AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Effects of Semaglutide on Myocardial Remodeling in a High-Fat Diet Swine Model of Chronic Ischemic Heart Disease
By Hamze J, Muir KC, Stone C et al.
Introduction: Ischemic heart disease (IHD) remains the leading cause of death worldwide, and many patients experience adverse myocardial remodeling inadequately addressed by current guideline-directed medical therapy. Semaglutide, a GLP-1 receptor agonist, has shown cardiovascular promise in metabolic syndrome, but its effects on myocardial fibrosis, redox balance, inflammation, and cell survival remain incompletely defined. Goals: To evaluate the effects of semaglutide in a clinically relevant swine model of IHD with diet-induced metabolic syndrome and its impact on adverse myocardial remodeling. Methods: 16 Yorkshire swine were fed a high fat diet for 5 weeks to induce metabolic syndrome followed by ameroid constrictor placement to mirror IHD. Animals were then randomized to semaglutide treatment (HSEM, n=8) or untreated control (HFC, n=8) for 5 weeks, followed by terminal harvest. Ischemic myocardial tissue was analyzed via histology, immunoblotting, and proteomic profiling. Results: Semaglutide-treated animals demonstrated reduced overall myocardial fibrosis on trichrome staining (p=0.03), associated with reduced SMAD Family Member 2 and 3 (SMAD2/3) signaling (p=0.04) and vimentin (p=0.01). Proteomic analysis nevertheless suggested persistent extracellular matrix remodeling, with upregulation of matrix- and collagen-associated proteins, including collagen 1A1 (COL1A1) and COL1A2. Despite reduced fibrosis, nitrosative stress, determined by 3-nitrotyrosine staining (3-NT), was increased in semaglutide-treated swine (p=0.004). Immunoblotting and proteomics demonstrated concurrent redox remodeling, including increased nuclear factor erythroid 2-related factor 2 (NRF2) expression (p=0.003) and paraoxonase 1 (PON1) upregulation. There was no difference between the two groups in global apoptosis quantified by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining; however, apoptotic signaling was altered, with reduced caspase-3 expression in HSEM swine (p=0.04). Inflammatory signaling appeared mitigated, with semaglutide treatment associated with increased inhibitor of kappa B (IκB) expression (p=0.03), no change in phospho-nuclear factor kappa B (p-NFκB) (p=0.9), and proteomic analysis demonstrating increased markers of the reparative M2 macrophage phenotype, including CD163. Conclusion: Semaglutide treatment attenuated several features of adverse myocardial remodeling in a clinically relevant swine model of chronic ischemic and metabolic syndrome, particularly myocardial fibrosis and inflammatory signaling, while simultaneously promoting dynamic ECM and redox remodeling. These nuanced findings support further investigation into the mechanistic role of GLP-1 receptor agonists in long-term ischemic myocardial adaptation and their potential as adjunctive therapies for chronic IHD.