Practical 2 pathology bds 2nd yearCVS.pptx

Pathology

1. Practical CVS

2. ARTERIOSCLEROSIS Arteriosclerosis literally means “hardening of the arteries” it is a term reflecting arterial wall thickening and loss of elasticity. Four distinct types are recognized, ARTERIOLOSCLEROSIS affects small arteries and arterioles and may cause downstream ischemic injury. The two variants, are Hyaline arteriolosclerosis and Hyperplastic arteriolosclerosis , related to hypertension.

3. Hyaline arteriolosclerosis Associated with benign hypertension. Marked by homogeneous, pink hyaline thickening of the arteriolar walls, with loss of underlying structural detail and luminal narrowing. The lesions stem from leakage of plasma components across injured ECs into vessel and increased ECM production by SMCs

4. Hyperplastic arteriolosclerosis more typical of severe hypertension. Vessels exhibit “onion skin,” concentric, laminated thickening of arteriolar walls and luminal narrowing laminations consist of SMCs and thickened, reduplicated basement membrane. In malignant hypertension, these changes are accompanied by fibrinoid deposits and vessel wall necrosis (necrotizing arteriolitis )

5. 2. Mönckeberg medial sclerosis Mönckeberg medial sclerosis Calcific deposits in muscular arteries Deposits may undergo metaplastic change into bone. Lesions do not encroach on the vessel lumen Usually not clinically significant. Patients typically >50 yrs old

6. 3 . Fibromuscular intimal hyperplasia non-atherosclerotic process that occurs in muscular arteries larger than arterioles. It is predominantly driven by inflammation (as in a healed arteritis or transplant-associated arteriopathy ; or by mechanical injury (e.g., associated with stents or balloon angioplasty, see later). Healing response causes stenosis of the vessel ; due to intimal hyperplasia Can cause in-stent restenosis and is the major long-term limitation of solid organ transplants

7. 4. Atherosclerosis “hardening,” is the most frequent and clinically important pattern important pattern and is the subject of the next section.

8. Pathogenesis of Atherosclerosis

9. Atherosclerosis is characterized by intimal lesions called atheromas (or atheromatous or atherosclerotic plaques) that impinge on the vascular lumen and can rupture to cause sudden occlusion.

10. Atherosclerosis Atherosclerotic Plaque Plaques vary from 0.3 to 1.5 cm in diameter Focal and sparsely distributed at first Lesions can become more numerous , and tend to coalesce to form large masses with time. Atherosclerotic lesions are patchy , usually involving only a portion of any given arterial wall , and are rarely circumferential ; on cross-section.

11. Atherosclerotic plaque Atheromatous plaques are raised lesions composed of soft friable ( grumous ) lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps

12. Sites of Atherosclerosis Large elastic arteries (aorta, carotid, and iliac) Medium-sized muscular arteries (coronary and popliteal) Vessels of the circle of Willis . Abdominal aorta is involved more than the thoracic aorta. Vessels of the upper extremities, mesenteric and renal arteries, are usually spared except at their ostia.

13. Normal Coronary artery and Atherosclerosis of Coronary artery

14. Epidemiology of Atherosclerosis prevalence and severity of atherosclerosis and IHD have been correlated with a number of risk factors These risk factors have roughly multiplicative effects. Thus, two factors increase the risk for myocardial infarction approximately 4-fold, and three (i.e., hyperlipidemia , hypertension, and smoking) increase the rate by a factor of 7

15. Risk factors for Atherosclerosis Prevalent all over the world, including Pakistan Several risk factors, Constitutional ( non-modifiable ) Acquired or related to behaviors that are potentially amenable to intervention ( modifiable ) Risk factors have a multiplicative effect Two risk factors increase the risk approximately fourfold . When three risk factors are present (e.g., hyperlipidemia , hypertension , and smoking ), the rate of myocardial infarction is increased seven times .

16. Non-modifiable risk factors Age AS typically progressive with advancing age. Between ages 40 and 60 the incidence of myocardial infarction increases fivefold . Death rates from IHD rise with each decade even into advanced age Gender premenopausal women are relatively protected against AS After menopause , however, the incidence and severity of atherosclerosis-related diseases increases Estrogen has a favorable protective influence Genetics Family history is a significant independent risk factor for AS. Familial predisposition to AS and IHD is usually multifactorial

17. Modifiable risk factors Hypertension major risk factor for AS both systolic and diastolic levels are important Hypertension increases the risk of IHD by approximately 60% Cigarette smoking a well-established risk factor Prolonged (years) smoking of one pack of cigarettes or more daily doubles the death rate from IHD Smoking cessation reduces the risk substantially Diabetes mellitus Induces hypercholesterolemia and increases the risk of AS. Myocardial infarction is twice as frequent in diabetics Increased risk of strokes and a 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities

18. Modifiable risk factors Hyperlipidemia hypercholesterolemia- a major risk factor The major component of serum cholesterol associated with increased risk is LDL-cholesterol [the form that is delivered to peripheral tissues]. HDL-cholesterol mobilizes cholesterol from tissue and transports it to the liver for excretion in the bile. [Higher levels of HDL correlate with reduced risk ].

19. Dietary and pharmacologic approaches that lower LDL or total serum cholesterol High dietary intake of cholesterol and saturated fats (egg yolk, animal fat, and butter) raises plasma cholesterol levels. Diets low in cholesterol with higher ratios of polyunsaturated fats lower plasma cholesterol levels. Exercise raises HDL levels, whereas obesity and smoking lower it Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A ( HMG-CoA ) reductase rate-limiting enzyme in hepatic cholesterol biosynthesis

20. Additional risk factors Inflammation present during all stages plays a significant role in ischemic heart disease Systemic marker CRP ( C- reactive protein ) correlate with IHD risk Strong independent marker of risk for MI , Stroke Peripheral arterial disease Normal vessels do not bind inflammatory cells. Early in atherogenesis,however , dysfunctional ECs express adhesion molecules that promote leukocyte adhesion, in particular, monocytes and T cells which migrate into the intima under the influence of locally produced chemokines

21. Additional risk factors Hyperhomocystinemia Elevated circulating homocysteine associated with premature vascular disease Rare inborn error of metabolism elevated levels and premature vascular disease Metabolic syndrome Central obesity Glucose intolerance Prone to hypertension Dyslipidemia leads to EC dysfunction secondary to increased oxidative stress; there is also a systemic proinflammatory state that further predisposes to vascular thrombosis.

22. Atheromatous plaques Superficial Fibrous cap : composed of smooth muscle cells and relatively dense collagen. Necrotic core , containing lipid (primarily cholesterol and cholesterol esters) as crystalline aggregates and empty " clefts ." foam cells (lipid-laden macrophages and smooth muscle cells) debris from dead cells variably organized thrombus fibrin and other plasma proteins Periphery of the lesions show neovascularization Plaques generally continue to change and progressively enlarge

23. Atherosclerotic Stenosis In small arteries, atherosclerotic plaques can gradually occlude vessel lumens, compromising blood flow and causing ischemic injury . Chronic arterial stenosis leads to progressive ischemia . Mesenteric occlusion and bowel ischemia , Chronic IHD, Angina pectoris Ischemic encephalopathy, Stroke Intermittent claudication (diminished extremity perfusion) Gangrene

24. Critical stenosis : In the coronary (and other) circulations, this typically occurs at approximately 70% fixed occlusion loss of area through which blood can flow at this degree of stenosis , patients classically develop chest pain ( angina ) on exertion

25. Vulnerable and stable atherosclerotic plaque

26. Progression of atherosclerosis

27. Pathogenesis of Atherosclerosis Chronic inflammatory and healing response of arterial wall to endothelial injury Lesion progression occurs through interaction of modified lipoprotein , monocyte-derived macrophages and T lymphocytes with endothelial cells and smooth muscle of arterial wall AS progresses in following sequence

28. Sequence of progression of AS Endothelial injury and dysfunction increased vascular permeability leukocyte adhesion and thrombosis Accumulation of lipoproteins mainly LDL and its forms in the vessel wall Monocyte adhesion of endothelium followed by migration into the intima and transformation into macrophages and foam cells Platelet adhesion Factor release from activated platelets macrophages and vascular wall cells inducing smooth muscle recruitment either from media or circulating precursors

29. Sequence of progression of AS Smooth muscle cell proliferation Extracellular matrix production Recruitment of T cells Lipid accumulation

30. Pathogenesis of Atherosclerosis Endothelial injury of any kind results in intimal thickening Early human lesions begin at sites of morphologically intact epithelium Non-denuding endothelial dysfuction underlies most human AS Etiology toxins from cigarette smoke homocysteine and even infectious agents Inflammatory cytokines TNF can also stimulate proatherogenic Two important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia

31. Pathogenesis of Atherosclerosis

32. Pathogenesis of Atherosclerosis Hemodynamic disturbance plaques tend to occur at ostia of existing vessel branch points and along the posterior wall of abdominal aorta Atheroprotective genes whose products protect against atherosclerosis Lipids transported in blood stream bound to specific apoproteins forming lipoprotein complexes Dyslipoproteinemias are lipoprotein abnormalities that may be present in general population 1 Increased LDL cholesterol level 2 decreased HDL cholesterol levels 3 Increased level of abnormal lipoprotein

33. Pathogenesis of Atherosclerosis Inflammation Chronic inflammation contributes to initiation and progression of atherosclerotic lesion Inflammation is triggered by accumulation of cholesterol and free fatty acids in macrophages and other cells Production of proinflammatory cytokine IL-1 which serves to recruit leucocytes including monocytes Local production of cytokines and chemokines that recruit and activate more inflammatory cells

34. Pathogenesis of Atherosclerosis Activated macrophages produce reactive oxygen species that enhance LDL oxidation and elaborate growth factors that drive smooth muscle Activated T cells elaborate inflammatory cytokines interferon-γ Which in turn can activate macrophages and endothelial cells and smooth muscle cells

35. Pathogenesis of atherosclerosis

36. Pathogenesis of atherosclerosis

37. Pathogenesis of Atherosclerosis Infection Linking as to Herpes virus, Cytomegalovirus Chlamydophila pneumoniae No established causal role for infection Smooth muscle proliferation and matrix synthesis Intimal smooth muscle cell proliferation and extracellular matrix deposition convert a fatty streak into a mature atheroma Several growth factors are implicated in smooth muscle cell proliferation including PDGF derived growth factor released by locally adherent platelets

38. Pathogenesis of Atherosclerosis Smooth Muscle Proliferation Intimal smooth muscle cell proliferation and ECM deposition convert a fatty streak , the earliest lesion, into a mature atheroma The intimal smooth muscle cells may be recruited from circulating precursors that may have a proliferative and synthetic activity Growth factors implicated in smooth muscle cell proliferation and ECM synthesis PDGF (released by locally adherent platelets, macrophages, ECs & SMCs) FGF , and TGF-α The recruited smooth muscle cells synthesize ECM (notably collagen) that stabilizes atherosclerotic plaques.

39. MORPHOLOGY The development of atherosclerosis tends to follow a series of morphologic changes

40. Seen in virtually all children >10 years Start as multiple minute flat yellow spots ; they eventually coalesce into elongated streaks 1 cm or more in length. Composed of lipid-filled foamy macrophages . Not significantly raised No flow disturbance The earliest lesions in AS? Fatty Streaks and AS

41. Morphology of atherosclerosis Fatty streaks are composed of lipid filled macrophages beginning as multiple minute yellow spots that eventually coalesce into streaks The lesions are not sufficiently raised to cause any flow disturbance Fatty streaks can evolve into plaques Aortas of infants can exhibit fatty streaks

42. Fatty streak Ostia

43. Morphology of atherosclerosis Atherosclerotic plaque intimal thickening and lipid accumulation together form the plaque white yellow plaque encroach on lumen of artery superimposed thrombus over ulcerated plaque is red brown as lesion is patchy involving only a portion of arterial wall on cross section appear eccentric

44. Normal and Atherosclerotic coronary artery

45. This high magnification microscopic view of an aortic atheroma shows prominent foam cells as well as cholesterol clefts.

46. This high magnification of the atheroma shows numerous foam cells and an occasional cholesterol cleft. A few dark blue inflammatory cells (lymphocytes) are scattered within the atheroma .

47. Foamy macrophages Cholesterol cleft Inflammatory cells Cholesterol clefts Foamy macrophages Inflammatory cells

48. Atherosclerosis and thrombosis Thrombus Atherosclerosis

49. Coronary artery thrombosis

50. Coronary atherosclerosis is shown here complicated by hemorrhage into the atheromatous plaque. Such hemorrhage acutely may narrow the arterial lumen.

51. Atherosclerotic plaque with thrombus

52. Atherosclerotic plaque with thrombus

53. Aortic aneurysm and Myocardial Infarction

54. Popliteal artery block Right leg