Transcriptomic Profiling of Canine Atrial Fibrillation Models After One Week of Sustained Arrhythmia

Abstract

Background - Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with increased morbidity, mortality, and health-care costs. AF develops over many years and is often related to substantial atrial structural and electrophysiological remodeling. AF may lack symptoms at onset and atrial biopsy samples are generally obtained in subjects with advanced disease, so it is difficult to study earlier-stage pathophysiology in humans. Methods - Here, we characterized comprehensively the transcriptomic (miRNAseq and mRNAseq) changes in the left atria of two robust canine AF-models after one week of electrically-maintained AF, without or with ventricular rate-control via atrioventricular node-ablation/ventricular pacing. Results - 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 highlighted 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 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. Interestingly (in the light of other recent observations), our analysis identified gene-targets of differentially expressed microRNAs at the DLK1-DIO3 locus implicating glutamate signaling in AF pathophysiology. Conclusions - 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 in humans.

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses

“…In the interest of providing an overview of AF-associated pathways and the overlap in differentially expressed genes within patient AF studies and large animal studies, DEGs found between SR and PeAF groups in the studies of Zeemering et al and Van den Berg et al are compared to DEGs found in the studies of LeBlanc et al and Alvarez Franco et al [ 9 , 10 , 64 , 65 ]. This data was available as supplementary information to the published articles.…”

“…Differential gene expression studies in AF models in rats and rabbit suggest involvement of cell cycle-related processes, inflammatory signaling, phagosome and calcium signaling pathways [ 58 , 62 ]. Canine and sheep studies have captured a rich collection of potential AF-related transcripts, including pathway elements for muscle structural development, ECM structure, intercellular glutamate and SLIT/ROBO signaling, intracellular calcineurin signaling and ion channels [ 64 , 65 ].…”

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

“…The evidence described above led to the hypothesis that exaggerated NMDAR activation could also contribute to abnormal excitability and conductivity in atrial fibrillation. In accord, a transcriptomic analysis conducted on a canine model of atrial fibrillation revealed that several genes encoding for glutamate signaling components were targeted by the differentially expressed microRNAs (miRNAs) of the DLK1-DIO3 locus [ 70 ]. Furthermore, Shi et al has previously shown that intraperitoneal injection of NMDA (3 mg/kg) in rats reduced heart rate variability, which is associated with higher adverse outcome of AMI [ 71 ], by causing a dramatic sympathovagal imbalance, with a depressed vagal tone and an enhanced sympathetic activity in rats [ 38 ].…”

Tbx5maintains atrial identity by regulating an atrial enhancer network

“…5c). Grid1 encodes a glutamate receptor related gene that has been shown to be increased in aCMs of humans and dogs in 36 . Smad6, a regulator of TGF and BMP signaling, had greater expression in KO aCMs compared to control (log2 fold-change = 1.21, Padj = 1.2E-94).…”