Systematic analysis of SCN5A variants associated with inherited cardiac diseases.

BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial. OBJECTIVE: We aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. RESULTS: The study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link. CONCLUSION: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable.

Clonal Hematopoiesis Is Associated With Long-Term Adverse Outcomes Following Cardiac Surgery.

BACKGROUND: Cardiac surgery triggers sterile innate immune responses leading to postoperative complications. Clonal hematopoiesis (CH) is associated with short-term inflammation-mediated outcomes after cardiac surgery. The impact of CH on long-term postoperative outcomes remains unknown. METHODS AND RESULTS: In this cohort study, patients undergoing elective cardiac surgery were included from January 2017 to September 2019. Patients were screened for CH using a predefined gene panel of 19 genes. Recorded clinical events were all-cause death, major adverse cardiac and cerebral events including cardiovascular death, myocardial infarction or nonscheduled coronary revascularization, stroke, and hospitalization for acute heart failure. The primary study outcome was time to a composite criterion including all-cause mortality and major adverse cardiac and cerebral events. Among 314 genotyped patients (median age: 67 years; interquartile range 59-74 years), 139 (44%) presented with CH, based on a variant allelic frequency ≥1%. Carriers of CH had a higher proportion of patients with a history of atrial fibrillation (26% for CH versus 17% for non-CH carriers, P=0.022). The most frequently mutated genes were DNMT3A, TET2, and ASXL1. After a median follow-up of 1203 [813-1435] days, the primary outcome occurred in 50 patients. After multivariable adjustment, CH was independently associated with a higher risk for the primary outcome (hazard ratio, 1.88 [95% CI, 1.05-3.41], P=0.035). Most adverse events occurred in patients carrying TET2 variants. CONCLUSIONS: In patients undergoing cardiac surgery, CH is frequent and associated with a 2-fold increased long-term risk for major adverse clinical outcomes. CH is a novel risk factor for long-term postcardiac surgery complications and might be useful to personalize management decisions. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03376165.

Impact of Catheter Ablation of Electrical Storm on Survival: A Propensity Score-Matched Analysis.

BACKGROUND: Electrical storm (ES) is a life-threatening condition, associated with substantial early and subacute mortality. Catheter ablation (CA) is a well-established therapy for ES. However, data regarding the impact of CA on the short-term and midterm survival of patients admitted for ES remain unclear. OBJECTIVES: This multicenter study aimed to investigate the impact of CA of ES on survival outcomes, while accounting for key patient characteristics associated with treatment selection. METHODS: A propensity score-matching (PSM) analysis was performed on 780 consecutive patients admitted for ES in 4 tertiary centers. PSM (1:1) based on the main characteristics associated with the use of CA or medical therapy alone was performed, resulting in 2 groups of 288 patients. RESULTS: After PSM, patients who underwent CA (n = 288) and those treated with medical therapy alone (n = 288) did not present any significant differences in the main demographic characteristics, ES presentation, and management. Compared with medical therapy alone, CA was associated with a significantly lower rate of ES recurrence at 1 year (5% vs 26%; P < 0.001). Similarly, CA was associated with a higher 1-year (91% vs 81%; P < 0.001) and 3-year (78% vs 71%; P = 0.017) survival after discharge. In subgroup analyses, effect of ablation therapy remained consistent in patients older than 70 years of age (HR: 0.39; 95% CI: 0.24-0.66), with substantial efficacy in patients with a LVEF <35% (HR: 0.39; 95% CI: 0.27-0.59). CONCLUSIONS: In propensity-matched analyses, this large study shows that CA-based management of patients admitted for ES is associated with a reduction in mortality compared with medical treatment, particularly in patients with a low ejection fraction.

Management and outcomes of pregnant women with cardiovascular diseases in a cardio-obstetric team.

BACKGROUND: Cardiovascular diseases (CVDs) are currently the leading cause of maternal death in Western countries. Although multidisciplinary cardio-obstetric teams are recommended to improve the management of pregnant women with CVD, data supporting this approach are scarce. AIMS: To describe the characteristics and outcomes of pregnant patients with CVD managed within the cardio-obstetric programme of a tertiary centre. METHODS: We included every pregnant patient with history of CVD managed by our cardio-obstetric team between June 2017 and December 2019, and collected all major cardiovascular events (death, heart failure, acute coronary syndromes, stroke, endocarditis and aortic dissection) that occurred during pregnancy, peripartum and the following year. RESULTS: We included 209 consecutive pregnancies in 202 patients. CVDs were predominantly valvular heart diseases (37.8%), rhythm disorders (26.8%), and adult congenital heart diseases (22.5%). Altogether, 47.4% were classified modified World Health Organization (mWHO)>II, 66.5% had CARdiac disease in PREGnancy score (CARPREG II)≥2 and 80 pregnancies (38.3%) were delivered by caesarean section. Major cardiovascular events occurred in 16 pregnancies (7.7%, 95% confidence interval [CI] 4.5-12.2) during pregnancy and in three others (1.5%, 95% CI 0.3-4.1) during 1-year follow-up. Most events (63.1%) occurred in the 16.3% of patients with unknown CVD before pregnancy. CONCLUSIONS: The management of pregnant patients with CVD within a cardio-obstetric team seems encouraging as we found a relatively low rate of cardiovascular events compared to the high-risk profile of our population. However, most of the remaining events occurred in patients without cardiac monitoring before pregnancy.

Genetic Factors Altering Immune Responses in Atrial Fibrillation: JACC Review Topic of the Week.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with a range of adverse clinical outcomes. Accumulating evidence points to inflammatory processes resulting from innate immune responses as a cornerstone in AF pathogenesis. Genetic and epigenetic factors affecting leukocytes have been identified as key modulators of the inflammatory response. Inherited variants in genes encoding proteins involved in the innate immune response have been associated with increased risk for AF recurrence and stroke in AF patients. Furthermore, acquired somatic mutations associated with clonal hematopoiesis of indeterminate potential, leukocyte telomere shortening, and epigenetic age acceleration contribute to increased AF risk. In individuals carrying clonal hematopoiesis of indeterminate potential, myocardial monocyte-derived macrophage shift toward a proinflammatory phenotype may precipitate AF. Further studies are needed to better understand the role of genetic regulation of the native immune response in atrial arrhythmogenesis and its therapeutic potential as a target for personalized medicine.

Low-Density Neutrophils and Neutrophil Extracellular Traps (NETs) Are New Inflammatory Players in Heart Failure.

BACKGROUND: Heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation. Circulating neutrophils regroup 2 subtypes termed high- and low-density neutrophils (HDNs and LDNs). LDNs represent less than 2% of total neutrophil under physiological conditions, but their counts increase in multiple pathologies, releasing more inflammatory cytokines and neutrophil extracellular traps (NETs). The aims of this study were to assess the differential count and role of HDNs, LDNs, and NETs-related activities in patients with heart failure (HF). METHODS: HDNs and LDNs were isolated from human blood by density gradient and purified by fluorescence-activated cell sorting (FACS) and their counts obtained by flow cytometry. Formation of NETs (NETosis) was quantified by confocal microscopy. Circulating inflammatory and NETosis biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Neutrophil adhesion onto human extracellular matrix (hECM) was assessed by optical microscopy. RESULTS: A total of 140 individuals were enrolled, including 33 healthy volunteers (HVs), 41 HFrEF (19 stable patients and 22 presenting acute decompensated HF [ADHF]), and 66 patients with HFpEF (36 stable patients and 30 presenting HF decompensation). HDNs and LDNs counts were significantly increased up to 39% and 2740%, respectively, in patients with HF compared with HVs. In patients with HF, the correlations among LDNs counts and circulating inflammatory (CRP, IL-6 and -8), troponin T, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and NETosis components were significant. In vitro, LDNs expressed more citrullinated histone H3 (H3Cit) and NETs and were more proadhesive, with ADHFpEF patients presenting the highest proinflammatory profile. CONCLUSIONS: Patients with HFpEF present higher levels of circulating LDNs- and NETs-related activities, which are the highest in the context of acute HF decompensation.

Left atrial cardiomyopathy: Pathophysiological insights, assessment methods and clinical implications.

Atrial cardiomyopathy is defined as any complex of structural, architectural, contractile or electrophysiological changes affecting atria, with the potential to produce clinically relevant manifestations. Most of our knowledge about the mechanistic aspects of atrial cardiomyopathy is derived from studies investigating animal models of atrial fibrillation and atrial tissue samples obtained from individuals who have a history of atrial fibrillation. Several noninvasive tools have been reported to characterize atrial cardiomyopathy in patients, which may be relevant for predicting the risk of incident atrial fibrillation and its related outcomes, such as stroke. Here, we provide an overview of the pathophysiological mechanisms involved in atrial cardiomyopathy, and discuss the complex interplay of these mechanisms, including aging, left atrial pressure overload, metabolic disorders and genetic factors. We discuss clinical tools currently available to characterize atrial cardiomyopathy, including electrocardiograms, cardiac imaging and serum biomarkers. Finally, we discuss the clinical impact of atrial cardiomyopathy, and its potential role for predicting atrial fibrillation, stroke, heart failure and dementia. Overall, this review aims to highlight the critical need for a clinically relevant definition of atrial cardiomyopathy to improve treatment strategies.

One-year mortality and causes of death after stereotactic radiation therapy for refractory ventricular arrhythmias: A systematic review and pooled analysis.

Patients treated with cardiac stereotactic body radiation therapy (radioablation) for refractory ventricular arrhythmias are patients with advanced structural heart disease and significant comorbidities. However, data regarding 1-year mortality after the procedure are scarce. This systematic review and pooled analysis aimed at determining 1-year mortality after cardiac radioablation for refractory ventricular arrhythmias and investigating leading causes of death in this population. MEDLINE/EMBASE databases were searched up to January 2023 for studies including patients undergoing cardiac radioablation for the treatment of refractory ventricular arrhythmias. Quality of included trials was assessed using the NIH Tool for Case Series Studies (PROSPERO CRD42022379713). A total of 1,151 references were retrieved and evaluated for relevance. Data were extracted from 16 studies, with a total of 157 patients undergoing cardiac radioablation for refractory ventricular arrhythmias. Pooled 1-year mortality was 32 % (95 %CI: 23-41), with almost half of the deaths occurring within three months after treatment. Among the 157 patients, 46 died within the year following cardiac radioablation. Worsening heart failure appeared to be the leading cause of death (52 %), although non-cardiac mortality remained substantial (41 %) in this population. Age≥70yo was associated with a significantly higher 12-month all-cause mortality (p<0.022). Neither target volume size nor radiotherapy device appeared to be associated with 1-year mortality (p = 0.465 and p = 0.199, respectively). About one-third of patients undergoing cardiac stereotactic body radiation therapy for refractory ventricular arrhythmias die within the first year after the procedure. Worsening heart failure appears to be the leading cause of death in this population.

Feasibility and prognostic significance of ventricular-arterial coupling after myocardial infarction: the RIGID-MI cohort.

AIMS: The clinical significance and feasibility of the recently described non-invasive parameters exploring ventricular-arterial coupling (VAC) remain uncertain. This study aimed to assess VAC parameters for prognostic stratification in stable patients with left ventricular ejection fraction (LVEF) ≥40% following myocardial infarction (MI). METHODS AND RESULTS: Between 2018 and 2021, patients with LVEF ≥40% were evaluated 1 month following MI using transthoracic echocardiography (TTE) and arterial tonometry at rest and after a handgrip test. VAC was studied via the ratio between arterial elastance (Ea) and end-systolic LV elastance (Ees) and between pulse wave velocity (PWV) and global longitudinal strain (GLS). Patients were followed for major adverse cardiovascular events (MACE): all-cause death, acute heart failure, stroke, AMI, and urgent cardiovascular hospitalization. Among the 374 patients included, Ea/Ees and PWV/GLS were obtained at rest for 354 (95%) and 253 patients (68%), respectively. Isometric exercise was workable in 335 patients (85%). During a median follow-up of 32 months (interquartile range: 16-42), 41 (11%) MACE occurred. Patients presenting MACE were significantly older and had a higher prevalence of peripheral arterial disease, lower GLS, higher Ea, PWV, and PWV/GLS ratio. The Ea/Ees ratio and standard TTE parameters during isometric exercise were not associated with MACE. After adjustment, the PWV/GLS ratio was the only VAC parameter independently associated with outcome. Receiver operating characteristic curve analysis identified a PWV/GLS ratio >0.70 (Youden's index = 0.37) as the best threshold to identify patients developing MACE: hazard ratio (95% confidence interval) = 2.2 (1.14-4.27), P = 0.02. CONCLUSION: The PWV/GLS ratio, assessed 1 month after MI, identifies a group of patients at higher risk of MACE providing additional value on top of conventional non-invasive parameters.

Genetic Atrial Cardiomyopathies: Common Features, Specific Differences, and Broader Relevance to Understanding Atrial Cardiomyopathy.

Atrial cardiomyopathy is a condition that causes electrical and contractile dysfunction of the atria, often along with structural and functional changes. Atrial cardiomyopathy most commonly occurs in conjunction with ventricular dysfunction, in which case it is difficult to discern the atrial features that are secondary to ventricular dysfunction from those that arise as a result of primary atrial abnormalities. Isolated atrial cardiomyopathy (atrial-selective cardiomyopathy [ASCM], with minimal or no ventricular function disturbance) is relatively uncommon and has most frequently been reported in association with deleterious rare genetic variants. The genes involved can affect proteins responsible for various biological functions, not necessarily limited to the heart but also involving extracardiac tissues. Atrial enlargement and atrial fibrillation are common complications of ASCM and are often the predominant clinical features. Despite progress in identifying disease-causing rare variants, an overarching understanding and approach to the molecular pathogenesis, phenotypic spectrum, and treatment of genetic ASCM is still lacking. In this review, we aim to analyze the literature relevant to genetic ASCM to understand the key features of this rather rare condition, as well as to identify distinct characteristics of ASCM and its arrhythmic complications that are related to specific genotypes. We outline the insights that have been gained using basic research models of genetic ASCM in vitro and in vivo and correlate these with patient outcomes. Finally, we provide suggestions for the future investigation of patients with genetic ASCM and improvements to basic scientific models and systems. Overall, a better understanding of the genetic underpinnings of ASCM will not only provide a better understanding of this condition but also promises to clarify our appreciation of the more commonly occurring forms of atrial cardiomyopathy associated with ventricular dysfunction.

Subcutaneous Implantable Cardioverter-Defibrillators in Patients With Congenital Heart Disease.

BACKGROUND: Very few data have been published on the use of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in patients with congenital heart disease (CHD). OBJECTIVES: The aim of this study was to analyze outcomes associated with S-ICDs in patients with CHD. METHODS: This nationwide French cohort including all patients with an S-ICD was initiated in 2020 by the French Institute of Health and Medical Research. Characteristics at implantation and outcomes were analyzed in patients with CHD. RESULTS: From October 12, 2012, to December 31, 2019, among 4,924 patients receiving an S-ICD implant in 150 centers, 101 (2.1%) had CHD. Tetralogy of Fallot, univentricular heart, and dextro-transposition of the great arteries represented almost one-half of the population. Patients with CHD were significantly younger (age 37.1 ± 15.4 years vs 50.1 ± 14.9 years; P < 0.001), more frequently female (37.6% vs 23.0%; P < 0.001), more likely to receive an S-ICD for secondary prevention (72.3% vs 35.9%; P < 0.001), and less likely to have severe systolic dysfunction of the systemic ventricle (28.1% vs 53.1%; P < 0.001). Over a mean follow-up period of 1.9 years, 16 (15.8%) patients with CHD received at least 1 appropriate shock, with all shocks successfully terminating the ventricular arrhythmia. The crude risk of appropriate S-ICD shock was twice as high in patients with CHD compared with non-CHD patients (annual incidences of 9.0% vs 4.4%; HR: 2.1; 95% CI: 1.3-3.4); however, this association was no longer significant after propensity matching (especially considering S-ICD indication, P = 0.12). The burden of all complications (HR: 1.2; 95% CI: 0.7-2.1; P = 0.4) and inappropriate shocks (HR: 0.9; 95% CI: 0.4-2.0; P = 0.9) was comparable in both groups. CONCLUSIONS: In this nationwide study, patients with CHD represented 2% of all S-ICD implantations. Our findings emphasize the effectiveness and safety of S-ICD in this particularly high-risk population. (S-ICD French Cohort Study [HONEST]; NCT05302115).

Heart transplantation as a rescue strategy for patients with refractory electrical storm.

AIMS: Heart transplantation (HT) can be proposed as a therapeutic strategy for patients with severe refractory electrical storm (ES). Data in the literature are scarce and based on case reports. We aimed at determining the characteristics and survival of patients transplanted for refractory ES. METHODS AND RESULTS: Patients registered on HT waiting list during the following days after ES and eventually transplanted, from 2010 to 2021, were retrospectively included in 11 French centres. The primary endpoint was in-hospital mortality. Forty-five patients were included [82% men; 55.0 (47.8-59.3) years old; 42.2% and 26.7% non-ischaemic dilated or ischaemic cardiomyopathies, respectively]. Among them, 42 (93.3%) received amiodarone, 29 received (64.4%) beta blockers, 19 (42.2%) required deep sedation, 22 had (48.9%) mechanical circulatory support, and 9 (20.0%) had radiofrequency catheter ablation. Twenty-two patients (62%) were in cardiogenic shock. Inscription on wait list and transplantation occurred 3.0 (1.0-5.0) days and 9.0 (4.0-14.0) days after ES onset, respectively. After transplantation, 20 patients (44.4%) needed immediate haemodynamic support by extracorporeal membrane oxygenation (ECMO). In-hospital mortality rate was 28.9%. Predictors of in-hospital mortality were serum creatinine/urea levels, need for immediate post-operative ECMO support, post-operative complications, and surgical re-interventions. One-year survival was 68.9%. CONCLUSION: Electrical storm is a rare indication of HT but may be lifesaving in those patients presenting intractable arrhythmias despite usual care. Most patients can be safely discharged from hospital, although post-operative mortality remains substantial in this context of emergency transplantation. Larger studies are warranted to precisely determine those patients at higher risk of in-hospital mortality.

Incidence, source, and prognostic impact of major bleeding across the spectrum of aortic stenosis.

BACKGROUND: Severe aortic stenosis (AS) has been associated with bleeding. However, there is a lack of prospective assessment of bleeding events and their clinical significance in a large population of outpatients with variable degree of AS severity. OBJECTIVES: To assess the incidence, source, determinants, and prognostic impact of major bleeding in patients with variable degree of AS severity. METHODS: Between May 2016 and December 2017, consecutive outpatients were included. Major bleeding was defined as type ≥3 bleed using the Bleeding Academic Research Consortium definition. Cumulative incidence was calculated with death as the competing event. Data was censored at time of aortic valve replacement. RESULTS: Among 2,830 patients, 46 major bleeding events occurred (0.7%/year) during a median follow-up of 2.1 years (interquartile range: 1.4-2.7). Most frequent sites of bleeding were gastrointestinal (50%) and intracranial (30.4%). Major bleeding was significantly associated with all-cause mortality (hazard ratio: 5.93 (95% confidence interval 3.64-9.65); P < .001). AS severity was associated with major bleedings (P = .041). By multivariable analysis, severe AS was an independent determinant of major bleeding (hazard ratio vs mild AS: 3.59 [95% confidence interval 1.56-8.29]; P = .003). The increased risk of bleeding associated with severe AS was significantly exacerbated in patients using oral anticoagulation. CONCLUSION: In AS patients, major bleeding is rare but a strong independent predictor of death. AS severity is a determinant of bleeding events. Severe AS and oral anticoagulation should be identified as an association at very high risk of major bleeding.

Hematopoietic Somatic Mosaicism Is Associated With an Increased Risk of Postoperative Atrial Fibrillation.

BACKGROUND: On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype. OBJECTIVES: The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery. METHODS: Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes. RESULTS: The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64+CD14+CD16- circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium. CONCLUSIONS: HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte-derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165).

Recurrences of Atrial Fibrillation Despite Durable Pulmonary Vein Isolation: The PARTY-PVI Study.

BACKGROUND: Recurrences of atrial fibrillation (AF) after pulmonary vein isolation (PVI) are mainly due to pulmonary vein reconnection. However, a growing number of patients have AF recurrences despite durable PVI. The optimal ablative strategy for these patients is unknown. We analyzed the impact of current ablation strategies in a large multicenter study. METHODS: Patients undergoing a redo ablation for AF and presenting durable PVI were included. The freedom from atrial arrhythmia after pulmonary vein-based, linear-based, electrogram-based, and trigger-based ablation strategies were compared. RESULTS: Between 2010 and 2020, 367 patients (67% men, 63±10 years, 44% paroxysmal) underwent a redo ablation for AF recurrences despite durable PVI at 39 centers. After durable PVI was confirmed, linear-based ablation was performed in 219 (60%) patients, electrogram-based ablation in 168 (45%) patients, trigger-based ablation in 101 (27%) patients, and pulmonary vein-based ablation in 56 (15%) patients. Seven patients (2%) did not undergo any additional ablation during the redo procedure. After 22±19 months of follow-up, 122 (33%) and 159 (43%) patients had a recurrence of atrial arrhythmia at 12 and 24 months, respectively. No significant difference in arrhythmia-free survival was observed between the different ablation strategies. Left atrial dilatation was the only independent factor associated with arrhythmia-free survival (HR, 1.59 [95% CI, 1.13-2.23]; P=0.006). CONCLUSIONS: In patients with recurrent AF despite durable PVI, no ablation strategy used alone or in combination during the redo procedure appears to be superior in improving arrhythmia-free survival. Left atrial size is a significant predictor of ablation outcome in this population.

Electrocardiographic findings in patients with arrhythmogenic cardiomyopathy and right bundle branch block ventricular tachycardia.

AIMS: Little is known about patients with right bundle branch block (RBBB)-ventricular tachycardia (VT) and arrhythmogenic cardiomyopathy (ACM). Our aims were: (i) to describe electrocardiogram (ECG) characteristics of sinus rhythm (SR) and VT; (ii) to correlate SR with RBBB-VT ECGs; and (iii) to compare VT ECGs with electro-anatomic mapping (EAM) data. METHODS AND RESULTS: From the European Survey on ACM, 70 patients with spontaneous RBBB-VT were included. Putative left ventricular (LV) sites of origin (SOOs) were estimated with a VT-axis-derived methodology and confirmed by EAM data when available. Overall, 49 (70%) patients met definite Task Force Criteria. Low QRS voltage predominated in lateral leads (n = 37, 55%), but QRS fragmentation was more frequent in inferior leads (n = 15, 23%). T-wave inversion (TWI) was equally frequent in inferior (n = 28, 42%) and lateral (n = 27, 40%) leads. TWI in inferior leads was associated with reduced LV ejection fraction (LVEF; 46 ± 10 vs. 53 ± 8, P = 0.02). Regarding SOOs, the inferior wall harboured 31 (46%) SOOs, followed by the lateral wall (n = 17, 25%), the anterior wall (n = 15, 22%), and the septum (n = 4, 6%). EAM data were available for 16 patients and showed good concordance with the putative SOOs. In all patients with superior-axis RBBB-VT who underwent endo-epicardial VT activation mapping, VT originated from the LV. CONCLUSIONS: In patients with ACM and RBBB-VT, RBBB-VTs originated mainly from the inferior and lateral LV walls. SR depolarization and repolarization abnormalities were frequent and associated with underlying variants.

Rapid ventricular tachycardia in patients with tetralogy of Fallot and implantable cardioverter-defibrillator: Insights from the DAI-T4F nationwide registry.

BACKGROUND: In repaired tetralogy of Fallot (TOF), little is known about characteristics of patients with rapid ventricular tachycardia (VT). Also, whether patients with a first episode of nonrapid VT may subsequently develop rapid VT or ventricular fibrillation (VF) has not been addressed. OBJECTIVES: The objectives of this study were to compare patients with rapid VT/VF with those with nonrapid VT and to assess the evolution of VT cycle lengths (VTCLs) overtime. METHODS: Data were analyzed from a nationwide registry including all patients with TOF and implantable cardioverter-defibrillator (ICD) since 2000. Patients with ≥1 VT episode with VTCL ≤250 ms (240 beats/min) formed the rapid VT/VF group. RESULTS: Of 144 patients (mean age 42.0 ± 12.7 years; 104 [72%] men), 61 (42%) had at least 1 VT/VF episode, including 28 patients with rapid VT/VF (46%), during a median follow-up of 6.3 years (interquartile range 2.2-10.3 years). Compared with patients in the nonrapid VT group, those in the rapid VT/VF group were significantly younger at ICD implantation (35.2 ± 12.6 years vs 41.5 ± 11.2 years; P = .04), had more frequently a history of cardiac arrest (8 [29%] vs 2 [6%]; P = .02), less frequently a history of atrial arrhythmia (11 [42%] vs 22 [69%]; P = .004), and higher right ventricular ejection fraction (43.3% ± 10.3% vs 36.6% ± 11.2%; P = .04). The median VTCL of VT/VF episodes was 325 ms (interquartile range 235-429 ms). None of the patients with a first documented nonrapid VT episode had rapid VT/VF during follow-up. CONCLUSION: Patients with TOF and rapid VT/VF had distinct clinical characteristics. The relatively low variation of VTCL over time suggests a room for catheter ablation without a backup ICD in selected patients with well-tolerated VT.

Sex Differences in Outcomes of Tetralogy of Fallot Patients With Implantable Cardioverter-Defibrillators.

BACKGROUND: Women with congenital heart disease at high risk for sudden cardiac death have been poorly studied thus far. OBJECTIVES: The aim of this study was to assess sex-related differences in patients with tetralogy of Fallot (TOF) and implantable cardioverter-defibrillators (ICDs). METHODS: Data were analyzed from the DAI-T4F (French National Registry of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator) cohort study, which has prospectively enrolled all patients with TOF with ICDs in France since 2010. Clinical events were centrally adjudicated by a blinded committee. RESULTS: A total of 165 patients (mean age 42.2 ± 13.3 years) were enrolled from 40 centers, including 49 women (29.7%). Among the 9,692 patients with TOF recorded in the national database, the proportion of women with ICDs was estimated to be 1.1% (95% CI: 0.8%-1.5%) vs 2.2% (95% CI: 1.8%-2.6%) in men (P < 0.001). The clinical profiles of patients at implantation, including the number of risk factors for ventricular arrhythmias, were similar between women and men. During a median follow-up period of 6.8 years (IQR: 2.5-11.4 years), 78 patients (47.3%) received at least 1 appropriate ICD therapy, without significant difference in annual incidences between women (12.1%) and men (9.9%) (HR: 1.22; 95% CI: 0.76-1.97; P = 0.40). The risk for overall ICD-related complications was similar in women and men (HR: 1.33; 95% CI: 0.81-2.19; P = 0.30), with 24 women (49.0%) experiencing at least 1 complication. CONCLUSIONS: Our findings suggest that women with TOF at high risk for sudden cardiac death have similar benefit/risk balance from ICD therapy compared with men. Whether ICD therapy is equally offered to at-risk women vs men warrants further evaluation in TOF as well as in other congenital heart disease populations. (French National Registry of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator [DAI-T4F]; NCT03837574).

Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis.

Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS.