Haihao Yan,1,2 Wenjing Yao,2 Yanhong Li,1 Tianxing Li,3 Kexin Song,1 Pan Yan,4 Yi Dang2 

1Department of Internal Medicine, Graduate School of Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China; 2Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3Department of Graduate School of Hebei North University, Zhangjiakou, Hebei, 075000, People’s Republic of China; 4Department of Internal Medicine, Yongnian District Traditional Chinese Medicine Hospital, Handan, Hebei, 057150, People’s Republic of China

Correspondence: Yi Dang, Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China, Tel +86-0311-85988645, Email dangyiemail@sina.com

Background: Acute myocardial infarction (AMI) is a significant clinical challenge. Semaglutide has therapeutic potential in cardiovascular disease management, but its specific impact and mechanisms in AMI are not fully understood.
Methods: Twenty-four male Sprague-Dawley rats were divided into three groups: control (Control), infarction-only (MI), and semaglutide-treated (SEMA). Weight, blood glucose, and lipid profiles were analyzed. Cardiac function was evaluated via echocardiography. Histopathological assessment and immunohistochemical analysis were performed. Untargeted metabolomic analysis using LC-MS/MS was utilized.
Results: Semaglutide treatment was associated with a reduction in body weight, blood glucose, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), as well as an enhancement in the left ventricular ejection fraction (Control vs MI vs SEMA, 69.13± 4.30 vs 30.16± 3.17 vs 39.81± 6.13, P < 0.05). It also had a lower collagen volume fraction (3.05 vs 34.05 vs 17.73, P < 0.05) and ameliorated the accumulation of glycogen in the myocardium. Metabolomic profiling revealed differentially expressed metabolites between the control/MI and MI/SEMA groups, predominantly within benzenoid, lipid, and organic acid categories. Pathway enrichment analysis highlighted amino sugar and nucleotide sugar metabolism, chlorocyclohexane and chlorobenzene degradation, and phenylalanine, tyrosine, and tryptophan biosynthesis. Random forest analysis identified key metabolites, including downregulated Docusate sodium, 1-(2-Thienyl)-1-heptanone, and Adenylyl-molybdopterin, alongside upregulated Methylenediphosphonic acid, Choline sulfate, and Lactosamine.
Conclusion: Semaglutide significantly ameliorated myocardial fibrosis and metabolic dysregulation in rats post-myocardial infarction. Its mechanism involves modulating glucose metabolism, lipid metabolism, and organic acid metabolism. Targeted metabolites, including Docusate sodium, 1-(2-Thienyl)-1-heptanone, Adenylyl-molybdopterin, Methylenediphosphonic acid, Choline sulfate, and Lactosamine, are implicated in the metabolic reprogramming induced by semaglutide.

Keywords: semaglutide, myocardial infarction, cardiometabolic, untargeted metabolomic analysis, glucagon-like peptide-1 receptor agonists