Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis -regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.

β-Blockers are an essential treatment for cardiovascular disease, the incidence of which is rising among women of childbearing age. Several large cohort and registry studies have reported an association between β-blocker exposure in pregnancy and reduced birth weight, but most have included women with hypertension or structural heart disease. Our study’s primary objective was to evaluate the impact of these medications on the birth weight of infants born to mothers with morphologically normal hearts, including women with long QT syndrome (LQTS) or Marfan syndrome (MFS). Secondary objectives were to evaluate the influence of β-blocker type on birth weight, diagnoses that fetuses were small for gestational age (SGA) or growth-restricted (FGR) during pregnancy and at birth, uterine Doppler abnormalities, and neonatal adverse effects (bradycardia and hypoglycemia), which are expected effects of in utero β-blocker exposure. This retrospective observational single-center study compared pregnancies in patients with LQTS or MFS treated with β-blockers with those of untreated matched control patients. Pregnancies were matched for maternal age, body mass index, parity, gestational age at birth, presence of gestational or pre-existing diabetes, and smoking status. Fifty-seven pregnancies of 40 mothers exposed to β-blockers were matched with 165 control pregnancies. This study’s main finding was that the mean birth weight of infants whose mothers used β-blockers during pregnancy was a significant 442 grams lower (unadjusted 2890 g vs 3285 g; p < 0.001) than that of the control group. SGA/FGR during pregnancy and at birth were diagnosed significantly more often in the treated patients, and their incidence of neonatal bradycardia was higher in the exposed group. Among the uterine Doppler examinations available, no clear differences were observed between groups. Data on neonatal hypoglycemia were inconclusive because of differential screening strategies and a high proportion of missing values, particularly in the control group. To our knowledge, this is the first study specifically focusing on β-blocker use in pregnant women with LQTS or MFS and structurally normal hearts, using matched controls to minimize confounding by underlying cardiac disease. β-Blocker use—mainly nadolol and bisoprolol—was associated with significantly lower birth weight and higher rates of FGR/SGA and neonatal bradycardia. Our findings support the continuation of β-blocker therapy when clinically indicated, combined with careful fetal growth monitoring and targeted neonatal surveillance.

AIMS:Loss-of-function (LOF) variants in SCN5A are associated with Brugada syndrome (BrS), progressive conduction slowing, and other arrhythmias. While the prognosis of SCN5A carriers with a positive sodium channel blocker challenge (SCBC) is established, data on those with negative SCBC are limited. OBJECTIVE:To assess the clinical presentation and prognosis of SCN5A variant carriers with negative SCBC, and compare them to relatives with positive SCBC. METHODS AND RESULTS:We retrospectively included patients from five university hospitals (2000-2024) carrying a pathogenic or likely pathogenic SCN5A variant and negative SCBC. Relatives with the same variant and positive SCBC were also analysed. Patients with spontaneous type 1 ECG, gain-of-function variants, double variants, or ACMG class 1-3 variants were excluded. Clinical, ECG, genetic, and follow-up data were collected. Conduction slowing was evaluated using the PR interval and QRS duration. The cohort included 162 patients from 43 families (median age 37 ± 19 years, 46% male), of whom 69 (43%) had negative SCBC. Among these 69 patients, 25 (36%) had baseline intraventricular conduction defects, and 19 (28%) had first-degree AV block. After a median follow-up of 75 [40-168] months, 52% of patients developed progressive conduction slowing. Negative SCBC patients had fewer conduction defects (36% vs. 70%, p = 0.002) and ICD implantations (1% vs. 23%, P < 0.001). Non-missense variants were associated with more conduction slowing (71% vs. 42%, P = 0.04). CONCLUSION:This multicentre study provides the largest analysis of SCN5A carriers with negative SCBC, showing excellent arrhythmic prognosis despite frequent progressive conduction slowing.

BACKGROUND AND AIMS:Current evidence on catheter ablation for patients with congenital heart disease (CHD) is derived from small, retrospective studies. This study aims to provide insights from a nationwide contemporary registry. METHODS:This prospective study included all CHD patients referred for catheter ablation from 2020 to July 2024 across 28 French centres. The primary outcome was the rate of per-procedural acute success. Secondary outcomes included complications as well as freedom from arrhythmia recurrence. RESULTS:A total of 1135 consecutive catheter ablation procedures were performed in 998 patients (mean age 46.1 ± 16 years, 55.5% male). The main primary clinical arrhythmias targeted were atrial flutter/tachycardia in 677 (59.6%), atrial fibrillation in 195 (17.2%), ventricular arrhythmia in 188 (16.6%), and atrioventricular reentrant tachycardia in 38 (3.3%), with significant variations in patterns observed based on the underlying substrate. Clinical arrhythmia was successfully ablated in 1071 patients (94.4%). The mean number of arrhythmias targeted per procedure was 1.5 ± 0.7, with overall acute success rates exceeding 90% for all arrhythmias except for ventricular arrhythmias (86.7%). Acute complication occurred in 43 procedures (3.8%), including 1 (0.1%) death. The overall 1- and 2-year recurrence-free rates were 77.3% (95% confidence interval 74.2%-80.4%) and 68.4% (95% confidence interval 64.7%-72.3%), respectively. Significant variations in recurrence rates were noted based on the type of arrhythmia and the underlying CHD. CONCLUSIONS:Catheter ablation in patients with CHD demonstrates highly favourable acute outcomes and a low complication rate. Recurrence rates during follow-up vary depending on the targeted arrhythmia and the underlying CHD. These findings should be considered in the benefit-risk assessment.

Background Recurrence rates of atrial arrhythmias after catheter ablation in patients with congenital heart disease (CHD) remain substantial. Given the high prevalence of peritricuspid flutter, systematic cavotricuspid isthmus (CTI) ablation may represent a rational preventive strategy. Objectives The objective of this study was to assess the impact of empirical CTI ablation in CHD patients. Methods This prospective nationwide study included all CHD patients referred for a first catheter ablation of an atrial arrhythmia between 2020 and 2024. Empirical ablation comprised probabilistic (noninducible arrhythmia with prior documentation) and prophylactic (no prior documentation) ablation. The primary endpoint was freedom from any atrial arrhythmia recurrence. Secondary endpoints included arrhythmia-related hospitalizations, redo ablations, and complications. Results Among 575 patients undergoing a first catheter ablation for atrial arrhythmia, 345 (60.0%) had CTI-dependent flutter. The remaining 230 patients formed the study population (mean age: 48.2 ± 16.4 years; 50.9% male). CHD complexity was predominantly moderate (57.4%). Targeted arrhythmias were atrial macro-re-entry (53.0%), atrial fibrillation (47.0%), and focal atrial tachycardia (17.4%), with multiple arrhythmias in 16.5%. Empirical CTI ablation was performed in 71 patients (30.9%) and was associated with significantly higher freedom from any atrial arrhythmia at 1 year (78.1% vs 65.6%, P = 0.010) and 2 years (71.2% vs 56.1%, P = 0.025), remaining independently associated with lower risk of recurrence after multivariable adjustment (HR: 0.47, 95% CI: 0.24-0.92, P = 0.027). This benefit was primarily observed in patients without atrial fibrillation history (interaction P = 0.005). Arrhythmia-related hospitalization was also significantly reduced (14.1% vs 25.8%, P = 0.048). Conclusions Empirical CTI ablation is associated with improved freedom from atrial arrhythmia and reduced rehospitalization in CHD patients.

While heart failure (HF) duration before left ventricular assist device (LVAD) implantation may influence postoperative outcomes, data evaluating this relationship remains limited. This study investigated the association between HF duration and outcomes following LVAD implantation. This international retrospective multicenter study included 1,071 patients who underwent LVAD implantation between 2006—2019. Patients were stratified into quartiles by HF duration before implantation: Q1 ≤ 3.9 months, Q2 > 3.9 months-4 years, Q3 > 4—10.7 years, and Q4 ≥ 10.7 years. Primary outcome was 3-year all-cause mortality. Secondary outcomes included cardiac death, early (≤ 30 days) and late ventricular arrhythmias (VAs), and left ventricular ejection fraction (LVEF) recovery. Multivariable Cox regression and restricted cubic spline analyses were performed. After 3-year follow-up, 426 patients died (31.1

BACKGROUND:Although ventricular arrhythmias (VAs) are common after left ventricular assist device (LVAD) implantation, the features of early electrical storm (ES) remain poorly characterized. OBJECTIVES:This study aimed to evaluate the incidence and clinical impact of early ES in LVAD recipients. METHODS:This international, multicenter, retrospective study included 1,309 recipients of LVADs implanted between 2006 and 2019. Early ES was defined as ≥3 sustained VA episodes within 24 hours during the first 30 days' postimplantation. The primary outcome was 3-month all-cause mortality. Secondary endpoints included 3-month cardiac mortality and early (≤30 days) right ventricular (RV) failure. RESULTS:Early ES occurred in 56 patients (4.3%), with a median onset at 5 days' postimplantation. Patients with early ES experienced higher 3-month all-cause mortality (adjusted HR [aHR]: 3.09; 95% CI: 1.91-5.01; P < 0.01) and increased early RV failure (aHR: 2.05; 95% CI: 1.10-3.92; P = 0.03). Notably, early VA without ES showed no prognostic impact. Multivariable analysis identified 4 independent predictors of early ES: pre-LVAD RV S' wave ≤9.5 cm/s (aHR: 2.25; 95% CI: 1.23-4.14), heart failure duration of ≥5 years (aHR: 2.41; 95% CI: 1.10-5.28), history of VAs (aHR: 4.43; 95% CI: 2.21-8.87), and prior mechanical circulatory support (aHR: 6.40; 95% CI: 2.12-19.33). The EarlyES-LVAD score, based on these variables, showed good discrimination (C-statistic 0.75) and stratified patients into low-risk (score 0-1), intermediate-risk (score 2-3), and high-risk (score 4-6) groups, with corresponding early ES rates of 1.1%, 3.9%, and 12.4%. CONCLUSIONS:Early ES, but not isolated early VAs, is associated with substantially worse outcomes in LVAD recipients. The EarlyES-LVAD score enables practical risk stratification, facilitating targeted therapeutic interventions in high-risk patients.

BACKGROUND:While guideline-directed medical therapy (GDMT) is recommended for left ventricular assist device (LVAD) recipients, real-world evidence supporting its clinical impact remains limited. This study evaluated the association between GDMT prescription and clinical outcomes in LVAD patients. METHODS:This international retrospective multicentre study included 875 LVAD patients from 22 centres. Patients were categorized based on the number of GDMT (ACE-I/ARBs, beta-blockers, MRAs) prescribed. Primary outcome was 6-month all-cause mortality. Secondary outcome was late ventricular arrhythmias (VAs) (>30 days post-implant). Multivariable Cox regression and ordinal logistic regression analyses were performed. RESULTS:Overall, only 261 patients (29.8%) received triple GDMT, while 97 (11.1%) received no GDMT. After multivariable adjustment, the number of prescribed GDMTs was independently associated with improved survival, with aHRs for all-cause mortality of 0.51 (0.33-0.75, P < .01) for triple therapy, 0.39 (0.26-0.59, P < .01) for dual therapy, and 0.45 (0.30-0.67, P < .01) for single therapy, all compared with no GDMT. Similarly, ACE-I/ARB were associated with a lower risk of late VAs (aHR 0.65 [0.50-0.84], P < .01). Female sex, diabetes, early VAs, and higher bilirubin levels were associated with lower GDMT prescription rates. Major LVEDD improvement (≥10 mm reduction) increased progressively from 51.5% without GDMT to 66.1% with triple therapy. CONCLUSION:In this large international study, the use of GDMT in LVAD patients was associated with improved survival, with benefits observed even with single-agent therapy. Despite these benefits, only 30% of patients received optimal triple therapy, highlighting the need for improved implementation strategies and standardized protocols in this population.

Background Data on the spontaneous onset of ventricular tachyarrhythmias (VTAs) in Brugada syndrome (BrS), including polymorphic ventricular tachycardia (PVT) and monomorphic ventricular tachycardia (MVT), remain limited. Objectives The goal of this study was to compare the clinical profile and mode of initiation of PVT and MVT in BrS. Methods This retrospective multicenter registry included 154 patients with BrS from 29 centers with documented VTA initiation captured by implantable cardioverter-defibrillator (94.9%) or electrocardiogram (5.1%). A total of 234 VTAs were analyzed, and initiation patterns were classified by using predefined electrocardiographic criteria. Results PVT was observed in 80.5% of patients, MVT in 16.9%, and both in 2.6%. Patients with MVT tended to be older, exhibit drug-induced Brugada electrocardiogram, and were more frequently White. Pause-dependent initiation occurred in approximately 25% of PVT and approximately 33% of MVT episodes. Coupling intervals initiating PVT were nonsignificantly shorter than for MVT (median 368 milliseconds vs 395 milliseconds), with a significantly lower prematurity index and faster early arrhythmia cycle length. Antecedent premature ventricular complexes were present in approximately 43% of both VTA types, commonly sharing morphology with the initiating premature ventricular complex. The prevalence of pathogenic/likely pathogenic SCN5A mutation did not differ between groups. Conclusions In this largest analysis to date of spontaneous VTA onset in BrS, MVT occurred in a substantial minority and was associated with older age, White ethnicity, drug-induced electrocardiogram pattern, and a preceding tachycardia. Initiation patterns were broadly similar across arrhythmia types, although PVT exhibited a significantly lower prematurity index and faster early cycle length despite only nonsignificant shorter coupling intervals. These findings refine the clinical and electrophysiological characterization of BrS-related arrhythmias and delineate distinct features of PVT and MVT initiation.

Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. 'Lethal events' were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. 'Cardiac events' were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Introduction Young-onset atrioventricular block (AVB) is a rare but clinically important condition that may require lifelong pacing. When immune-mediated and structural causes are excluded, the underlying cause often remains unknown. Although monogenic causes have been described in various cardiac and syndromic disorders, the genetic basis of isolated sporadic AVB is poorly defined. We therefore performed trio-based whole-genome sequencing (WGS) to identify candidate coding and regulatory de novo variants in sporadic young-onset AVB. Methods We performed WGS in eight trios comprising probands diagnosed before 20 years of age and their unaffected parents. All probands had non-immune AVB without structural heart disease and no pathogenic variants in known AVB genes on prior panel testing. Trio analysis was used to identify heterozygous de novo variants. Coding and splice-site variants were analyzed alongside non-coding variants, the latter restricted to cardiac open chromatin regions defined using integrated ATAC-seq datasets from healthy human cardiac tissues. Results All probands were females and the median age at diagnosis was 4.0 years (IQR 1.5–10.0). We identified 11 rare de novo coding variants and 14 rare de novo non-coding variants within cardiac open chromatin regions. One potentially deleterious coding variant was identified in SOS2, a gene reported in congenital heart disease. The other two coding variants involved genes with cardiac phenotypes in animal models. One non-coding variant was located upstream of a gene expressed in the atrioventricular canal during cardiac development. Several candidate genes showed supporting RNA and/or protein expression in cardiac tissue. No recurrent variants or genes were identified. Conclusion These preliminary findings suggest that sporadic young-onset AVB has a genetically heterogeneous basis and that both coding and regulatory de novo variants may contribute to disease pathogenesis. Although replication and functional validation are needed, WGS including regulatory genome analysis may improve the investigation of otherwise unexplained early-onset conduction disease.

INTRODUCTION:Radiofrequency ablation is a cornerstone therapy for patients with ischemic cardiomyopathy (ICM) presenting with ventricular tachycardia (VT). In this context, ablation is typically performed endocardially as a first-line approach. However, despite acute procedural success, the risk of recurrence remains high, potentially due to the presence of epicardial substrate. Several observational studies have suggested the potential benefits of a first-line endo-epicardial approach in decreasing recurrence. In this context, the EPIC-VT trial was designed to compare endocardial-only ablation versus combined endo-epicardial ablation as a first-line approach in ICM patients with VT. METHODS:The EPIC-VT trial is a prospective, multicenter, controlled, randomized, open-label superiority trial with two parallel groups (endocardial-only approach vs. combined endo-epicardial approach) in a 1:1 ratio. The primary objective of this study is to demonstrate that a combined endo-epicardial approach reduces the risk of VT recurrence compared to an endocardial approach alone in patients with ICM. Patients will be followed for 2 years after the procedure. RESULTS AND CONCLUSION:To date, only retrospective studies have compared VA recurrences in patients with ICM, depending on whether ablation was performed using an endocardial or an endo-epicardial approach, with conflicting results. A meta-analysis suggested an advantage of the endo-epicardial approach over the endocardial approach (odds ratio = 0.39 [95% CI: 0.18-0.83]). However, the level of evidence remains low, and no controlled randomized study has confirmed this hypothesis. If the EPIC-VT study confirms the superiority of a first-line endo-epicardial approach, such strategy could become the preferred option for VT ablation in ICM, thereby reducing the risk of VA recurrence.