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Home / Equine Research Bank / Circ Arrhythm Electrophysiol / Metformin Protects Against Persistent Atrial Fibrillation in...
Circulation. Arrhythmia and electrophysiology2025; 18(12); e013850; doi: 10.1161/CIRCEP.125.013850

Metformin Protects Against Persistent Atrial Fibrillation in an Equine Model.

Abstract: 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. Unassigned: 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. Unassigned: 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. Unassigned: 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.
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Publication Date: 2025-12-02 PubMed ID: 41328576PubMed Central: PMC12711282DOI: 10.1161/CIRCEP.125.013850Google Scholar: Lookup
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Cite This Article

APA
Haugaard SL, Schneider MJ, Kjeldsen ST, Sattler SM, Bastrup JA, Saljic A, Birk JB, Hansen C, Synnestvedt JN, van Hunnik A, Sobota V, Carstensen H, Hopster-Iversen C, Schwarzwald CC, Altintaş A, Barrès R, Jepps TA, Larsen S, Kjøbsted R, Wojtaszewski JFP, Barrado Ballestero S, Roostalu U, Herum KM, Jespersen T, Nattel S, Nissen SD, Buhl R. (2025). Metformin Protects Against Persistent Atrial Fibrillation in an Equine Model. Circ Arrhythm Electrophysiol, 18(12), e013850. https://doi.org/10.1161/CIRCEP.125.013850

Publication

Circulation. Arrhythmia and electrophysiology
ISSN: 1941-3084
NlmUniqueID: 101474365
Country: United States
Language: English
Volume: 18
Issue: 12
Pages: e013850

Researcher Affiliations

Haugaard, Simon Libak
  • 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).
Schneider, Mélodie J
  • 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).
Kjeldsen, Sofie Troest
  • 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).
Sattler, Stefan Michael
  • 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.
Bastrup, Joakim Armstrong
  • Vascular Biology Group, Department of Biomedical Sciences (J.A.B., T.A.J.), University of Copenhagen, Denmark.
Saljic, Arnela
  • 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.
Birk, Jesper Bratz
  • 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.
Hansen, Caroline
  • 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.
Synnestvedt, Josefine Natalie
  • 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).
van Hunnik, Arne
  • Department of Physiology, Maastricht University, the Netherlands (A.v.H.).
Sobota, Vladimír
  • IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, France (V.S.).
  • Institut de Mathématiques de Bordeaux, University of Bordeaux, UMR 5251, Talence, France (V.S.).
Carstensen, Helena
  • 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).
Hopster-Iversen, Charlotte
  • 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).
Schwarzwald, Colin C
  • Clinic for Equine Internal Medicine, Vetsuisse Faculty, University of Zurich, Switzerland (C.C.S.).
Altintaş, Ali
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences (A.A., R. Barrès), University of Copenhagen, Denmark.
Barrès, Romain
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences (A.A., R. Barrès), University of Copenhagen, Denmark.
  • Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur and Centre National pour la Recherche Scientifique (CNRS), Valbonne, France (R. Barrès).
Jepps, Thomas Andrew
  • Vascular Biology Group, Department of Biomedical Sciences (J.A.B., T.A.J.), University of Copenhagen, Denmark.
Larsen, Steen
  • Department of Biomedical Sciences, Faculty of Health and Medical Sciences (S.L.), University of Copenhagen, Denmark.
  • Clinical Research Center, Medical University of Bialystok, Poland (S.L.).
  • Department of Orthopedic Surgery M, Institute of Sports Medicine Copenhagen, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Denmark (S.L.).
Kjøbsted, Rasmus
  • 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.
Wojtaszewski, Jørgen F P
  • 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.
Barrado Ballestero, Sheyla
  • Gubra ApS, Hørsholm (S.B.B., U.R.).
Roostalu, Urmas
  • Gubra ApS, Hørsholm (S.B.B., U.R.).
Herum, Kate M
  • Research and Early Development, Novo Nordisk A/S, Maaloev, Denmark (K.M.H.).
Jespersen, Thomas
  • 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.
Nattel, Stanley
  • Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Canada (S.N.).
  • Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Germany (S.N.).
Nissen, Sarah Dalgas
  • 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).
  • 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.
Buhl, Rikke
  • 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).

MeSH Terms

  • Animals
  • Metformin / pharmacology
  • Atrial Fibrillation / physiopathology
  • Atrial Fibrillation / prevention & control
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / drug therapy
  • Horses
  • Disease Models, Animal
  • Atrial Remodeling / drug effects
  • Heart Atria / drug effects
  • Heart Atria / physiopathology
  • Heart Atria / metabolism
  • Heart Rate / drug effects
  • AMP-Activated Protein Kinases / metabolism
  • Action Potentials / drug effects
  • Anti-Arrhythmia Agents / pharmacology
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Male

Conflict of Interest Statement

Dr Herum is an employee and shareholder of Novo Nordisk A/s. The other authors report no conflicts.

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