{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T03:47:06Z","timestamp":1774324026310,"version":"3.50.1"},"reference-count":113,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Horses are one of the few animals that spontaneously develop atrial fibrillation (AF), making them a powerful model for studying AF mechanisms and treatment effects. Despite the initial effectiveness of treatment in horses and humans, AF-induced atrial remodeling compromises its long-term success. Observational studies have suggested that metformin may reduce the risk of AF, but its effects on progressive AF-induced atrial remodeling have yet to be evaluated in a high-fidelity large animal model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Here, we used a longitudinal horse model of tachypacing-induced self-sustained AF to characterize the electrical, molecular, and metabolic atrial changes over 4 months of disease, with and without metformin treatment (30 mg\/kg orally, twice daily; initiated before AF induction, N=24 horses). Electrophysiological and multiomic approaches were combined with histology, echocardiography, biochemical, and mitochondrial analyses to evaluate disease progression and treatment response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>The horse model replicated critical aspects of AF-induced atrial remodeling observed in Humans, including electrical and structural changes. Despite upregulation of metabolic genes and proteins in AF, no significant ultrastructural mitochondrial changes were detected. Metformin plasma trough levels confirmed stable therapeutic exposure. Metformin-treated horses were protected against early AF stabilization and sustained a less complex AF substrate in the right atrium after 4 months of disease. These protective effects were associated with increased right atrial activity of the metabolic regulator, AMPK (AMP-activated protein kinase), changes in metabolic pathways, and modulation of ion-channel gene expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Metformin treatment conferred protection against early AF stabilization and selectively attenuated right atrial substrate complexity in a translationally relevant preclinical model. These findings support metformin as a lead molecule for AF prevention, warranting further mechanistic and clinical studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circep.125.013850","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T10:04:48Z","timestamp":1764669888000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Metformin Protects Against Persistent Atrial Fibrillation in an Equine Model"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1787-134X","authenticated-orcid":true,"given":"Simon Libak","family":"Haugaard","sequence":"first","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark (S.L.H., M.J.S., S.T.K., J.N.S., H.C., C.H.-I., S.D.N., R. Buhl)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8739-8223","authenticated-orcid":true,"given":"M\u00e9lodie J.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark (S.L.H., M.J.S., S.T.K., J.N.S., H.C., C.H.-I., S.D.N., R. Buhl)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9828-5494","authenticated-orcid":true,"given":"Sofie Troest","family":"Kjeldsen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark (S.L.H., M.J.S., S.T.K., J.N.S., H.C., C.H.-I., S.D.N., R. Buhl)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-8329","authenticated-orcid":true,"given":"Stefan Michael","family":"Sattler","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences (S.M.S., A.S., C.H., T.J., S.D.N.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4292-5234","authenticated-orcid":true,"given":"Joakim Armstrong","family":"Bastrup","sequence":"additional","affiliation":[{"name":"Vascular Biology Group, Department of Biomedical Sciences (J.A.B., T.A.J.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-0902","authenticated-orcid":true,"given":"Arnela","family":"Saljic","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences (S.M.S., A.S., C.H., T.J., S.D.N.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9775-4789","authenticated-orcid":true,"given":"Jesper Bratz","family":"Birk","sequence":"additional","affiliation":[{"name":"August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science (J.B.B., R.K., J.F.P.W.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7609-3308","authenticated-orcid":true,"given":"Caroline","family":"Hansen","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences (S.M.S., A.S., C.H., T.J., S.D.N.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0313-575X","authenticated-orcid":true,"given":"Josefine Natalie","family":"Synnestvedt","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark (S.L.H., M.J.S., S.T.K., J.N.S., H.C., C.H.-I., S.D.N., R. 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Barr\u00e8s), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0158-519X","authenticated-orcid":true,"given":"Romain","family":"Barr\u00e8s","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences (A.A., R. Barr\u00e8s), University of Copenhagen, Denmark."},{"name":"Institut de Pharmacologie Mol\u00e9culaire et Cellulaire, Universit\u00e9 C\u00f4te d\u2019Azur and Centre National pour la Recherche Scientifique (CNRS), Valbonne, France (R. Barr\u00e8s)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-714X","authenticated-orcid":true,"given":"Thomas Andrew","family":"Jepps","sequence":"additional","affiliation":[{"name":"Vascular Biology Group, Department of Biomedical Sciences (J.A.B., T.A.J.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5170-4337","authenticated-orcid":true,"given":"Steen","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences (S.L.), University of Copenhagen, Denmark."},{"name":"Clinical Research Center, Medical University of Bialystok, Poland (S.L.)."},{"name":"Department of Orthopedic Surgery M, Institute of Sports Medicine Copenhagen, Copenhagen University Hospital\u2014Bispebjerg and Frederiksberg, Denmark (S.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0628-4994","authenticated-orcid":true,"given":"Rasmus","family":"Kj\u00f8bsted","sequence":"additional","affiliation":[{"name":"August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science (J.B.B., R.K., J.F.P.W.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-3408","authenticated-orcid":true,"given":"J\u00f8rgen F.P.","family":"Wojtaszewski","sequence":"additional","affiliation":[{"name":"August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science (J.B.B., R.K., J.F.P.W.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheyla","family":"Barrado Ballestero","sequence":"additional","affiliation":[{"name":"Gubra ApS, H\u00f8rsholm (S.B.B., U.R.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7849-2055","authenticated-orcid":true,"given":"Urmas","family":"Roostalu","sequence":"additional","affiliation":[{"name":"Gubra ApS, H\u00f8rsholm (S.B.B., U.R.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-6613","authenticated-orcid":true,"given":"Kate M.","family":"Herum","sequence":"additional","affiliation":[{"name":"Research and Early Development, Novo Nordisk A\/S, Maaloev, Denmark (K.M.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6575-360X","authenticated-orcid":true,"given":"Thomas","family":"Jespersen","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences (S.M.S., A.S., C.H., T.J., S.D.N.), University of Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-3311","authenticated-orcid":true,"given":"Stanley","family":"Nattel","sequence":"additional","affiliation":[{"name":"Department of Medicine and Research Center, Montreal Heart Institute and Universit\u00e9 de Montr\u00e9al, Canada (S.N.)."},{"name":"Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Germany (S.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8598-7147","authenticated-orcid":true,"given":"Sarah Dalgas","family":"Nissen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark (S.L.H., M.J.S., S.T.K., J.N.S., H.C., C.H.-I., S.D.N., R. 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aspects of pathogenesis of atrial fibrillation: remodelling of intercalated discs.","volume":"66","author":"Tribulova N","year":"2015","unstructured":"Tribulova N, Egan Benova T, Szeiffova Bacova B, Viczenczova C, Barancik M. 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