1. Vascular Diseases

2. Diseases System FunctionalStructural Developmental/ Genetic Inflammatory Degenerative/ Aging Neoplastic

3. Atherosclerosis

4. Definition Atherosclerosis is a fibroinflammatory lipid plaque affecting blood vessels, usually elastic and muscular arteries. It develops over several decades. It starts as early as infancy and childhood, and progress very slowly during life. It results from accumulation of lipid, connective tissue, inflammatory cells, smooth muscle cells in the intima.

6. The disease is a chronic process but superimposed by acute events. Risk factors accelerate the progression. Pathogenesis includes genetic and environmental factors. There are many names used to describe atherosclerosis including: atheroma, fibrous plaques, fibrofatty lesion, atherosclerotic plaques.

7. Arteriosclerosis is non-specific term used to describe hardening of arteries. It can be caused by atherosclerosis or by other less common degenerative changes. Arteriolosclerosis is thickening of the wall of arterioles.

8. Atherosclerosis affects almost all people with variable severity. Complications of atherosclerosis are very common, important and serious clinical problems. These are: –ischemic heart disease, –myocardial infarction, stroke, and –gangrene of extremities. Ischemic heart disease is the leading cause of death in the US.

9. Pathogenesis: Insudation Hypothesis: –Accumulation of fat in vessel wall –Source: plasma lipoproteins –Most important: low-density lipoproteins LDL –Through: endothelial receptors for LDL –Or transported inside macrophages to vessel walls

10. Pathogenesis: Encrustation Hyposthesis: –Small mural thrombi –With organization –Followed by plaque formation –This hypothesis does not explain the initiation of atherosclerosis, but it explains critical part of the progression.

11. Pathogenesis: Reaction to Injury Hypothesis: –Dysfunctional endothelial cells –Inflammatory cells, macrophages –Response to injury –PDGF, FGF, TGF-beta Monoclonal Hypothesis: –Monoclonal proliferation of smooth muscle cells

12. Stages of Atherosclerosis: 1.Initiation and Formation Stage 2.Adaptation Stage 3.Clinical Stage

13. Initiation and Formation Stage: 1.Intimal lesions: At site of shear and stress eg. Bifurcation of vessels (hemodynamic factors) Endothelial dysfunction Subendothelial smooth muscle Hemodynamic forces induces: EGF-2, Plasminogen activator, endothelin, also induces: NO, Plasminogen activator inhibitors.

14. Initiation and Formation Stage: 2. Lipid accumulation: Disruption of endothelium integrity Or endothelial dysfunction LDL, macrophages Accumulation of lipid

15. Initiation and Formation Stage: 3. Macrophage role: Growth factors Oxidized lipoprotein induces tissue damage PDGF, FGF, TNF, IL-1

16. Initiation and Formation Stage: 4. Mural thrombi Smooth muscle proliferation Organization 5. Necrosis of deep part of intima Angiogenesis

17. Initiation and Formation Stage: 6. Formation of fibroinflammatory lipid plaque with: Central necrotic core, and Fibrous cap

18. Adaptation Stage: 7. Atheromatous plaque results in stenosis of vessels Remodeling of vessels occur Delay in clinical diagnosis

19. Clinical Stage 8. Hemorrhage into the plaque T-cell immune response 9. Complications: Ulceration Fissure formation Calcification Aneurysm Stenosis, occlusion Thrombosis

20. Initial Lesions of Atherosclerosis 1. Fatty Streak: Flat or slightly elevated yellow lesion in the intima Intracellular or extracellular lipid Young children and adults Most lipid in macrophages (Foam cells) Common in thoracic aorta

21. Initial Lesions of Atherosclerosis 2. Intimal Cell Mass: White thick area at branch points of vessels Smooth muscle and connective tissue “ cushions ”

22. Lesions in Atherosclerosis Fibroinflammatory lipid plaque (simple plaque, athrosclerotic plaque): –Focal, elevated, pale-yellow, smooth, irregular –Oval, eccentric –Consists of: –1. Fibrous Cap: smooth muscle cells, macrophages, lymphocytes, foam cells, and connective tissue –2. Central necrotic Core: necrotic debris, cholesterol crystals, giant cells –3. Neovascularization from vasa vasorum resulting in hemorrhage.

24. Complicated Atherosclerotic Plaques: Erosion, Ulceration Fissuring Hemorrhage Mural thrombi Calcification: in necrotic core Aneurysm Plaque rupture resulting in Destabilization of atheroma

26. Complications of Atherosclerosis 1. Acute occlusion: Thrombosis Occlusion Ischemia, infarction 2. Chronic Stenosis: Chronic ischemia Atrophy Eg. Renal atrophy in renal artery stenosis, ischemic atrophy of skin in DM

27. Complications of Atherosclerosis 3. Aneurysm Formation: Extension to media Aneurysm Aneurysmal rupture eg. Abdominal aortic aneurysm 4. Embolism: Of atherosclerotic plaque or of thrombi

28. Risk Factors of Atherosclerosis 1. Hypertension: >160 mmHg increase the risk for MI 3x 2. Blood cholesterol level: Serum cholesterol is the most important factor lying behind the geographic differences in the incidence of coronary artery disease. Related directly to diet intake of saturated fat There are inherited defects of cholesterol metabolisms resulting in hypercholesterolemia

29. Risk Factors of Atherosclerosis 3. Smoking: dose related 4. Diabetes mellitus 5. Increasing age and male sex 6. Physical inactivity and stressful life style 7. Homocysteine Homocysteinuria is autosomal recessive disorder associated with severe atherosclerosis. Homocysteine is toxic to endothelial cells 8. C-Reactive Protein

30. Restenosis after Angioplasty Angioplasty: balloon catheter to dilate the vessels. –restenosis occurs in up to 30-40% of case within 3-6 months. –Stents to keep the lumen of the vessels open and prevent stenosis. CABG: –Saphenous vein graft –changes that compromise the blood flow. These are: Intimal thickening (phlebosclerosis) Medial calcification Muscle hypertrophy Scarring of the adventitia –50% of the grafts occlude in 5-10 years.

31. Hypertension

32. Hypertension affects 20% of the population. It is seen in more that half of cases of myocardial infarction, stroke and chronic renal failure. Hypertension is more severe in blacks and results in complications. Hypertension is seen in more than ¾ of cases of dissecting aortic aneurysm, intracerebral hemorrhage, and rupture of myocardial wall. 95% of hypertension is due to unknown cause, “essential” or primary hypertension.

33. Definition: –WHO: systolic pressure >160 mmHg, and/or diastolic >90 In 20 year-old men the normal blood pressure range is 105-150 (mean 130) In 80 year-old men the normal blood pressure range is 125-220 (mean 170)

34. Pathogenesis Blood pressure is the product of cardiac output and the systemic peripheral resistance. Hypertension results from imbalance between factors controlling cardiac output and systemic peripheral resistance.

35. Renin-Angiotensin system In experiment: renal artery occlusion - production of renin - converts Angiotensinogen to AngiotensinI - AngiotensinII which result in: a.Increase sympathetic activity leading to vasoconstriction b.Increase aldosterone production leading to Na and water retention c.Direct vasoconstriction action The end result is increase in cardiac output and increase in the systemic peripheral resistance.

36. Atrial Natriuretic Factor (ANF) With atrial distention, there is release of ANF by specialized cells in the atrium. ANF acts on specific receptors in the kidney and results in Na excretion. This leads to decrease in blood volume and in cardiac output.

37. In Hypertension there is disturbance of the balance and the control of these systems. The end result is high blood pressure, mainly due to increase in systemic peripheral resistance.

38. Therapy Sympathetic antagonists (beta-adrenergic blockers) Diuretics ACE inhibitors

39. Secondary Hypertension Renal artery stenosis Chronic renal diseases Conn syndrome Cushing syndrome Pheochromocytoma Hyperthyroidism Coarctation of aorta Renin-secreting tumors Atherosclerosis

40. Pathology Compromised lumen of small muscular arteries and arterioles by: Active contraction of vessels Increase thickness of vessel wall Benign Arterioslerosis and Arteriolosclerosis: –Mild chronic hypertension –Increase thickness of vessel wall with hyaline change due to accumulation of basement membrane material and plasma proteins. –Redublication of internal elastic lamina –Changes seen in kidneys called nephrosclerosis

42. Pathology Malignant (accelerated) hypertension: –Elevated blood pressure >160/110 –Progressive vascular compromise –Affecting brain, heart, kidneys –Retina: segmental constriction and dilatation of arterioles, micro aneurysm, focal hemorrhage, necrosis, edema –Fibrinoid necrosis of muscular small arteries –Smooth muscle proliferation with concentric pattern: “onion-skin” appearance.

44. Hypertensive Heart disease left ventricular hypertrophy in a person with hypertension. –Other causes of left ventricular hypertrophy must be excluded. –This results as an adaptive response to the increase in mechanical stress. –There is change in the genes controlling the expression of myosin and actin and other cellular constituents.

46. Hypertensive Heart disease There is increase in the metabolic requirement, but the hypertrophy makes the left ventricle stiff resulting in increase in the wall tension, and decrease the diastolic filling, and the cardiac output. The changes make the heart at increase risk of ischemic disease, myocardial infarction, arrhythmias and heart failure

47. The heart weight usually exceeds 450g. There is concentric hypertrophy of the left ventricle In long-standing cases dilatation of the left ventricle occurs Cardiac muscles show enlargement of size, and nuclei Coronary artery disease is present in most cases Heart failure may occur

48. Home Work List the causes of dyspnea. Describe the dyspnea in the following: –Bronchial Asthma –COPD –Idiopathic pulmonary fibrosis –Pneumonia –Pulmonary embolism/Pulmonary infarction –Heart failure What is orthopnea? What is paroxysmal noctornal dyspnea?