Genetic Testing in Brugada Syndrome: A 30-Year Experience.

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.

Adding Electroanatomical Mapping to Cryoballoon Pulmonary Vein Isolation Improves 1-Year Clinical Outcome and Durability of Pulmonary Vein Isolation: A Propensity Score-Matched Analysis.

Background: Adding electroanatomical left atrial (LA) voltage mapping to cryoballoon ablation (CBA) improves validation of acute pulmonary vein isolation (PVI). Aims: To determine whether the addition of mapping can improve outcome and PVI durability. Methods: One-year outcome and PV reconnection (PVR) rate at first repeat ablation were studied in 400 AF patients in a propensity-matched analysis (age, AF type, CHA2DS2-VASc score) between Achieve catheter-guided CBA with additional EnSite LA voltage maps performed pre- and post-CBA (mapping group; N = 200) and CT- and Achieve catheter-guided CBA (control group; N = 200). Clinical success was defined as freedom of documented AF or atrial tachycardia (AT) > 30 s. PV reconnection patterns were characterized in repeat ablations. Results: At 1 year, 77 (19.25%) patients had recurrence of AF/AT, significantly lower than in the mapping group: 21 (10.5%) vs. 56 (28%), p < 0.001. Procedure time was shorter (72.2 ± 25.4 vs. 78.2 ± 29.3 min, p = 0.034) and radiation exposure lower (4465.0 ± 3454.6 Gy.cm2 vs. 5940.5 ± 4290.5 Gy.cm2, p = 0.037). Use of mapping was protective towards AF/AT recurrence (HR = 0.348; 95% CI 0.210-0.579; p < 0.001), independent of persistent AF type (HR = 1.723; 95% CI 1.034-2.872; p = 0.037), and LA diameter (HR = 1.055; 95% CI 1.015-1.096; p = 0.006). At repeat ablation (N = 90), persistent complete PVI was seen in 14/20 (70.0%) versus 23/70 (32.9%) in the mapping and conventional group, respectively (p = 0.03). Reconnection rate of the right inferior PV was lower with mapping (10.0% vs. 34,3%, p = 0.035). Conclusions: Adding electroanatomical LA voltage mapping to CBA improves 1-year clinical outcome and lowers both procedure time and radiation exposure. At repeat, use of mapping increases complete persistent PVI mainly by improving PVI durability of the RIPV.

Impact of anesthetic management on catheter ablation for premature ventricular complexes: insights during the COVID-19 outbreak.

BACKGROUND: The influence of divergent anesthesia types during ablation of premature ventricular complexes (PVCs) is not known. While previously performed under general anesthesia (GA) at our institution, these procedures were exclusively performed under local anesthesia (LA) ± minimal sedation during the COVID-19 outbreak for logistic reasons. METHODS: One hundred and eight consecutive patients (82 GA versus 26 LA) undergoing PVC ablation at our center were evaluated. Intraprocedural PVC burden (over 3 min) pre-ablation was measured twice: (1) at the start (before GA induction) and (2) before catheter insertion (after GA induction). Upon cessation of ablation and after a waiting period of ≥ 15 min, acute ablation success (AAS) was defined as absence of PVCs until the end of the recording period. RESULTS: Intraprocedural PVC burden was not significantly different between LA versus GA group: (1) 17.8 ± 3% vs 12.7 ± 2%, P = 0.17 and (2) 10.0 ± 3% vs 7.4 ± 1%, P = 0.43, respectively. Activation mapping-based ablation was performed significantly more in the LA vs GA group (77% vs 26% of patients, P < 0.001, respectively). AAS was significantly higher in LA vs GA group: 22/26 (85%) vs 41/82 (50%), respectively, P < 0.01. After multivariable analysis, LA was the only independent predictor for AAS (OR 13, 95% CI 1.57-107.4, P = 0.017). CONCLUSION: Ablation of PVC under LA presented significantly higher AAS rate compared to GA. The procedure under GA might be complicated by PVC inhibition (after catheter insertion/during mapping) and PVC disinhibition post-extubation.

Genetic testing in children with Brugada syndrome: results from a large prospective registry.

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.

Heart rate variability and microvolt T wave alternans changes during ajmaline test may predict prognosis in Brugada syndrome.

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) ms2 versus 129.5 (52.7-286) ms2, 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.

Ajmaline-Induced Abnormalities in Brugada Syndrome: Evaluation With ECG Imaging.

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.

High-density epicardial mapping in Brugada syndrome: Depolarization and repolarization abnormalities.

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.

Procedural Safety and Efficacy for Pulmonary Vein Isolation with the Novel Polarx™ Cryoablation System: A Propensity Score Matched Comparison with the Arctic Front™ Cryoballoon in the Setting of Paroxysmal Atrial Fibrillation.

BACKGROUND: The novel Polarx™ cryoablation system is currently being studied for atrial fibrillation (AF) ablation. To the best of our knowledge, no study comparing the novel cryoablation system with the standard Arctic Front™ cryoballoon is available in today's literature. This study aims to compare Polarx™ and Arctic Front™ cryoballoon in terms of safety and efficacy. METHODS: From a total cohort of 202 patients who underwent pulmonary vein (PV) isolation for paroxysmal AF through cryoablation, a population of 30 patients who used Polarx™ were compared with 30 propensity-score matched patients who used Arctic Front™. RESULTS: Pulmonary vein occlusion and electrical isolation were achieved in all (100%) veins with a mean number of 1.09 ± 0.3 occlusion per vein using Polarx™ and 1.19 ± 0.5 occlusion per vein using Arctic Front™ (p = 0.6). Shorter procedure and fluoroscopy time were observed with Polarx™ group (60.5 ± 14.23 vs 73.43 ± 13.26 mins, p = 0.001; 12.83 ± 6.03 vs 17.23 ± 7.17 mins, p = 0.01, respectively). Lower cumulative freeze duration per vein was also observed with Polarx™ (203.38 ± 72.03 vs 224.9 ± 79.35 mins, p = 0.02). There was no significant difference in isolation time between the two groups (34.47 ± 21.23 vs 34.18 ± 26.79 secs, p = 0.9). CONCLUSIONS: The novel Polarx™ cryoablation system showed similar efficacy in vein occlusion and isolation and safety profile when compared to Arctic Front™ cryoablation system. Procedure time, fluoroscopy time, and cumulative freeze duration were significantly lower with Polarx™ cryoablation system.

High vagal tone predicts pulmonary vein reconnection after cryoballoon ablation for paroxysmal atrial fibrillation.

BACKGROUND: Pulmonary vein (PV) isolation is an established treatment for paroxysmal drug-refractory atrial fibrillation (AF). High parasympathetic tone and reconnection of PVs have demonstrated to be possible culprits of AF recurrence after ablation. Our aim was to investigate the association between parasympathetic tone and reconnected PVs in patients with paroxysmal AF. METHODS: Consecutive patients who underwent a redo catheter ablation procedure for atrial tachyarrhythmia recurrence by means of 3D electroanatomic mapping with documentation of presence or absence of PVs reconnection following an initial procedure of cryoballoon (CB) ablation for symptomatic drug-refractory paroxysmal AF were screened for the study. RESULTS: A total of 92 patients were included, of whom 50 (54.35%) were males. Reconnected PVs were found in 64 (69%) patients. PVs reconnection could be predicted by DC (C-statistic = .770), by SDNNI (C-statistic = .714) and by absolute VLF power (C-statistic = .722), while right-sided PVs reconnection could be better predicted by DC (C-statistic = .848) and by SDNNI (C-statistic = .761). In multivariate binary logistic regression analysis, a DC value ≥6.45 ms and an absolute VLF power value ≥160 ms2 were associated with three times and five times higher odds of PVs reconnection, respectively. On a vein-per-vein analysis, absolute VLF power ≥160 ms2 was associated with three times higher odds, while reaching of -40°C within 60 s was associated with three times lower odds of PVs reconnection. CONCLUSION: High parasympathetic tonus accurately predicts PVs reconnection. On a vein-per-vein analysis, parasympathetic markers along with biophysical parameters predicted PVs reconnection. On a case-by-case analysis, parasympathetic markers were the only predictors of PVs reconnection, thus being a robust PVs reconnection prediction tool.

Repeat procedures for recurrent persistent atrial fibrillation: A propensity-matched score comparison between left atrial linear ablation with radiofrequency and posterior wall isolation with the cryoballoon.

AIMS: To evaluate the clinical outcome in patients undergoing repeat procedures for recurrent persistent atrial fibrillation following an index cryoballoon (CB-A) pulmonary vein isolation ablation on a mid-term follow-up of 12 months. METHODS: In this propensity score-matched comparison, 50 patients undergoing left atrial posterior wall isolation (LAPWI) with the CB-A were matched to 50 patients treated with additional linear ablation using radiofrequency catheter ablation (RFCA). RESULTS: Meantime to repeat the procedure was 9.74 ± 4.36 months. At 12 months follow-up freedom from atrial tachyarrhythmias (ATas) was achieved in 82% of patients in the LAPWI group and in 62% of patients in the linear ablation group (P = .03). Regression analysis demonstrated that relapses during the blanking period and LA dimensions were independent predictors of ATas recurrences following the repeat procedure. CONCLUSION: LAPWI using CB-A is associated with a significantly higher freedom from atrial arrhythmias when compared with the RFCA mediated left atrial linear lesions on a mid-term follow-up of 12 months in patients with persAF undergoing a redo procedure.

Heart rate variability after radiofrequency ablation of epicardial ganglionated plexuses on the ovine left atrium.

BACKGROUND: Ganglionated plexuses (GP) are terminal parts of cardiac autonomous nervous system (ANS). Radiofrequency ablation (RFA) for atrial fibrillation (AF) possibly affects GP. Changes in heart rate variability (HRV) after RFA can reflect ANS modulation. METHODS: Epicardial RFA of GP on the left atrium (LA) was performed under the general anesthesia in 15 mature Romanov sheep. HRV was used to assess the alterations in autonomic regulation of the heart. A 24 - hour ECG monitoring was performed before the ablation, 2 days after it and at each of the 12 following months. Ablation sites were evaluated histologically. RESULTS: There was an instant change in HRV parameters after the ablation. A standard deviation of all intervals between normal QRS (SDNN), a square root of the mean of the squared differences between successive normal QRS intervals (RMSSD) along with HRV triangular index (TI), low frequency (LF) power and high frequency (HF) power decreased, while LF/HF ratio increased. Both the SDNN, LF power and the HF power changes persisted throughout the 12 - month follow - up. Significant decrease in RMSSD persisted only for 3 months, HRV TI for 6 months and increase in LF/HF ratio for 7 months of the follow - up. Afterwards these three parameters were not different from the preprocedural values. CONCLUSIONS: Epicardial RFA of GP's on the ovine left atrium has lasting effect on the main HRV parameters (SDNN, HF power and LF power). The normalization of RMSSD, HRV TI and LF/HF suggests that HRV after epicardial RFA of GPs on the left atrium might restore over time.