Role of the CXCL8-CXCR2 axis in obesity-related atrial fibrillation: integrated bioinformatics and experimental validation

Background: Obesity is a common risk factor for atrial fibrillation (AF), two conditions which frequently coexist in modern populations. Therefore, this study aimed to identify the genes associated with increased AF susceptibility in obese individuals and to identify biomarkers for obesity-related AF. Methods: We identified hub genes by integrating the transcriptomic datasets of patients with AF and those of obese individuals with plasma proteomics data from the UK Biobank. A diet-induced obesity (DIO) mouse model was then established, and AF was induced via the injection of s acetylcholine-calcium chloride mixture into the tail vein. Transcriptomic analysis, quantitative polymerase chain reaction (qPCR), and Western blotting were used to validate the expression of hub genes. Finally, the Microenvironment Cell Populations-counter method was used to characterize the atrial immune landscape in AF-susceptible DIO mice. Results: Five AF-related genes involved in obesity were identified through the intersection of differentially expressed genes (DEGs) with a weighted gene coexpression network module. Using machine learning algorithms and RNA sequencing, we identified C-X-C motif chemokine receptor 2 ( CXCR2 ) as a biomarker for obesity-related AF. Analysis of the plasma proteomics data from the UK Biobank showed that higher plasma C-X-C motif chemokine ligand 8 (CXCL8) levels were associated with a higher body mass index and an increased risk of AF and flutter. According to bioinformatics analysis, CXCL8 expression was non-significantly increased in the atria of obese patients and was significantly increased in the whole blood and epicardial adipose tissue (EAT) of overweight/obese individuals. AF susceptibility was heightened in DIO mice, and AF-susceptible DIO mice exhibited elevated atrial murine functional analogs of human CXCL8 and CXCR2 expression. Immune infiltration analysis and gene set enrichment analysis revealed immune dysfunction in the atria of AF-susceptible DIO mice. Conclusions: Our findings suggest that the CXCL8-CXCR2 axis may be involved in the increased susceptibility to AF of obese individuals, highlighting its potential as a biomarker and warranting further therapeutic investigation.