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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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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigated whether metformin could prevent the progression of atrial fibrillation (AF) in horses, an animal model that naturally develops AF similarly to humans.
  • The research demonstrated that metformin treatment protected against persistent AF and reduced the complexity of atrial remodeling, suggesting potential for metformin as a preventative therapy in AF.

Background and Significance

  • Horses spontaneously develop atrial fibrillation, making them a valuable model for studying AF mechanisms and potential treatments that are relevant to humans.
  • Atrial fibrillation causes both electrical and structural remodeling of the heart’s atria, which compromises the long-term success of existing treatments.
  • Previous observational studies indicated that metformin, a common metabolic drug, might reduce AF risk, but its impact on AF progression and atrial remodeling had not been studied in large animal models with high fidelity to human disease.

Study Design and Methods

  • A longitudinal equine model was used, where AF was induced by tachypacing to create self-sustaining AF over four months.
  • Twenty-four horses were divided into two groups: one treated with metformin (30 mg/kg orally, twice daily) starting before AF induction and a control group without metformin.
  • Multiple techniques were employed to study the disease and treatment effects:
    • Electrophysiology to assess electrical properties of the atria.
    • Multiomics to analyze molecular and metabolic changes.
    • Histology and echocardiography to evaluate structural remodeling.
    • Biochemical and mitochondrial analyses to investigate cellular metabolism and mitochondria.

Key Findings

  • The horse AF model replicated key features of human AF, including:
    • Electrical changes in the atria that promote AF maintenance.
    • Structural remodeling of atrial tissues.
  • Metabolic genes and proteins were upregulated in AF; however, no significant changes in mitochondrial ultrastructure were observed.
  • Metformin plasma measurements confirmed stable therapeutic drug levels throughout the study.
  • Horses treated with metformin:
    • Were protected from early stabilization of AF, meaning the arrhythmia was less likely to become persistent and self-sustaining.
    • Had reduced complexity of the AF substrate in the right atrium after 4 months, indicating less severe electrical and structural remodeling.
  • Protective effects of metformin were linked to:
    • Increased activity of AMP-activated protein kinase (AMPK), a key metabolic regulator, specifically in the right atrium.
    • Modulation of several metabolic pathways, suggesting improved metabolic balance.
    • Changes in ion-channel gene expression that could stabilize electrical activity.

Conclusions and Implications

  • This study established that metformin provides protection against the persistence and progression of atrial fibrillation in a clinically relevant large animal model.
  • The findings suggest metformin acts on metabolic and electrical remodeling processes to reduce AF severity, particularly targeting the right atrium.
  • Metformin should be considered a promising candidate for AF prevention and warrants further exploration in both mechanistic studies and clinical trials.
  • This research supports the repurposing of metformin, a commonly used diabetes medication, as a potential novel therapeutic approach to AF management.

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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