Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

A worldwide survey on incidence, management and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: The POTTER-AF study.

AIMS Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management and outcome are sparse. METHODS AND RESULTS This international multicenter registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553,729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed at 214 centers in 35 countries. In 78 centers 138 patients (0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (p<0.0001)) were diagnosed with an oesophageal fistula. Periprocedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8%, and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) (odds ratio 7.463 (2.414, 23.072) p<0.001). CONCLUSIONS Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

The second generation cryoballoon has improved durable isolation of left but not right pulmonary veins new insights from amulticentre study

International audienceAims Pulmonary vein isolation (PVI) using second-generation cryoballoon (CB2) is associated with improved outcomes compared with first generation (CB1). We aimed at investigating the characteristics of left and right PV reconnections after CB1 and CB2 ablations in patients with clinical recurrences requiring redo ablation. Methods and results From 2010 to 2016, 776 patients underwent 28-mm cryoballoon PVI for symptomatic paroxysmal atrial fibrillation (AF) in 3 centres, 279 with CB1 and 497 with CB2. Among them, 94 patients (12.1%) had symptomatic AF recurrences requiring a redo ablation [43 (15.4%) CB1 and 51 (10.3%) CB2]. The benefit of CB2 over CB1 was compared for each PV. Durable PVI was confirmed in 7 CB1 (16.3%) and 14 CB2 (27.4%) patients, and 2.7 +/- 2.1 and 1.4 +/- 1.4 gaps per patient were found, respectively (P = 0.002). Significantly more left superior and left inferior PVs were found to be isolated in CB2 compared with CB1 group (78.4% vs. 48.8%, P = 0.005 and 78.4% vs. 46.5%, P = 0.003, respectively) while the rate of durable right superior and right inferior PVs isolation were similar (68.6% vs. 60.5%, P = 0.542 and 66.7% vs. 55.8%, P = 0.387, respectively). Significantly fewer gaps were found in left PVs in CB2 patients, while there was no significant difference for right PVs. Gaps localization was similar in both groups. Conclusion Fewer reconnection gaps are observed during redo ablations of paroxysmal AF in patients primarily ablated with CB2. This difference is driven by less reconnection gaps observed in both left PVs, while no difference was observed for right PVs

Safety, feasibility, and outcome results of cardiac resynchronization with triple-site ventricular stimulation compared to conventional cardiac resynchronization.

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Exclusion of Intra-Atrial Thrombus Diagnosis Using D-Dimer Assay Before Catheter Ablation of Atrial Fibrillation

International audienceObjectives: This study hypothesized that the association of D-dimer blood level and several clinical items in a new risk score could predict the absence of atrial thrombus.Background: Symptomatic and drug resistant atrial fibrillation (AF) can be treated by catheter ablation. The procedure-related risk of thromboembolism is limited by the pre-operative use of transesophageal echocardiography (TEE) to detect atrial thrombi.Methods: Patients admitted for catheter ablation of AF (n = 2,494) were prospectively included in a multicenter study. TEE was systematically performed before the procedure to search for atrial thrombus (primary endpoint). D-dimer level, CHADS2 score, left ventricular ejection fraction, pre-operative anticoagulation regimen, and medical history were collected. A logistic regression model was used to identify factors associated with the presence of atrial thrombus (hypertension, history of stroke, heart failure, D-dimer level >270 ng/ml). These factors were aggregated in a new score called atrial thrombus exclusion (ATE).Results: The incidence of atrial thrombus was 1.92%. CHADS2 score and D-dimer level were significantly associated with atrial thrombus (p < 0.0001 and p < 0.0001, respectively). A zero CHADS2 score failed to exclude all atrial thrombi (5 false negatives; sensitivity: 89.58%, specificity: 52.2%). No false negative was found with a zero ATE score, which had a specificity of 37% and a higher sensitivity (100%) than the CHADS2 score (p < 0.031) to predict the absence of intra-atrial thrombi on TEE. Conversely, the positive predictive value was poor, and the ATE score should not be used to conclude a positive diagnosis of thrombus.Conclusions: An ATE score of zero was strongly associated with the absence of atrial thrombus. This new score could be useful to rule out a diagnosis of atrial thrombus before catheter ablation of AF

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

International audienceBACKGROUND: 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

NEXN gene in cardiomyopathies and sudden cardiac deaths: prevalence, phenotypic expression, and prognosis

International audienceBACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene’s involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0–49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25–50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed—especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established