K 305 23 June 03

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

8. 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

9. 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

14. Treatment of Atherosclerosis

15. 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

16. 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

17. 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