Introduction
Brugada syndrome (BrS) is an inherited cardiac condition characterized by a coved-shaped ST-segment elevation (Type 1) on 12-lead electrocardiography (ECG) and is associated with risk of sudden cardiac death. Following appropriate risk stratification, insertion of implantable cardioverter defibrillator (ICD) may prevent sudden cardiac death from ventricular arrhythmias (VA) in high-risk individuals [
1]. Recurrent lethal VA in this population occurs at an estimate rate of 17% over a follow-up period of ~ 7 years [
2]. Furthermore, ~ 2% may experience electrical storm which typically tends to cause recurrent ventricular fibrillation (VF) almost exclusively occurring in those patients with a prior resuscitated cardiac arrest. Recurrent VA can lead to significant morbidity and adverse psychological sequelae from repeated shocks.
Catheter ablation has emerged as an important therapeutic option for BrS. Initial reports targeted premature ventricular complex (PVC) and/or ventricular tachycardia (VT) felt to be responsible for triggering VF, however these triggers were frequently absent during an ablation procedure [
3]. Recently, an approach targeting abnormal substrate for BrS has emerged. Abnormal electrograms (EGMs) with low voltage, fractionated or delayed potentials, and areas of slow conduction were identified predominantly on epicardial, but also endocardial surface of BrS patients, serving as putative targets for ablation. The epicardial right ventricular outflow tract (RVOT) notably harboured abnormal EGM [
3] with post-mortem studies showing this to correlate with interstitial fibrosis and reduced gap junction expression [
4]. In the absence of substrate abnormalities at baseline sinus rhythm, intravenous sodium channel blockers may uncover substrate regions that could be targeted for ablation, sometimes even beyond the epicardial RVOT [
5]. Indeed, a substrate-based catheter ablation appears to provide an attractive adjunct to ICD insertion in high-risk patients with BrS. A number of studies have subsequently described catheter ablation for BrS. We conducted an updated systematic review with a pooled analysis to assess the safety and efficacy of catheter ablation as a therapeutic option for patients with BrS, as published in the literature over the past two decades.
Methods
Search strategy
This systematic review was registered in PROSPERO (registration number: CRD42021267328). Pubmed/Medline, EMBASE, and Cochrane Central Register of Controlled Trials databases from inception to 11th of August 2021 were systematically searched to identify all relevant studies. The search terms used were “Brugada syndrome” and “Ablation”. No language restriction was applied at the beginning, however only articles in English were included in the final analysis. The reference list of all identified articles was also reviewed for relevant publications fitting the eligibility criteria. No restriction was applied to the publication date or the age of participants in each study. Due to the paucity of published data on catheter ablation of BrS, we included case reports in the present review.
Definition of Brugada syndrome
BrS was defined as the presence of a type 1 ECG that was present spontaneously or induced by pharmacological provocation with a sodium channel blocker based on updated expert consensus statement [
1].
Inclusion criteria
The inclusion criteria for this review were studies with the following characteristics:
1.
Included patients with a diagnosis of BrS [
1].
2.
Ablation approach (endocardial, epicardial or combined) was clearly defined.
3.
Ablation strategy (substrate-based ablation and/or targeting of PVC/VT) was clearly defined.
Study eligibility and data extraction are outlined in online resource.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation, or median and 25–75% interquartile range (IQR) when data were skewed. Procedural success rates, incidence of procedural complications and recurrence rate were pooled using DerSimonian–Laird random-effects models to take into account the anticipated clinical and methodological diversity between studies. Summary estimates were reported with 95% confidence intervals (CI). The I2 statistic was used to represent the proportion of variation between the sample estimates. Statistical analysis was conducted with Comprehensive Meta Analysis v3.3 (Biostat Inc, Englewood, NJ, US).
Discussion
A body of research spanning almost two decades describes the potential utility of catheter ablation as a therapeutic option for reduction or complete abolition of recurrent arrhythmic risk in BrS. This review summarizes localization of abnormal substrate, the ablation strategy, and clinical outcomes following catheter ablation in patients with BrS. This review provides several novel observations pertaining to catheter ablation for ventricular substrate in BrS. The main findings of this study are:
The vast majority of patients (87%) underwent catheter ablation based on the substrate modification, however, a significant minority of patients (13%) underwent mapping and ablation of PVC-triggered VF (10%) or ablation for sustained monomorphic VT (3%).
Eighty percent of patients received sodium channel blocker as a provocation strategy prior to catheter ablation to uncover the necessary “substrate” for ablation.
Almost all abnormal substrates were localized in epicardial RVOT with possible extension. Beyond RVOT in 6% of cases to the RV free wall, 14% to RV anterior wall, and 17% to RV inferior wall. In contrast, all PVC-triggered VF and sustained VTs were localized to endocardium RVOT with highly variable involvement of multiple regions among both RV and LV endocardium.
Non-inducibility of VA was achieved in 87.1% and 17.6% had recurrence of sustained VA during approximately 2 years’ follow-up; complications occurred in 9.3% suggesting that catheter ablation is an excellent therapeutic option for treatment of VA associated with BrS.
Contemporary work has focused upon the epicardial RVOT as the region of interest in BrS, supported by the findings of epicardial RVOT fibrosis on autopsy in six patients [
4]. However, in our study, we found that the abnormal substrate extended beyond the RVOT in approximately one third of patients for both endocardial and epicardial mapping. Some reported that many spontaneous episodes of VF in patients with BrS were preceded by PVCs [
60]. In corresponding with these reports, 13% of patients underwent ablation of VF-triggering PVCs or VT ablation with or without substrate ablation.
Pharmacologic provocation with a sodium channel blocker was the cornerstone of identifying ablation targets. Salghetti, et al. reported that the substrate was visible in 17/36 (47%) of patients but required provocation for revelation in 19/36 (53%) of patients [
12]. In almost all cases, provocation revealed a significant increase in abnormal substrate. Furthermore, the same pharmacological provocation could be used to test the efficacy of catheter ablation, where re-testing revealed abolishment of targeted substrate. An important point to note is that the definition of “abnormal substrate” encompassed both abnormal low bipolar voltage (< 1.5 mV) as well as late potential and fractionated potentials and low frequency (up to 100 Hz) prolonged duration (> 200 ms) bipolar signals with delayed activity extending beyond the end of QRS complex, which could be present in a low voltage area. These differing definitions of abnormal substrate are thematically consistent with the fiercely debated pathophysiologic mechanism of BrS, which is thought to be due to depolarization and/or repolarization abnormalities. It is considered that low bipolar voltage may reflect depolarization abnormalities and low-frequency, prolonged duration signals may reflect repolarization abnormalities. Although the underlying pathophysiology of BrS remains controversial, nevertheless, the provocation strategy is thought to be effective for both definitions of abnormal substrate as provocation showed a significant increase of abnormal substrate area not only low voltage area, but also slow conduction area in previous studies, with excellent procedural outcomes with targeting of substrate with catheter ablation. Ajmaline was the most frequently used for provocation drug in this pooled analysis. It is unclear which sodium channel blocker is the optimal drug, at the most appropriate dose. Further studies will be required to elucidate the optimal provocation strategy. A combined epicardial and endocardial approach might be required with sodium channel blocker augmentation, in addition to PVC and VT ablation where VF triggering PVCs and VTs have been identified.
Looking at the procedural outcomes, acute procedural endpoints of non-inducibility of VA were achieved in a large proportion of patients (87.1%) and long-term recurrence of sustained VA during median follow-up period of 28 months occurred in 17.6%. This data suggest reasonable success with the procedures. Complications occurred in 9.3% with the majority related to epicardial access including pericardial effusions or pericarditis, managed with a pericardial drain or medication, none requiring cardiac surgery. Death was observed in two patients who did not underwent ICD implantation out of 388, and unrelated to procedural complication. These results highlight the necessity for ICD in these patients given the risk of recurrent arrhythmia even if catheter ablation is apparently successful.
Considering highly variable distribution of abnormal substrate and ectopy with small proportion of SCN5A mutation suggest that BrS might be a heterogeneous entity because current definition of HRS/EHRA/APHRS expert consensus statement is based on ECG criteria alone. Theoretically, any disease that affects the epicardial RVOT myocardium can manifest with a coved‐type ECG and should be designated as Brugada phenocopy. The abnormal substrate, whilst initially localizing to epicardial RVOT, now appears to involve all aspects of the RV, suggesting that we need to start reconfirming the diagnosis, and look for alternative diagnosis, such as ARVC [
61] or coronary ischemia (e.g., right coronary artery) which is also known to produce a coved‐type ST‐elevation and emulate BrS [
62]. More careful phenotyping might be required to diagnose BrS as a unique entity. Nevertheless, contemporary catheter ablation of BrS should be the good adjunctive to ICD implantation to prevent recurrent VA.
One previous systematic review has described catheter ablation of BrS. Fernandes, et al. reported the efficacy of epicardial substrate modification in patients with BrS [
63]. However, detailed localization of abnormal substrate and VF-triggered PVC/VT origin in BrS, and detailed comprehensive verification of clinical outcomes was still lacking. The efficacy of catheter ablation was reported to be favorable in this study similar to ours, but included only 11 case series and 11 case reports with 233 patients. Our study has several advantages, including an updated review, including a larger cohort of 388 patients, a comprehensive description of substrate location, in particular beyond epicardial RVOT and the reporting of procedural outcome using single-arm meta-analysis of case series and case reports. Uniquely, we included case series and case reports, to provide a more comprehensive representation of published literature on catheter ablation of BrS.