, Lamaison D, Bordachar P, Pierre B, Jaïs P, Pasquié JL, Hocini M, Legal F, Defaye P, Boveda S, Iesaka Y, Mabo P, Haïssaguerre M . Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2.Circulation. 2013; 128:1739–1747. doi: 10.1161/CIRCULATIONAHA.113.001941.LinkGoogle Scholar - 18.
Di Diego JM, Cordeiro JM, Goodrow RJ, Fish JM, Zygmunt AC, Pérez GJ, Scornik FS, Antzelevitch C . Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males.Circulation. 2002; 106:2004–2011.LinkGoogle Scholar - 19.
Shimizu W, Matsuo K, Kokubo Y, Satomi K, Kurita T, Noda T, Nagaya N, Suyama K, Aihara N, Kamakura S, Inamoto N, Akahoshi M, Tomoike H . Sex hormone and gender difference–role of testosterone on male predominance in Brugada syndrome.J Cardiovasc Electrophysiol. 2007; 18:415–421. doi: 10.1111/j.1540-8167.2006.00743.x.CrossrefMedlineGoogle Scholar - 20.
Ezaki K, Nakagawa M, Taniguchi Y, Nagano Y, Teshima Y, Yufu K, Takahashi N, Nomura T, Satoh F, Mimata H, Saikawa T . Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone.Circ J. 2010; 74:2448–2454.CrossrefMedlineGoogle Scholar - 21.
James AF, Choisy SC, Hancox JC . Recent advances in understanding sex differences in cardiac repolarization.Prog Biophys Mol Biol. 2007; 94:265–319. doi: 10.1016/j.pbiomolbio.2005.05.010.CrossrefMedlineGoogle Scholar - 22.
Song M, Helguera G, Eghbali M, Zhu N, Zarei MM, Olcese R, Toro L, Stefani E . Remodeling of Kv4.3 potassium channel gene expression under the control of sex hormones.J Biol Chem. 2001; 276:31883–31890. doi: 10.1074/jbc.M101058200.CrossrefMedlineGoogle Scholar - 23.
Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, Tunsanga K, Kuasirikul S, Malasit P, Tansupasawadikul S, Tatsanavivat P . Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men.Circulation. 1997; 96:2595–2600.CrossrefMedlineGoogle Scholar - 24.
Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA . Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.Hum Mol Genet. 2002; 11:337–345.CrossrefMedlineGoogle Scholar - 25.
Shin DJ, Jang Y, Park HY, Lee JE, Yang K, Kim E, Bae Y, Kim J, Kim J, Kim SS, Lee MH, Chahine M, Yoon SK . Genetic analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome.J Hum Genet. 2004; 49:573–578. doi: 10.1007/s10038-004-0182-z.CrossrefMedlineGoogle Scholar - 26.
Cheng J, Makielski JC, Yuan P, Shi N, Zhou F, Ye B, Tan BH, Kroboth S . Sudden unexplained nocturnal death syndrome in Southern China: an epidemiological survey and SCN5A gene screening.Am J Forensic Med Pathol. 2011; 32:359–363. doi: 10.1097/PAF.0b013e3181d03d02.CrossrefMedlineGoogle Scholar - 27.
Liu C, Tester DJ, Hou Y, Wang W, Lv G, Ackerman MJ, Makielski JC, Cheng J . Is sudden unexplained nocturnal death syndrome in Southern China a cardiac sodium channel dysfunction disorder?Forensic Sci Int. 2014; 236:38–45. doi: 10.1016/j.forsciint.2013.12.033.CrossrefMedlineGoogle Scholar - 28.
Zheng J, Zhou F, Su T, Huang L, Wu Y, Yin K, Wu Q, Tang S, Makielski JC, Cheng J . The biophysical characterization of the first SCN5A mutation R1512W identified in Chinese sudden unexplained nocturnal death syndrome.Medicine (Baltimore). 2016; 95:e3836. doi: 10.1097/MD.0000000000003836.CrossrefMedlineGoogle Scholar - 29.
Gaw AC, Lee B, Gervacio-Domingo G, Antzelevitch C, Divinagracia R, Jocano F . Unraveling the enigma of bangungut: is sudden unexplained nocturnal death syndrome (SUNDS) in the Philippines a disease allelic to the Brugada syndrome?Philipp J Intern Med. 2011; 49:165–176.MedlineGoogle Scholar - 30.
Raju H, Papadakis M, Govindan M, Bastiaenen R, Chandra N, O’Sullivan A, Baines G, Sharma S, Behr ER . 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; 57:2340–2345. doi: 10.1016/j.jacc.2010.11.067.CrossrefMedlineGoogle Scholar - 31.
Sieira J, Conte G, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, Di Giovanni G, Saitoh Y, Irfan G, Casado-Arroyo R, Juliá J, La Meir M, Wellens F, Wauters K, Pappaert G, Brugada P . Clinical characterisation and long-term prognosis of women with Brugada syndrome.Heart. 2016; 102:452–458. doi: 10.1136/heartjnl-2015-308556.CrossrefMedlineGoogle Scholar - 32.
Conte G, de Asmundis C, Ciconte G, Julià J, Sieira J, Chierchia GB, Brugada P . Follow-up from childhood to adulthood of individuals with family history of Brugada syndrome and normal electrocardiograms.JAMA. 2014; 312:2039–2041. doi: 10.1001/jama.2014.13752.CrossrefMedlineGoogle Scholar
