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Metformin Protects Against Persistent Atrial Fibrillation in an Equine Model

ABSTRACT: 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 both horses and humans, AF-induced atrial remodelling compromises long-term success. Observational studies have suggested that metformin reduces the risk of AF, but its effects on progressive AF-induced atrial remodelling have not yet been evaluated in a high-fidelity large animal model. Methods: Here, we employed a longitudinal horse model of tachypacing-induced self-sustained AF to characterize the electrical, molecular, and metabolic atrial changes over four months of disease, with and without metformin treatment. Electrophysiological and multi-omic 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 remodelling 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-treated horses were less susceptible to AF and sustained a less complex AF substrate in the right atrium after four months of disease. These effects were associated with increased activity of the metabolic regulator, AMP-activated kinase (AMPK) , changes in metabolic pathways and modulation of ion-channel gene expression. Metformin did not appear to alter left atrial substrate remodelling. Conclusion: Metformin treatment conferred electrical protection in both the early and later stages of AF in a translationally relevant preclinical model. These findings support metformin as a lead molecul ar for AF-prevention, warranting further mechanistic and clinical studies.

INSTRUMENT(S):

ORGANISM(S): Equus Caballus (horse)

TISSUE(S): Heart

SUBMITTER: Joakim Bastrup

LAB HEAD: Thomas Jepps

PROVIDER: PXD059963 | Pride | 2025-12-03

REPOSITORIES: Pride

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Project description:Background: Horses and humans are among the few mammals prone to developing spontaneous atrial fibrillation (AF), both suffering from high recurrence rates after treatment. Treatment resistance is often attributed to functional, structural, and metabolic remodeling of the atria. The aim of this explorative study was to evaluate the molecular pathways associated with early stages of AF in horses and to compare the AF proteomes between horses and humans. Methods: We performed data-independent acquisition mass spectrometry on myocardial biopsies collected from the right atrium (RA), left atrium (LA), and left ventricular chamber (LV) in horses with early stages of naturally occurring persistent AF and controls (n=8 in each group). Results: We identified a total of 3400 quantifiable proteins, several of which were differentially regulated between AF horses and controls (268 in RA, 324 in LA, and 284 in LV, p<0.05). Pathway enrichment analyses identified changes in metabolic, contractile, and extracellular matrix (ECM) proteins. Atrial hypocontractility and ECM remodeling were confirmed by echocardiography and histology, respectively. Key proteomic changes in horses with AF overlapped with human AF public datasets, underscoring the translational relevance of the equine AF model. Particularly, contractile proteins, such as cardiac troponins (TNNT2), myosin (MYH6) and tropomyosin (TPM2), along with metabolic regulators as heat shock protein family A (HSPA4) and Proteasome 26S Subunit, Non-ATPase 13 (PSMD13) were shared between horses and humans with AF. Moreover, a significant increase in several ECM glycoproteins was detected in both species, highlighting the importance of early ECM remodeling that extends beyond the fibrotic changes often associated with AF. Conclusion: The horse and human cardiac proteome share similar AF-related changes. Metabolic, functional, and structural protein changes identified in early-stage AF may provide clues to pharmacological targets for preventing AF-associated atrial remodeling and improving treatment success across species.

			Action	DRS
	10A_RA11_1_24830.d.zip	Other
	10A_RA11_1_24832.d.zip	Other
	10B_RE1_1_24868.d.zip	Other
	10C_RG3_1_24894.d.zip	Other
	11A_RB1_1_24833.d.zip	Other

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Metformin Protects Against Persistent Atrial Fibrillation in an Equine Model

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