401
edits
Atherosclerosis: Difference between revisions
Jump to navigation
Jump to search
no edit summary
No edit summary |
|||
| Line 67: | Line 67: | ||
Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer within the intima, 3) migration of leukocytes and smooth muscle cells to the vessel wall, 4) foam cells formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents clinical complications of atherosclerosis.<br /> | Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer within the intima, 3) migration of leukocytes and smooth muscle cells to the vessel wall, 4) foam cells formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents clinical complications of atherosclerosis.<br /> | ||
[[File:Figure_7_-_Fatty_streak_formation_revealing_platelet_aggregation_on_the_endothelial_surface.png|right|thumb|Figure | [[File:Figure_7_-_Fatty_streak_formation_revealing_platelet_aggregation_on_the_endothelial_surface.png|right|thumb|Figure 5. Fatty streak formation]] | ||
=== Initiation and formation of atherosclerotic plaque === | === Initiation and formation of atherosclerotic plaque === | ||
The earliest visible signs of atherogenesis are the fatty streak and pre-existing lesions of adaptive intimal thickening. Fatty streak is yellow discoloration on the surface of the artery lumen, which is flat or slightly elevated in the intima and contains accumulations of intracellular and extracellular lipid. At this stage of initiation, the fatty streak doesn’t protrude substantially into the artery wall nor impede blood flow. This process is already visible in most people by the age of 20. At this stage, there are no symptoms and this lesion may even diminish over time. Initiation of fatty streak development is most likely caused by endothelial dysfunction, since it involves entry and modification of lipids within the subintima. This modified layer of lipids creates a proinflammatory environment and initiates the migration of leukocytes and formation of foam cells (Figure | The earliest visible signs of atherogenesis are the fatty streak and pre-existing lesions of adaptive intimal thickening. Fatty streak is yellow discoloration on the surface of the artery lumen, which is flat or slightly elevated in the intima and contains accumulations of intracellular and extracellular lipid. At this stage of initiation, the fatty streak doesn’t protrude substantially into the artery wall nor impede blood flow. This process is already visible in most people by the age of 20. At this stage, there are no symptoms and this lesion may even diminish over time. Initiation of fatty streak development is most likely caused by endothelial dysfunction, since it involves entry and modification of lipids within the subintima. This modified layer of lipids creates a proinflammatory environment and initiates the migration of leukocytes and formation of foam cells (Figure 5). Intimal thickening mainly contains smooth muscle cells and proteoglycan-collagen matrix with a few or no infiltrating inflammatory cells.<br /> | ||
==== ''Endothelial dysfunction'' ==== | ==== ''Endothelial dysfunction'' ==== | ||
{| class="wikitable" border="0" style='float: left' | |||
|- align='left' | |||
!Figure 6. Factors correlated with endothelial dysfunction<br /> | |||
|- align='left' | |||
| | |||
* Increased age | |||
*Male sex | |||
*Family history of coronary heart disease | |||
*Tobacco smoking | |||
*Elevated cholesterol in blood | |||
* Low HDL-cholesterol in blood | |||
*Elevated homocysteine in blood | |||
*Diabetes mellitus | |||
*Hypertension | |||
*Obesity | |||
*High fat consumption | |||
|} | |||
<br /> | |||
Endothelial dysfunction is a primary event in atherogenesis, which can be caused by various agents, such as physical stress and chemical irritants. Endothelial dysfunction is also observed in other pathological conditions, which are often related to atherosclerosis such as hypercholesterolemia, diabetes, hypertension, heart failure, cigarette smoking and aging.<br /> | Endothelial dysfunction is a primary event in atherogenesis, which can be caused by various agents, such as physical stress and chemical irritants. Endothelial dysfunction is also observed in other pathological conditions, which are often related to atherosclerosis such as hypercholesterolemia, diabetes, hypertension, heart failure, cigarette smoking and aging.<br /> | ||
Endothelial cells can display different reactions according to various levels of physical stress. There are two atheroprotective endothelial functions from physical stress. When endothelial cells are exposed to laminar flow, which contains minimal physical stress, they secrete NO. NO functions as an anti-atherosclerotic substance through vasodilation, inhibition of platelet aggregation and anti-inflammatory effects. The second function is executed, when exposed to laminar flow by an expression of the antioxidant enzyme superoxide dismutase by the endothelium. This enzyme performs anti-atherosclerotic role by acting against reactive oxygen species, which are produced by chemical irritants or transient ischemia in the vessel.<br /> | Endothelial cells can display different reactions according to various levels of physical stress. There are two atheroprotective endothelial functions from physical stress. When endothelial cells are exposed to laminar flow, which contains minimal physical stress, they secrete NO. NO functions as an anti-atherosclerotic substance through vasodilation, inhibition of platelet aggregation and anti-inflammatory effects. The second function is executed, when exposed to laminar flow by an expression of the antioxidant enzyme superoxide dismutase by the endothelium. This enzyme performs anti-atherosclerotic role by acting against reactive oxygen species, which are produced by chemical irritants or transient ischemia in the vessel.<br /> | ||
{| class="wikitable" border="1" style='float: right' | |||
|- | |||
! Figure 7. Interventions that enhance endothelial function | |||
|- | |||
| | |||
* L-arginine | |||
* Estrogen | |||
* Antioxidants | |||
* Quit smoking | |||
* Reducing cholesterol in blood | |||
* Exercise | |||
* Reducing homocysteine in blood | |||
|}<br /> | |||
Unfortunately, these two atheroprotective endothelial functions can be impaired by several factors. | Unfortunately, these two atheroprotective endothelial functions can be impaired by several factors. The first factor is disturbed flow (low shear stress with rapid fluctuation), which is typically located at arterial branch points and bifurcations and can impair the protective functions. This is well illustrated by the difference in prevalence of atherosclerosis between branched arteries and bifurcated vessels. Bifurcation areas such as the common carotid and left coronary arteries are relatively more common deposition sites for atherosclerosis than arteries with few branches such as the internal mammary artery. Thus, many observations show that the distribution of atherosclerotic lesions is common in large vessels and they vary in location and frequency among different vascular beds. These findings encourage a belief that hemodynamic factors play an important role in atherogenesis. Furthermore, the fact that hypertension intensifies the severity of atherosclerotic lesions additionally supports this belief.<br /> | ||
[[File:Figure_8_-_Endothelial_dysfunction_-_Leukocyte_adhesion_and_migration_into_the_deep_layer_of_the_intima.png|thumb|left|Figure 8. Endothelial dysfunction: Leukocyte adhesion and migration into the deep layer of the intima.]]<br /> | |||
Another major factor that can impair the atheroprotective endothelial function is chemical irritants such as cigarette smoking, abnormally high circulating lipid levels and high sugar levels (diabetes mellitus). They can contribute to endothelial dysfunction and are all well- known risk factors for atherosclerosis. Exposure to chemical irritants promotes endothelial dysfunction by increasing endothelial production of reactive oxygen species, which alter the metabolic and synthetic functions of endothelial cells. As a result, the endothelium is inclined to exhibit proinflammatory processes, such as secreting inflammatory cytokines.<br /> | Another major factor that can impair the atheroprotective endothelial function is chemical irritants such as cigarette smoking, abnormally high circulating lipid levels and high sugar levels (diabetes mellitus). They can contribute to endothelial dysfunction and are all well- known risk factors for atherosclerosis. Exposure to chemical irritants promotes endothelial dysfunction by increasing endothelial production of reactive oxygen species, which alter the metabolic and synthetic functions of endothelial cells. As a result, the endothelium is inclined to exhibit proinflammatory processes, such as secreting inflammatory cytokines.<br /> | ||
In conclusion, hemodynamic and chemical stressors contribute to disturbance of the endothelial homeostasis and promote endothelial dysfunction. This results in impairment of permeability barrier function, secretion of inflammatory cytokines, stimulation of adhesion molecules on the cell surface that promote leukocyte recruitment, and altered antithrombotic properties and release of vasoactive molecules (Figure 8). Consequently, these effects establish the groundwork for further advancement of atherosclerosis.<br /> | In conclusion, hemodynamic and chemical stressors contribute to disturbance of the endothelial homeostasis and promote endothelial dysfunction. This results in impairment of permeability barrier function, secretion of inflammatory cytokines, stimulation of adhesion molecules on the cell surface that promote leukocyte recruitment, and altered antithrombotic properties and release of vasoactive molecules (Figure 8). Consequently, these effects establish the groundwork for further advancement of atherosclerosis.<br /> | ||
<br /><br /><br /> | |||
==== ''Lipoprotein entry and modification'' ==== | ==== ''Lipoprotein entry and modification'' ==== | ||
Disruption of the integrity of endothelial barrier due to endothelial dysfunction allows the passage of circulating lipoproteins (low-density lipoprotein, LDL) into the intima. By binding to proteoglycans, LDL starts accumulating. This accumulation is a critical process in atherogenesis since LDL may undergo chemical modifications while residing longer in intima. It is needless to say that an elevated circulating LDL concentration strongly contributes to this accumulating process. Another major risk factor for this process is hypertension since it causes augmented vessel wall stress. Elevated vessel wall stress influences smooth muscle cells to synthesize proteoglycans in the intima, promoting LDL-binding with proteoglycans and therefore contributing to “trapping” of lipoproteins and lipid accumulation within the intima. At this point, macrophages adhere to dysfunctional endothelial cells and transmigrate into the intima. These macrophages are called ‘foam cells’ after they have taken up lipids.<br /> | Disruption of the integrity of endothelial barrier due to endothelial dysfunction allows the passage of circulating lipoproteins (low-density lipoprotein, LDL) into the intima. By binding to proteoglycans, LDL starts accumulating. This accumulation is a critical process in atherogenesis since LDL may undergo chemical modifications while residing longer in intima. It is needless to say that an elevated circulating LDL concentration strongly contributes to this accumulating process. Another major risk factor for this process is hypertension since it causes augmented vessel wall stress. Elevated vessel wall stress influences smooth muscle cells to synthesize proteoglycans in the intima, promoting LDL-binding with proteoglycans and therefore contributing to “trapping” of lipoproteins and lipid accumulation within the intima. At this point, macrophages adhere to dysfunctional endothelial cells and transmigrate into the intima. These macrophages are called ‘foam cells’ after they have taken up lipids.<br /> | ||
| Line 93: | Line 126: | ||
==== ''Foam cell formation'' ==== | ==== ''Foam cell formation'' ==== | ||
When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t phagocyte LDL with a classic cell surface LDL-receptor, since it does not recognize modified LDL, but with a family of ‘scavenger’ receptors that do bind and internalize modified LDL. Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells. This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however since these foam cells have impaired trafficking, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines. | When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t phagocyte LDL with a classic cell surface LDL-receptor, since it does not recognize modified LDL, but with a family of ‘scavenger’ receptors that do bind and internalize modified LDL. Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells. This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however since these foam cells have impaired trafficking, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines. | ||
=== Plaque progression === | === Plaque progression === | ||
[[File:Figure_9_-_Fibrous_cap_formation.png|thumb|left|Figure 9. Fibrous cap formation and the necrotic core.]]<br /> | [[File:Figure_9_-_Fibrous_cap_formation.png|thumb|left|Figure 9. Fibrous cap formation and the necrotic core.]] | ||
<br /><br /> | |||
The atherosclerotic plaque at this stage is called fibrous cap atheroma featuring two characteristics, which are lipid-rich necrotic core and encapsulation by fibrous cap (Figure 9). The fibrous cap is an area between the vessel lumen and the core of the plaque, which contains dead foam cells, macrophages, smooth muscle cells, lymphocytes and extracellular matrix. A distinctive hallmark of this phase is necrosis with macrophage infiltration around a lipid pool and loss of proteoglycans or collagen. At this point, the deposition of free cholesterol is not easily visible and the plaque does not always cause luminal restriction of blood flow due to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may evade detection by angiography. Continuous plaque growth at a later stage contains cellular debris, higher free cholesterol and results into complete depletion of extracellular matrix. From this stage, the fibrous cap atheroma may go through episodes of hemorrhage with or without calcification and even fibrous cap disruption. Progressive vessel narrowing may result in ischemia and can cause ischemic symptoms such as angina pectoris or intermittent claudication.<br /> | |||
==== ''Smooth muscle cell migration'' ==== | ==== ''Smooth muscle cell migration'' ==== | ||
Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induces the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion. Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthrombus contains activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparin sulfate, which normally counteracts this process.<br /> | Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induces the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion. Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthrombus contains activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparin sulfate, which normally counteracts this process.<br /> | ||
| Line 167: | Line 199: | ||
==== ''Lack of physical activity'' ==== | ==== ''Lack of physical activity'' ==== | ||
[[File:Figure_14_-_Recommendations_for_physical_activity.png|right|Figure 14. Recommendations for physical activity]] | |||
INTERHEART study showed that lack of exercise was accountable for 12% of the population-attributable risk of a first MI. Recent evidence shows that physical activity of even moderate degree can protect against coronary heart disease and all-cause mortality .The beneficial effects of physical exercise are decrease of triglyceride levels and blood pressure, elevation of HDL, enhancement of insulin sensitivity and production of NO by the endothelial cells, and weight loss. Although large scale randomized primary prevention trials are lacking, physical activity should be promoted to anyone with risk of developing atherosclerosis.<br /> | INTERHEART study showed that lack of exercise was accountable for 12% of the population-attributable risk of a first MI. Recent evidence shows that physical activity of even moderate degree can protect against coronary heart disease and all-cause mortality .The beneficial effects of physical exercise are decrease of triglyceride levels and blood pressure, elevation of HDL, enhancement of insulin sensitivity and production of NO by the endothelial cells, and weight loss. Although large scale randomized primary prevention trials are lacking, physical activity should be promoted to anyone with risk of developing atherosclerosis.<br /> | ||