PORCINE MODELS OF CORONARY ARTERY DISEASE IN DIABETES

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DESCRIPTION (provided by applicant): The central purpose of this project is to characterize porcine models of diabetes and CAD/restenosis by endocrine, metabolic, and cardiovascular criteria and provide this animal resource for studies of cellular and molecular mechanisms. The investigators have shown that Diabetic Dyslipidemic (DD) pigs have accelerated coronary atheroma, thus making it feasible to stent natural atherosclerotic lesions, not balloon-injured healthy arteries. Overall hypothesis: CAD progression in non-stented conduits and/or microvascular dysfunction contribute to the increased mortality after coronary stenting in diabetes. Overall experimental design: Weanling pigs are screened for optimal cholesterol responses and diabetes is studied from juvenile through adult. Pig groups are maintained as low fat fed healthy controls (C), high fat/cholesterol fed hyperlipidemic and atherosclerotic (H), and diabetic dyslipidemic and atherosclerotic (DD), then natural atherosclerotic lesions are stented, followed by recovery. The porcine model enables tight control of variables, invasive measures of CAD, and provides ample plasma and arteries for in vitro tissue and cell/molecular studies. This powerful experimental design also enables the study of natural progression of atherosclerosis in arteries that are not stented. These capabilities are not possible in widely used rodent and transgenic mouse models. Specific Aims are: 1) Describe the endocrine and metabolic indices of diabetes. In vivo glucose tolerance and insulin sensitivity will determine whether these models represent type 1, type 2, or IGT forms of diabetes; 2) Describe diabetic dyslipidemia. Traditional fasting lipids (LDL, HDL) and more novel phospholipid, fatty acid, and ApoB lipoprotein characterization will describe unique features of diabetic dyslipidemia. Uptake of lipoproteins into arteries and effects on cell proliferation in vitro will assess atherogenicity. Postprandial lipids will assess the atherogenic milieu presented to coronary arteries; 3) Determine whether in-stent restenosis is not increased; instead, progression of CAD in non-stented conduits and microvascular dysfunction are increased. Intravascular ultrasound will provide high spatial resolution of in vivo morphology and intravascular Doppler FIoWires will assess microvascular dysfunction for comparison to non-invasive vascular ultrasound and echocardiography. 4) Determine the extent of coronary artery structural CAD. Histology will determine the extent of intimal thickening and growth in conduits; in contrast, microvessels are predicted to be essentially devoid of atheroma. HPLC analysis of artery lipids and lipid metabolism in stented and non-stented regions will complement IVUS evaluation. Comparison to internal mammary artery and peripheral arteries (brachial and femoral) will characterize vascular heterogeneity; and 5) Provide this animal resource to other investigators. A tissue bank will be established. Development of porcine models provides the fundamental basis for virtually all of our future studies, including pharmacotherapy, evaluation of other coronary interventions, exercise training, and detailed studies of cellular/molecular mechanisms of CAD/restenosis in diabetes.