Abstract 16369: Characterization of Streptozotocin Induced Diabetes and Evaluation of Vascular Response to Current Drug-Eluting Stents in a Swine Model
Introduction: Characterization of long-term diabetes in large animal models is needed to advance the understanding of drug-eluting stent performance in diabetics. We hypothesized that streptozotocin (STZ) would induce physiologic changes characteristic of diabetes in a swine model with differential arterial responses to everolimus and paclitaxel-eluting stents.
Methods: STZ was administered to 12 swine to induce hyperglycemia, with insulin therapy maintaining pre-prandial blood glucose level (∼20mM). After 2 months, physiologic diabetic changes were assessed by blood serum chemistry/ELISA, and each animal received one ML VISION® (ML), one XIENCE V® (XV), and one Taxus Liberte (TL) stent respectively in each coronary artery. After 3 months, angiography and histomorphometry were performed. Effects of everolimus and paclitaxel on insulin stimulated p-Akt and p-ERK levels were analyzed by Western blot/ELISA using carotid arteries from these animals cultivated in vitro.
Results: In comparison to baseline, STZ-injected swine displayed significant elevation of blood glucose (2.5 fold, p<0.05), increased inflammation and kidney dysfunction evidenced by elevated levels of TNF-α (1.8 fold, p=0.15), serum creatinine (1.5 fold, p<0.05) and blood urea nitrogen (1.4 fold, p<0.05). When compared to TL, XV and ML exhibited a significant reduction in neointimal area (XV 1.61±0.39, ML 1.19±0.24, TL 2.75±0.61, p<0.05) and strong trends in reduction of % stenosis (XV 11.2%±9.8%, ML 9.3%±7.7%, TL 19.3%±14.7%, p=0.118) and angiographic late-loss (XV 0.28±0.30, ML 0.15±0.18, TL 0.55±0.52, p=0.058). Western blot/ELISA assays revealed paclitaxel significantly decreased insulin stimulated p-Akt levels whereas everolimus had little effect. Induction of p-ERK by insulin was not inhibited by either drug.
Conclusions: Our results indicate that STZ injection created a clinically relevant animal model that displayed several features of the diabetic pathophysiology. XV and ML significantly reduced neointimal area when compared to TL in this model. Molecular investigation of signaling pathways suggested that decreased Akt activation and increased p-ERK/p-Akt ratio may be linked with increases in restenosis.
- © 2010 by American Heart Association, Inc.