Abstract Body: Introduction/Background: Heart failure with preserved ejection fraction (HFpEF) is a prevalent, morbid syndrome with limited effective therapies. Obesity increases the risk of HFpEF and Glucagon-like Peptide-1 (GLP-1) agonists have been shown to improve outcomes in obese HFpEF, however the mechanisms remain poorly understood.

Research Question/Aim: We investigated myocardial proteomic changes in a pre-clinical model of cardiometabolic HFpEF and the effects of low dose semaglutide to investigate the direct mechanisms of GLP-1 agonist therapy.
Methods/Approach: 10-week-old male ZSF1 obese rats (HFpEF) were treated with low-dose semaglutide (30 nmol/kg subcutaneously twice weekly, n=5) or vehicle (n=5) for 16 weeks. Male Wistar Kyoto (n=6) rats served as healthy control. Myocardial tissue was collected for mass spectrometry-based proteomics and electron microscopy.

Results: Semaglutide improved exercise capacity in the absence of significant body weight loss in HFpEF (Panel A-B). Myocardial lipid droplet quantity and size were also reduced by semaglutide (Panel C). A total of 1874 proteins were measured across all conditions, with 344 significantly upregulated and 240 down-regulated proteins in HFpEF vs Control. Enriched pathways for proteins upregulated in HFpEF were related to lipid and cholesterol metabolism. Downregulated proteins were enriched in pathways related to oxidative phosphorylation, TCA cycle, fatty acid metabolism, and the ribosome. This model corresponds to the human myocardial HFpEF proteome revealing a defect in fuel metabolism and mitochondrial function. There were 72 significantly upregulated and 133 down-regulated proteins in HFpEF + semaglutide vs HFpEF (Panel D). Enriched pathways for proteins upregulated by semaglutide were related to TCA cycle and the ribosome. Downregulated proteins were enriched in pathways related to cholesterol metabolism and the lysosome.

Conclusion: These studies provide the first proteomic atlas of a pre-clinical model of cardiometabolic HFpEF and systematically characterize changes in response to GLP-1 agonism. We also observed improved exercise capacity and blunted myocardial lipid droplet content following semaglutide treatment; changes that were independent of weight loss.