Transcriptomic profiling of canine atrial fibrillation models after one week of sustained arrhythmia

Abstract

Atrial fibrillation (AF), the most common arrhythmia with an overall prevalence of 0.51%, is associated with increased morbidity and mortality, as well as important healthcare costs. AF develops over many years and is often associated with substantial changes in the structural and electrophysiological properties of the atria. Because AF may lack subclinical symptoms at onset, it has been difficult to study the molecular and cellular events associated with earlier stages of this pathology in humans. Here, we characterized comprehensively the transcriptomic changes that occur in the atria of two robust canine AF models, electrically maintained AF without and with a controlled ventricular rate achieved by radiofrequency-ablation of the atrioventricular node (ventricular pacing), after one week of maintenance. Our RNA-sequencing experiments identified thousands of genes that are differentially expressed, including a majority that have never before been implicated in AF. Gene set enrichment analyses identified known (e.g. extracellular matrix structure organization) but also many novel pathways (e.g. muscle structure development, striated muscle cell differentiation) that may play a role in tissue remodeling and/or cellular trans-differentiation. Of interest, we found dysregulation of a cluster of non-coding ribonucleic acids (RNAs), including many microRNAs but also the MEG3 long non-coding RNA orthologue, located in the syntenic region of the imprinted human DLK1-DIO3 locus. Our results capture molecular events that occur at an early stage of disease development using well-characterized animal models, and may therefore inform future studies that aim to further dissect the causes of AF and factors involved in its progression in humans.