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The effects of uncontrolled hyperglycemia on thrombosis and formation of neointima after coronary stent placement in a novel diabetic porcine model of restenosis

Carter, Andrew J. a; Bailey, Lynn a; Devries, Jennifer a; Hubbard, Brad b

Pathophysiology and Natural History
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Background Results of recent clinical studies suggest that patients with diabetes mellitus have a higher than normal rate of restenosis after percutaneous transluminal coronary angioplasty or coronary stenting. The mechanism for this exaggerated neointimal response is not known.

Objectives To determine the technical feasibility of a model of in-stent restenosis in swine with streptozotocin-induced hyperglycemia and to compare the late arterial responses to injury induced by placement of oversized coronary stents in diabetic and nondiabetic animals.

Methods Eighteen 25–40 kg castrated male or intact female Yucatan miniature swine aged 6 months were obtained from a commercial supplier. Twelve of the miniature swine were randomly selected for intravenous treatment with 125 mg/kg streptozotocin to induce a hyperglycemic state. Twelve weeks after treatment, all animals underwent placement of oversized balloon-expandable stainless steel stents in the coronary arteries. After 28 days, histomorphometric analysis of the stented coronary arteries to determine the neointimal responses for the diabetic and nondiabetic animals was completed.

Results Sudden death due to stent thrombosis occurred for five of 11 (45%) of the diabetic animals and none of the age-matched nondiabetic control animals (P  = 0.05). For histology after 28 days, the neointimal response was correlated to the extent of arterial injury for the diabetic (r  = 0.79, P  < 0.0001) and nondiabetic (r  = 0.86, P  < 0.0001) animals. The surviving diabetic animals had areas of neointimal (1.67 ± 0.74 mm2) and percentages of in-stent stenosis (28 ± 14) similar to those of the nondiabetic swine (1.36 ± 0.40 mm2, P  = 0.26; 22 ± 6, P  = 0.17). Multiple regression analysis also demonstrated that arterial injury (P  < 0.0001) alone, not hyperglycemia (P  = 0.237), was independently correlated to formation of neointima.

Conclusions Uncontrolled hyperglycemia results in greater than normal thrombosis after coronary-stent placement in swine with streptozotocin-induced diabetes. These data suggest that greater than normal early formation of thrombus rather than proliferation of smooth muscle cells contributes to restenosis after coronary stenting in patients with diabetes mellitus.

aStanford University Medical Center, Stanford, California, USA. bGuidant Corporation, Santa Clara, California, USA.

Correspondence and requests for reprints to Andrew J. Carter, DO, FACC, Director, Experimental Coronary Intervention Laboratories, Stanford University Medical Center, Stanford, CA 94305-5218, USA. Fax: +1 650 725 6766; e-mail: a_carter@cvmed.stanford.edu

Received 4 November 1999

Accepted 11 February 2000

Sponsorship: This study was funded by a grant from Guidant, Inc., Santa Clara, California, USA.

© 2000 Lippincott Williams & Wilkins, Inc.