Abstract
Atrial fibrillation (AF) is associated with atrial remodeling including fatty-fibrotic infiltrations, which may contribute to impairments of the sinoatrial node (SAN) that can promote AF maintenance. Comorbidities including chronic hypertension (HTN), can further increase SAN fatty-fibrotic remodeling. However, mechanisms involved in AF+HTN SAN fatty-fibrotic remodeling are not known. To identify unique molecular signatures of fatty-fibrotic remodeling in SAN and RA in a translational canine model of persistent AF+HTN. A translational canine model of AF+HTN was developed by two weeks right atrial pacing leading to persistent self-sustained AF (>4 months) and HTN (3 months) induced by compressing both kidneys. Differential RNA expression patterns of >500 fibrotic proteins were quantified (nCounter Fibrosis panel, Nanostring) from the SAN and RA (right atrial appendage (RAA) and inferior free wall (RAInf)) in 3 AF+HTN and 4 Controls. In contrast to the intrinsically high fibrotic tissue levels in the Control SAN, AF+HTN SAN had more extensive fibrosis and fat infiltration (Figure). AF+HTN vs Control SAN-specific signatures showed upregulated Lox, Smad4, Pecam1, Acta2, Smad2 and Tgfbr1 along with downregulation of Eln, Reln, Mapk1, Nlrp3 and Fap. Jak1, Nlrp3 and Postn (Periostin) were upregulated in the AF+HTN vs Control RA. Importantly, adipokines including AdipoQ was expressed in SAN tissues. Serpine1, Plin4 were specifically higher in the AF+HTN RA. Collagens 1A1, 3A1, 5A1 and 14A1 were lower in both, AF+HTN SAN and RA. Comparing AF+HTN SAN vs Control SAN, gene ontology pathways including extracellular matrix (ECM) processes, collagen trimers, macrophage migration were activated and pathways related to carbohydrate homeostasis, chemokine-related pathways and JAK-STAT signaling were suppressed in AF+HTN SAN. Results show that unique sets of genes involved in fatty-fibrotic remodeling are up or downregulated in the SAN vs RA in control or AF+HTN indicating potentially different mechanisms of pathophysiological fibrosis. Structural (activated ECM mechanisms) as well as metabolic and inflammation related pathways (suppressed regulation of fatty acid biosynthesis and upregulation of pathways related to chemokine activities) underlie increased SAN fatty-fibrotic remodeling in this translational model of persistent AF+ HTN, which may lead to pacemaker cell uncoupling and SAN conduction blocks.
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