Transcriptomic Remodeling of Pulmonary Vein Sleeves Suggests a Role in Atrial Arrhythmogenesis in Thoroughbred Horses.
Abstract: The initiation and maintenance of atrial fibrillation have been associated with physiological alterations in myocardial sleeves of the pulmonary veins (PVs). Gene expression profiles of the myocardial sleeves of the PVs in healthy (n = 3) and paroxysmal atrial fibrillation (PAF) (n = 6) thoroughbred horses (Equus caballus) were studied. Tissue collected from the left superior PV, adjacent to the left atrium, was analyzed by RNA sequencing. Gene Set Enrichment Analysis demonstrated positive enrichment of gene ontology biological processes related to muscle and endothelial cell development, cell shape, and structure organization in horses with PAF. Enrichment analysis of cellular and molecular functions showed upregulation of genes involved in transport and extracellular matrix components in horses with PAF. SCN5A and MYH7, which are associated with cardiac electrophysiology and contraction function, were both significantly upregulated in the PAF group (fold change 1.1 and 2.2, respectively). Cell deconvolution revealed a trend, although not significant, of increased numbers of fibroblasts. Our results suggest there are transcriptomic alterations in myocardial sleeves of PVs in horses with PAF, alterations related to both cardiac electrophysiology and tissue structure. These data shed further light on the potential role of PV myocardial sleeves in the pathophysiology of PAF.
© 2025 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.
Publication Date: 2025-12-15 PubMed ID: 41395931PubMed Central: PMC12917935DOI: 10.1111/nyas.70170Google Scholar: Lookup
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Summary
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Overview
- This study investigated changes in gene expression in the myocardial sleeves of pulmonary veins (PVs) in Thoroughbred horses with paroxysmal atrial fibrillation (PAF) compared to healthy controls.
- The findings suggest that transcriptomic remodeling in PV myocardial sleeves may contribute to the development and maintenance of atrial arrhythmias in horses.
Background and Purpose
- Atrial fibrillation (AF) is a common cardiac arrhythmia linked to abnormal electrical activity originating in pulmonary vein myocardial sleeves.
- Paroxysmal atrial fibrillation (PAF) is a form where episodes start and stop spontaneously.
- Understanding molecular changes in PV myocardial sleeves could clarify mechanisms behind AF initiation and maintenance.
- The study aimed to profile gene expression in PV myocardial sleeves from horses with PAF versus healthy controls using RNA sequencing.
Methodology
- Tissue samples were collected from the left superior pulmonary vein (adjacent to the left atrium) of 3 healthy horses and 6 horses diagnosed with PAF.
- RNA sequencing was performed to quantify gene expression profiles in these tissues.
- Gene Set Enrichment Analysis (GSEA) was used to identify biological processes and molecular functions that were differentially expressed in PAF horses.
- Additional analyses included evaluating key genes linked to cardiac electrophysiology and contraction, and cell composition estimates (cell deconvolution) focusing on fibroblast populations.
Main Findings
- Biological processes upregulated in PAF horses included:
- Muscle and endothelial cell development
- Cell shape regulation
- Structural organization within the tissue
- At the molecular and cellular function level, genes involved in:
- Transport mechanisms
- Extracellular matrix components
were upregulated in PAF-affected PV sleeves, suggesting tissue remodeling.
- Two key genes of interest:
- SCN5A — encodes a cardiac sodium channel critical for electrophysiology, showed a modest but significant increase (fold change 1.1) in PAF horses.
- MYH7 — encodes a myosin heavy chain involved in muscle contraction, was significantly upregulated (fold change 2.2), indicating changes in contractile protein expression.
- Cell deconvolution suggested a trend towards an increased number of fibroblasts in PAF samples, though this was not statistically significant and indicates possible fibrotic remodeling or changes in cell composition.
Interpretation and Significance
- The transcriptomic differences indicate that PAF is associated with remodeling of both electrical properties and structural components within pulmonary vein myocardial sleeves.
- Upregulation of SCN5A may influence electrical conduction properties and arrhythmogenesis.
- Increased MYH7 and extracellular matrix-related genes imply altered contractility and tissue architecture, which can contribute to arrhythmia substrate.
- The trend towards fibroblast enrichment aligns with tissue fibrosis known to affect conduction and rhythm stability.
- These findings highlight the pulmonary vein myocardial sleeves as an important site for arrhythmia initiation and maintenance in horses, paralleling observations in human AF research.
- Understanding these changes could guide future interventions targeting PV sleeves to prevent or treat atrial fibrillation in equine medicine and potentially inform human therapies.
Cite This Article
APA
Arevalo-Turrubiarte M, Edling CE, Moller-Levet C, Forbes B, Kemp V, Weir J, Marr C, Lewis R, Jeevaratnam K.
(2025).
Transcriptomic Remodeling of Pulmonary Vein Sleeves Suggests a Role in Atrial Arrhythmogenesis in Thoroughbred Horses.
Ann N Y Acad Sci, 1556(1), e70170.
https://doi.org/10.1111/nyas.70170 Publication
Researcher Affiliations
- School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK.
- School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK.
- School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK.
- Hong Kong Jockey Club, Sha Tin racecourse, Sha Tin, Hong Kong.
- Hong Kong Jockey Club, Sha Tin racecourse, Sha Tin, Hong Kong.
- Hong Kong Jockey Club, Sha Tin racecourse, Sha Tin, Hong Kong.
- Rossdales Equine Hospital and Diagnostic Centre, Newmarket, UK.
- School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK.
- School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK.
MeSH Terms
- Animals
- Horses
- Pulmonary Veins / metabolism
- Pulmonary Veins / pathology
- Atrial Fibrillation / genetics
- Atrial Fibrillation / veterinary
- Atrial Fibrillation / physiopathology
- Atrial Fibrillation / metabolism
- Transcriptome / genetics
- Horse Diseases / genetics
- Heart Atria / metabolism
- Heart Atria / pathology
- NAV1.5 Voltage-Gated Sodium Channel / genetics
- NAV1.5 Voltage-Gated Sodium Channel / metabolism
- Myocardium / metabolism
- Myocardium / pathology
- Male
- Arrhythmias, Cardiac / genetics
Grant Funding
- MRG2021101261 / The Hong Kong Jockey Club Equine Welfare Research Foundation
Conflict of Interest Statement
The authors declare no conflicts of interest.
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