Does the Age of Sudden Cardiac Death in Family Members Matter in Brugada Syndrome?

Abstract

Background

Brugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden cardiac death (SCD) as a risk predictor of MAE remains controversial. We aimed to examine the association between family history of SCD and MAEs stratified by age of SCD with a systematic review and meta‐analysis.

Methods and Results

We searched the databases of MEDLINE and EMBASE from January 1992 to January 2020. Data from each study were combined using the random‐effects model. Fitted metaregression was performed to evaluate the association between the age of SCD in families and the risk of MAE. Twenty‐two studies from 2004 to 2019 were included in this meta‐analysis involving 3386 patients with Brugada syndrome. The overall family history of SCD was not associated with increased risk of MAE in Brugada syndrome (pooled odds ratio [OR], 1.11; 95% CI, 0.82–1.51; P=0.489, I²=45.0%). However, a history of SCD in family members of age younger than 40 years of age did increase the risk of MAE by ≈2‐fold (pooled OR, 2.03; 95% CI, 1.11–3.73; P=0.022, I²=0.0%). When stratified by the age of cut point at 50, 45, 40, and 35 years old, a history of SCD in younger family member was significantly associated with a higher risk of MAE (pooled OR, 0.49, 1.30, 1.51, and 2.97, respectively; P=0.046).

Conclusions

A history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE.

Nonstandard Abbreviations and Acronyms

BrS

Brugada syndrome

MAE

major arrhythmic event

SCA

sudden cardiac arrest

SCD

sudden cardiac death

Clinical Perspective

What Is New?

• A history of sudden cardiac death among family members of age younger than 40 years was associated with a higher risk of major arrhythmic event.

• A mere presence of a family history of sudden cardiac death without a clear age definition is not a risk predictor in Brugada syndrome.

What Are the Clinical Implications?

• We propose that a family history of sudden cardiac death in the young could be a prognostic factor to predict major arrhythmic event in patients with Brugada syndrome.

Brugada syndrome (BrS) is a heterogeneous genetic ion channel disorder that is associated with an increased risk of major arrhythmic events (MAE) and sudden cardiac death (SCD).¹ Brugada syndrome is characterized by coved‐type (Type‐1) ST elevation appearances in the right precordial leads.¹, ² The prevalence of patients with a Brugada ECG Type‐1 pattern varies among different populations, ranging from 0% to 0.4%.¹, ³ The most common mutation responsible for BrS is the SCN5A mutation, which is present in 20% to 30% of patients and has an autosomal dominant inheritance pattern.⁴ Several studies have demonstrated the importance of a family history of SCD in characterizing the disease and prognosis.² However, data from other studies report conflicting results and suggest that a family history of SCD is not useful as a risk stratification tool.⁵, ⁶, ⁷, ⁸ Risk stratification for ventricular arrhythmias and increased risk of SCD remains challenging in asymptomatic patients with Brugada syndrome. In this study, we aimed to assess whether a family history of SCD is associated with an increased risk of MAE in patients with BrS by performing a systematic review and meta‐analysis.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Search Strategy

Two investigators (C.K. and W.V.) independently searched for published studies indexed in MEDLINE and EMBASE databases from inception to January 2020 using a search strategy as described in Data S1. Only full articles in English were included. A manual search for additional pertinent studies and review articles using references from retrieved articles was also completed.

Inclusion Criteria

The eligibility criteria included the following:

1. Cohort, case‐control, or cross‐sectional studies reporting end points of MAE in patients with BrS with and without a family history of SCD or MAE.

2. The calculation by the studies of odds ratios (OR) or hazard ratios with 95% CI, or the presence of sufficient raw data for manual calculation. Patients without a family history of SCD were used as controls. The risk ratio and hazard ratio were converted to OR by previously reported principal equations.⁹

Study eligibility was independently determined by 2 investigators (A.S. and N.K.), and differences were resolved by mutual consensus. In case of an overlap or duplication between populations among studies, the study with largest sample size and clear age of cut point definition from each representative population was selected, whereas the rest of the overlap or duplicated populations were excluded. If the identity of the declared participating institutions was unclear, the corresponding author of each study was contacted. The Newcastle‐Ottawa quality assessment scale was used to assess each study's quality.¹⁰ This study complies with the Meta‐analysis of Observational Studies in Epidemiology reporting guideline¹¹ (Table S1).

Data Extraction

A standardized data collection form was used to obtain the information. Two investigators (J.K. and C.K.) independently performed this data extraction process to ensure accurate data extraction. Any data discrepancy was resolved by referring back to the original articles.

Definition

Family History

Positive family history was defined as at least 1 first‐ or second‐degree relative who had sudden unexplained death, sudden cardiac death (SCD), or sudden cardiac arrest or as defined in each study (Table).¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹

Table 1.

Summary Characteristics of Individual Included in Studies of Patients With BrS

Study/Year	Study Design	N	Major Arrhythmic Events	Country	Centers (N)	Men (%)	Mean Age±SD (y)	Symptomatic BrS (%)	Follow‐Up (mo)	Analysis Model	Positive Family History (%)	Positive SCN5A (% [N])	Definition of Family History	Outcomes
Daoulah et al, 201212	Retrospective cohort	25	6	Kingdom of Saudi Arabia, United Arab Emirates, Oman, Bahrain, and Kuwait	6	100%	28±7	80%	41.2±17.6	Univariate	32%	NA	SCD in a family member older than 45 y old	Appropriate ICD discharge, SCA
Deliniere et al, 201913	Retrospective cohort	80	28	France, Switzerland, Romania	13	91%	45.1±12.8	36%	12	Univariate	18%	9% [57]	SCD in a family member younger than 50 y old in the first or second degree relatives	VF, SCA
Garcia‐Iglesias et al, 201914	Prospective cohort	155	14	Spain, Mexico, India	6	70%	41.0±14.7	40%	55.8±39.4	Multivariate	47%	NA	SCD in a family member younger than 45 y old	VF, appropriate ICD discharge, SCA
Gray et al, 201715	Prospective cohort	54	18	Australia	4	81%	44±13	26%	27.6±30	Univariate	20%	20% [54]	SCD or SCA in a family member younger than 45 y old	Sustained VT, SCA
Huang et al, 200916	Prospective cohort	43	7	China	7	56%	45.2±10.8	55.8%	32.2±8.6	Multivariate	NA	12% [43]	SCD in a family member younger than 45 y old	Sustained VT, VF, SCD
Juang et al, 201517	Case‐control	14	5	Taiwan	2	100%	40±13	100%	NA	Univariate	10%	100%	SCD in a family member younger than 45 y old	Sustained VT, VF, SCD
Kharazi et al, 200718	Prospective Cohort	11	2	Iran	1	92%	46.5±11.8	83%	27.83±11.25	Univariate	16%	NA	Family history of SCD	Sustained VT, VF, appropriate ICD discharge
Leong et al, 201919	Prospective cohort	133	10	United Kingdom	2	61%	45±15	53%	42±25	Univariate	33%	NA	SCD in a family member younger than 40 y old	Sustained VT, VF, appropriate ICD discharge, SCA
Letsas et al, 201920	Prospective cohort	111	7	Greece and United States	9	77%	45.3±13.3	33%	54±42	Univariate	6.3%	NA	SCD in a family member younger than 45 y old	Sustained VT, VF, appropriate ICD discharge
Makarawate et al, 201721	Prospective cohort	40	14	Thailand	2	96%	43.5±12.7	100%	28.3±11.3	Multivariate	35%	23% [40]	SCD or SCA in a family member younger than 45 y old	Appropriate ICD discharge
Migliore et al, 201922	Prospective cohort	272	17	Italy	2	82%	43±12	30%	85±55	Univariate	27%	NA	SCD in a family member younger than 40 y old in male and 50 y old in female*	Sustained VT, VF, appropriate ICD discharge
Mok et al, 200423	Retrospective cohort	50	26	China	7	94%	41±12	40%	25.8±10.5	Univariate	14%	14% [36]	Family history of SCD	SCD
Nagase et al, 201824	Retrospective cohort	209	8	Japan	1	96%	45±14	38%	56±48	Univariate	17%	18% [93]	SCD in a family member younger than 45 y	VF
Oaili et al, 201125	Prospective cohort	24	1	Tunisia	4	92%	40.8±13.7	21%	26±21	Univariate	46%	NA	Family history of SCD	Sustained VT, VF, appropriate ICD discharge, SCD
Ohkubo et al, 200726	Prospective cohort	34	1	Japan	1	97%	52±13	32%	47.1±33.7	Univariate	9%	NA	Family history of SCD	SCD
Pappone et al, 201827	Case‐control	191	88	Italy	1	78%	40.3±11.2	45%	NA	Univariate	24%	18% [191]	Family history of SCD	Sustained VT
Probst et al, 20102	Prospective cohort	1017	43	France, Italy, Netherlands	13	72%	45±5.7	36%	33.3±12.0	Univariate	26%	28% [850]	SCD in a family member younger than 45 y	Appropriate ICD discharge, SCD
Rivard et al, 201628	Retrospective cohort	105	16	Canada	3	79%	46.2±13.3	44.7%	59.6±16.4	Univariate	26.7%	20.6% [63]	Family history of SCD	Appropriate ICD discharge, SCD
Sieira et al, 201729	Prospective cohort	400	20	Belgium	1	58%	41.1±17.8	32%	80.7±57.2	Univariate	46%	26% [53]	SCD in a family member younger than 35 y	Sustained VT, VF, appropriate ICD discharge, SCD
Son et al, 201430	Prospective cohort	69	38	Korea	5	98%	46.2±13.5	80%	59±46	Multivariate	19%	NA	Family history of SCD	Appropriate ICD discharge
Subramanian et al, 201931	Prospective cohort	103	13	India	2	86%	47.8±7.2	12%	85.3	Univariate	32%	NA	Family history of SCD	Sustained VT, VF, appropriate ICD discharge
Tokioka et al, 20148	Retrospective cohort	246	24	Japan	1	96%	47.6±13.6	21.6%	47.6±13.6	Univariate	28%	14% [123]	SCD in a family member younger than 45 y	VF, SCD

BrS indicates Brugada syndrome; ICD, implantable cardioverter defibrillator;NA, not applicable; SCA, sudden cardiac arrest; SCD, sudden cardiac death; VF, ventricular fibrillation; and VT, ventricular tachycardia.

^*Migliore et al, 2019 was included in age‐stratified analysis as <40‐years‐old group because of male predominance in BrS.

Brugada Syndrome

BrS was diagnosed according to recently published guidelines.¹ Only studies evaluating a type‐1 Brugada pattern were included in this meta‐analysis.

End Point: Major Arrhythmic Event

Major arrhythmic events were defined by either of SCD, sudden cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia, or appropriate implantable cardioverter defibrillator discharge. Nonsustained ventricular tachycardia and inappropriate implantable cardioverter defibrillator discharge were not considered as end points of interest.

Statistical Analysis

Meta‐Analysis

We performed a meta‐analysis of the included studies using a random‐effects model using the generic inverse‐variance method of Der Simonian and Laird.³² The event rate was pooled using variance‐stabilizing arcsine transformation method of Freeman‐Tukey.³³ The heterogeneity of effect size estimates across these studies was quantified using the I² statistic (I²<25%, low; I²=25–50%, moderate; and I²>50%, substantial).³⁴ Subgroup analyses and metaregression were performed if the heterogeneity was moderate or substantial to explore the source of heterogeneity.³⁴, ³⁵ Publication bias was assessed using a funnel plot and the Egger's regression test.³⁶ A P value of <0.05 was considered significant. All data analyses were performed using the STATA SE version 14.2.

Sensitivity Analysis

A sensitivity analysis was performed to assess the influence of the individual studies on the overall results by omitting 1 study at a time, as described by Patsopoulos et al, to examine whether overall estimates were influenced by the substantial heterogeneity observed.³⁷

Subgroup Analysis

The subgroup analysis was performed in a family history of younger than 40 and 45 years old SCD, family history of SCD in spontaneous Type‐1 population, analysis type (univariate versus multivariate), and ethnicity. The subgroup analysis was also performed to explore the source of heterogeneity (moderate or substantial) in analysis type (univariate versus multivariate) and ethnicity (White and Asian) in overall analysis as well as studies with a family history of younger than 45 years old SCD.

Metaregression

Fitted random‐effects model with truncated Knapp–Hartung method metaregression was performed to evaluate the association between the age of cut point of SCD in family members in each study and the risk of MAE (OR of each study). The metaregression was also performed to explore the source of heterogeneity.

Results

Search Results

Our search strategy yielded 821 potentially relevant articles (223 articles from EMBASE and 598 articles from MEDLINE). After the exclusion of duplicate articles, 693 articles underwent title and abstract review. Following the review, 580 articles were excluded as they were not cohort, case‐control, or randomized controlled trials, were not conducted in patients with BrS, or had irrelevant titles and abstracts. 113 articles remained for a full‐length review. An additional 47 studies were further excluded as they did not report data regarding family history of SCD. Additionally, they did not provide sufficient data to calculate hazard ratio (HR), risk ratio, or odds ratio (OR). Forty‐four studies were excluded because of a duplicated population. Therefore, a total of 22 studies were included in this meta‐analysis. Figure 1

Figure 1. Search methodology and selection process.

BrS indicates Brugada syndrome; SCD, sudden cardiac death; and VF, ventricular fibrillation.

outlines the search and literature review process.

Description of Included Studies

A total of 22 (20 cohorts and 2 case‐control) studies from 27 countries (95 studied centers) involving 3386 patients with BrS during the study period of 2004–2019 were included in our meta‐analysis.², ⁸, ³¹ The ages of cut point of SCD among family members in different studies were >45 years old,¹² <50 years old,¹³ <45 years old,⁸, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ²⁰, ²¹, ²⁴, ²⁹ <40 years old,¹⁹, ²² and <35 years old.²⁹ a Nine studies did not report age of cut point of SCD among family members. The mean age was 43.9±12.2 years. Patients were predominantly men (77.3%), White (86.0%), and asymptomatic (63.5%). The mean follow‐up was 50.88±39.6 months. SCN5A was reported in 12 studies. A family history of SCD and SCN5A was positive in 23.6% and 21.0%, respectively.

Twelve studies were included in subgroup analysis of a history of younger than 45 years old SCD in the family involving 2694 patients with BrS.², ²⁹ The mean age was 44.0±12.2 years. Patients were predominantly men (80.0%), White (86.7%), and asymptomatic (62.2%). The mean follow‐up was 51.3±40.6 months. A family history of SCD and SCN5A was positive in 21.6% and 21.9%, respectively. A summary of study characteristics is shown in Table.

Three studies were included in subgroup analysis in cohorts with history of SCD among family members of age younger than 40 years involving 805 patients BrS.¹⁹, ²², ²⁹ The mean age was 42.4±15.6 years. Patients were predominantly men (66.6%), White (100%), and asymptomatic (65.2%). The mean follow‐up was 75.8±54.5 months. Family history of SCD and SCN5A were positive in 37.4% and 26.0%, respectively. A summary of study characteristics is shown in Table.

Quality Assessment of Included Studies

The Newcastle‐Ottawa quality assessment scale scores of included studies are described in Table S2. The scale uses a star system (0–9) to evaluate included studies on 3 domains: selection, comparability, and outcomes. Higher scores represent a higher study quality (8–9: high, 6–7: moderate, and 0–5: low). Two studies were categorized as moderate quality,¹⁷, ¹⁸ whereas the remainder of the studies were categorized as high quality.

Meta‐Analysis Results

Family History of Sudden Cardiac Death on Major Arrhythmic Event

In the overall analysis, a family history of SCD was not significantly associated with increased risk of MAE in patients with BrS (pooled OR, 1.11; 95% CI, 0.82–1.51; P=0.489). The statistical heterogeneity was moderate, with an I² of 46.1%. Eleven studies reported OR <1.0 (decreased risk of MAE) and the majority (7 of 11) did not report age of cut point or used age of cut point more than 45 years old. A forest plot of this meta‐analysis is shown in Figure 2. The subgroup analysis of a family history of SCD in spontaneous Type‐1 population was performed from 5 studies with 280 patients with BrS¹³, ¹⁷, ²⁴, ²⁵, ²⁶; this subgroup analysis increased the overall pooled OR by 9% (pooled OR, 1.20; 95% CI, 0.45–3.18; I²=30.7%, P=0.716). The pooled event rate in patients with BrS with and without a family history of SCD were 16% (95% CI, 9–23%) and 15% (95% CI, 9–22%) respectively (Figures S1 and S2).

Figure 2. Forest plot demonstrating the association of family history of sudden cardiac death and major arrhythmic event in patients with Brugada syndrome.

OR indicates odds ratio.

Among the 12 studies that defined a family history of SCD <45 years of age (9 studies used 45 years old,², ⁸, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ²⁰, ²¹, ²⁴ 2 studies used 40 years old,¹⁹, ²² and 1 study used 35 years old²⁹ as ages of cut point), the majority (8 of 12) showed an increased risk of MAE (OR, >1.0)⁸, ¹⁵, ¹⁶, ¹⁷, ²⁰, ²¹, ²², ²⁹ (Figure 3); of the 8 studies, 3 studies¹⁵, ²⁰, ²⁹ showed the associations were statistically significant.

Figure 3. Forest plot demonstrating the association of family history of sudden cardiac death at age <45 and <40 years old and major arrhythmic event in patients with Brugada syndrome.

OR indicates odds ratio; and SCD, sudden cardiac death.

For the age‐specific analysis, a family history of younger than 45 years old SCD, from 12 studies with 2694 patients with BrS,², ²⁹ showed an increased risk of MAE by ≈45%, and although not statistically significant (pooled OR, 1.45; 95% CI, 0.98–2.13; P=0.060), there was substantial heterogeneity (I²=50.8). A family history of younger than 40 years old with SCD, from 3 studies with 807 patients with BrS,¹⁹, ²², ²⁹ was associated with an increased risk of MAE by ≈2‐fold (pooled OR, 2.03; 95% CI, 1.11–3.73; P=0.022) without heterogeneity (I²=0.0%). The forest plot of this meta‐analysis is shown in Figure 3.

The pooled event rate in patients with BrS with and without a family history of SCD younger than 45 years old was 15% (95% CI, 8–24%) and 9% (95% CI, 6–13%) respectively; whereas, SCD younger than 40 years old was 9% (95% CI, 5–15%) and 5% (95% CI, 3–7%) respectively (Figures S3 and S4).

When stratified by age of cut point, at 50, 45, 40, and 35 years old, the risk of MAE increased in association with decremented age of cut point of SCD in the family (pooled OR, 0.49; CI, 0.16–1.52; OR, 1.30; CI, 0.85–1.99; OR, 1.51; CI, 0.67–3.39; and OR, 2.97; CI, 1.19–7.44, respectively) (Figure 4). Metaregression of age cut point showed that a history of SCD in younger family members was significantly associated with a higher risk of MAE (P=0.046) (Figure 5). The bubble plot and fitted metaregression line are shown in Figure 5.

Figure 4. Forest plot demonstrating an increase in the major arrhythmic event odds ratio with decrementing age definition of sudden cardiac death in the family of Brugada syndrome patient.

OR indicates odds ratio; and SCD, sudden cardiac death.

Figure 5. The bubble plot and fitted metaregression line demonstrating a strong trend of the association between the increasing of major arrhythmic event odds ratio and decrementing of age definition of sudden cardiac death in the family of a patient with Brugada syndrome.

OR indicates odd ratio; and SCD, sudden cardiac death.

To examine the source of heterogeneity, subgroup analysis of analysis type (Figures S5 and S6) and ethnicity (Figures S7 and S8) were performed. There was substantial heterogeneity in univariate analysis and White population but no heterogeneity (I²=0) in multivariate analysis and Asian population; therefore, univariate analysis and White ethnicity were likely the sources of heterogeneity. Metaregression of the percentage of SCD at presentation, male sex, symptomatic patients, family history of SCD, positive SCN5A, ethnicity, mean age, and follow‐up duration showed no significant effect on the pooled results in both overall (Table S3) and younger than 45 years old (Table S4) analysis. However, mean age had significant effects of heterogeneity in the younger than 45 years old analysis (P=0.022).

Sensitivity Analysis

To assess the stability of the results of the meta‐analysis, we conducted a sensitivity analysis by excluding 1 study at a time. None of the results was significantly altered in the overall analysis (Figure S9). However, sensitivity analysis of younger than 45 years old showed that the results would become significant if Probst et al, García‐Iglesias et al, or Nagase et al², ¹⁴, ²⁴ were omitted (Figure S10A). Sensitivity analysis of younger than 40 years old also showed that the results would become nonsignificant if Migliore et al or Siera et al²², ²⁹ were omitted (Figure S10B). This is because of a lack of power of the analysis.

Publication Bias

To investigate potential publication bias, we examined the contour‐enhanced funnel plot of the included studies in assessing change in log OR of MAE and Egger's test.³⁸, ³⁹ No publication bias was observed on the funnel plots or Egger's test in overall analysis (P=0.190) and family history younger than 40 years old analysis (P=0.208). However, there was a significant small study effect in the family history of younger than 45 years old SCD (P=0.017). An asymmetric funnel plot was observed in a family history of younger than 45 years old SCD (Figures S11 through S13).

Discussion

The main finding from this meta‐analysis is that a history of SCD in family members younger than 40 years of age increased the risk of MAE by ≈2‐fold in patients with BrS. When stratified by age decrement, the history of SCD in younger family members showed a statistically significant difference with a higher risk of MAE in younger patients with BrS. However, a pooled analysis of the mere presence of family history of SCD without an age specificity in BrS was not associated with MAE.

Identifying prognostic factors of MAE in patients with BrS is essential in order to prevent undesirable outcomes. Few risk factors have been identified as predictors of MAE among patients with BrS. A family history of SCD is common among patients with BrS (27.5% from our pooled analysis). The prognostic significance of a family history of SCD has been reported in previous studies but remains inconclusive.², ⁶, ¹⁵, ¹⁸, ²⁹ Kamakura and colleagues reported that a family history of SCD increased the risk of MAE up to 5‐fold in a Japanese cohort.⁶ Siera and colleagues also reported similar findings with increased risk of MAE 3‐fold in Belgian patients.²⁹ However, a family history of SCD was not a significant prognostic factor in the FINGER (France, Italy, Netherlands, Germany) registry.²

Our meta‐analysis shows that pooled analysis of the mere presence of family history of SCD in BrS was not associated with MAE. However, we illustrated that a family history of SCD in members younger than 40 years was associated with MAE in BrS with statistical significance in the meta‐analysis (P=0.022) and a metaregression analysis showed that the history of SCD in younger family member was significantly associated with a higher risk of MAE (P=0.046). In the general population, the most common cause of SCD in adult >35 years old is coronary artery disease, especially in men.⁴⁰ It is plausible that the cause of SCD in age‐undifferentiated family cohorts is less BrS specific, that is, higher prevalence of ischemic or structural heart disease‐mediated SCD in older family members.

Eleven studies reported an OR <1.0 (family history of SCD decreased risk of MAE in BrS)^* and the majority (7 of 11) did not report an age of cut point or used age of cut point more than 45 years old.¹², ¹³, ¹⁸, ²³, ²⁷, ²⁸, ³¹ Similar to a large registry from Belgium, without a specific age of cut point, the HR was <1.0 (HR, 0.6; 95% CI, 0.3–1.3; P=0.20). On the contrary, in the same population, with a definition of a family history of SCD <35 years old, the presence of a family history of SCD was associated with a significant increase in the risk of MAE by 3‐fold in BrS (HR, 2.9; 95% CI, 1.2–7.0; P=0.02). Moreover, our study highlighted that a history of SCD in younger family members was significantly associated with a higher risk of MAE by a fitted linear metaregression model (Figure 5). These findings support our hypothesis that confounders such as ischemic or structural heart disease‐mediated SCD in older patients may have been introduced in studies without a clear delineation of age.

Siera et al ²⁹ used the lowest age of cut point of SCD in family member among the included studies (<35 years old). Interestingly, the mean age of the population included in this study was relatively low and the proportion of positive family history (46%) as well as proportion of positive SCN5A (26%) were relatively high when compared with other studies. These findings may suggest that SCN5A gene mutation may explain earlier and more severe manifestation of BrS similar to previous reports. However, the correlation between SCN5A positivity and the younger SCD in family member is not yet to be determined.

Earlier meta‐analyses by Wu and colleagues included 7 studies,⁴¹ and Gehi and colleagues included only 2 studies,⁴² compared with 22 studies in the current meta‐analysis. Both of the earlier studies did not stratify the family history by age, and metaregression was not performed. Sample size, power of meta‐analysis, and statistic methodology were significant limitations of the previous studies. Our study included more studies, pooled the risk of MAE according to the SCD age definition, and confirmed the association of stratified age of SCD in the family and MAE with fitted linear metaregression model. The larger sample size, regression validation methodology, and a more contemporary data set render our results with higher certainty. Furthermore, the majority of the included studies with a family history of SCD <45 years old (8 of 12)⁸, ¹⁵, ¹⁶, ¹⁷, ²⁰, ²¹, ²², ²⁹ and <40 years old²², ²⁹ (2 of 3) reported increased risk of MAE (OR>1), which supported our findings.

The 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on SCD prevention and 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society expert consensus stated that positive family history of SCD is not a significant predicting factor of SCD in BrS.¹, ⁴³ Additionally, the 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society expert consensus stated that defibrillator implantation in asymptomatic BrS is not indicated with a family history of SCD alone.¹ However, both guidelines did not specify an age cutoff because there was a lack of consistent data regarding the specific age of SCD in the family. Moreover, early sudden cardiac death in the family member was also included the composite score model to predict MAE in BrS. Our meta‐analysis is the first study to provide compelling evidence demonstrating a significant association between a family history of SCD in the young and MAE in BrS. We propose that a family history of SCD in the young in BrS could be considered as a prognostic factor to predict MAE in patients with BrS. Larger prospective cohort studies are needed to support our proposal.

Limitations

There are some inevitable discrepancies of end points definition among studies. There are substantial heterogeneities observed in this analysis owing to analysis types and ethnicity. The percentage of patients with a family history of SCD in our analysis is lower than previously reported in European registries. This is likely from lower SCD rates reported from the Asian studies included in the study. SCD is a largely heterogeneous condition, which is attributable to multiple etiologies, including coronary artery diseases, especially when SCD occurs in patients at older age. A large number studies were excluded because of insufficient data for analysis, which may have introduced publication and selection bias. Available data were not sufficient to perform subgroup analysis in asymptomatic patients and those who presented with SCD. Moreover, only 3 studies were included in the analysis in patients <40 years old and 1 in patients <35 years of age. Additional cohort studies are needed to explore the association between MAE and family history of SCD in the young in BrS.

Conclusions

Our study demonstrated that a history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE. A mere presence of a family history of SCD without a clear age definition is not a risk predictor in BrS. We propose that a family history of SCD in the young could be a prognostic factor to predict MAE in patients with BrS. Larger prospective cohort studies are needed to valid our observation.

Sources of Funding

This publication was supported and funded by Mayo Clinic Arizona Cardiovascular Clinical Research Center. We are thankful for their generous support. Contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the Mayo Clinic Arizona Cardiovascular Clinical Research Center.

Disclosures

None.

Supporting information

Data S1

Tables S1–S4

Figures S1–S13

(J Am Heart Assoc. 2021;10:e019788. DOI: 10.1161/JAHA.120.019788.)