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atherosclerosisA new.pptx

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DrAshish Chaudhary

Atherosclerosis is a disease characterized by the buildup of plaque in arteries. It is caused by a combination of genetic and environmental factors that damage the endothelium and allow lipids and inflammatory cells to accumulate. Over time, plaques grow and can rupture, leading to thrombosis and blockage of blood vessels. This causes cardiovascular diseases like heart attacks and strokes. The major modifiable risk factors are hyperlipidemia, hypertension, smoking, and diabetes.

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atherosclerosisA new.pptx
atherosclerosisA new.pptx
ATHEROSCLEROSIS
Atherosclerosis underlies the pathogenesis of coronary, cerebral and peripheral vascular disease combination of acquired and inherited risk factors initimal lesions ---- atheromas (atheromatous or atherosclerotic plaques) Mechanically obstruction, rupture---- thrombosis aneurysms.
atherosclerosisA new.pptx
Epidemiology reduced mortality from infectious , Western lifestyles --- increased prevalence of ischemic heart disease in developing nations number of risk factors multiplicative effect.
atherosclerosisA new.pptx
Genetics most important independent risk factor. Polygenic Age dominant influence. middle age or later------ risk increases five-fold. Gender Premenopausal women are relatively protected compared to age-matched men. After menopause exceeds that of men Favorable influence of estrogen
Modifiable Major Risk Factors Hyperlipidemiaspecifically hypercholesterolemia low-density lipoprotein (LDL) cholesterol high-density lipoprotein (HDL) High dietary intake of cholesterol and saturated fats raises plasma cholesterol levels. high in polyunsaturated fats lower plasma cholesterol levels Omega-3 fatty acids (abundant in fish oils) are beneficial Exercise and moderate consumption of ethanol raise HDL levels whereas obesity and smoking lower it. Statins --- lower ----inhibiting HMG CoA reductase
Hypertension major risk factor both systolic and diastolic levels hypertension increase the risk by approximately 60%
Cigarette smoking well-established risk factor in men increasing incidence and severity of atherosclerosis in women.
Diabetes mellitus induces hypercholesterolemia incidence of myocardial infarction is twice increased risk of stroke 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities
Additional Risk Factors 20% cases --absence of overt risk factors Indeed, more than 75% of cardiovascular events in previously healthy women occur with LDL cholesterol levels below 160 mg/dL
Inflammation present during all stages of atherogenesis C-reactive protein (CRP) most sensitive. CRP is an acute phase reactant synthesized primarily by the liver. increased by --- particularly IL-6
Hyperhomocystinemia Correlate with coronary atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. associated with premature vascular disease. low folate and vitamin B12 levels can increase homocysteine
Metabolic syndrome. central obesity characterized by insulin resistance, hypertension, dyslipidemia, hypercoagulability, and a proinflammatory state.
Lipoprotein a [Lp(a)] altered form of LDL Lp(a) levels are associated with coronary and cerebrovascular disease risk
Factors affecting hemostasis. Several markers of hemostatic and/or fibrinolytic function (e.g., elevated plasminogen activator inhibitor 1) ------- risk for major atherosclerotic events Other factors lack of exercise; competitive, stressful life style (type A personality); Obesity Hormones infections
Fig. 11.7 AHA Classification of atherosclerosis
Pathogenesis of Atherosclerosis response to injury hypothesis. This model views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury Lesion progression occurs through interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with endothelial cells and smooth muscle cells of the arterial wall.
sequence: Endothelial injury and dysfunction, causing increased vascular permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall Monocyte adhesion to the endothelium--- 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 cell recruitment, either from the media or from circulating precursors Smooth muscle cell proliferation, extracellular matrix production, and recruitment of T cells. Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cell)
atherosclerosisA new.pptx
Response to Injury
Endothelial Dysfunction
Initiation of Fatty Streak
Fatty Streak
Fibro-fatty Atheroma
Endothelial Injury Cornerstone of the response-to-injury hypothesis. Endothelial loss ---- experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals results in intimal thickening intact but dysfunctional endothelial cells exhibit increased endothelial permeability, enhanced leukocyte adhesion, and altered gene expression. However, the two most important hemodynamic disturbances hypercholesterolemia.
Hemodynamic Disturbances. Plaques tend to occur at ostia of exiting vessels, branch points, and along the posterior wall of the abdominal aorta, where there are disturbed flow patterns
Lipids Lipids are transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes) Dyslipoproteinemias --- increased LDL cholesterol levels, decreased HDL and increased levels of the abnormal lipoprotein (a).
The mechanisms ----- Chronic hyperlipidemia-------choles. directly impair endothelial cell function by increasing ROS causing membrane and mitochondrial damage, With chronic hyperlipidemia, lipoproteins accumulate within the intima Such modified LDL is then accumulated by macrophages ---- foam cells lipoproteins binding and uptake also stimulates the release of growth factors, cytokines, and chemokines- --- monocyte recruitment and activation
Inflammation Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions
Infection. herpesvirus, cytomegalovirus, and Chlamydophila pneumonia no established causal role for infection
Smooth Muscle Proliferation and Matrix Synthesis convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions growth factors PDGF, FGF, TGF-留 synthesize extracellular matrix (notably collagen),which stabilizes atherosclerotic plaques.
atherosclerosisA new.pptx
MORPHOLOGY Fatty streaks. composed of lipid-filled foamy macrophages. Beginning as multiple minute flat yellow spots, they eventually coalesce into streaks 1 cm long or longer. fatty streaks can evolve into plaques, not all are destined to become advanced lesions. coronary fatty streaks begin to form in adolescence Atherosclerotic Plaque intimal thickening and lipid accumulation, which together form plaques white-yellow and encroach on the lumen of the artery; superimposed thrombus over ulcerated plaques is red-brown. form larger masses cross-section, the lesions therefore appear eccentric with time atherosclerotic lesions can become larger, more numerous, and more broadly distributed
atherosclerosisA new.pptx
extensively involved vessels lower abdominal aorta the coronary arteries the popliteal arteries the internal carotid arteries, vessels of the circle of Willis.
Atherosclerotic plaques --- three principal components: (1) smooth muscle cells, macrophages, and T cells (2) extracellular matrix, including collagen, elastic fibers, and proteoglycans (3) intracellular and extracellular lipid Typically, there is a superficial fibrous cap composed of smooth muscle cells and relatively dense collagen. Beneath and to the side of the cap (the shoulder) is a more cellular area containing macrophages, T cells, and smooth muscle cells. Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipidladen macrophages and smooth muscle cells), fibrin, variably organized thrombus, and other plasma proteins periphery of the lesions demonstrate neovascularization Plaques generally continue to change and progressively enlarge often undergo calcification
atherosclerosisA new.pptx
CHANGES: Rupture, ulceration, or erosion --- leads to thrombosis -- occlude the vessel lumen Hemorrhage into a plaque. Rupture /thin-walled vessels in the areas of neovascularization---- hemorrhage---hematoma Atheroembolism -- discharge microemboli Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media.
atherosclerosisA new.pptx
atherosclerosisA new.pptx
Consequences of Atherosclerotic Disease Large elastic arteries and large and medium-sized muscular arteries are the major targets of atherosclerosis the heart, brain, kidneys, and lower extremities Myocardial infarction cerebral infarction (stroke), aortic aneurysms, and peripheral vascular disease (gangrene of the legs)
atherosclerosisA new.pptx
Atherosclerotic Stenosis plaques can gradually occlude vessel lumina, compromising blood flow and causing ischemic injury --- Critical stenosis In coronary circulations--- 70% decrease in luminal cross-sectional area mesenteric occlusion and bowel ischemia, sudden cardiac death, chronic ischemic heart disease, ischemic encephalopathy, and intermittent claudication
Acute Plaque Change Plaque erosion or rupture ---partial or complete vascular thrombosis Plaque changes fall into three general categories: Rupture/fissuring, exposing highly thrombogenic plaque constituents Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood Hemorrhage into the atheroma, expanding its volume
a large number of now asymptomatic adults may be at risk for a catastrophic coronary event. Plaques rupture when they are unable to withstand mechanical stresses generated by vascular shear forces The events that trigger abrupt changes in plaques and subsequent thrombosis are complex and include both intrinsic factors (e.g., plaque structure and composition) and extrinsic elements (e.g., blood pressure, platelet reactivity, vessel spasm). The composition of plaques is dynamic Thus, plaques -- large areas of foam cells and lipid, fibrous caps are thin or contain few smooth muscle cells or have clusters of inflammatory cells--- more likely to rupture------ vulnerable plaques
atherosclerosisA new.pptx
Thrombosis. partial or total thrombosis superimposed on a disrupted plaque is a central factor in acute coronary syndromes. luminal obstruction by the thrombus is incomplete, and may even wax and wane with time. Mural thrombi in a coronary artery can also embolize.
Vasoconstriction. compromises lumen size, and, by increasing the local mechanical forces, can potentiate plaque disruption. stimulated by (1) circulating adrenergic agonists (2) locally released platelet contents (3) endothelial cell dysfunction with impaired secretion of NO (4) mediators released from perivascular inflammatory cells
Altered Vessel Function Vessel change Consequence Plaque narrows lumen Wall weakened Thrombosis Breaking loose of plaque Loss of elasticity Ischemia, turbulence Aneurysms, vessel rupture Narrowing, ischemia, embolization Athero-embolization Increase systolic blood pressure
atherosclerosisA new.pptx
Hemorhage into Plaque
Ulceration/Hemorrhage/Cholesterol Crystals
Complicated Lesion/Calcification
Foam Cells/Cholesterol Crystals
Cholesterol Crystals/Foam Cells
Thrombosis/Complicated Lesion

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atherosclerosisA new.pptx

  • 4. Atherosclerosis underlies the pathogenesis of coronary, cerebral and peripheral vascular disease combination of acquired and inherited risk factors initimal lesions ---- atheromas (atheromatous or atherosclerotic plaques) Mechanically obstruction, rupture---- thrombosis aneurysms.
  • 6. Epidemiology reduced mortality from infectious , Western lifestyles --- increased prevalence of ischemic heart disease in developing nations number of risk factors multiplicative effect.
  • 8. Genetics most important independent risk factor. Polygenic Age dominant influence. middle age or later------ risk increases five-fold. Gender Premenopausal women are relatively protected compared to age-matched men. After menopause exceeds that of men Favorable influence of estrogen
  • 9. Modifiable Major Risk Factors Hyperlipidemiaspecifically hypercholesterolemia low-density lipoprotein (LDL) cholesterol high-density lipoprotein (HDL) High dietary intake of cholesterol and saturated fats raises plasma cholesterol levels. high in polyunsaturated fats lower plasma cholesterol levels Omega-3 fatty acids (abundant in fish oils) are beneficial Exercise and moderate consumption of ethanol raise HDL levels whereas obesity and smoking lower it. Statins --- lower ----inhibiting HMG CoA reductase
  • 10. Hypertension major risk factor both systolic and diastolic levels hypertension increase the risk by approximately 60%
  • 11. Cigarette smoking well-established risk factor in men increasing incidence and severity of atherosclerosis in women.
  • 12. Diabetes mellitus induces hypercholesterolemia incidence of myocardial infarction is twice increased risk of stroke 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities
  • 13. Additional Risk Factors 20% cases --absence of overt risk factors Indeed, more than 75% of cardiovascular events in previously healthy women occur with LDL cholesterol levels below 160 mg/dL
  • 14. Inflammation present during all stages of atherogenesis C-reactive protein (CRP) most sensitive. CRP is an acute phase reactant synthesized primarily by the liver. increased by --- particularly IL-6
  • 15. Hyperhomocystinemia Correlate with coronary atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. associated with premature vascular disease. low folate and vitamin B12 levels can increase homocysteine
  • 16. Metabolic syndrome. central obesity characterized by insulin resistance, hypertension, dyslipidemia, hypercoagulability, and a proinflammatory state.
  • 17. Lipoprotein a [Lp(a)] altered form of LDL Lp(a) levels are associated with coronary and cerebrovascular disease risk
  • 18. Factors affecting hemostasis. Several markers of hemostatic and/or fibrinolytic function (e.g., elevated plasminogen activator inhibitor 1) ------- risk for major atherosclerotic events Other factors lack of exercise; competitive, stressful life style (type A personality); Obesity Hormones infections
  • 19. Fig. 11.7 AHA Classification of atherosclerosis
  • 20. Pathogenesis of Atherosclerosis response to injury hypothesis. This model views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury Lesion progression occurs through interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with endothelial cells and smooth muscle cells of the arterial wall.
  • 21. sequence: Endothelial injury and dysfunction, causing increased vascular permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall Monocyte adhesion to the endothelium--- 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 cell recruitment, either from the media or from circulating precursors Smooth muscle cell proliferation, extracellular matrix production, and recruitment of T cells. Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cell)
  • 28. Endothelial Injury Cornerstone of the response-to-injury hypothesis. Endothelial loss ---- experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals results in intimal thickening intact but dysfunctional endothelial cells exhibit increased endothelial permeability, enhanced leukocyte adhesion, and altered gene expression. However, the two most important hemodynamic disturbances hypercholesterolemia.
  • 29. Hemodynamic Disturbances. Plaques tend to occur at ostia of exiting vessels, branch points, and along the posterior wall of the abdominal aorta, where there are disturbed flow patterns
  • 30. Lipids Lipids are transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes) Dyslipoproteinemias --- increased LDL cholesterol levels, decreased HDL and increased levels of the abnormal lipoprotein (a).
  • 31. The mechanisms ----- Chronic hyperlipidemia-------choles. directly impair endothelial cell function by increasing ROS causing membrane and mitochondrial damage, With chronic hyperlipidemia, lipoproteins accumulate within the intima Such modified LDL is then accumulated by macrophages ---- foam cells lipoproteins binding and uptake also stimulates the release of growth factors, cytokines, and chemokines- --- monocyte recruitment and activation
  • 32. Inflammation Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions
  • 33. Infection. herpesvirus, cytomegalovirus, and Chlamydophila pneumonia no established causal role for infection
  • 34. Smooth Muscle Proliferation and Matrix Synthesis convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions growth factors PDGF, FGF, TGF-留 synthesize extracellular matrix (notably collagen),which stabilizes atherosclerotic plaques.
  • 36. MORPHOLOGY Fatty streaks. composed of lipid-filled foamy macrophages. Beginning as multiple minute flat yellow spots, they eventually coalesce into streaks 1 cm long or longer. fatty streaks can evolve into plaques, not all are destined to become advanced lesions. coronary fatty streaks begin to form in adolescence Atherosclerotic Plaque intimal thickening and lipid accumulation, which together form plaques white-yellow and encroach on the lumen of the artery; superimposed thrombus over ulcerated plaques is red-brown. form larger masses cross-section, the lesions therefore appear eccentric with time atherosclerotic lesions can become larger, more numerous, and more broadly distributed
  • 38. extensively involved vessels lower abdominal aorta the coronary arteries the popliteal arteries the internal carotid arteries, vessels of the circle of Willis.
  • 39. Atherosclerotic plaques --- three principal components: (1) smooth muscle cells, macrophages, and T cells (2) extracellular matrix, including collagen, elastic fibers, and proteoglycans (3) intracellular and extracellular lipid Typically, there is a superficial fibrous cap composed of smooth muscle cells and relatively dense collagen. Beneath and to the side of the cap (the shoulder) is a more cellular area containing macrophages, T cells, and smooth muscle cells. Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipidladen macrophages and smooth muscle cells), fibrin, variably organized thrombus, and other plasma proteins periphery of the lesions demonstrate neovascularization Plaques generally continue to change and progressively enlarge often undergo calcification
  • 41. CHANGES: Rupture, ulceration, or erosion --- leads to thrombosis -- occlude the vessel lumen Hemorrhage into a plaque. Rupture /thin-walled vessels in the areas of neovascularization---- hemorrhage---hematoma Atheroembolism -- discharge microemboli Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media.
  • 44. Consequences of Atherosclerotic Disease Large elastic arteries and large and medium-sized muscular arteries are the major targets of atherosclerosis the heart, brain, kidneys, and lower extremities Myocardial infarction cerebral infarction (stroke), aortic aneurysms, and peripheral vascular disease (gangrene of the legs)
  • 46. Atherosclerotic Stenosis plaques can gradually occlude vessel lumina, compromising blood flow and causing ischemic injury --- Critical stenosis In coronary circulations--- 70% decrease in luminal cross-sectional area mesenteric occlusion and bowel ischemia, sudden cardiac death, chronic ischemic heart disease, ischemic encephalopathy, and intermittent claudication
  • 47. Acute Plaque Change Plaque erosion or rupture ---partial or complete vascular thrombosis Plaque changes fall into three general categories: Rupture/fissuring, exposing highly thrombogenic plaque constituents Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood Hemorrhage into the atheroma, expanding its volume
  • 48. a large number of now asymptomatic adults may be at risk for a catastrophic coronary event. Plaques rupture when they are unable to withstand mechanical stresses generated by vascular shear forces The events that trigger abrupt changes in plaques and subsequent thrombosis are complex and include both intrinsic factors (e.g., plaque structure and composition) and extrinsic elements (e.g., blood pressure, platelet reactivity, vessel spasm). The composition of plaques is dynamic Thus, plaques -- large areas of foam cells and lipid, fibrous caps are thin or contain few smooth muscle cells or have clusters of inflammatory cells--- more likely to rupture------ vulnerable plaques
  • 50. Thrombosis. partial or total thrombosis superimposed on a disrupted plaque is a central factor in acute coronary syndromes. luminal obstruction by the thrombus is incomplete, and may even wax and wane with time. Mural thrombi in a coronary artery can also embolize.
  • 51. Vasoconstriction. compromises lumen size, and, by increasing the local mechanical forces, can potentiate plaque disruption. stimulated by (1) circulating adrenergic agonists (2) locally released platelet contents (3) endothelial cell dysfunction with impaired secretion of NO (4) mediators released from perivascular inflammatory cells
  • 52. Altered Vessel Function Vessel change Consequence Plaque narrows lumen Wall weakened Thrombosis Breaking loose of plaque Loss of elasticity Ischemia, turbulence Aneurysms, vessel rupture Narrowing, ischemia, embolization Athero-embolization Increase systolic blood pressure