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Aims: Chronic kidney disease (CKD) significantly increases the risk of atrial fibrillation (AF). Although alterations in the gut microbiota have been linked to CKD progression, its exact involvement in CKD-associated AF remains unclear. We aim to investigate the role of gut microbiota in the development of CKD-associated AF and to uncover potential mechanisms that could serve as effective targets for prevention and treatment.

Methods and results: A rat model of CKD was induced by an adenine-enriched diet. 16S rRNA sequencing and faecal microbiota transplantation (FMT) were utilized to study the involvement of gut microbiota. AST-120, gut barrier protectants, and mono-colonization experiments were performed to investigate potential mechanism. CKD rats exhibited gut microbiota dysbiosis and a significantly increased susceptibility to AF. FMT from CKD rats transferred this heightened AF susceptibility to healthy recipient rats, linked to the activation of the NLRP3 inflammasome. Mechanistically, gut dysbiosis in CKD patients leads to elevated indoxyl sulphate (IS) levels, causing gut barrier dysfunction and increased circulating lipopolysaccharide (LPS). Elevated LPS activates atrial Toll-like receptor 4 (TLR4) receptors, triggering NLRP3 inflammasome activation, which contributes to AF pathogenesis. Treatment with the IS scavenger AST-120 or gut barrier protectants successfully prevented CKD-associated AF. Furthermore, supplementation with Lactobacillus gasseri reduced circulating IS levels and mitigated AF susceptibility in CKD rats.

Conclusion: This study demonstrates that gut dysbiosis-driven elevation of IS and subsequent activation of the atrial NLRP3 inflammasome are key mechanisms in CKD-associated AF. Modulating the gut microbiota could provide a new therapeutic strategy for CKD-associated AF.

Background: The burden of atrial fibrillation and atrial flutter (AF/AFL) has increased, but age-specific patterns across World Bank income levels (WBILs) remain unclear.

Methods: Using the Global Burden of Disease 2023 estimates, we assessed age- and WBIL-stratified trends in prevalence, incidence, mortality, and disability-adjusted life years (DALYs) for AF/AFL from 1990 to 2023, employing age-period-cohort analysis and joinpoint regression. Mortality attributable to six modifiable risk factors was quantified based on comparative risk assessment estimates. Projections of AF/AFL burden for 2024-2048 were generated using Bayesian age-period-cohort models.

Results: In 2023, AF/AFL affected 58.99 million prevalent cases, 5.02 million incident cases, 376862 deaths, and 9.26 million DALYs, with the absolute burden concentrated in adults aged ≥ 65 years. From 1990 to 2023, age-standardized prevalence (ASPR) and incidence rate (ASIR) increased, while mortality rate (ASMR) and disability-adjusted life year rate (ASDR) remained stable. High-income countries showed increases across all metrics, upper-middle-income countries had rising ASPR/ASIR and decreasing ASMR/ASDR, and lower-middle- and low-income countries showed consistent increases across all metrics. Among younger (30-44 years) and middle-aged (45-64 years) adults, all metrics increased, while in older adults, only ASPR rose. High systolic blood pressure was the leading attributable risk factor, with larger contributions from high body mass index, smoking, and alcohol use in younger and middle-aged adults. Projections indicated modest declines in ASPR, stable ASIR, and increasing ASMR/ASDR through 2048.

Conclusions: Despite the concentrated burden in older adults, mortality- and disability-related burden is rising in younger and middle-aged populations, with significant variation across WBILs.

Aims: To evaluate differences in clinical characteristics and outcomes based on physical activity levels in patients with atrial fibrillation (AF), comparing Europeans and Asians.

Methods and results: Post-hoc analysis of two prospective registries from Europe and the Asia-Pacific. Patients were classified as inactive (no exercise or <3 h/week) or active (≥3 h/week). The primary outcome was a composite of all-cause death and major adverse cardiovascular events (MACE). Secondary outcomes included all-cause death, MACE, major bleeding, individual MACE components. Cox model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes. Subgroup analyses were performed by clinically relevant variables and enrolment setting. Of 13 126 participants (69 ± 12 years; 39% female), 3639 (28%) were physically active and 9487 (72%) physically inactive. Across both groups, Asians had lower odds of obesity, symptomatic AF and heart failure, but higher odds of cardiovascular risk factors than Europeans. After a median follow-up of 514 days, physically active AF patients had a lower risk of composite outcome (HR 0.66, 95%CI 0.56-0.78), all-cause death (HR 0.52, 95%CI 0.42-0.65), MACE (HR 0.80, 95%CI 0.65-0.99), cardiovascular death (HR 0.60, 95%CI 0.42-0.86), with no significant differences between Europeans and Asians (pinteraction for composite outcome = 0.298). The risk of the composite outcome decreased progressively with increasing levels of physical activity, with no significant differences between Europeans and Asians (pinteraction = 0.845).

Conclusion: In patients with AF, self-reported physical activity is associated with a lower risk of adverse events, consistently across Europe and Asia. Physical activity may represent a component of a lower-risk clinical profile in AF.

Background and aims: The KCNH2 (hERG) gene encodes the Kv11.1 protein, the pore-forming subunit of the rapid delayed rectifier potassium channel, which plays a key role in cardiac repolarization. We aimed to investigate the function of two Kv11.1 variants in trans, S1021Qfs*98 and A228V, identified in a patient suffering from idiopathic ventricular fibrillation (VF).

Methods: A detailed clinical and genetic investigation was followed by functional analysis using the whole-cell patch clamp technique, western blot, and mathematical simulations in a human ventricular cell model.

Results: In comparison with wild type, the current was decreased by 69.5 and 69.2% in S1021Qfs*98 and S1021Qfs*98/A228V, respectively, which agreed well with a significant decrease in the expression of S1021Qfs*98 channels, but no differences were observed in A228V. The voltage dependence of activation and inactivation and the time course of activation and deactivation remained unchanged. Minor changes were observed in the time course of inactivation and recovery from inactivation in S1021Qfs*98 and S1021Qfs*98/A228V. Arrhythmogenesis based on early afterdepolarizations (EADs) at rest, provoked by hypokalemia, and during β-adrenergic stimulation was suggested by simulations in a human ventricular cell model.

Conclusion: To conclude, A228V is a benign variant, whereas S1021Qfs*98 exhibits a loss-of-function defect and dominant negativity. EADs-related arrhythmogenesis was predicted, which explains the pathogenic phenotype of the proband carrying both these variants and experiencing repetitive VF episodes. Based on the findings, we reclassify S1021Qfs*98 as a pathogenic, LQT2-associated variant. The data highlight the importance of functional analysis for the correct management of patients with idiopathic VF and genetic variants.