Linagliptin Exerts a Sex-Specific Effect on Cardiac Function, Collateralization, and Metabolism in a Swine Model of Cardiometabolic Disease.
Publication/Presentation Date
4-17-2025
Abstract
OBJECTIVE: There are striking sex disparities among cardiometabolic disorders; however, the understanding of its underlying disease pathology remains uncertain, creating insufficient preventative and therapeutic approaches. Our study investigates the sex-specific response to the DPP-4 inhibitor, linagliptin, in a clinically meaningful model of metabolic syndrome and chronic myocardial ischemia.
METHODS: Yorkshire swine were fed a high-fat diet for 5 weeks to induce metabolic syndrome and subsequently underwent placement of an ameroid constrictor to the left circumflex coronary artery (LCx), inducing chronic myocardial ischemia. Swine received either no drug (n=8; 4 female, 4 male) or 2.5mg linagliptin daily (n=8; 3 male, 5 female). Five weeks later, swine underwent hemodynamic measurements, microsphere injections to determine perfusion, and terminal harvest for left ventricular sectioning and molecular and proteomic analysis.
RESULTS: Linagliptin-treated female swine demonstrated improved cardiac function compared to treated males and controls, including cardiac output, stroke work, and left ventricular end diastolic volume (all p< 0.05). There was an increase in arteriolar and capillary density in treated females compared to control (p=0.002, p=0.031; respectively), with associated sex-specific changes in angiogenic proteins. Treated males had reduced glycogen stores by PAS staining compared to control (p=0.017). In contrast, female treated swine had a non-significant reduction in glycogen stores, and an upregulation of proteins associated with overall mitochondrial function and glycolysis.
CONCLUSIONS: Linagliptin treatment resulted in a preferential improvement in left ventricular function, angiogenesis, and "metabolic flexibility" in female swine as compared to males and controls in the setting of metabolic syndrome and coronary artery disease.
ISSN
1097-685X
Published In/Presented At
Muir, K. C., Harris, D. D., Stone, C., Kanuparthy, M., Broadwin, M., Hamze, J., & Sellke, F. W. (2025). Linagliptin Exerts a Sex-Specific Effect on Cardiac Function, Collateralization, and Metabolism in a Swine Model of Cardiometabolic Disease. The Journal of thoracic and cardiovascular surgery, S0022-5223(25)00306-X. Advance online publication. https://doi.org/10.1016/j.jtcvs.2025.04.017
Disciplines
Medicine and Health Sciences
PubMedID
40324745
Department(s)
Department of Surgery, Fellows and Residents
Document Type
Article