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.

中文翻译：

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二甲双胍调节心外膜脂肪组织中的脂联素信号传导并降低心房颤动的脆弱性。

心外膜脂肪组织（EAT）的重塑与房颤（AF）的发病机理密切相关。我们调查了二甲双胍（MET）是否能预防犬依赖AF的EAT重塑和AF脆弱性。通过6周快速心房起搏（RAP）建立了犬AF模型，并测量了电生理参数。左，右心耳以及左心房（LA）和右心房（RA）的有效不应期（ERP）减少。MET减弱了RAP导致的ERP离散度增加，易损性累积窗口，AF诱发性和AF持续时间的增加。RAP增加了活性氧（ROS）的产生和核因子kappa-B（NF-κB）的磷酸化；LA和EAT中的白介素-6（IL-6），肿瘤坏死因子-α（TNF-α）和转化生长因子-β1（TGF-β1）水平上调；EAT中过氧化物酶体增殖物激活受体γ（PPARγ）和脂联素（APN）表达降低，并伴有心房纤维化和脂肪浸润。MET扭转了这些变化。体外，脂多糖（LPS）暴露可增加3T3-L1脂肪细胞中IL-6，TNF-α和TGF-β1的表达，并降低PPARγ/ APN的表达，在MET给药后均被逆转。HL-1细胞与LPS刺激的3T3-L1条件培养基（CM）的间接共培养可显着增加IL-6，TNF-α和TGF-β1的表达，并降低SERCA2a和p-PLN的表达，而LPS + MET CM和APN处理减轻了炎症反应和肌浆网Ca ²⁺处理功能障碍。MET减弱了RAP引起的房颤易感性增加，心房重构和EAT脂肪因子生成特征。APN可能在MET预防AF依赖的EAT重塑和AF脆弱性方面发挥关键作用。