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.

AIMS:Heart failure (HF) and clinical atrial fibrillation are closely linked, but the relationship between device-detected subclinical atrial fibrillation (SCAF) and HF is unclear. We aimed to determine incidence and clinical risk factors for HF events among patients with SCAF. METHODS:We included 3986 patients from the ARTESiA (Apixaban for the Reduction of Thromboembolism in Patients with Device-Detected Subclinical Atrial Fibrillation) trial. ARTESiA investigated the effect of apixaban versus aspirin for stroke prevention in patients with episodes of SCAF ≤24 hours. In this secondary analysis, we explored the number and duration of SCAF episodes at baseline as risk markers for HF hospitalization or HF-related death. SCAF progression was analysed as a time-dependent covariate and defined as the development of SCAF >24 hours or clinical atrial fibrillation. RESULTS:Over a mean follow-up of 4.1 ± 1.7 years, SCAF progression was observed in 1244 patients (31%). Heart failure hospitalization or HF-related death occurred in 515 (13%) patients at a rate of 3.3 [95% confidence interval (CI) 3.1-3.6] per 100 person-years. A total of 172 HF-related events occurred after SCAF progression (7.2 events, 95% CI 6.2-8.3, per 100 PY). SCAF progression was an independent risk factor for HF hospitalization or HF-related death (hazard ratio 2.72, 95% CI 2.24-3.31). CONCLUSION:Heart failure hospitalization and HF-related death are common in patients with SCAF. Progression to longer SCAF episodes or clinical AF were associated with HF events, but episodes <24 h were not. These findings underscore the need for close surveillance of SCAF patients to detect complications and potentially improve outcomes.

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.

Background Therapeutic strategies for electrical storm (ES) in patients with hypertrophic cardiomyopathy (HCM) are not well defined, yet this population is at risk for ventricular arrhythmias (VAs). Objectives The aim of this study was to analyze acute management, in-hospital mortality, and long-term outcomes of patients with HCM experiencing ES. Methods This multicenter study retrospectively enrolled patients with ES complicating HCM between 2017 and 2023 in 6 tertiary centers. Results Twenty-three patients were included (mean age 61.5 ± 15.2 years, 73.9% male, left ventricular ejection fraction 50% ± 14%). Five patients (22%) had an apical aneurysm. Ten (43.4%) patients had a history of VA, including 3 with previous ES. The majority of VAs were monomorphic ventricular tachycardias (18 patients [78%]). Most patients received amiodarone (n = 20 [87%]) and beta-blockers (n = 16 [70%]). For 10 patients (44%), a radiofrequency catheter ablation was performed (including 2 endo-epicardial ablations), resulting in negative programmed ventricular stimulation in 4 patients. During their hospital management, 8 patients experienced recurrences of VA (2 [25%] previously ablated and 6 [75%] nonablated). Two (9%) patients died during the index hospitalization and 4 other patients died following discharge (median follow-up 18 months). Seven patients (30%) experienced recurrences of arrhythmias, including 4 who had undergone ablation. Radiofrequency ablation was not associated with better outcomes (recurrence rate or overall survival) in this study. Conclusions ES in HCM frequently resolves using antiarrhythmic drugs. Many patients will present with VA recurrences. Long-term outcomes were poor, and one-fourth of the patients ended up dying at 18 months. Further studies are warranted to better analyze radiofrequency outcomes in this specific population.

Electrical storm represents an urgent challenge in electrophysiology. Despite the use of antiarrhythmic medications and catheter ablation, refractory ventricular arrhythmias may persist, prompting the use of neuromodulation. This approach has evolved over the years, facing initial challenges owing to the intricacies of the autonomic nervous system. Animal studies have significantly enhanced our understanding of this system, paving the way for human studies on sympathetic modulation, which gained momentum in the early 2000s and expanded notably in cardiology in the 2010s. Presently, a variety of techniques coexist and offer diverse alternatives. Additionally, there are promising avenues for development that are primarily explored in animal models. This review aims to shed light on the diverse approaches currently available in this field.

La place des dispositifs implantables dans le traitement de l’insuffisance cardiaque chronique a connu un essor considérable au cours des vingt dernières années, principalement dans le contexte de l’insuffisance cardiaque à fraction d’éjection du ventricule gauche altérée. À côté du défibrillateur automatique implantable, dont la mise en œuvre et les indications ne seront pas abordées ici, les systèmes de stimulation permettent d’optimiser l’hémodynamique avec un double objectif, amélioration fonctionnelle et réduction de la morbi-mortalité. Seront successivement envisagées la resynchronisation cardiaque, réservée aux patients présentant un asynchronisme électromécanique, la modulation de la contractilité et la stimulation du système nerveux autonome. Seule la stimulation biventriculaire, évaluée dans le cadre de nombreuses études prospectives randomisées, a démontré un bénéfice sur la morbi-mortalité, sous-tendu par un remodelage du ventricule gauche, et associé à une amélioration fonctionnelle. C’est la seule technique avec un niveau de recommandation élevé. Les autres modalités de stimulation nécessitent d’être plus largement évaluées afin de mieux définir leur positionnement dans la stratégie thérapeutique.

BACKGROUND:The ARTESiA trial randomized patients with a pacemaker (PM), implantable cardioverter-defibrillator (ICD), or implantable cardiac monitor (ICM) and with subclinical atrial fibrillation to either apixaban or aspirin. OBJECTIVE:We aimed to explore the effects of apixaban in the subset of patients with an ICM. METHODS:We assessed the efficacy outcome of stroke or systemic embolism and the safety outcome of major bleeding, stratifying by device type. RESULTS:Of 4012 participants, 209 (5.2%) had ICM and 3803 (94.8%) had PM/ICD. Patients with ICM were younger (74.9 ± 7.4 vs 76.9 ± 7.6 years) and more likely to be female (50.2% vs 35.3%) and to have a previous stroke (24.9% vs 7.7%) than those with PM/ICD. In the ICM cohort, stroke/systemic embolism occurred in 1 of 103 in the apixaban group (0.3%/year) vs 9 of 106 in the aspirin group (2.6%/year) (hazard ratio [HR], 0.11; [95% confidence interval {CI}, 0.01-0.88]; absolute risk reduction [ARR] 2.31%/year [95% CI, 0.55-4.07]). The corresponding rates in the PM/ICD cohort were 0.8%/year with apixaban vs 1.2%/year with aspirin (HR, 0.69 [95% CI, 0.49-0.98]; ARR 0.36%/year [95% CI, 0.02-0.70]; Pinteraction = .078 and .002, respectively). Among patients with ICM, major bleeding occurred at 1.3%/year vs 1.1%/year for apixaban vs aspirin (HR, 1.13 [95% CI, 0.30-4.31]). No significant difference in HR or ARR was observed across the device types (Pinteraction = .808 and .406, respectively). CONCLUSION:In ARTESiA, patients with ICM experienced a stroke rate of 2.6%/year on aspirin, higher than that in the remaining trial population. The risk was significantly reduced by apixaban, consistent with the overall ARTESiA results.

BACKGROUND:Antithrombotic management in patients with chronic coronary syndrome and previous stent implantation who require long-term oral anticoagulation is highly challenging in daily practice, especially in those at high residual risk of coronary and vascular events. Dual therapy with oral anticoagulation and aspirin may lead to a higher risk of bleeding, whereas stopping aspirin in high-risk patients with coronary artery disease after percutaneous coronary intervention may lead to recurrent ischaemic events. AIM:To assess the optimal antithrombotic regimen that should be pursued long term (often lifelong) in these patients. METHODS:The AQUATIC study is a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicentre study conducted in patients with chronic coronary syndrome at high risk of ischaemic events (i.e., stent implantation [> 6 months before inclusion] in a context of previous acute coronary syndrome and/or with high-risk features of ischaemic event recurrences) and requiring long-term oral anticoagulation. For superiority, we ensure 80% power at level α=0.05 to detect a 25% reduction in hazard in the experimental group relative to the control group. Overall, 2000 patients will be randomized in a 1:1 ratio to receive either oral anticoagulation and aspirin or oral anticoagulation and placebo. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization and acute limb ischaemia. Major bleeding according to the International Society on Thrombosis and Haemostasis definition is a secondary safety endpoint that will be assessed as a priority. CONCLUSION:The AQUATIC trial will test the efficacy and safety of adding aspirin to long-term oral anticoagulation in patients with chronic coronary syndrome and previous coronary stenting who are at high residual risk of recurrent ischaemic events and require oral anticoagulation.

BACKGROUND:The Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Subclinical Atrial Fibrillation (ARTESiA) trial enrolled patients with subclinical atrial fibrillation (SCAF) lasting < 24 hours. OBJECTIVE AND METHODS:We assessed the association of SCAF progression to clinical atrial fibrillation or SCAF > 24 hours with adverse outcomes and predictors of SCAF progression. RESULTS:During follow-up (4.1 ± 1.7 years), SCAF progressed in 1250 of 4012 patients (31.2%) at a rate of 9.3% per patient-year. SCAF progression was associated with adverse outcomes, with the following hazard ratios (HRs) and 95% confidence intervals (CIs): all-cause death, 2.12 (1.83-2.45); heart failure death, 4.81 (3.19-7.27); and arrhythmic death, 2.62 (1.58-4.35). The rate of stroke/systemic embolism in patients who remained on blinded aspirin therapy after SCAF progression was 1.42% per patient-year. If one limits the definition of progression to SCAF lasting > 24 hours, the rate was 1.75% per patient-year. Baseline variables modestly predicted SCAF progression (C statistic 0.59; 95% CI 0.57-0.61), including age (HR 1.02 per year; 95% CI 1.01-1.03 per year), male sex (HR 1.30; ; 95% CI 1.14-1.47), heart failure (HR 1.28; 95% CI 1.13-1.46), diabetes mellitus (HR 1.18; 95% CI 1.04-1.34), left atrial diameter > 4.1 cm (HR 1.28; 95% CI 1.08-1.52), and longest baseline SCAF episode duration > 1 hour (HR 1.59; 95% CI 1.42-1.79). CONCLUSION:SCAF progression occurred in >9% of patients per year and was associated with a doubling of the risk of all-cause mortality, driven by increases in both heart failure-related and arrhythmic deaths. Patients who remained on aspirin after SCAF progression had an annual rate of stroke/systemic embolism of 1.42%, which is higher than the threshold currently proposed for oral anticoagulant prophylaxis.

The role of implantable devices in the treatment of chronic heart failure has grown considerably over the past twenty years, mainly in the context of heart failure with impaired left ventricular ejection fraction. In addition to the implantable cardioverter defibrillator, the implementation and indications of which will not be discussed here, stimulation systems were developed to optimize hemodynamics with a dual objective, functional improvement and reduction of morbidity and mortality. Cardiac resynchronization therapy, reserved for patients with electromechanical asynchrony, modulation of contractility and stimulation of the autonomic nervous system, will be successively considered. Only bi-ventricular pacing, evaluated in numerous prospective randomized studies, has demonstrated a benefit on morbidity and mortality, related to remodeling of the left ventricle, and associated with functional improvement. This is the only technique with a high level of recommendation. The other stimulation modalities need to be more widely evaluated to better define their positioning in the therapeutic strategy. (c) 2025 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Background. - Following implantation/replacement of an implantable cardioverter-defibrillator, patients are legally subjected to variable lengths of driving restrictions based on the indication (1 and 3 months after primary and secondary prevention, respectively; 1 week after device replacement). Aim. - To assess the incidence of ventricular arrhythmia during the theoretical driving restriction period in a large cohort of patients. Methods. - Patients who underwent implantable cardioverter-defibrillator implantation for primary or secondary prevention or device replacement between 2015 and 2021 were included retrospectively. The primary endpoint was the occurrence of ventricular arrhythmia during the theoretical driving restriction period, as defined by guidelines. Results.- A total of 914 patients were analysed, including 654 first implantations (438 and 216 for primary and secondary prevention, respectively) and 260 device replacements. The primary outcome occurred in 2/438 patients (0.004%) during the 1-month period following device implantation for primary prevention and in 25/216 patients (11.5%) during the 3-month period following device implantation for secondary prevention; it did not occur in the 1-week period following device replacement. The monthly calculated risk of harm remained below the accepted threshold of 0.005% for each group. Conclusions. - Primary prevention patients, such as those who have undergone device replacement, have a low risk of ventricular arrhythmia, which could lead to a reduction in their driving restriction period. Secondary prevention patients experienced a higher risk of recurrent ventricular arrhythmia, supporting the 3-month driving restriction period. (c) 2024 Les Auteurs. Publie par Elsevier Masson SAS. Cet article est publie en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

Quinidine, the first antiarrhythmic drug, was widely used during the 20th century. Multiple studies have been conducted to provide insights into the pharmacokinetics and pleiotropic effects of Class Ia antiarrhythmic drugs. However, safety concerns and the emergence of new drugs led to a decline in their use during the 1990s.Despite this, recent studies have reignited the interest in quinidine, particularly for ventricular arrhythmias, where other antiarrhythmics have failed. In conditions such as Brugada syndrome, idiopathic ventricular fibrillation, early repolarization syndrome, short QT syndrome, and electrical storms, quinidine remains a valuable asset. Starting from the European and American recommendations, this comprehensive review aimed to explore the various indications for quinidine and the studies that support its use. We also discuss the potential future of quinidine, including the necessary research to optimize its use and patient selection. Additionally, it addresses the imperative task of mitigating the iatrogenic burden associated with quinidine usage and confronts the challenge of ensuring drug accessibility.