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Background: A rare gene variant in SCN5A can be found in approximately 20%-25% of patients with Brugada syndrome (BrS)., Objective: The aim of this systematic review and meta-analysis was to evaluate the differences in clinical characteristics of BrS patients with and without SCN5A rare variants and the prognostic role of SCN5A for ventricular arrhythmias in BrS., Methods: PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched from inception to January 2024 to identify all relevant studies. Studies were analyzed if they included patients diagnosed with BrS in whom genetic testing for SCN5A variants was performed and arrhythmic outcomes were reported., Results: A total of 17 studies with 3568 BrS patients, of whom 3030 underwent genetic testing for SCN5A variants, fulfilled the eligibility criteria and were included. Compared with SCN5A- patients, SCN5A+ BrS patients more frequently had spontaneous type 1 electrocardiogram, history of syncope, and documented arrhythmias. Furthermore, higher PQ and QRS intervals in SCN5A+ BrS patients compared with SCN5A- have been found. The pooled analysis demonstrated a significant association between the presence of SCN5A rare variants in BrS patients and the risk of major arrhythmic events, with a pooled odds ratio of 2.14 (95% confidence interval, 1.53-2.99; I 2 = 29%)., Conclusion: SCN5A+ BrS patients showed a worse clinical phenotype compared with SCN5A-. The pooled analysis demonstrated a significant association between SCN5A+ mutation status and the risk of major arrhythmic events in BrS patients., Competing Interests: Disclosures A.S. received research grants from Daiichi Sankyo and Bayer and has received speaker fees from Menarini and Bayer. M.L.M. is a consultant for AtriCure. P.B. received compensation for teaching purposes from Biotronik. G.C. received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Boston Scientific, and Acutus Medical. C.dA. receives research grants on behalf of the center from Biotronik, Medtronic, Abbott, LivaNova, Boston Scientific, AtriCure, Philips, and Acutus; and received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, LivaNova, Boston Scientific, AtriCure, and Acutus Medical Daiichi Sankyo. The remaining authors have nothing to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Brugada syndrome (BrS) has been associated with sudden cardiac death in otherwise healthy subjects, and drug-induced BrS accounts for 55% to 70% of all patients with BrS. This study aims to develop a deep convolutional neural network and evaluate its performance in recognizing and predicting BrS diagnosis., Methods and Results: Consecutive patients who underwent ajmaline testing for BrS following a standardized protocol were included. ECG tracings from baseline and during ajmaline were transformed using wavelet analysis and a deep convolutional neural network was separately trained to (1) recognize and (2) predict BrS type I pattern. The resultant networks are referred to as BrS-Net. A total of 1188 patients were included, of which 361 (30.3%) patients developed BrS type I pattern during ajmaline infusion. When trained and evaluated on ECG tracings during ajmaline, BrS-Net recognized a BrS type I pattern with an AUC-ROC of 0.945 (0.921-0.969) and an AUC-PR of 0.892 (0.815-0.939). When trained and evaluated on ECG tracings at baseline, BrS-Net predicted a BrS type I pattern during ajmaline with an AUC-ROC of 0.805 (0.845-0.736) and an AUC-PR of 0.605 (0.460-0.664)., Conclusions: BrS-Net, a deep convolutional neural network, can identify BrS type I pattern with high performance. BrS-Net can predict from baseline ECG the development of a BrS type I pattern after ajmaline with good performance in an unselected population.

Background: A pathogenic/likely pathogenic variant can be found in 20% to 25% of patients with Brugada syndrome (BrS) and a pathogenic/likely pathogenic variant in SCN5A is associated with a worse prognosis. The aim of this study is to define the diagnostic yield of a large gene panel with American College of Medical Genetics and Genomics variant classification and to assess prognosis of SCN5A and non-SCN5A variants., Methods: All patients with BrS, were prospectively enrolled in the Universitair Ziekenhuis Brussel registry between 1992 and 2022. Inclusion criteria for the study were (1) BrS diagnosis; (2) genetic analysis performed with a large gene panel; (3) classification of variants following American College of Medical Genetics and Genomics guidelines. Patients with a pathogenic/likely pathogenic variant in SCN5A were defined as SCN5A + . Patients with a reported variant in a non-SCN5A gene or with no reported variants were defined as patients with SCN5A - . All variants were classified as missense or predicted loss of function., Results: A total of 500 BrS patients were analyzed. A total of 104 patients (20.8%) were SCN5A + and 396 patients (79.2%) were SCN5A - . A non-SCN5A gene variant was found in 75 patients (15.0%), of whom, 58 patients (77.3%) had a missense variant and 17 patients (22.7%) had a predicted loss of function variant. At a follow-up of 84.0 months, 48 patients (9.6%) experienced a ventricular arrhythmia (VA). Patients without any variant had higher VA-free survival, compared with carriers of a predicted loss of function variant in SCN5A + or non-SCN5A genes. There was no difference in VA-free survival between patients without any variant and missense variant carriers in SCN5A + or non-SCN5A genes. At Cox analysis, SCN5A + or non-SCN5A predicted loss of function variant was an independent predictor of VA., Conclusions: In a large BrS cohort, the yield for SCN5A + is 20.8%. A predicted loss of function variant carrier is an independent predictor of VA., Competing Interests: Disclosures Dr La Meir is consultant for Atricure. Dr Brugada received compensation for teaching purposes from Biotronik. Dr Battista Chierchia received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Boston Scientific, Acutus Medical. Dr de Asmundis receives research grants on behalf of the center from Biotronik, Medtronic, Abbott, LivaNova, Boston Scientific, AtriCure, Philips, and Acutus; Dr de Asmundis received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Livanova, Boston Scientific, Atricure, Acutus Medical Daiichi Sankyo. The other authors report no conflicts.

Background: Patients with Brugada syndrome (BrS) have an increased risk of arrhythmias, including atrial tachyarrhythmias (ATas)., Objectives: The purpose of this study was to assess underlying atrial cardiomyopathy in BrS and the effect of ajmaline (AJM) test on the atrium of BrS patients using electrocardiogram imaging (ECGI)., Methods: All consecutive patients diagnosed with BrS in a monocentric registry were screened and included if they met the following criteria: 1) BrS diagnosed following current recommendations; and 2) ECGI map performed before and after AJM with a standard protocol. Consecutive patients with no structural heart disease or BrS who had undergone ECGI were included as a control group. Genetic analysis for SCN5A was performed in all BrS patients. Total atrial conduction time (TACT) and local atrial conduction time (LACT) were calculated from atrial ECGI. The primary endpoint was ATas during follow-up., Results: Forty-three consecutive BrS patients and 40 control patients were included. Both TACT and LACT were significantly prolonged in BrS patients compared with control patients. Furthermore, TACT and LACT were significantly higher after AJM administration and in BrS patients who were carriers of a pathogenic/likely pathogenic SCN5A variant. After a mean follow-up of 40.9 months, 6 patients experienced a first ATa occurrence (all in the BrS group, 13.9%). TACT was the only independent predictor of ATas with a cutoff of >138.5 ms (sensitivity 0.92 [95% CI: 0.83-0.98], specificity 0.70 [95% CI: 0.59-0.81])., Conclusions: ECGI-calculated TACT and LACT are significantly prolonged in BrS patients compared with control patients, and in BrS patients after AJM. This may be consistent with a concealed atrial cardiomyopathy in BrS., Competing Interests: Funding Support and Author Disclosures Dr La Meir is a consultant for Atricure. Dr Brugada has received compensation for teaching purposes from Biotronik. Dr Chierchia has received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Boston Scientific, and Acutus Medical. Dr de Asmundis receives research grants on behalf of the center from Biotronik, Medtronic, Abbott, LivaNova, Boston Scientific, AtriCure, Philips, and Acutus; and has received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Livanova, Boston Scientific, Atricure, Acutus Medical, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: A pathogenic/likely pathogenic (P/LP) variant in SCN5A is found in 20-25% of patients with Brugada syndrome (BrS). However, the diagnostic yield and prognosis of gene panel testing in paediatric BrS is unclear. The aim of this study is to define the diagnostic yield and outcomes of SCN5A gene testing with ACMG variant classification in paediatric BrS patients compared with adults., Methods and Results: All consecutive patients diagnosed with BrS, between 1992 and 2022, were prospectively enrolled in the UZ Brussel BrS registry. Inclusion criteria were: (i) BrS diagnosis; (ii) genetic analysis performed with a large gene panel; and (iii) classification of gene variants following ACMG guidelines. Paediatric patients were defined as ≤16 years of age. The primary endpoint was ventricular arrhythmias (VAs). A total of 500 BrS patients were included, with 63 paediatric patients and 437 adult patients. Among children with BrS, 29 patients (46%) had a P/LP variant (P+) in SCN5A and no variants were found in 34 (54%) patients (P-). After a mean follow-up of 125.9 months, 8 children (12.7%) experienced a VA, treated with implanted cardioverter defibrillator shock. At survival analysis, P- paediatric patients had higher VA-free survival during the follow-up, compared with P+ paediatric patients. P+ status was an independent predictor of VA. There was no difference in VA-free survival between paediatric and adult BrS patients for both P- and P+., Conclusion: In a large BrS cohort, the diagnostic yield for P/LP variants in the paediatric population is 46%. P+ children with BrS have a worse arrhythmic prognosis., Competing Interests: Conflict of interest: A.B. is a consultant for Biotronik. A.S. received research grants from Daiichi-Sankyo and Bayer; he has received speaker fees from Menarini and Bayer. V.M. received an educational grant from the Foundation ‘Enrico and Enrica Sovena’. M.L.M. is consultant for Atricure. P.B. received compensation for teaching purposes from Biotronik. G.B.C. received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Boston Scientific, and Acutus Medical. C.d.A. receives research grants on behalf of the centre from Biotronik, Medtronic, Abbott, LivaNova, Boston Scientific, AtriCure, Philips, and Acutus; C.d.A. received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, LivaNova, Boston Scientific, Atricure, Acutus Medical Daiichi Sankyo. The remaining authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Drug-induced type I Brugada syndrome (BrS) is associated with a ventricular arrhythmia (VA) rate of 1 case per 100 person-years. This study aims to evaluate changes in electrocardiographic (ECG) parameters such as microvolt T wave alternans (mTWA) and heart rate variability (HRV) at baseline and during ajmaline testing for BrS diagnosis., Methods: Consecutive patients diagnosed with BrS during ajmaline testing with 5-year follow-up were included in this study. For comparison, a negative ajmaline control group and an isoproterenol control group were also included. ECG recordings during ajmaline or isoproterenol test were divided in two timeframes from which ECG parameters were calculated: a 5-min baseline timeframe and a 5-min drug timeframe., Results: A total of 308 patients with BrS were included, 22 (0.7%) of which suffered VAs during follow-up. One hundred patients were included in both isoproterenol and negative ajmaline control groups. At baseline, there was no difference in ECG parameters between control groups and patients with BrS, nor between BrS with and without VAs. During ajmaline testing, BrS with VAs presented longer QRS duration [159 ± 34 ms versus 138 (122-155) ms, p = 0.006], higher maximum mTWA [33.8 (14.0-114) µV versus 8.00 (3.67-28.2) µV, p = 0.001], and lower power in low frequency band [25.6 (5.8-53.8) ms 2 versus 129.5 (52.7-286) ms 2 , p < 0.0001] when compared to BrS without VAs., Conclusions: Ajmaline induced important HRV changes similar to those observed during isoproterenol. Increased mTWA was observed only in patients with BrS. BrS with VAs during follow-up presented worse changes during ajmaline test, including lower LF power and higher maximum mTWA which were independent predictors of events., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background Pharmacological treatment of atrial fibrillation (AF) in the setting of Brugada syndrome (BrS) is challenging. In addition, patients with BrS with an implantable cardioverter-defibrillator (ICD) might experience inappropriate shocks for fast AF. Long-term outcome of pulmonary vein isolation in BrS has not been well established yet, and it is still unclear whether pulmonary vein triggers are the only pathophysiological mechanism of AF in BrS. The aim of the study is to assess the long-term outcomes in patients with BrS undergoing pulmonary vein isolation for paroxysmal AF compared with a matched cohort of patients without BrS. Methods and Results Sixty patients with BrS undergoing pulmonary vein isolation with cryoballoon catheter ablation for paroxysmal AF were matched with 60 patients without BrS, who underwent the same procedure. After a mean follow-up of 58.2±31.7 months, freedom from atrial tachyarrhythmias was achieved in 61.7% in the BrS group and in 78.3% in the non-BrS group (log-rank P =0.047). In particular, freedom from AF was 76.7% in the first group and in 83.3% in the second ( P =0.27), while freedom from atrial tachycardia/atrial flutter was 85% and 95% ( P =0.057). In the BrS group, 29 patients (48.3%) had an ICD and 8 (27.6%) had a previous ICD-inappropriate shock for fast AF. In the BrS cohort, ICD-inappropriate interventions for AF were significantly reduced after ablation (3.4% versus 27.6%; P =0.01). Conclusions Pulmonary vein isolation in patients with BrS was associated with higher rate of arrhythmic recurrence. Despite this, catheter ablation significantly reduced inappropriate ICD interventions in BrS patients and can be considered a therapeutic strategy to prevent inappropriate device therapies.

Background: Brugada syndrome (BrS) is caused by mutations in SCN5A gene in 15%-20% of cases. Previous studies showed worse prognosis in SCN5A mutation carriers (SCN5A+). To date, there are no data on genotype-phenotype correlation with electrocardiographic (ECG) imaging (ECGI) and high-density epicardial electroanatomic map., Objective: This study aimed to correlate SCN5A mutation with substrate severity in BrS assessed by ECGI and high-density electroanatomic map., Methods: All consecutive BrS patients undergoing ECGI and high-density epicardial electroanatomic map with HD Grid Mapping Catheter were retrospectively analyzed. On ECGI, the following parameters were analyzed before and after ajmaline administration: right ventricular outflow tract (RVOT) activation time (RVOT-AT) and RVOT recovery time (RVOT-RT). On electroanatomic map, the parameters analyzed before and after ajmaline were high-frequency potential activation time (HFPat), high-frequency potential duration (HFPd), high-frequency potential amplitude (HFPa), low-frequency potential activation time (LFPat), low-frequency potential duration (LFPd), and low-frequency potential amplitude (LFPa)., Results: Thirty-nine BrS patients with ECGI were included. Eight patients (20.5%) were SCN5A+. At baseline ECGI map, mean RVOT-RT was longer in SCN5A+ (P = .024). After ajmaline administration, SCN5A+ patients showed longer RVOT-AT (125.6 vs 100.8 ms; P = .045) and longer RVOT-RT (426.4 vs 397 ms; P = .033). After ajmaline administration, SCN5A+ showed longer HFPat (164.1 vs 119.5 ms; P = .041); longer LFPat (272.7 vs 200.5 ms; P = .018); and longer LFPd (211.9 vs 151.2 ms; P = .033)., Conclusion: In BrS, SCN5A+ patients compared with SCN5A- patients exhibit marked depolarization and repolarization abnormalities as assessed by ECGI and epicardial high-density electroanatomic map., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of Brugada syndrome (BrS) and consequently of abnormal electrograms (aEGMs) found in the epicardium of the right ventricular outflow tract (RVOT-EPI) is controversial., Objective: The purpose of this study was to analyze aEGM from high-density RVOT-EPI electroanatomic mapping (EAM)., Methods: All patients undergoing RVOT-EPI EAM with the HD-Grid catheter for BrS were retrospectively included. Maps were acquired before and after ajmaline, and all patients had concomitant noninvasive electrocardiographic imaging with annotation of RVOT-EPI latest activation time (RVOTat). High-frequency potentials (HFPs) were defined as ventricular potentials occurring during or after the far-field ventricular EGM showing a local activation time (HFPat). Low-frequency potentials (LFPs) were defined as aEGMs occurring after near-field ventricular activation showing fractionation or delayed components. Their activation time from surface ECG was defined as LFPat., Results: Fifteen consecutive patients were included in the study. At EAM before ajmaline, 7 patients (46.7%) showed LFPs. All patients showed HFPs before and after ajmaline and LFPs after ajmaline. Mean HFPat (134.4 vs 65.3 ms, P <.001), mean LFPat (224.6 vs 113.6 ms, P <.001), and mean RVOTat (124.8 vs 55.9 ms, P <.001) increased after ajmaline. RVOTat correlated with HFPat before (ρ = 0.76) and after ajmaline (ρ = 0.82), while RVOTat was shorter than LFPat before (P <.001) and after ajmaline (P <.001). BrS patients with history of aborted sudden cardiac death had longer aEGMs after ajmaline., Conclusion: Two different types of aEGMs are described from BrS high-density epicardial mapping. This might correlate with depolarization and repolarization abnormalities., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background The rate of sudden cardiac death (SCD) in Brugada syndrome (BrS) is ≈1%/y. Noninvasive electrocardiographic imaging is a noninvasive mapping system that has a role in assessing BrS depolarization and repolarization abnormalities. This study aimed to analyze electrocardiographic imaging parameters during ajmaline test (AJT). Methods and Results All consecutive epicardial maps of the right ventricle outflow tract (RVOT-EPI) in BrS with CardioInsight were retrospectively analyzed. (1) RVOT-EPI activation time (RVOT-AT); (2) RVOT-EPI recovery time, and (3) RVOT-EPI activation-recovery interval (RVOT-ARI) were calculated. ∆RVOT-AT, ∆RVOT-EPI recovery time, and ∆RVOT-ARI were defined as the difference in parameters before and after AJT. SCD-BrS patients were defined as individuals presenting a history of aborted SCD. Thirty-nine patients with BrS were retrospectively analyzed and 12 patients (30.8%) were SCD-BrS. After AJT, an increase in both RVOT-AT [105.9 milliseconds versus 65.8 milliseconds, P <0.001] and RVOT-EPI recovery time [403.4 milliseconds versus 365.7 milliseconds, P <0.001] was observed. No changes occurred in RVOT-ARI [297.5 milliseconds versus 299.9 milliseconds, P =0.7]. Before AJT no differences were observed between SCD-BrS and non SCD-BrS in RVOT-AT, RVOT-EPI recovery time, and RVOT-ARI ( P =0.9, P =0.91, P =0.86, respectively). Following AJT, SCD-BrS patients showed higher RVOT-AT, higher ∆RVOT-AT, lower RVOT-ARI, and lower ∆RVOT-ARI ( P <0.001, P <0.001, P =0.007, P =0.002, respectively). At the univariate logistic regression, predictors of SCD-BrS were the following: RVOT-AT after AJT (specificity: 0.74, sensitivity 1.00, area under the curve 0.92); ∆RVOT-AT (specificity: 0.74, sensitivity 0.92, area under the curve 0.86); RVOT-ARI after AJT (specificity 0.96, sensitivity 0.58, area under the curve 0.79), and ∆RVOT-ARI (specificity 0.85, sensitivity 0.67, area under the curve 0.76). Conclusions Noninvasive electrocardiographic imaging can be useful in evaluating the results of AJT in BrS.

Brugada syndrome (BrS) diagnosis requires the presence of a typical type 1 ECG pattern. Owing to the spontaneous ECG variability, the real BrS prevalence in the general population remains unclear. The aim of the present study was to evaluate the prevalence of positive ajmaline challenge for BrS in a cohort of consecutive patients who underwent electrophysiological evaluation for different clinical reasons. All consecutive patients from 2008 to 2019 who underwent ajmaline testing were prospectively included. A total of 2,456 patients underwent ajmaline testing, 742 (30.2%) in the context of familial screening for BrS. In non-familial screening group (1,714) ajmaline testing resulted positive in 186 (10.9%). Indications for ajmaline testing were: suspicious BrS ECG in 23 cases (12.4%), palpitations in 27 (14.5%), syncope in 71 (38.2%), presyncope in 7 (3.8%), family history of sudden cardiac death in 18 (9.7%), documented ventricular arrhythmias in 12 (6.5%), unexplained cardiac arrest in 4 (2.2%), atrial fibrillation in 16 (8.5%), brady-arrhythmias in 1 (0.5%), and cerebrovascular accidents in 7 (3.7%). Compared with the overall population, ajmaline testing positive patients were younger (42.8 ± 15.5 vs 48.9 ± 20.4; p <0.001) and more frequently male (65.1% vs 56.3%; p = 0.023). Implantable cardioverter defibrillator was implanted in 84 patients (45.2%). During a median follow-up of 42.4 months, 12 appropriate shocks and 13 implantable cardioverter defibrillator related complications were reported. In conclusion, the BrS was diagnosed in an unexpected high proportion of patients that underwent ajmaline testing for a variety of cardiovascular symptoms. This can lead to an adequate counseling and clinical management in BrS patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)