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PATHOLOGY: ArteriosclerosisnianderthalNOTES
ARTERIOSCLEROSISDEF:-hardening of the arteries-generic term reflecting arterial wall thickening and  loss of elasticityTHR...
1. Arteriolosclerosis-affects small arteries and arterioles-anatomic variants:a. hyalineb. hyperplastic
2. Monckeberg medial sclerosis-has calcific deposits in muscular arteries that   may undergo metaplasia to bone-lesions do...
3. Atherosclerosis-most frequent and clinically important pattern-characterized by intimal lesions called  ATHEROMAS that ...
3. AtherosclerosisEPIDEMIOLOGY-Risk factors have a multiplicative effect-Constitutional Risk Factors in IHDa. Age – clinic...
3. AtherosclerosisEPIDEMIOLOGY-Modifiable Risk Factors in IHDa. Hyperlipidemia – esp. hypercholesterolemia,   increased LD...
3. AtherosclerosisEPIDEMIOLOGY-Modifiable Risk Factors in IHDb. Hypertension – both systolic and diastolic   components ar...
3. AtherosclerosisEPIDEMIOLOGY-Modifiable Risk Factors in IHDd. Diabetes mellitus – induces   hypercholesterolemia
3. AtherosclerosisEPIDEMIOLOGY-Additional Risk Factorsa. Inflammation – present during all stages of   atherogenesis and i...
3. AtherosclerosisEPIDEMIOLOGY-Additional Risk Factorsb. Hyperhomocysteinemia – seen in CAD, PAD,   stroke and venous thro...
3. AtherosclerosisEPIDEMIOLOGY-Additional Risk Factorsd. Lipoprotein (a) – an altered form of LDL,   associated with CAD a...
3. AtherosclerosisPATHOGENESISHypotheses:a. Intimal Cellular Proliferationb. Repetitive Formation and Organization of Thro...
3. AtherosclerosisPATHOGENESISc. Response-To-Injury    -PATHOGENIC EVENTS INVOLVED:       i. Endothelial Injury           ...
3. AtherosclerosisPATHOGENESISc. Response-To-Injury    -PATHOGENIC EVENTS INVOLVED:       iv. Platelet adhesion       v. F...
3. AtherosclerosisPATHOGENESISMAJOR MECHANISMS+Endothelial Cell Injury   -results in intimal thickening   -early human les...
3. AtherosclerosisPATHOGENESISMAJOR MECHANISMS+Endothelial Cell Injury   2 MOST IMPORTANT CAUSES OF   ENDOTHELIAL DYSFUNCT...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Hemodynamic Disturbances-plaques tend to occur at areas of disturbe...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Hemodynamic Disturbances-nonturbulent laminar flow in normal   vasc...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids-Lipoprotein abnormalities present in many MI survivors:    -...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids-Lowering serum cholesterol by diet or drugs   slows the rate...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids-Mechanisms by which HYPERLIPIDEMIA   contributes to ATHEROGE...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids   -Oxidized LDL is ingested by macrophages   through a SCAVE...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Inflammation-dysfunctional arterial endothelial cells express adhes...
3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Infection-Microorganisms detected in atherosclerotic   plaques:   -...
3. AtherosclerosisPATHOGENESIS+Smooth Muscle Proliferation-intimal smooth muscle cell proliferation and ECM    deposition ...
3. AtherosclerosisPATHOGENESIS+Smooth Muscle Proliferation-Smooth muscle cells synthesize ECM that   stabilizes atheroscle...
3. AtherosclerosisMORPHOLOGY*FATTY STREAKS-EARLIEST LESIONS IN ATHEROSCLEROSIS-begin as minute, flat yellow spots and then...
3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-KEY PROCESSES: Intimal Thickening & Lipid    Accumulation-Gross:    -C...
3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Commonly involved Vessels (Descending Order):   1. Lower Abdominal Aor...
3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Principal Components (CEL):1. Cells  -smooth muscle cells, macrophages...
3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Configuration:  1. Fibrous cap – superficial; made of smooth muscle  c...
3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-The periphery of the lesions show  neovascularization-Plaques enlarge ...
3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Plaques are susceptible to the following  CLINICAL CHANGES:1. Rupture,...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE-Large Elastic and Large and Medium Muscular arteries   are the M...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ATHEROSCLEROTIC STENOSIS-plaques can gradually occlude vessel lu...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGE-plaque erosion or rupture is typically promp...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGE-the precipitating lesion in patients who dev...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGEINTRINSIC and EXTRINSIC FACTORS THAT  INFLUEN...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGEVULNERABLE Plaques:-contain large areas of fo...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGE-Peak time of onset of acute myocardial  infa...
3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*THROMBOSIS*VASOCONSTRICTION-compromises lumen size and by increa...
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PATHOLOGY - Arteriosclerosis

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PATHOLOGY - Arteriosclerosis

  1. 1. PATHOLOGY: ArteriosclerosisnianderthalNOTES
  2. 2. ARTERIOSCLEROSISDEF:-hardening of the arteries-generic term reflecting arterial wall thickening and loss of elasticityTHREE GENERAL PATTERNS:1. Arteriolosclerosis2. Monckeberg medial sclerosis3. Atherosclerosis
  3. 3. 1. Arteriolosclerosis-affects small arteries and arterioles-anatomic variants:a. hyalineb. hyperplastic
  4. 4. 2. Monckeberg medial sclerosis-has calcific deposits in muscular arteries that may undergo metaplasia to bone-lesions do not encroach vessel lumen thus NOT CLINICALLY SIGNIFICANT
  5. 5. 3. Atherosclerosis-most frequent and clinically important pattern-characterized by intimal lesions called ATHEROMAS that protrude into the vessel lumen-consists of a raised lesion:a. Grumuous Core – made of lipid, (cholesterol or cholesterol ester) yellow, softb. Fibrous Cap – white
  6. 6. 3. AtherosclerosisEPIDEMIOLOGY-Risk factors have a multiplicative effect-Constitutional Risk Factors in IHDa. Age – clinically manifests middle age or laterb. Gender – premenopausal women are relatively protected due to favorable influence of estrogen -but clinical trials have failed to demonstrate any utility of hormonal therapy for vascular diseases preventiona. Genetics – MOST SIGNIFICANT INDEPENDENT RISK FACTOR
  7. 7. 3. AtherosclerosisEPIDEMIOLOGY-Modifiable Risk Factors in IHDa. Hyperlipidemia – esp. hypercholesterolemia, increased LDL, decreased HDL, increased lipoprotein a*STATINS – a class of drugs that lower circulating cholesterol levels by inhibiting HMG-Coa reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis
  8. 8. 3. AtherosclerosisEPIDEMIOLOGY-Modifiable Risk Factors in IHDb. Hypertension – both systolic and diastolic components are important - MOST IMPORTANT CAUSE OF LEFT VENTRICULAR HYPERTROPHYc. Cigarette smoking – prolonged smoking of one pack of cigarettes or more daily doubles the death rate from IHD
  9. 9. 3. AtherosclerosisEPIDEMIOLOGY-Modifiable Risk Factors in IHDd. Diabetes mellitus – induces hypercholesterolemia
  10. 10. 3. AtherosclerosisEPIDEMIOLOGY-Additional Risk Factorsa. Inflammation – present during all stages of atherogenesis and is intimately linked with atherosclerotic plaque formation and rupture*C-reactive Protein (CRP) has emerged as one of the simplest and most sensitive inflammatory markers; decreased by STATINS
  11. 11. 3. AtherosclerosisEPIDEMIOLOGY-Additional Risk Factorsb. Hyperhomocysteinemia – seen in CAD, PAD, stroke and venous thrombosis -elevated homocysteine levels can be caused by low folate and Vitamin B12 intakec. Metabolic syndrome
  12. 12. 3. AtherosclerosisEPIDEMIOLOGY-Additional Risk Factorsd. Lipoprotein (a) – an altered form of LDL, associated with CAD and CVDe. Factors affecting Hemostasisf. Other Factors – lack of exercise; competitive stressful lifestyle (type A personality); obesity
  13. 13. 3. AtherosclerosisPATHOGENESISHypotheses:a. Intimal Cellular Proliferationb. Repetitive Formation and Organization of Thrombic. Response-To-Injury -views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to injury -lesion progression occurs through the interaction of modified lipoproteins, monocyte-derived macrophages, and T-lymphocytes with the normal cellular constituents of the arterial wall
  14. 14. 3. AtherosclerosisPATHOGENESISc. Response-To-Injury -PATHOGENIC EVENTS INVOLVED: i. Endothelial Injury -increased vascular permeability -leukocyte adhesion -thrombosis ii. Accumulation of Lipoproteins in vessel wall -usually LDL and its oxidized forms iii. Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells
  15. 15. 3. AtherosclerosisPATHOGENESISc. Response-To-Injury -PATHOGENIC EVENTS INVOLVED: iv. Platelet adhesion v. Factor release from activated platelets, macrophages and vascular wall cells, inducing smooth muscle cell recruitment vi. Smooth muscle cell proliferation and ECM production vii. Lipid accumulation -extracellular and within cells (macropahes and smooth muscle cells)
  16. 16. 3. AtherosclerosisPATHOGENESISMAJOR MECHANISMS+Endothelial Cell Injury -results in intimal thickening -early human lesions begin at sites of morphologically intact endothelium, THUS, endothelial dysfunction underlies human atherosclerosis -can be caused by: -hypertension -hyperlipidemia -toxins from cigarette smoke -infectious agents -inflammatory cytokines -homocysteine
  17. 17. 3. AtherosclerosisPATHOGENESISMAJOR MECHANISMS+Endothelial Cell Injury 2 MOST IMPORTANT CAUSES OF ENDOTHELIAL DYSFUNCTION -hemodynamic disturbances -hypercholesterolemia
  18. 18. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Hemodynamic Disturbances-plaques tend to occur at areas of disturbed flow patterns:a. Ostia of exiting vesselsb. Branch pointsc. Along the Posterior wall of the abdominal aorta
  19. 19. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Hemodynamic Disturbances-nonturbulent laminar flow in normal vasculature leads to the induction of endothelial genes whose products protect against atherosclerosis e.g. SUPEROXIDE DISMUTASE
  20. 20. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids-Lipoprotein abnormalities present in many MI survivors: -Increased LDL -Decreased HDL - Increased Lipoprotein (a)-DOMINANT LIPIDS IN ATHEROMATOUS PLAQUES ARE: -Cholesterol -Cholesterol Esters
  21. 21. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids-Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk of cardiovascular events
  22. 22. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids-Mechanisms by which HYPERLIPIDEMIA contributes to ATHEROGENESIS: -impair endothelial cell function by increasing local oxygen free radical production -accumulate lipoproteins within the intima, which are then oxidized by oxygen free radicals
  23. 23. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Lipids -Oxidized LDL is ingested by macrophages through a SCAVENGER RECEPTOR, distinct from LDL receptor -MACROPHAGES become FOAM CELLS after accumulation of Oxidized LDL within the phagocyte
  24. 24. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Inflammation-dysfunctional arterial endothelial cells express adhesion molecules that encourage leukocyte adhesion-VCAM1 – binds monocytes and T cells-Monocyte recruitment and differentiation is theoretically protective because they remove harmful lipid particles, but the presence of OXIDIZED LDL AUGMENTS Macrophage activation and cytokine production
  25. 25. 3. AtherosclerosisPATHOGENESIS+Endothelial Cell Injury*Infection-Microorganisms detected in atherosclerotic plaques: -Herpesvirus -Cytomegalovirus -Chlamydiae pneumoniae
  26. 26. 3. AtherosclerosisPATHOGENESIS+Smooth Muscle Proliferation-intimal smooth muscle cell proliferation and ECM deposition convert a fatty streak into a mature atheroma *FATTY STREAK = EARLIEST LESION-Growth Factors involved: -PDGF -FGF -TGF-a
  27. 27. 3. AtherosclerosisPATHOGENESIS+Smooth Muscle Proliferation-Smooth muscle cells synthesize ECM that stabilizes atherosclerotic plaques- Active Inflammatory cells in atheromas can cause intimal smooth muscle cell apoptosis, and increase ECM catabolism leading to unstable plaques
  28. 28. 3. AtherosclerosisMORPHOLOGY*FATTY STREAKS-EARLIEST LESIONS IN ATHEROSCLEROSIS-begin as minute, flat yellow spots and then colaesce-not significantly raised and do not cause flow disturbance-virtually in all children older than 10 years-coronary fat streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques
  29. 29. 3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-KEY PROCESSES: Intimal Thickening & Lipid Accumulation-Gross: -Color: White or Yellow (Ulcerated Plaques: Red- brown) -Size: 0.3-1.5 cm in diameter (can coalesce)-In humans, the ABDOMINAL AORTA affected MORE than THORACIC AORTA
  30. 30. 3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Commonly involved Vessels (Descending Order): 1. Lower Abdominal Aorta 2. Coronary Arteries 3. Popliteal Arteries 4. Internal Carotid Arteries 5. Circle of Willis
  31. 31. 3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Principal Components (CEL):1. Cells -smooth muscle cells, macrophages, T cells2. ECM -collagen, elastic fibers, proteoglycans3. Lipids -intracellular and extracellular
  32. 32. 3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Configuration: 1. Fibrous cap – superficial; made of smooth muscle cells, collagen 2. Shoulder – beneath and to the side of the cap; more cellular with macrophages, T cells, smooth muscle cells 3. Necrotic core – deep into cap, made of lipid primarily cholesterol and cholesterol esters, debris from dead cells, foam cells, fibrin, thrombus, other plasma proteins
  33. 33. 3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-The periphery of the lesions show neovascularization-Plaques enlarge due to: 1. Cell death and degenration 2. Synthesis and degradation of ECM 3. Organization of thrombus-Atheromas often undergo CALCIFICATION
  34. 34. 3. AtherosclerosisMORPHOLOGY*ATHEROSCLEROTIC PLAQUE-Plaques are susceptible to the following CLINICAL CHANGES:1. Rupture, ulceration, erosion2. Hemorrhage into a plaque3. Atheroembolism4. Aneurysm formation
  35. 35. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE-Large Elastic and Large and Medium Muscular arteries are the MAJOR TARGETS of ATHEROSCLEROSIS-Smaller vessels can become occluded, compromising distal tissue perfusion-Ruptured plaque can embolize atherosclerotic debris and cause distal vessel obstruction, or can lead to acute thrombosis-Destruction of the underlying vessel wall can lead to aneurysm formation, which can rupture and/or be a thrombi
  36. 36. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ATHEROSCLEROTIC STENOSIS-plaques can gradually occlude vessel lumens, compromising blood flow causing ischemic injury-outward remodeling preserves lumen diameter-effects of vascular occlusion depend on arterial supply and metabolic demand of affected tissue
  37. 37. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGE-plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis resulting in acute tissue infarction-THREE CATEGORIES OF PLAQUE CHANGES:1. Rupture/Fissuring – exposing thrombogenic constituents2. Erosion/Ulceration – exposing subendothelial basement membrane to blood3. Hemorrhage into the atheroma
  38. 38. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGE-the precipitating lesion in patients who develop MI or other coronary syndromes is NOT NECESSARILY a severely stenotic and hemodynamically significant lesion BEFORE ITS ACUTE CHANGE
  39. 39. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGEINTRINSIC and EXTRINSIC FACTORS THAT INFLUENCE RISK OF PLAQUE RUPTURE: INTRINSIC EXTRINSIC Plaque Structure Blood PressurePlaque Composition Platelet Reactivity Adrenergic stimulation
  40. 40. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGEVULNERABLE Plaques:-contain large areas of foam cells and extracellular lipids-with thin fibrous caps *collagen represents the major structural component of the fibrous cap and accounts for its mechanical strength and stability-contain few smooth muscle cells-have clusters of inflammatory cells *STATINS stabilize plaques by reducing plaque inflammation
  41. 41. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*ACUTE PLAQUE CHANGE-Peak time of onset of acute myocardial infarction is between 6 AM and 12 NOON
  42. 42. 3. AtherosclerosisCONSEQUENCES OF ATHEROSCLEROTIC DISEASE*THROMBOSIS*VASOCONSTRICTION-compromises lumen size and by increasing local mechanical forces can potentiate plaque disruption-stimulated by:1. Adrenergic agonists2. Local platelet contents3. impaired secretion of cell relaxing factors4. mediators released from perivascular inflammtory cells

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