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Equine veterinary journal2025; doi: 10.1111/evj.70115

The horse cardiac transcriptome: Moving towards a molecular understanding of atrial fibrillation.

Abstract: High recurrence rates after atrial fibrillation (AF) treatment may be driven by myocardial changes induced by the arrhythmia itself. Understanding the molecular mechanisms behind these changes is crucial for developing targeted therapies and improving outcomes. Objective: To characterise the cardiac transcriptome of healthy horses and explore transcriptional changes associated with persistent AF (naturally occurring and tachypacing-induced). Methods: Case-control study. Methods: RNA-sequencing was performed on atrial and ventricular tissue samples collected from six horses with naturally occurring persistent AF (lasting 2-12 weeks) and six healthy controls. Differential gene expression and pathway enrichment analyses were conducted to identify chamber-specific differences and molecular pathways associated with AF. Findings were integrated with proteomic data and compared with transcriptional changes in a separate cohort of 10 horses with tachypacing-induced AF. Atrial metabolic remodelling was further investigated by evaluating the activity of AMP-activated protein kinase (AMPK), a central metabolic regulator and measuring local glycogen content. Results: The transcriptomes of the four heart chambers had distinct molecular identities. Expression of ion channels and genes encoding calcium handling proteins was largely similar to humans, despite important differences in the ventricular expression of repolarising potassium channels. Persistent AF was associated with minimal ion channel changes but significant upregulation of metabolic, fibrotic and myofibrillar pathways. Metabolic remodeling included upregulation of fatty acid and glycolytic pathways, increased glycogen content in the left atrium and preserved AMPK activity in the right atrium. Transcriptomic profiles of naturally occurring persistent AF correlated well with those of tachypacing-induced AF. Conclusions: The study cannot distinguish changes predisposing to AF from those caused by it. Conclusions: Persistent AF was associated with changes in metabolic and fibrotic pathways in the atria, with minimal ion channel remodeling. Targeting these pathways, rather than focusing solely on the electrical disturbance, may improve treatment outcomes in equine AF.
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Publication Date: 2025-11-14 PubMed ID: 41236081DOI: 10.1111/evj.70115Google 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 analyzed the heart tissue gene expression (transcriptome) of healthy horses and horses with persistent atrial fibrillation (AF) to understand the molecular changes associated with AF.
  • The research identified significant metabolic and fibrotic pathway alterations in the atria of horses with persistent AF, suggesting new targets for treatment beyond electrical abnormalities.

Background

  • Atrial fibrillation (AF) is a common heart rhythm disorder with high rates of recurrence after treatment.
  • Recurrent AF may be driven by structural and molecular changes in the heart muscle caused by the arrhythmia itself.
  • Understanding these underlying molecular changes is vital for developing better, more targeted therapies.
  • Horses serve as an important large animal model for AF due to similarities with human heart physiology.

Objectives

  • Characterize the cardiac transcriptome (gene expression profile) of healthy horses to establish baseline molecular signatures of different heart chambers.
  • Identify changes in gene expression associated with persistent AF, both naturally occurring and artificially induced by tachypacing.
  • Investigate metabolic remodeling in AF by studying pathways related to fatty acid and glucose metabolism, as well as activity of AMP-activated protein kinase (AMPK).

Methods

  • Conducted a case-control study with 6 horses having naturally occurring persistent AF (2-12 weeks duration) and 6 healthy controls.
  • Collected tissue samples from all four heart chambers (atria and ventricles) to perform RNA-sequencing for transcriptomic profiling.
  • Performed differential gene expression analyses to identify chamber-specific molecular differences and pathways altered by AF.
  • Integrated transcriptomic data with proteomics to validate key molecular findings.
  • Compared natural persistent AF profiles with data from a separate group of 10 horses having tachypacing-induced AF to assess consistency of changes.
  • Assessed metabolic remodeling by measuring AMPK activity and glycogen content in atrial tissues, reflecting energy metabolism changes.

Key Findings

  • Each heart chamber had a distinct transcriptomic signature, indicating unique molecular identities within the heart.
  • Gene expression of ion channels and calcium handling proteins in horses closely resembled human hearts, but with notable differences in ventricular potassium channel expression involved in repolarization.
  • Persistent AF caused minimal changes in ion channel gene expression, suggesting electrical remodeling was limited.
  • Significant upregulation was observed in metabolic genes, fibrotic pathways (related to tissue scarring), and myofibrillar components in the atria during AF.
  • Metabolic remodeling included increased expression of genes involved in fatty acid metabolism and glycolysis, indicating altered energy usage in AF.
  • Left atrial tissue of AF horses showed greater glycogen storage, and right atrial tissue maintained AMPK activity, a key regulator of cellular energy homeostasis.
  • The transcriptional changes in naturally occurring AF showed strong correlation with those from tachypacing-induced AF, supporting model validity.

Interpretation

  • The study highlights that AF-associated remodeling in horses primarily affects metabolic and fibrotic pathways rather than ion channel expression.
  • These findings suggest that recurring AF may perpetuate and worsen by changing the heart’s metabolism and structure rather than just altering electrical properties.
  • Since changes predisposing to AF cannot be clearly distinguished from those caused by AF itself, this cross-sectional study cannot establish causality.
  • The similarity between natural and induced AF transcriptomes supports the use of tachypacing models for future research.

Implications and Future Directions

  • The minimal electrical remodeling observed shifts focus toward metabolic and fibrotic pathways as potential therapeutic targets in equine AF.
  • Targeting metabolic alterations (e.g., fatty acid/glycolytic pathways, AMPK modulation) and fibrosis could improve treatment outcomes beyond current strategies that mainly address electrical disturbances.
  • Further longitudinal studies are needed to differentiate molecular changes that lead to AF from those that result from AF.
  • Understanding species-specific differences in ion channel expression can inform translational relevance to human AF research.

Cite This Article

APA
Haugaard SL, Nissen SD, Schneider MJ, Birk JB, Carstensen H, Hopster-Iversen C, Altıntaş A, Barrès R, Kjøbsted R, Wojtaszewski JFP, Herum KM, Jespersen T, Buhl R. (2025). The horse cardiac transcriptome: Moving towards a molecular understanding of atrial fibrillation. Equine Vet J. https://doi.org/10.1111/evj.70115

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English

Researcher Affiliations

Haugaard, Simon Libak
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Nissen, Sarah Dalgas
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
  • Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Schneider, Mélodie Jil
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Birk, Jesper Bratz
  • August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Carstensen, Helena
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Hopster-Iversen, Charlotte
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Altıntaş, Ali
  • Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Barrès, Romain
  • Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Kjøbsted, Rasmus
  • August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Wojtaszewski, Jørgen F P
  • August Krogh Section for Human and Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Herum, Kate M
  • Research and Early Development, Novo Nordisk A/S, Måløv, Denmark.
Jespersen, Thomas
  • Cardiac Physiology Laboratory, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Buhl, Rikke
  • Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

Grant Funding

  • NNF20SA0067242 / Danish Cardiovascular Academy
  • PhD 2022002-HF / Danish Cardiovascular Academy
  • 1032-00053B / Independent Research Fund Denmark

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