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K 305 23 June 03

K 305 23 June 03. Atherosclerosis. Etiology Classic Risk Factors Dyslipidemia Low HDL Epidemiological Studies (e.g. Framingham) Genetic Disorders Tangier Disease. Atherosclerosis. Etiology Classic Risk Factors Hypertension Obesity Diabetes (uncontrolled) Inactivity Smoking

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K 305 23 June 03

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  1. K 305 23 June 03

  2. Atherosclerosis • Etiology • Classic Risk Factors • Dyslipidemia • Low HDL • Epidemiological Studies (e.g. Framingham) • Genetic Disorders • Tangier Disease

  3. Atherosclerosis • Etiology • Classic Risk Factors • Hypertension • Obesity • Diabetes (uncontrolled) • Inactivity • Smoking • Gender

  4. Atherosclerosis • Emerging Risk Factors • Homocysteine (folic acid) • C Reactive Protein • Lipoprotein a • platelet reactivity • small dense LDL particle size • elevated Fe

  5. Etiology of Atherosclerosis

  6. oxidized LDL hypothesis • Excess LDL cholesterol accumulates in arterial wall • Oxidation of LDL phospholipids containing arachidonic • Ox-LDL stimulate endothelial cell to display sVCAM-1 • monocytes and T cells to adhere to the intimal wall • penetrate intima due to the effect of macrophage chemoattractant protein-1 (MCP-1) • Inside the initma the monocytes differentiate into macrophages

  7. oxidized LDL hypothesis (con’t) • LDL oxidized by OFR and taken up into macrophages via scavenger receptor - become foam cells and fatty streak • Ox-LDL can inhibit normal endothelial functions causing reduced NOS activity and a procoagulant surface • cytokines and growth factors released by cells within region cause VSM proliferation and migration • tough fibrous cap is produced by cells within  plaque. Inflammatory substances secreted by foam cells may cause plaque to weaken  by proteolysis of matrix proteins • foam cells may display a factor which promotes blood clotting possibly causing a thrombus

  8. response-to-injury hypothesis • Various damaging agents chronically present alter endothelial function • Increased presence of soluble vascular cell adhesion molecule-1 (sVCAM-1) • Platelet and leukocyte aggregation which is normally kept in check by healthy endothelial cells occur • Release of growth factors from platelets (e.g. platelet derived growth factor - PDGF) which can stimulate VSM proliferation and change in phenotype

  9. Treatment of Atherosclerosis

  10. Lifestyle changes • Diet •  intake of saturated and hydrogenated fats • total calories from fats • cholesterol intake • total caloric intake • intake of soluble fibre •  intake of omega-3 FA • Exercise • decreases morbidity and mortality from CAD • stress management • quit smoking • manage diabetes

  11. Pharmacological •  LDL [cholesterol] by statins • HMG CoA reductase inhibitors • Statin therapy reduces coronary artery disease morbidity and mortality in primary and secondary prevention trials • [cholesterol] uptake by GI tract • take folic acid to reduce [homocysteine] • aspirin to reduce chance of clotting • MAP • manage blood glucose if diabetic

  12. Surgical procedures • CABG • Angioplasty • restenosis through intimal hyperplasia is a serious problem – may use stents • use gene therapy to reduce this side effect • Genes that disrupt cell cycle • transcription factors and intracellular signals • inducible form of iNOS - NO which is a potent vasodilator also inhibits platelet and leukocyte adhesion, VSM proliferation and migration

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