Europace最新文献

Aims: Methyltransferase like 3 (METTL3) plays a crucial role in cardiovascular diseases, but its involvement in atrial fibrillation (AF) remains unclear. The study aims to explore the relationship between METTL3 and AF in atrial myocytes.

Methods and results: The protein level of METTL3 was evaluated in left atrial appendages (LAAs) from patients with persistent AF and in experimental AF models. cAMP-responsive element modulator (CREM) transgenic mice and CaCl2-acetylcholine (ACh)-injected mice were used as AF mice models. Methyltransferase like 3 was globally and atrial conditionally deleted in vivo to assess its role in AF. Confocal fluorescence microscopy was employed to examine calcium handling in atrial myocytes. Methylated RNA immunoprecipitation sequencing was performed to identify the downstream target genes of METTL3. Methyltransferase like 3 protein and RNA N6-methyladenosine (m6A) modification levels were significantly reduced in the LAAs of patients with AF and experimental AF models. Genetic inhibition of METTL3 promoted the development of AF in CREM transgenic mice and CaCl2-ACh-injected mice. Knockdown of METTL3 in atrial myocytes resulted in enhanced calcium handling. Reduced METTL3 levels increased SR Ca2+-ATPase Type 2a activity by up-regulating protocadherin gamma subfamily A, 10. Decreased METTL3 protein in atrial myocytes was attributed to down-regulation of cAMP-responsive element-binding protein 1/ubiquitin-specific peptidase 9 X-linked axis.

Conclusion: Our study established the pathophysiological role of METTL3 involved in the development of AF and provided a potential mechanism-based target for its treatment.

Aims: The variant in SCN5A with the loss of function (LOF) effect in the cardiac Na+ channel (Nav1.5) is the definitive cause for Brugada syndrome (BrS), and the functional analysis data revealed that LOF variants are associated with poor prognosis. However, which variant types (e.g. missense or non-missense) affect the prognoses of those variant carriers remain unelucidated.

Methods and results: We defined SCN5A LOF variants as all non-missense and missense variants that produce peak INa < 65% of wild-type previously confirmed by patch-clamp studies. The study population consisted of 76 Japanese BrS patients (74% patients were male and the median age [IQR] at diagnosis was 28 [14-45] years) with LOF type of SCN5A variants: 40 with missense and 36 with non-missense variants. Non-missense variant carriers presented significantly more severe cardiac conduction disorder compared to the missense variant carriers. During follow-up periods of 9.0 [5.0-14.0] years, compared to missense variants, non-missense variants were significant risk factors of lifetime lethal arrhythmia events (LAEs) (P = 0.023). When focusing only on the missense variants that produce no peak INa, these missense variant carriers exhibited the same clinical outcomes as those with non-missense (log-rank P = 0.325). After diagnosis, however, both variant types were comparable in risk of LAEs (P = 0.155).

Conclusion: We identified, for the first time, that SCN5A non-missense variants were associated with higher probability of LAE than missense variants in BrS patients though it did not change significantly after diagnosis.

Aims: Exercise stress test (EST) represents the gold standard for diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed to determine the relevance of exercise induced VT for the occurrence of LAE at follow-up.

Methods and results: In RYR2-related CPVT patients who underwent a baseline EST, we assessed the incidence and severity of ventricular arrhythmias (VA). Data were analysed using logistic regression models and Cox proportional hazards models. The primary outcome was the occurrence of life-threatening arrhythmic event (LAE; composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated VT) at follow-up. In 102 RYR2-related CPVT patients (65 females; median age 16 years, IQR: 11-36 years), exercise-induced VT (bidirectional in 64% of cases) was elicited in 56% patients. VT could not be induced in pre-school children. Lower basal heart rate, early onset VA (within the first step of EST) and heart rate at the first minute of recovery were associated with exercise-induced VT. Cox analyses showed that early onset VA (HR 6.0, 95% CI: 1.3-27.9, P = 0.022) and exercise-induced VT (HR 6.6, 95% CI: 1.5-29.1, P = 0.012) at baseline EST were significantly associated with the occurrence of LAE at follow-up, and remained associated even after correction for symptoms.

Conclusion: Early onset VA and exercise-induced VT at baseline EST was associated with LAE at follow-up, allowing to identify a sub-set of patients at higher risk already at diagnosis.

Aims: Electronic healthcare records (EHR) are at the forefront of advances in epidemiological research emerging from large-scale population biobanks and clinical studies. Hospital admissions, diagnoses, and procedures (HADP) data are often used to identify disease cases. However, this may result in incomplete ascertainment of chronic conditions such as atrial fibrillation (AF), which are principally managed in primary care (PC). We examined the relevance of EHR sources for AF ascertainment, and the implications for risk factor associations, patient management, and outcomes in UK Biobank.

Methods and results: UK Biobank is a prospective study, with HADP and PC records available for 230 000 participants (to 2016). AF cases were ascertained in three groups: from PC records only (PC-only), HADP only (HADP-only), or both (PC + HADP). Conventional statistical methods were used to describe differences between groups in terms of characteristics, risk factor associations, ascertainment timing, rates of anticoagulation, and post-AF stroke and death. A total of 7136 incident AF cases were identified during 7 years median follow-up (PC-only: 22%, PC + HADP: 49%, HADP-only: 29%). There was a median lag of 1.3 years between cases ascertained in PC and subsequently in HADP. AF cases in each of the ascertainment groups had comparable baseline demographic characteristics. However, AF cases identified in hospital data alone had a higher prevalence of cardiometabolic comorbidities and lower rates of subsequent anticoagulation (PC-only: 44%, PC + HADP: 48%, HADP-only: 10%, P < 0.0001) than other groups. HADP-only cases also had higher rates of death [PC-only: 9.3 (6.8, 12.7), PC + HADP: 23.4 (20.5, 26.6), HADP-only: 81.2 (73.8, 89.2) events per 1000 person-years, P < 0.0001] compared to other groups.

Conclusion: Integration of data from primary care with that from hospital records has a substantial impact on AF ascertainment, identifying a third more cases than hospital records alone. However, about a third of AF cases recorded in hospital were not present in the primary care records, and these cases had lower rates of anticoagulation, as well as higher mortality from both cardiovascular and non-cardiovascular causes. Initiatives aimed at enhancing information exchange of clinically confirmed AF between healthcare settings have the potential to benefit patient management and AF-related outcomes at an individual and population level. This research underscores the importance of access and integration of de-identified comprehensive EHR data for a definitive understanding of patient trajectories, and for robust epidemiological and translational research into AF.

Aims: Atrial fibrillation and atrial flutter (AF/AFL) are critical global health concerns, yet studies on burden trends and sex differences remain limited. This study aims to investigate the global burden trends of AF/AFL, with an in-depth analysis of differences between sexes and future trends, in order to address gaps in the current research field.

Methods and results: This study utilized data from the Global Burden of Disease 2021 study, applying methods such as age-period-cohort analysis and joinpoint regression models to evaluate trends and sex differences in the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of AF/AFL among individuals aged 30 and above from 1990 to 2021, and employed Bayesian age-period-cohort (BAPC) analysis to predict future trends from 2022 to 2046. In 2021, AF/AFL affected around 52.6 million people globally, with significant increases in cases, deaths, and DALYs since 1990. While the age-standardized prevalence rate (ASPR) remained stable, the age-standardized incidence rate (ASIR) slightly declined, and the age-standardized mortality rate (ASMR) increased. Moreover, there were significant differences in the disease burden between male and female patients. Males had higher prevalence and DALYs, with older age contributing to higher rates. Key risk factors included high systolic blood pressure, body mass index (BMI), and alcohol use, with female patients exhibiting a higher age-standardized rates associated with elevated BMI compared with their male counterparts. Bayesian age-period-cohort predicted stable ASPR and ASIR in males but rising rates in females, with ASMR expected to decline for both sexes.

Conclusion: The global burden of AF/AFL is rising, particularly among women, and in low-socio-demographic index regions. This underscores the urgent need for targeted prevention strategies and optimized management of modifiable risk factors, with a specific focus on these vulnerable groups.

Aims: Early rhythm control therapy in atrial fibrillation (AF) results in higher freedom from atrial arrhythmia (AA) recurrence and improved cardiovascular outcomes. The optimal timing of cryoballoon ablation (CBA) is unknown.

Methods and results: We evaluated AA recurrence and procedure-related complications of early vs. late CBA (≤12 vs. >12 months from diagnosis) in patients enrolled in the prospective Cryo Global Registry (121 centres in 37 countries, NCT02752737). A total of 3447 subjects were followed through 12 months and 1220 through 24 months. In summary, 1573 patients (46%) had early ablation at a median (IQR) of 0.3 (0.1-0.6) years from AF diagnosis (age 62 ± 12 years., 35.8% female, 71.4% paroxysmal), and 1874 (54%) had late ablation at a median of 3.4 (1.9-6.7) years after diagnosis (age 61 ± 11 years, 36.2% female, 75.0% paroxysmal). Early ablation patients were less hypertensive (53.5% vs. 57.9%, P = 0.01) and less symptomatic (1.5 ± 1.1 vs. 1.8 ± 1.1 symptoms/patient, P < 0.01) and had smaller left atrial diameters (41 ± 7 mm vs. 42 ± 7 mm, P < 0.01). Freedom from AA recurrence was 81.5% (95% CI: 78.7-83.9%) in the early vs. 71.7% (95% CI: 68.9-74.3%) in the late ablation group at 24 months (P < 0.01). The risk of cardioversion was 41% lower in the early ablation group [HRAdj: 0.59 (0.42-0.83), P < 0.01]. Serious procedure-related adverse events occurred in 2.4 and 3.5% of patients in the early and late ablation groups (P = 0.045), respectively.

Conclusion: CBA within 12 months from AF diagnosis resulted in higher freedom from AA recurrence and is associated with fewer safety events in a real-world evaluation.

Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT02752737.