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Published on: February 16, 2016
Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease
Christopher Stone1, Dwight D Harris1, Mark Broadwin1
1Department of Cardiothoracic Surgery, Brown University, Providence, RI.
Insights
Semaglutide (SEM), a GLP-1 agonist, improved heart function and blood flow in a swine model of coronary artery disease. This suggests SEM may offer benefits for treating ischemic heart conditions beyond diabetes management.
Area of Science:
- Cardiology
- Pharmacology
- Translational Medicine
Background:
- Coronary artery disease (CAD) is a leading global cause of death, often resulting in debilitating symptoms and residual disease.
- Current treatments for advanced CAD, including procedural and pharmacological options, are insufficient for many patients.
- Semaglutide (SEM), a glucagon-like peptide-1 (GLP-1) agonist, shows potential for cardiovascular risk reduction, but its direct impact on CAD sequelae, independent of diabetes or obesity, requires investigation.
Purpose of the Study:
- To investigate the effects of oral Semaglutide (SEM) on cardiac function and myocardial perfusion in a large animal model of coronary artery disease.
- To determine the underlying mechanisms of SEM's action in the context of chronic myocardial ischemia, independent of diabetes or obesity.
Main Methods:
- Yorkshire swine underwent surgical induction of coronary artery disease via ameroid constrictor placement.
- Postoperatively, animals received oral SEM (3 mg) for 5 weeks, while a control group received no treatment.
- Cardiac function, myocardial perfusion, fibrosis, apoptosis, and key molecular pathways (AMPK, eNOS) were assessed in the ischemic myocardium.
Main Results:
- SEM-treated animals demonstrated improved left ventricular ejection fraction at rest and during pacing (P<0.03).
- Enhanced myocardial perfusion in ischemic regions (P<0.03) and reduced cardiac fibrosis and apoptosis were observed in SEM-treated animals (P<0.03 and P=0.008, respectively).
- SEM treatment increased activation of the endothelial-protective AMPK pathway (P=0.005) and eNOS (P=0.014).
Conclusions:
- Oral SEM effectively improved cardiac function and perfusion in a large animal model of chronic ischemic heart disease.
- The beneficial effects of SEM appear to be mediated by enhanced endothelial function and increased perfusion to ischemic myocardium, likely via the AMPK pathway.
- This study provides translational evidence for SEM's potential therapeutic role in managing sequelae of coronary artery disease.
Background:
Coronary artery disease is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy and up to one-thirds with debilitating angina amenable neither to procedures, nor to current pharmacological options. Semaglutide (SEM), a GLP-1 (glucagon-like peptide 1) agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of SEM on the sequelae of coronary artery disease, independently of comorbid diabetes or obesity, are lacking.
Methods:
Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce coronary artery disease. Oral SEM was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (n=8) for a total of 5 weeks, while control animals (n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation.
Results:
SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both P<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both P<0.03); reduced perivascular and interstitial fibrosis (both P<0.03); and apoptosis (P=0.008). These changes were associated with increased activation of the endothelial-protective AMPK (AMP-activated protein kinase) pathway (P=0.005), coupled with downstream increases in eNOS (endothelial NO synthase; P=0.014).
Conclusions:
This study reveals the capacity of oral SEM to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.
