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We investigated whether metformin (MET) prevents AF\u2010dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6\u2010week 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\u2010induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa\u2010B (NF\u2010\u03baB) phosphorylation; up\u2010regulated interleukin\u20106 (IL\u20106), tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21) levels in LA and EAT; decreased peroxisome proliferator\u2010activated receptor gamma (PPAR\u03b3) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro\n                    <jats:italic>,<\/jats:italic>\n                    lipopolysaccharide (LPS) exposure increased IL\u20106, TNF\u2010\u03b1 and TGF\u2010\u03b21 expression and decreased PPAR\u03b3\/APN expression in 3T3\u2010L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL\u20101 cells with LPS\u2010stimulated 3T3\u2010L1 conditioned medium (CM) significantly increased IL\u20106, TNF\u2010\u03b1 and TGF\u2010\u03b21 expression and decreased SERCA2a and p\u2010PLN expression, while LPS\u00a0+\u00a0MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling dysfunction. MET attenuated the RAP\u2010induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF\u2010dependent EAT remodelling and AF vulnerability by MET.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.15407","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T06:01:25Z","timestamp":1590127285000},"page":"7751-7766","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability"],"prefix":"10.1111","volume":"24","author":[{"given":"Biao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology\/Cardiac Catheterization Lab Second Xiangya Hospital Central South University Changsha City Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny S.","family":"Po","sequence":"additional","affiliation":[{"name":"Heart Rhythm Institute and Department of Medicine 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