Background: Significant sex differences exist in atrial fibrillation (AF). Better understanding of its underlying mechanism would help AF management. This study aimed to investigate the contribution of circulating metabolites to sex differences in AF and the association between them. Methods: A total of 108 patients with AF were enrolled. Untargeted metabolomics were performed in plasma samples of male and female patients. Correlation analysis with clinical characteristics and Mendelian randomization were used to identify sex-specific metabolites associated with AF, which was further validated in additional patients. Transcriptomics data of the left atrium were used to investigate the molecular alteration of the left atrium responding to identified sex-specific circulating metabolites. The effect of selected sex-specific metabolites on cardiomyocytes was further investigated. Results: A total of 60 annotated metabolites were found with different levels between male and female patients. Among these sex-specific metabolites, three metabolites, 7-Methylguanosine, succinic acid, and N-Undecylbenzenesulfonic acid, were positively related to the left atrial remodeling. Additionally, succinic acid was significantly associated with increased risk of AF (OR = 1.26; 95% CI: 1.13 to 1.40; p < 0.001). And, SUCLA2, the gene of succinic acid metabolism, was significantly increased in the left atrium of male patients (fold change = 1.53; p = 0.008). Treatment with succinic acid led to cardiomyocyte hypertrophy and mitochondrial dysfunction. Conclusions: This study highlights sex differences in circulating metabolites in patients with AF and identifies the associations between sex-specific metabolites and AF. succinic acid, which is much higher in male patients, contributes to the process of AF.

Background and objective: Evidence of percutaneous left atrial appendage closure (LAAC) and oral anticoagulants (OACs) in non-valvular atrial fibrillation (NVAF) patients with intermediate-to-borderline high stroke risk is scarce. We aimed to compare the efficacy and safety of these treatments in the latter clinical population. Methods: This retrospective cohort study included NVAF patients with CHA₂DS₂-VA scores of 1–2 and used 1:1 propensity score matching (184 patients per group) to compare efficacy and safety outcomes. The primary efficacy outcome was a composite of stroke, transient ischemic attacks, systemic embolism, and cardiovascular death during follow-up. Adverse safety events were categorized into peri-procedure (LAAC group) and non-procedural (both groups) events. Results: Over a mean follow-up of 48.93 ± 28.50 months, a total of 26 patients (7.07%) reached the primary composite efficacy endpoint. The LAAC group showed a significantly higher incidence of the efficacy endpoint compared to the OAC group (HR = 3.09; 95% CI 1.22–7.85; log-rank p = 0.01). Procedure-related events occurred in five LAAC patients (one contributing to primary endpoint), while non-procedural bleeding rates were similar (0.54% vs. 1.09%; p = 0.56). Subgroup analyses suggested concomitant ablation of NVAF in LAAC group did not significantly improve efficacy composite endpoints (HR = 0.47). Conclusions: In NVAF patients with intermediate-to-high stroke risk, OACs were more effective than LAAC in preventing thromboembolic events, with comparable rates of clinically relevant bleeding.