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.

Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF‐dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6‐week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP‐induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa‐B (NF‐κB) phosphorylation; up‐regulated interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and transforming growth factor‐β1 (TGF‐β1) levels in LA and EAT; decreased peroxisome proliferator‐activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL‐6, TNF‐α and TGF‐β1 expression and decreased PPARγ/APN expression in 3T3‐L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL‐1 cells with LPS‐stimulated 3T3‐L1 conditioned medium (CM) significantly increased IL‐6, TNF‐α and TGF‐β1 expression and decreased SERCA2a and p‐PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca²⁺ handling dysfunction. MET attenuated the RAP‐induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF‐dependent EAT remodelling and AF vulnerability by MET.

Atrial lipid metabolic remodeling is critical for the process of atrial fibrillation (AF). Abnormal Fatty acid (FA) metabolism in cardiomyocytes is involved in the pathogenesis of AF. MET (Metformin), an AMPK (AMP-activated protein kinase) activator, has been found to be associated with a decreased risk of AF in patients with type 2 diabetes. However, the specific mechanism remains unknown. Fifteen mongrel dogs were divided into three groups: SR, ARP (pacing with 800 beats/min for 6 h), ARP plus MET (treated with MET (100 mg/kg/day) for two weeks before pacing). We assessed metabolic factors, speed limiting enzymes circulating biochemical metabolites (substrates and products), atrial electrophysiology and accumulation of lipid droplets. The expression of AMPK increased in the ARP group and significantly increased in the MET+ARP group comparing to the SR group. In the ARP group, the expressions of PPARα、PGC-1α and VLCAD were down-regulated, while the concentration of free fatty acid and triglyceride and the lipid deposition in LAA (left atrial appendage) increased. Moreover, AERP and AERPd have also been found abnormally in this process. Pretreatment with MET before receiving ARP reversed the alterations aforementioned. The FA metabolism in LAA is altered in the ARP group, mainly characterized by the abnormal expression of the rate-limiting enzyme. Metformin reduces lipid accumulation and promotes β-oxidation of FA in AF models partially through AMPK/PPAR-α/VLCAD pathway. Our study indicates that MET may inhibit the FA lipid metabolic remodeling in AF.