Linagliptin enhances coronary microvascular function and collateralization in a large animal model of cardiometabolic syndrome

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. 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. 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). Linagliptin represents a promising therapeutic shown to improve collateralization, enhance arteriolar reactivity, and quell endothelial dysfunction in a translational model of metabolic syndrome. • Cardiometabolic disease lacks effective therapies. • First study to test linagliptin in translational model of cardiometabolic disease • Linagliptin increased ischemic microvascular densities within the left ventricle. • Linagliptin improved coronary microvascular reactivity and reduced oxidative stress.