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Linagliptin enhances coronary microvascular function and collateralization in a large animal model of cardiometabolic
Kelsey C Muir1, Dwight D Harris1, Christopher Stone1
1Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, RI, United States of America; Cardiovascular Research Center, Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence, RI, United States of America.
Introduction:
Metabolic syndrome has been shown to double the risk of cardiovascular-related mortality. Therefore, it deems efficacious not only to treat the underlying systemic metabolic pathways but also aim to improve cardiovascular function. Thus, we sought to determine the cardiovascular effects of dipeptidyl peptidase 4 (DPP-4) inhibition with linagliptin in a clinically relevant model of coronary artery disease in the setting of metabolic syndrome.
Methods:
To induce metabolic syndrome, Yorkshire swine were fed a high-fat diet for 5 weeks and then underwent ameroid constrictor placement to the left circumflex artery, causing coronary artery disease. Swine were treated with either no drug (n = 8) or daily linagliptin (n = 8). After 5 weeks, swine underwent terminal harvest for hemodynamic characterization and tissue collection. To assess microvascular reactivity, coronary arterioles were dissected and mounted to visualize the in-vitro response to vasorelaxation agents.
Results:
Linagliptin treatment did not improve overall cardiac function, including ejection fraction and cardiac output (p > 0.05). Linagliptin treatment was associated with upregulation of the glucagon-like peptide-1 receptor, protein kinase A signaling and several other angiogenic markers, and increased collateralization within the ischemic myocardium. Correspondingly, treated swine exhibited enhanced ischemic microvascular vasorelaxation to both endothelial-dependent adenosine diphosphate (ADP) and endothelial-independent sodium nitroprusside (SNP) (p = 0.004, p = 0.024; respectively), accompanied by increased expression of phosphorylated endothelial nitric oxide synthase (eNOS) and the ratio of phospho-to-total eNOS (p = 0.009, p = 0.002; respectively).
Conclusions:
Linagliptin represents a promising therapeutic shown to improve collateralization, enhance arteriolar reactivity, and quell endothelial dysfunction in a translational model of metabolic syndrome.
Insights
Linagliptin improved blood vessel function in a metabolic syndrome model, enhancing blood flow to the heart muscle despite not improving overall heart function. This suggests potential for treating coronary artery disease.
Area of Science:
- Cardiovascular Research
- Metabolic Disease Research
- Pharmacology
Background:
- Metabolic syndrome significantly increases cardiovascular mortality risk.
- Effective treatment requires addressing metabolic pathways and improving cardiovascular function.
- Coronary artery disease (CAD) in metabolic syndrome necessitates targeted therapies.
Purpose of the Study:
- To evaluate the cardiovascular effects of dipeptidyl peptidase 4 (DPP-4) inhibition using linagliptin.
- To assess linagliptin's impact in a relevant preclinical model of CAD with metabolic syndrome.
- To determine if linagliptin improves microvascular function and collateralization in ischemic heart tissue.
Main Methods:
- A Yorkshire swine model was established with diet-induced metabolic syndrome and surgically induced CAD.
- Swine received either linagliptin or no drug for five weeks.
- Hemodynamic assessment, microvascular reactivity testing, and molecular analysis of heart tissue were performed.
Main Results:
- Linagliptin treatment did not improve global cardiac function (ejection fraction, cardiac output).
- Linagliptin upregulated the glucagon-like peptide-1 receptor, PKA signaling, and angiogenic markers, increasing myocardial collateralization.
- Enhanced microvascular vasorelaxation and increased phosphorylated endothelial nitric oxide synthase (eNOS) were observed.
Conclusions:
- Linagliptin demonstrated therapeutic benefits in a translational model of metabolic syndrome.
- The drug improved coronary collateralization and arteriolar reactivity.
- Linagliptin effectively addressed endothelial dysfunction in this preclinical setting.
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