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23 Cards in this Set
- Front
- Back
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Sites of greatest predilection for development of atherosclerosis
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Vertebral and basilar arteries and circle of willis
Internal carotid Proximal coronary Thoracic aorta Lower aorta and iliac arteries Femoral and popliteal arteries |
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Key functions of the endothelium
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Permeability barrier (tightly opposed cells)
-No lipoprotein receptors, plasma proteins transferred via transcytosis proportionally to concentration Anti-thrombogenic surface Control of vascular reactivity |
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The natural history of atherosclerosis
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Fatty streaks in 2nd decade
Fibrous plaques in 3rd decade Calcification, complicated lesion, hemorrhage, ulceration, thrombosis in 4th decade -clinical horizon |
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Cells involved in atherosclerotic plaques
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Endothelial cells – endothelial dysfunction occurs early in development of atherosclerosis. Actual desquamation (loss) of endothelial cells does not occur until later.
Macrophages - early and late (major intimal cell type early) T-cells - early and late, but in smaller numbers than macrophages Smooth muscle cells – accumulate in the intima at a later stage than macrophages, (major intimal cell type late) Neutrophils - Not usually found in atherosclerotic plaques, except following plaque rupture. |
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Lipids in atherosclerotic plaques
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Intracellular (early event)
- Accumulation of esterified cholesterol (EC) in macrophage foam cells (first) and in some smooth muscle cell foam cells (later) - Some increase in phospholipids to help solublize increased cellular FC Extracellular (later event) - Free Cholesterol (FC) crystals and droplets of EC, associated with necrosis of macrophage foam cells - Little accumulation of triglycerides |
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Connective tissue in atherosclerotic plaques
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Produced primarily by smooth muscle cells
Collagen - Provides tensile strength to the arterial wall - Synthesis is stimulated by SMCs of Athero. Plaques Elastin - Provides elasticity to the arterial wall Proteoglycans - Binds LDL/VLDL in sub-endothelial space, which increases retention and facilitates oxidation, aggregation, etc. |
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Other changes (besides cells, lipids and connective tissues) in atherosclerotic plaques
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Minerals
-calcium and magnesium Bone formation Blood products -fibrin (old) -thrombus (new) |
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Pathogenesis of atherosclerosis
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Transcytosis of lipoproteins into the sub-endothelial space of the arterial wall
Retention of LDL/VLDL by matrix proteoglycans -facilitates oxidation and aggregation of lipoproteins Expression of monocyte adhesion molecules (VCAM-1, ICAM-1) on the endothelial cells Recruitment of monocytes into the artery wall Monocyte differentiation into macrophages -Turn on scavenger receptors -Can then recognize abnormal lipoproteins |
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How do foam cells form once macrophages accumulate in sub-endothelium of arterial wall
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Once scavenger receptors (SR-A, CD-36) on macrophages take up abnormal proteins, they are taken to lysozomes
Hydrolyes cholesterol esters to free cholesterol Cell either has to get rid of free cholesterol either by putting it onto an acceptor such as HDL or: Re-esterifies it back to cholesterol ester, which accumulates as droplets, giving the cell the foamy appearance |
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Atherosclerosis, macrophages, and chronic inflammatory response
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Because of the Key Role Monocyte/Macrophages Play in the Pathogenesis of Atherosclerosis, it is apparent that this Process has many of the Elements of a Chronic Inflammatory Response.
But chronic Inflammation alone will not cause atherosclerosis. Some degree of hypercholesterolemia must also be present. In most animal models atherosclerosis will not develop if the plasma cholesterol concentration is below 120 mg/dl. Hypercholesterolemia is the only risk factor that by itself will cause atherosclerosis. The disease “Familial Hypercholesterolemia” is an example of this. |
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Fate of macrophage foam cells
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Initially, the formation of macrophage foam cells is probably beneficial in that it removes potentially damaging abnormal lipoproteins, lipids and cell debris from the arterial wall.
If plasma cholesterol concentrations are lowered at this stage, the foam cells can be nearly completely cleared from the arterial intima. If macrophage foam cells are allowed to accumulate some will become necrotic and die, releasing their contents within the intima, which activates adjacent macrophage foam cells to produce additional inflammatory cytokines (TNF-α, IL-1, MCP-1, etc.) This perpetuates the inflammatory cycle and leads to further damage that can make the plaque unstable resulting in plaque rupture and what has been called, “the acute coronary syndrome”. |
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Immune cells and pathogenesis of atherosclerosis
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T Cells are found in atherosclerotic plaques, although at a later stage and in smaller numbers than macrophages. They have an important role in promoting plaque rupture.
1. Macrophages [and perhaps other antigen-presenting cells (APC), such as dendritic cells], take up ox-LDL and present on their surface ox-LDL antigens along with MHC class II molecules, to which T-cells bind and become activated. 2. Activated T-cells (largely CD4+, TH1 cells) produce inflammatory cytokines such as IFNγ and TNFa. 3. These T-cell cytokines further activate macrophages which stimulates production of additional inflammatory mediators, adhesion molecules, cytokines and prothrombotic proteins such as Tissue Factor. 4. Death of some macrophage foam cells causes necrotic material to accumulate in the intima. At the same time, smooth muscle cell proliferation and collagen production are inhibited by activated T-cell cytokines. 5. All of the above promote plaque rupture and thrombosis, which is the major cause of an acute coronary event. |
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Plaque rupture and thrombosis and acute coronary syndrome
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Macrophage foam cells secrete many products, one of which is matrix metalloproteinases (MMPs), that breakdown collagen.
Foam cells often concentrate at the edge (shoulder) of plaques where the plaques are structurally the weakest. Secretion of MMPs breakdown collagen at the edge of the plaque making it susceptible to rupture. Rupture of the plaque interrupts the anti-thrombogenic endothelial cell surface, which exposes blood platelets to underlying collagen and to macrophages that also secrete Tissue Factor. This causes platelet aggregation which initiates thrombosis. |
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Fate of macrophage foam cells in patient with reduced plasma cholesterol
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Depending on the severity of the atherosclerotic plaque and the degree of lowering of plasma cholesterol concentrations, plaque cholesterol content and macrophage foam cells will decrease, while connective tissue increases.
This is known as plaque remodeling. The result is a more stable plaque, less susceptible to rupture |
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Stages of coronary artery disease
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The first stages of atherosclerosis are characterized by the accumulation of lipoproteins, particularly low density lipoproteins (LDL), that bind to proteoglycans in the intima.
In response to LDL accumulation, monocytes, and subsequently, T-cells, infiltrate the vessel wall. The monocytes differentiate to macrophages, which then take up the lipoproteins to give rise to cholesterol-engorged ‘foam cells’, a hallmark of early atherogenesis. Some of these foam cells eventually die, resulting in a necrotic core of cholesterol and cellular debris. This is accompanied by the migration and proliferation of smooth muscle cells, which form a fibrous cap that overlies the necrotic core. The most common cause of a myocardial infarction (MI) is the rupture of an atherosclerotic lesion, exposing tissue factor and leading to the formation of a thrombus that blocks the flow of blood. In general, a thick fibrous cap appears to protect against such rupture. |
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Risk factors for Atherosclerosis
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Age
Gender Primary modifiable risk factors -Elevated LDL -Low HDL -HTN -Smoking -Diabetes Secondary modifiable risk factors -Obesity -Sedentary lifestyle -Type A personality |
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Pros and cons of female sex hormones and atherosclerosis
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Hormone replacement therapy (HRT) with CEE (conjugated equine estrogens) + MPA, given to women well after menopause, increases the risk of stroke and breast cancer, with little protection from CHD.
CEE alone given to women who have had a hysterectomy, reduces the risk of CHD if started close to the time of menopause. These studies have not answered the question of whether HRT (estrogen plus progestin) will reduce development of CHD if given at the time of menopause. It remains unclear whether estrogens are the only reason women have less atherosclerosis than men. About 50% of the protective effects of estrogens on atherosclerosis can be attributed to its beneficial effects on the lipoprotein profile (lower LDL and higher HDL). The other 50% appears to be due to direct effects of estrogens on the arterial wall. Potentially, the most important of these effects is to reduce the expression of lymphocyte adhesion molecules on endothelial cells, which reduces the influx of monocytes and their ultimate conversion to macrophages. |
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How does hypercholesterolemia increase atherosclerosis?
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Transport of plasma low density lipoproteins (LDL, VLDL) across endothelial cells is via a non-receptor mediated process called “Transcytosis”.
Higher plasma lipoprotein concentrations means there are more lipoproteins in the same volume of plasma for transcytosis. Higher concentrations of these atherogenic lipoproteins in the arterial wall provide more substrate for oxidation of LDL, which are taken up by macrophages via scavenger receptors. These macrophages accumulate cholesteryl esters and become “foam Cells”. |
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Prevention of CHD and stroke by aggressive lowering of plasma cholesterol by statins
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Both primary and secondary prevention reduces CHD and mortality
Both primary and secondary prevention reduces stroke events. The results of 5 major clinical trials has shown that even greater lowering of LDL-C concentrations with statins and statins in combination with other drugs, will further reduce risk of CHD. This is true for people whose plasma cholesterol concentrations are in the traditionally normal range as well, and in the elderly. There appears to be a log-linear relationship between LDL-C and risk of CHD. For every 30 mg/dL change in LDL-C, the relative risk for CHD is changed by ~30%. |
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Relationship of HDL to coronary heart disease
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Increasing HDL lowers rate of CHD and MI
Mediates cholesterol efflux (via binding to macrophage foam cell ABCA1 and ABCG1 transporters) from atherosclerotic plaques and other tissues which is the first step in reverse cholesterol transport. Anti-inflammatory by reducing expression of adhesion molecules (p-selectin, VCAM-1, etc.) on endothelial cells. Stimulates nitric oxide production (eNOS) in endothelial cells which stimulates vasodilation. Anti-oxidant properties. |
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Relationship of HTN to coronary heart disease
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Flow/Shear mediated damage to the barrier function of ECs.
Damage due to greater stretching |
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Relationship of smoking and CHD
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Increased atherosclerosis
Increased chance of sudden death. This is the major effect of smoking and is probably due to an increased tendency for thrombosis caused by some component(s) in smoke. Cessation of smoking reduces the risk of CHD to nearly that of a nonsmoker in < 3 years. |
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Relationship of diabetes and CVD
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The mechanism by which diabetes exacerbates atherosclerosis is not well understood.
In type 2 diabetics (about 90% of all diabetics) there is usually an abnormal lipoprotein profile ( ↑ LDL and VLDL and ↓ HDL), obesity, hyperinsulinemia, and a procoagulant state. Whether an abnormality in glucose metabolism at the level of the arterial wall plays a role in the enhanced atherosclerosis is not known. Something like this must be important, however, since insulin treated Type 1 diabetics also have increased risk of CVD, but generally have normal plasma lipoprotein concentrations. |
