VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE

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DESCRIPTION (provided by applicant): Increased prevalence of coronary artery disease is very high and almost 50% of elderly population of the world is vitamin D-deficient. Low levels of vitamin D have increased risks of heart disease, stroke, hypertension, and diabetes. The incidence of angiographic restenoses following balloon angioplasty/stent implantation correlates well with the incidence of vitamin D deficiency/insufficiency. There is no data to predict which patient will develop intimal hyperplasia and in-stent restenosis following coronary intervention. The purpose of this study is to evaluate the effect of vitamin D status on the outcome measures of coronary patency following intervention in a well-controlled swine model of atherosclerosis and to determine the underlying cellular and molecular mechanisms. The central hypothesis is that intimal hyperplasia after coronary intervention depends on vitamin D status and supplementation with vitamin D inhibits inflammation. We propose to utilize a hyperlipidemic and atherosclerotic microswine model fed with vitamin D-deficient, vitamin D-sufficient, and vitamin D-supplemented diet. Animals will undergo balloon angioplasty or intravascular stenting. The hypothesis in Aim 1 predicts that vitamin D deficiency will increase intimal hyperplasia and restenosis following coronary artery intervention by increasing smooth muscle cell proliferation (SMC) and enhancing inflammation. The hypothesis in Aim 2 predicts that vitamin D supplementation will decrease intimal hyperplasia and restenosis following coronary artery intervention by decreasing SMC proliferation and inhibiting inflammation. The hypothesis of Aim 3 predicts that vitamin D decreases intimal hyperplasia and restenosis by inhibiting inflammation and decreasing smooth muscle cell proliferation by decreasing translocation of NF-kB to the nucleus via inhibition of transcription and translation of importin-¿3. Hypercholesterolemic and atherosclerotic microswine with vitamin D deficiency, sufficiency and supplementation will be followed over a period of six months following coronary intervention with left ventriculogram and optical coherence tomography to assess cardiac function and quantify in-segment minimal luminal diameter, diameter stenosis, late loss and intimal hyperplasia. Also, serum levels of 25-hydroxyvitamin D, inflammatory mediators and cytokines, lipid profile and other biochemical and clinical variables. Histological and immunohistochemical evaluation of coronary arteries for intimal thickness, intimal hyperplasia, lumen area, intima-media ratio, plaque development and plaque ulceration, and re-occlusion, and infiltration of inflammatory cells will be performed. Also the mRNA and protein expression of VDR, CYP24A1, CYP27B1, NF-kB, importin-¿3, and prohibitin in isolated smooth muscle cells will be examined. These studies will provide the conceptual support of our hypothesis and position us to assess the effectiveness of vitamin D supplementation in the prevention of clinical complications following coronary interventions in patients with coronary artery disease. PUBLIC HEALTH RELEVANCE: Re-narrowing of coronary arteries in the heart after balloon angioplasty or placement of stents is a serious problem. This is primarily due to uncontrolled growth of smooth muscle cells at the site of injury due to balloon angioplasty or the placement of stent in coronary artery. The incidence of re- narrowing of coronary arteries is about 20% patients within the first year and about 35-50% within 5 years of angioplasty. Since the prevalence of vitamin D deficiency/insufficiency is high in our population, we proposed to examine if vitamin D status determines the outcome results on the re- narrowing of coronary arteries following interventional procedures. The goal is to test the hypothesis that the vitamin D supplementation is beneficial in preventing the blockade of coronary arteries following angioplasty and intravascular stenting. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in patients wit coronary artery disease.