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

Abstract

BACKGROUND: 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. OBJECTIVES: To characterise the cardiac transcriptome of healthy horses and explore transcriptional changes associated with persistent AF (naturally occurring and tachypacing-induced). STUDY DESIGN: 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. MAIN LIMITATIONS: The study cannot distinguish changes predisposing to AF from those caused by it. CONCLUSION: 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.