Abstract 2719: Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Myocardial Ischemia in Diabetes
Background: Ischemic heart disease is the most common cause of death in diabetic patients. While therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to ischemia. The aims of this study were to
establish a large animal model of diabetes and chronic myocardial ischemia,
evaluate the effects of diabetes on the angiogenic response, and
elucidate the molecular pathways involved.
Methods: Diabetes was induced in Yucatan miniswine using a pancreatic β-cell specific toxin, alloxan (150 mg/kg; n = 8). Age-matched swine served as controls (n = 8). Eight weeks following induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated.
Results: Collateral dependent perfusion and LV function were significantly impaired in diabetic animals (Figure 1⇓). Diabetic animals also demonstrated reduced endothelial cell density (173 ± 14 vs. 234 ± 23 cells/hpf, p = 0.03). Expression of VEGF, Ang-1 and Tie-2 was reduced, while anti-angiogenic proteins, angiostatin (4.4 ± 0.9 fold increase, p < 0.001) and endostatin (2.9 ± 0.4 fold increase, p = 0.03) were significantly elevated in the diabetic myocardium.
Conclusions: Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and anti-angiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.