TY - JOUR
T1 - Metformin Protects Against Persistent Atrial Fibrillation in an Equine Model
AU - Haugaard, Simon Libak
AU - Schneider, Melodie J.
AU - Kjeldsen, Sofie Troest
AU - Sattler, Stefan Michael
AU - Bastrup, Joakim Armstrong
AU - Saljic, Arnela
AU - Birk, Jesper Bratz
AU - Hansen, Caroline
AU - Synnestvedt, Josefine Natalie
AU - Van Hunnik, Arne
AU - Sobota, Vladimir
AU - Carstensen, Helena
AU - Hopster-Iversen, Charlotte
AU - Schwarzwald, Colin C.
AU - Altintas, Ali
AU - Barres, Romain
AU - Jepps, Thomas Andrew
AU - Larsen, Steen
AU - Kjobsted, Rasmus
AU - Wojtaszewski, Jorgen F. P.
AU - Barrado Ballestero, Sheyla
AU - Roostalu, Urmas
AU - Herum, Kate M.
AU - Jespersen, Thomas
AU - Nattel, Stanley
AU - Nissen, Sarah Dalgas
AU - Buhl, Rikke
PY - 2025/12/1
Y1 - 2025/12/1
N2 - BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS: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.
AB - BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS: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.
KW - atrial remodeling
KW - electrophysiology
KW - horses
KW - metformin
KW - models
KW - animal
KW - ECHOCARDIOGRAPHIC-ASSESSMENT
KW - POTENTIAL ROLE
KW - STRUCTURAL-CHANGES
KW - SINUS RHYTHM
KW - KINASE
KW - HEART
KW - CONTRACTILE
KW - EXPRESSION
KW - FIBROSIS
KW - PACKAGE
U2 - 10.1161/CIRCEP.125.013850
DO - 10.1161/CIRCEP.125.013850
M3 - Article
SN - 1941-3149
VL - 18
JO - Circulation-Arrhythmia and Electrophysiology
JF - Circulation-Arrhythmia and Electrophysiology
IS - 12
M1 - e013850
ER -