Key result
Obesity-driven reprogramming of epicardial adipose macrophages drives atrial fibrosis and AF progression.
Why the study?
The specific immunometabolic mechanisms linking epicardial adipose tissue macrophages to atrial fibrillation pathogenesis in obesity remain unclear.
Immunometabolic reprogramming of epicardial adipose tissue macrophages is a key driver of atrial structural and electrical remodeling, offering a novel mechanistic target for treating obesity-related atrial fibrillation.
May support immunometabolic targeting of epicardial macrophages in obesity-related AF; leaves open prospective clinical validation.
Obesity is a crucial risk factor for atrial fibrillation (AF). The underlying mechanism is partly related to increased epicardial adipose tissue (EAT). EAT directly contacts the adjacent cardiac myocardium where immune and metabolic activities interact. Obesity induces inflammatory and metabolic signals within EAT, which directly influence atrial structure and electrical remodeling. However, the specific immunometabolic mechanisms linking EAT macrophages to atrial arrhythmogenesis remain unclear. We highlight evidence that nutrient excess, hypoxia, oxidative stress, and adipocyte-derived inflammatory signals reprogram glucose, lipid, and amino acid metabolism in EAT macrophages, promoting persistent pro-inflammatory and profibrotic states. Metabolic pathways involving mechanistic target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) signaling, fatty acid and ceramide metabolism, the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and metabolic-epigenetic interactions may sustain macrophage activation and amplify local inflammation. These metabolically reprogrammed macrophages subsequently promote atrial fibrosis, electrical heterogeneity, and autonomic dysfunction, while systemic inflammation, insulin resistance, and neurohumoral activation further reinforce the EAT-atrial pathological circuit. Emerging evidence also suggests that EAT characteristics may improve AF risk stratification and that weight loss and metabolic interventions can attenuate EAT inflammation. More importantly, targeting macrophage immunometabolism may offer a mechanistically distinct approach to interrupt the link between obesity and atrial remodeling rather than treating AF solely after its substrate has developed. Collectively, targeting EAT immunometabolism may shift obesity-related AF management from treating an established arrhythmia toward identifying and modifying the metabolic-inflammatory substrate that promotes its development and recurrence, potentially complementing conventional rhythm-control and ablation strategies. Future studies should establish causal relationships and identify clinically actionable metabolic targets for EAT macrophage-directed therapy.
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Xia et al. (2026) conducted a review in Obesity-related Atrial Fibrillation. Epicardial adipose tissue macrophage immunometabolic reprogramming was evaluated. Obesity-driven metabolic reprogramming of epicardial adipose tissue macrophages promotes continuous local inflammation and atrial fibrosis, increasing the progression of atrial fibrillation.
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