Semaglutide’s Role in Cardiac Metabolism and Remodeling Post-Myocardial Infarction: A Metabolomic Analysis

Introduction

Acute myocardial infarction (AMI) is a serious medical emergency that leads to heart cell death, inflammation, scarring, and energy metabolism issues. Heart failure following myocardial infarction is a significant cause of cardiovascular death. Current treatments include β-blockers, angiotensin II receptor blockers, and ACE inhibitors; however, adverse heart remodeling after myocardial infarction remains common. There is a pressing need for new drugs to slow down cardiac remodeling following myocardial infarction.

The heart needs a lot of energy to function. Normally, it generates energy from fatty acids and carbohydrates. After a myocardial infarction, the heart’s energy needs increase while blood supply decreases, disrupting normal metabolic pathways and contributing to heart remodeling. Research indicates that correcting glucose and fatty acid metabolism can help minimize harmful changes in the heart muscle after an infarction.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are new drugs that lower blood sugar, blood pressure, and lipids. Research shows that GLP-1RAs may protect the heart by improving cardiac metabolism.

Liquid chromatography–tandem mass spectrometry (LC–MS/MS) is a powerful technique used in metabolomics to identify changes in metabolite levels, providing sensitive and specific results. Previous studies demonstrated semaglutide’s beneficial impact in stress-induced heart failure in mice, but the metabolic effects of semaglutide after myocardial infarction in rats needed further exploration.

This study investigates the metabolic patterns and changes in the hearts of rats with myocardial infarction treated with semaglutide through untargeted metabolomics. By evaluating energy metabolism markers, cardiac function, and tissue changes, we aim to identify mechanisms behind semaglutide’s protective effects on the heart.

Materials and Methods

Animals and Experimental Design

Male Sprague-Dawley rats (300g) were kept in a controlled environment with sufficient food and water. After one week of adaptation, rats were anesthetized, and myocardial infarction was induced via surgery. We used three groups: control, myocardial infarction (MI), and semaglutide (SEMA). The SEMA group received semaglutide post-surgery, while the other two groups received saline. Treatment lasted for four weeks. Body weight and food intake were monitored weekly before heart tissue and serum were collected for analysis.

Echocardiography

Cardiac function was assessed with echocardiography. We measured left ventricular dimensions and function parameters, including left ventricular ejection fraction (LVEF) and fractional shortening (LVFS). All assessments were performed in a blinded manner to ensure objective results.

Detection of Serum Parameters

After a 24-hour fast, blood was collected, centrifuged, and serum samples analyzed for glucose, cholesterol, and low-density lipoprotein levels using standard kits. GLP-1 concentration was determined by ELISA.

Histopathological Examination

Heart tissues from each group were collected and prepared for histopathological analysis to assess structural damage and fibrosis.

Immunohistochemical Staining

Heart sections underwent immunohistochemical staining to measure GLP-1R expression levels following a defined protocol that included antigen retrieval and specific antibody incubation.

Untargeted Metabolomic Analysis

Cardiac tissue samples were processed for untargeted LC–MS/MS analysis to identify differentially abundant metabolites. Statistical methods were applied to identify variations between groups.

Statistical Analysis

Statistical significance was determined using one-way ANOVA followed by post-hoc tests to compare groups, with a significance level set at P < 0.05.

Results

Effect of Semaglutide on Body Weight, Blood Glucose, and Lipid Levels

After four weeks, body weight increased less in the SEMA group compared to the MI group. Fasting blood glucose, total cholesterol, and low-density lipoprotein levels were significantly lower in the SEMA group compared to MI, indicating improved metabolic health.

Cardiac Ultrasound Assessment

Echocardiography revealed significantly reduced LVEF and LVFS in both the MI and SEMA groups compared to controls, indicating compromised cardiac function post-infarction.

Serum GLP-1 Detection

Serum GLP-1 levels decreased in the MI group but increased significantly in the SEMA group after treatment, suggesting beneficial metabolic effects from semaglutide.

Improvement in Cardiac Remodeling

Histological analysis showed significant muscle structure damage and fibrous tissue proliferation in the MI group, with improvements noted in the SEMA group. Sirius Red staining confirmed decreased collagen deposition in the SEMA group compared to MI.

Enhanced Myocardial Glucose Metabolism

Semaglutide administration led to improved glucose metabolism within the heart, as evidenced by significant histological changes.

Effects of Semaglutide on Myocardial Metabolomics

PLS-DA analysis distinguished metabolomic profiles among control, MI, and SEMA groups. We identified numerous differentially expressed metabolites, with semaglutide reversing multiple metabolic disturbances caused by myocardial infarction.

KEGG Pathway Analysis

Pathway analysis indicated enrichment in various metabolic pathways, highlighting the impact of semaglutide on rat cardiac metabolism.

Machine Learning Insights

Machine learning identified key biomarkers affected by semaglutide treatment. Notable metabolites reversed by semaglutide include a spectrum of molecules integral to cardiac function and metabolism.

Discussion

Cardiovascular diseases pose a global health issue. Myocardial fibrosis, characterized by increased collagen deposition, leads to cardiac dysfunction. This study revealed that semaglutide positively affects metabolic and structural changes in the heart following infarction.

Further research is needed to explore the mechanisms and efficacy of semaglutide and compare it to other therapeutic options.

Conclusion

Semaglutide shows promise in improving metabolic function and structural integrity in the heart post-myocardial infarction, suggesting potential therapeutic value in reducing adverse cardiac remodeling.