Abstract Body (Do not enter title and authors here): Background: HFpEF accounts for over 50% of heart failure cases and has limited treatment options. A central feature of HFpEF is myocardial fibrosis, which is correlated with diastolic dysfunction and increased risk of hospitalization. Semaglutide, a GLP-1 receptor agonist (GLP-1RA), has proven clinical benefits in individuals with HFpEF. Secondary analyses of the STEP-HFpEF trial suggest that beneficial actions of GLP-1RA extend beyond weight loss and provide evidence of direct cardiac effects. However, the specific impact of semaglutide on fibrosis in HFpEF remains unexplored.

Hypothesis: Semaglutide exerts a direct effect on myocardial and hepatic fibrosis in HFpEF, independent of any anti-obesity effects.

Methods: Ten-week-old male ZSF1 obese rats (n=6/group) received either vehicle or semaglutide (30 nmol/kg, SC, biweekly) for 16 weeks. Echocardiography, exercise tolerance, invasive hemodynamics, and histopathology were performed. Hearts and livers were subjected to snRNA-seq. Differential gene expression analysis was conducted on cardiac fibroblast and hepatocyte populations. Histological analysis was also performed on multiple organs from female Göttingen minipigs (n=5/group) with HFpEF that received low-dose semaglutide (8 nmol/kg, IM, once weekly).

Results: In ZSF1 obese rats, low-dose semaglutide treatment failed to decrease body weight. Semaglutide improved diastolic function, enhanced exercise tolerance and reduced cardiac fibrosis. snRNA seq of cardiac fibroblasts from semaglutide-treated rats revealed a downregulation of multiple collagen isoforms, periostin, Smad3/7, and components of the complement cascade. Similarly, snRNA-seq from semaglutide-treated rats revealed an increase in amino acid metabolism in hepatocytes and a decrease in inflammatory pathways (TNF, IL-17) and extracellular matrix genes like collagens, Thbs1, and Ecm1 in hepatic stellate cells. Supporting the clinical relevance of these findings, histological analysis of tissues from minipigs with HFpEF revealed significant fibrosis across multiple organs, i.e., heart, liver, kidney, and skeletal muscle. Notably, low-dose semaglutide led to a substantial resolution of fibrosis in all these organs without a reduction in body weight.

Summary and Conclusion: Low-dose GLP-1 receptor agonist therapy significantly improved LV diastolic function and reduced fibrosis in HFpEF animal models, suggesting direct antifibrotic effects with potential clinical relevance beyond HFpEF.