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. 2019 Jul 29;24(6):e12676. doi: 10.1111/anec.12676

Atrial fibrillation and risk of major arrhythmic events in Brugada syndrome: A meta‐analysis

Jakrin Kewcharoen 1, Pattara Rattanawong 1,2,✉, Chanavuth Kanitsoraphan 1, Raktham Mekritthikrai 1, Narut Prasitlumkum 1, Prapaipan Putthapiban 3, Poemlarp Mekraksakit 4, Robert J Pattison 1, Wasawat Vutthikraivit 4
PMCID: PMC6931417  PMID: 31353765

Abstract

Background

Brugada syndrome (BrS) is a common cause of sudden cardiac death (SCD). There is recent evidence that atrial fibrillation (AF) is associated with increased risk of SCD in general population. However, whether AF increases a risk of major arrhythmic events (MAE) in patients with BrS is still unclear. We performed a systematic review and meta‐analysis to explore the effect of AF on MAE in BrS population.

Methods

We searched the databases of MEDLINE and EMBASE from inception to March 2019. Included studies were published cohort studies reporting rates of MAE (ventricular fibrillation, sustained ventricular tachycardia, SCD, or sudden cardiac arrest) in BrS patients, with and without previous documented AF. Data from each study were combined using the random‐effects model.

Results

Six studies from 1,703 patients were included. There was a significant association between AF and an increased risk of MAE in patients with BrS (pooled OR = 2.37, 95% CI = 1.36–4.13, p‐value = .002, I 2 = 40.3%).

Conclusions

Our meta‐analysis demonstrated that AF is associated with an increased risk of MAE in patients with BrS.

Keywords: atrial fibrillation, Brugada syndrome, sudden cardiac death, ventricular fibrillation, ventricular tachycardia

1. INTRODUCTION

Brugada syndrome (BrS) is a common cause of sudden cardiac death (SCD), most commonly found in South‐East Asia population at 3.7 per 1,000 and up to 17.7 per 1,000 in Thailand (Rattanawong et al., 2017; Vutthikraivit et al., 2018). This inherited disease was first described in 1992 and was found to be associated with several lethal arrhythmias, including ventricular fibrillation (VF), premature sudden arrhythmic death syndrome, and aborted SCD (Brugada & Brugada, 1992; Probst et al., 2010). Patients typically present with arrhythmias or other symptoms such as syncope, during the third or fourth decade of life; however, pediatric presentation is also common (Pappone & Santinelli, 2019). Although most newly diagnosed Brugada patients are asymptomatic (around 63%), malignant arrhythmias occur at a rate of 12% over a 10‐year follow‐up (Antzelevitch et al., 2016; Brugada, Campuzano, Arbelo, Sarquella‐Brugada, & Brugada, 2018). Implantable cardioverter defibrillators (ICD) are among the limited treatment options for BrS and are indicated in symptomatic BrS patients (Priori et al., 2015). Identifying asymptomatic patients who are at high risk of SCD and would need ICD placement is a challenging yet necessary.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia with the worldwide prevalence of more than 33.5 million people (Rahman, Kwan, & Benjamin, 2014) and is known to be associated with other cardiovascular conditions such as heart failure and myocardial infarction, leading to unfavorable outcomes (Rahman et al., 2014). The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48 (ENGAGE AF‐TIMI 48) trial showed that among patients with AF, SCD is the most common cause of death contributing up to 31.7% of all deaths (Eisen et al., 2016). A recent meta‐analysis also showed a similar finding (Rattanawong, Upala, et al., 2018).

The prevalence of AF in BrS in previous studies has ranged from 6% to 39% (Francis & Antzelevitch, 2008; Giustetto et al., 2014) and was found to be the most common atrial arrhythmia in BrS (Juang et al., 2013). It is suspected that electrical abnormality may exist in the atrium as well as in the ventricle and this could indicate more advanced disease (Kusano et al., 2008). Nevertheless, the prognostic value of AF among patients with BrS regarding SCD and overall mortality is still not known. We conducted a systematic review and meta‐analysis to evaluate the effect of previously documented AF on major arrhythmic events (MAE), including SCD, sudden cardiac arrest (SCA), VF, sustained ventricular tachycardia (sVT), and appropriate shock.

2. METHOD

2.1. Search strategy

Two investigators (CK and NP) independently searched for published studies indexed in MEDLINE and EMBASE databases from inception to March 2019 using a search strategy that including the terms “atrial fibrillation” and “brugada” as described in Supporting Information. Only full articles in English and studies conducted in cohorts were included. A manual search for additional pertinent studies and review articles using references from retrieved articles was also completed.

2.2. Inclusion criteria

The eligibility criteria included the following:

(a) Cohort studies (prospective or retrospective) or randomized control trials reporting MAE including SCD, SCA, VF, sVT, and appropriate shock in BrS patients with and without previously documented AF. (b) Adjusted or unadjusted relative risk (RR), odds ratio (OR), and hazard ratio (HR) with 95% confidence interval (CI), or sufficient raw data for the calculation were provided. Patients without previously documented AF were used as controls.

Study eligibility was independently determined by two investigators (CK and NP), and differences were resolved by mutual consensus. The Newcastle–Ottawa quality assessment scale (NOS) was used to assess each study's quality in three domains: recruitment and selection of the participants, similarity and comparability between the groups, and ascertainment of the outcome of interest among cohort and case–control studies (Stang, 2010).

2.3. Data extraction

A standardized data collection form was used to obtain the following information from each study: title of study, name of first author, year of publication, study design, country of origin, number, gender and age of the participants, prevalence of AF, Brugada ECG pattern, incidence of MAE, available MAE outcome, follow‐up duration, and confounders that were adjusted in the multivariable analysis, if available.

Two investigators (CK and NP) independently performed this data extraction process to ensure accurate data extraction. Any data discrepancy was resolved by referring back to the original articles.

2.4. Definition

2.4.1. Atrial fibrillation

Atrial fibrillation was defined as electrocardiographic recording of AF (paroxysmal, persistent, or permanent) from standard 12‐lead ECG, holter monitoring, device interrogation, and/or documented diagnosis of AF by International Classification of Diseases, Ninth Revision, or as defined in each study.

2.4.2. Brugada syndrome

Brugada syndrome was diagnosed in patients with ST‐segment elevation with type 1 morphology ≥2 mm in ≥1 lead in the right precordial leads V1, V2, positioned in the 2nd, 3rd, or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of class I antiarrhythmic drugs (Sieira & Brugada, 2017).

2.4.3. Major arrhythmic event

Major arrhythmic events were defined by either of SCD, SCA, VF, sVT, or appropriate shock.

Sudden cardiac death was defined as an unexpected, nontraumatic death that occurred within 60 min from the onset of new or worsening symptoms or within 24 hr of last being observed alive (Kuriachan, Sumner, & Mitchell, 2015). Sudden cardiac arrest was defined as a sudden cessation of cardiac activity with hemodynamic collapse which an intervention or spontaneous reversion restores circulation.

Ventricular fibrillation was defined as documented VF rhythm from standard 12‐lead ECG or Holter monitoring, or as defined in each study. Sustained ventricular tachycardia was defined as a sustained ventricular rhythm, documented from standard 12‐lead ECG or holter monitoring, faster than 100 beats per minute lasting at least 30 s or requiring termination earlier due to hemodynamic instability. Only sVT, VF, and appropriate defibrillator intervention were included in this study. Nonsustained VT and inappropriate shock were not considered an outcome of interest.

2.5. Statistical analysis

We performed a meta‐analysis of the included studies using a random‐effects model. Studies were excluded if they did not include an outcome in each intervention group or did not have enough information required for continuous data comparison. We pooled the point estimates of risk ratio and rate ratio from each study using the generic inverse‐variance method of DerSimonian and Laird (DerSimonian & Laird, 1986). The heterogeneity of effect size estimates across these studies was quantified using the I 2 statistic. The I 2 statistic ranges in value from 0% to 100% (I 2  < 25%, low heterogeneity; I 2  = 25%–50%, moderate heterogeneity; and I 2  > 50%, substantial heterogeneity) (Higgins, Thompson, Deeks, & Altman, 2003). A sensitivity analysis was performed to assess the influence of the individual studies on the overall results by omitting one study at a time. Publication bias was assessed using a funnel plot and the Egger's regression test (Sterne & Egger, 2001) (p  < 0.05 was considered significant). All data analyses were performed using the STATA SE version 14.2.

2.6. Sensitivity analysis

We used a sequential exclusion strategy, as described by Patsopoulos, Evangelou, & Ioannidis (2008), to examine whether overall estimates were influenced by the substantial heterogeneity observed. We sequentially and cumulatively excluded studies that accounted for the largest share of heterogeneity until I 2 was less than 50%. We then examined whether RR estimates were consistent.

3. RESULT

3.1. Search results

Our search strategy yielded 1,318 potentially relevant articles (597 articles from EMBASE and 721 articles from MEDLINE). After the exclusion of 463 duplicated articles, 855 articles underwent title and abstract review. At this stage, 825 articles were excluded since they were not cohort or randomized controlled trials, and were not conducted in BrS patients, or the titles and abstracts were not relevant. This left 30 articles for full‐length review. Further 24 studies were excluded as they did not report the prevalence of AF or did not report the incidence of MAE during follow‐up. Therefore, a total of six studies were included in this meta‐analysis. Figure 1 outlines the search and literature review process.

Figure 1.

Figure 1

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Search methodology and selection process

3.2. Description of included studies

A total of six studies from 2007 to 2017 were included in our meta‐analysis (n = 1,703). The prevalence of AF ranged from 5.2% to 17.9%. Major arrhythmic events occurred between 2.3% and 10.0%. A summary of study characteristics is shown in Table 1.

Table 1.

Study characteristics

First author, publication year Study design N Country Male gender (%) Age (years) AF type, prevalence (%) Brugada ECG type MAE definition MAE during follow‐up (%) Follow‐up (months) Adjusted variables
Asmundis, 2017 Retrospective cohort 289 Belgium 70.2 Mean 45 ± 16 Paroxysmal, 10.7% Spontaneous or drug‐induced type I SCD, appropriate shock 10% Mean 120.6 ± 55.7 months None
Calò, 2016 Prospective cohort 347 Italy 78.4 Mean 45.0 ± 13.1 Persistent and paroxysmal, 5.2% Spontaneous type I SCD, aborted SCD, VF, sVT 9.2% Mean 48.0 ± 38.6 months Male gender, History of syncope, Family history of SCD, Positive EPS, SCN5A mutation, QRS characteristics, QTc duration, fQRS
Giustetto, 2009 Prospective cohort 560 Italy 75.7 Mean age 47 ± 15, 59 ± 11, 44 ± 14 in groups 1, 2 and 3 respectively Persistent and paroxysmal, 9% Spontaneous or drug‐induced type I SCD, VF, appropriate shock 2.3% Median 46, 68, 41 months in groups 1, 2 and 3 respectively None
Kusano, 2008 Prospective cohort 73 Japan 98.6 Mean 49 ± 12 Paroxysmal, 13.7% Spontaneous or drug‐induced type I VF 17.8% N/A None
Takagi, 2007 Prospective cohort 188 Japan 94.7 Mean 53.0 ± 14.0 Paroxysmal, 17% Spontaneous or drug‐induced type I SCD, VF 6.9% Mean 37.0 ± 16.0 months Family history of SCD, VT/VF inducibility, QRS duration
Tokioka, 2014 Retrospective cohort 246 Japan 95.9 47.6 ± 13.6 Paroxysmal, 17.9% Spontaneous or drug‐induced type I SCD, VF, appropriate shock 9.7% 45.1 ± 44.3 None
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Abbreviations: AF, atrial fibrillation; EPS, electrophyiology study; MAE, major arrhythmic events; QTc, corrected QT interval; SCD, sudden cardiac death; sVT, sustained ventricular tachycardia; VF, ventricular fibrillation.

3.3. Quality assessment of included studies

The NOS of included studies is described in Table 2. The NOS uses a star system (0–9) to evaluate included studies on three domains: selection, comparability, and outcomes. Higher scores represent higher study quality.

Table 2.

Newcastle–Ottawa quality assessment scale of included studies in meta‐analysis

First author, publication year Selection Comparability Outcome Total
Representative of exposed cohort Selection of the nonexposed cohort Ascertainment of exposure Endpoint not present at start Comparability (Confounding) Assessment of outcome Follow‐up duration Adequacy follow‐up
Asmundis, 2017 * * * *   * * * 7
Calò, 2016 * * * * ** * * * 9
Giustetto, 2009 * * * * ** * * * 9
Kusano, 2008 * * * * * * * * 8
Takagi, 2007 * * * * ** * * * 9
Tokioka, 2014 * * * * ** * * * 9
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The Newcastle–Ottawa scale uses a star system (0 to 9) to evaluate included studies on three domains: selection, comparability, and outcomes. Star (*) = item presents. Maximum 1 star (*) for selection and outcome components and 2 stars (**) for comparability components. Higher scores represent higher study quality.

3.4. Meta‐analysis results

3.4.1. Atrial fibrillation and MAE

Outcomes regarding MAE were available in all six studies (Calo et al., 2016; de Asmundis et al., 2017; Giustetto et al., 2014; Kusano et al., 2008; Takagi, Yokoyama, Aonuma, Aihara, Hiraoka, 2007; Tokioka et al., 2014). There was a significant association between the presence of AF and an increased risk of MAE in patients with BrS (pooled OR = 2.37, 95% CI = 1.36–4.13, p‐value = 0.002, I 2 = 40.3%). Forest plot is demonstrated in Figure 2.

Figure 2.

Figure 2

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Forest plot demonstrating the association of atrial fibrillation and major arrhythmia events in patients with Brugada syndrome

3.4.2. Sensitivity analysis

To assess the stability of the results of the meta‐analysis, we conducted a sensitivity analysis for each outcome by excluding one study at a time. For every outcome, none of the results were significantly altered, as the results after removing one study at a time were similar to that of the main meta‐analysis, indicating that our results were robust.

3.4.3. Publication bias

We aimed to investigate potential publication bias via funnel plot and Egger's test. However, as we only have six studies included in our meta‐analysis, the number is insufficient to reject the assumption of no funnel plot asymmetry. Thus, we did not perform a funnel plot or Egger's test (Debray, Moons, & Riley, 2018; Simmonds, 2015).

4. DISCUSSION

The main finding from this meta‐analysis is that the previously documented AF is associated with an increased risk of MAE in patients with BrS.

The management goal of BrS is preventing cardiovascular mortality from life‐threatening arrhythmia by ICD. In patients who have a documented history of SCD, SCA, VF, or sVT, ICD placement is a class I recommendation to prevent recurrent episode (Belhassen, 2016; Sieira & Brugada, 2016). However, a majority of patients with newly diagnosed BrS are asymptomatic and may not meet an indication for ICD therapy (Casado‐Arroyo et al., 2016). To assess and identify asymptomatic patients who are at a high risk of a cardiac event to received ICD is a challenging topic (Sieira & Brugada, 2016). To date, a well‐established risk factor for SCD in BrS population is spontaneous type I ECG pattern with symptoms (previous SCD or syncope) (Conte et al., 2015; Probst et al., 2010). Other factors that are still controversial include male gender, proband status, family history of SCD, presence of SCN5A gene mutation, prolonged QRS duration, fragmented QRS, fever, and inducible of ventricular arrhythmia during the electrophysiological study (Benito et al., 2008; Calo et al., 2016; Kewcharoen et al., 2019; Raharjo et al., 2018; Rattanawong et al., 2019, 2016; Rattanawong, Riangwiwat, et al., 2018; Sarkozy et al., 2011; Sieira, Ciconte, et al., 2015; Sieira, Conte, et al., 2015; Sieira et al., 2016; Sroubek et al., 2016; Takagi et al., 2007).

Multiple mechanisms were proposed to explain the ventricular arrhythmia in BrS (Tse et al., 2016). Three well‐known major pathways include the repolarization, the depolarization, and the neural crest models, which are all originated from the abnormality of the right ventricular outflow tract found in BrS patients (Antzelevitch, 2001; Meregalli, Wilde, & Tan, 2005). Although the SCN5A gene mutation is the first and the most common mutation found in BrS, it was only found in less than 30% of the patients with BrS (Kapplinger et al., 2010; Tse et al., 2016). Moreover, the SCN5A mutation was only shown to be associated with MAE in Asian populations but not Caucasian populations (Rattanawong et al., 2019; Yamagata et al., 2017). This indicates that there are other causal genes yet to be discovered, and thus, there may exist an unknown pathway that contributes to ventricular arrhythmias in BrS patients.

Although life‐threatening ventricular arrhythmias are the hallmark of BrS, atrial arrhythmias, most commonly AF, are getting more recognized in patients with BrS. The mutation of the SCN5A gene, which encodes for the cardiac sodium channel, is the most common genetic mutation found in patients with BrS. However, since this sodium channel is found not only in the ventricular but also in the atrial tissue, this could lead to a re‐entrant tachyarrhythmia in the atrium (Bordachar et al., 2004). The recently discovered minor BrS‐susceptibility genes involving calcium channels (CACNA1C, CACNB2B, CACNA2D1) could also be a link to the development of AF (Mizusawa & Wilde, 2012). Studies reported BrS patients who have SCN5A mutations were found to have prolongation of both atrio His and His ventricular (HV) interval (Smits et al., 2002; Yokokawa et al., 2007), which are consistent with a decreased excitability in the conduction system secondary to the loss of sodium channel activity. Accordingly, Bordachar et al. found that patients with an HV interval > 55 msec had significantly more atrial arrhythmias than those with a normal HV interval. The author also suspected that the presence of atrial arrhythmia in BrS patients might be a sign of a more advanced disease process. These patients may be at an increased risk of VF/SCD as BrS patient with AF were more commonly found to be inducible of VF than those without AF (Bordachar et al., 2004).

Current evidence revealed that the prevalence of AF in patients in BrS vastly differs among publish studies, ranged from 6% to 39%, while inducibility ranged from 3% to 100% (Giustetto et al., 2014; Rattanawong, Upala, et al., 2018). Despite the possible association of pathophysiology between BrS and AF, the predictive value of AF regarding the risk of SCD/VF in this population is still unclear. Previously published studies showed mixed results. This is the first systematic review and meta‐analysis to evaluate this association.

Of all of the included studies, only the study by de Asmundis et al. (2017) reported a negative correlation between AF and MAE, although the outcome was not statistically significant. The other five studies demonstrated an association between AF and the increased risk of MAE in BrS, but only results from two studies by Calo et al. (2016) and Tokioka et al. (2014) were statistically significant. The other three studies did not show significant association between AF and MAE (Giustetto et al., 2014; Kusano et al., 2008; Takagi et al., 2007). Interestingly, in spite of the difference in AF prevalence, ethnicity, incidence, and definition of MAE, and the strength of the association between AF and MAE, we found only moderate heterogeneity on the meta‐analysis (I 2 = 40.3%).

In the general population, despite strong evidence that AF is associated with an increased risk of SCD in BrS, the exact mechanism is not clearly known (Rattanawong, Upala, et al., 2018). In theory, the rapid ventricular rate induced by AF would directly reduce ventricular refractoriness, facilitating the induction of ventricular tachyarrhythmias. Moreover, the irregular rhythm of AF could also lead to the short‐long‐short sequence that is a potential proarrhythmic (Chen, Benditt, & Alonso, 2014; Chugh et al., 2008). In patients with BrS, is it unclear which is the main mechanism in regard to whether AF contributes to MAE in a similar pathway to the general population, or in fact, there is an exacerbation of the ventricular arrhythmia via the three main models of BrS.

Nevertheless, management of BrS with AF remains a difficult task, as medication for AF, such as sodium channel blockers, confers their risk owing to their proarrhythmic effects in patients with BrS. In addition, other than quinidine (Mizusawa, Sakurada, Nishizaki, & Hiraoka, 2006) and bepridil (Aizawa et al., 2013), the safety of other drugs in BrS has not been thoroughly investigated, especially when used for AF treatment. Moreover, if left untreated, the presence of AF can lead to more inappropriate shock in BrS patients with AF (Giustetto et al., 2014). Recent evidence suggested that catheter ablation could be utilized as a first‐line therapy for paroxysmal AF in BS patients (Rodriguez‐Manero et al., 2019).

4.1. Limitations

Our study is not without limitations. First, there is a limited number of studies and patients included in our meta‐analysis. Second, extracted data from the included studies were not all adjusted for other variables. Only two studies by Calo et al. and Takagi et al. reported outcomes that were adjusted for confounders. Third, although we demonstrated association between AF and SCD/AF in BrS population, causation between this association could not be concluded from our analysis.

5. CONCLUSION

From this systematic review and meta‐analysis, we found that the presence of AF is associated with an increased risk of MAE in patients with BrS. Further research is needed to explore the exact mechanisms behind this association and whether treatment of AF can reduce MAE in BrS population.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of intetest.

Supporting information

 

Click here for additional data file. (12KB, docx)

ACKNOWLEDGMENT

None.

Kewcharoen J, Rattanawong P, Kanitsoraphan C, et al. Atrial fibrillation and risk of major arrhythmic events in Brugada syndrome: A meta‐analysis. Ann Noninvasive Electrocardiol. 2019;24:e12676 10.1111/anec.12676

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