Biology of Atheroma and Plaque Types and Evolution
Atherosclerosis is an intimal disease of arteries ranging in size from the aorta to the epicardial coronary artery i.e. characterized by discrete intimal plaques, although at an advanced stage the lesions may coalesce. Each plaque has combinations of extracellular lipid, lipid contained within cells that have foamy cytoplasm, and connective tissue matrix proteins, such as collagen,produced by smooth muscle cells. The majority of the foam cells are derived from monocytes,which enter the plaque from the arterial lumen.
Lipid is a fundamental component of the atherosclerotic plaque, which is essentially an inflammatory/repair response in the vessel wall invoked by lipid. The intimal surface of an opened human coronary artery reveals several types of plaques. Some are flat yellow dots or lines (fatty streaks), and others are raised above the surface as oval humps, which range in color from white to yellow (raised fibrolipid plaques). In children from 5 to 10 years of age, fatty streaks are often present in the coronary arteries, suggesting that they are the initial point in a sequence of plaque development. Raised plaques appear latter in life, and, by 20 years of age, are present in areas such as the proximal left anterior descending coronary artery, where fatty streaks are most prevalent in earlier life. By middle age, most subjects will have coronary plaques initiation and this continues throughout life. The initial lesion (type I) develops when monocytes migrate from the lumen of the artery across the intact endothelium to accumulate in the intima.
The type II lesion is the fatty streak, which consists of a focal accumulation of lipid-filled foam cells immediately beneath the intact endothelium. The type III lesion also contains small pools of extracellular lipid. Stage I to stage III plaques are the precursors of more advanced lesions, and they do not cause clinical symptoms. Stage IV is characterized by two additional features.Smooth muscle cells appear within the lesion beneath the endothelium, and the pools of extracellular lipid coalesce to form a lipid core. Stage V shows significant connective tissue deposition and the formation of a fibrous capsule containing the lipid core. The portion of this capsule separating the core from the lumen is the plaque cap.
Endothelial cells have receptors for many different molecules on their surface, including receptors for low-density lipoproteins (LDL), growth factors and a number of pharmacological agents. A special capacity of endothelium that may be particularly important in atherogenesis is its ability to oxidize LDL. Oxidized LDL play an important role in initiating and in inducing increased adherence and migration of monocytes and T- lymphocytes from the lumen into the artery wall. Plaques with a lipid core and a fibrous cap are designated as type Va. Type VI plaques are those complicated by thrombosis, which predominantly develops in Va plaques.
Another development attribute of plaques is heavy calcification (type Vb). Another form of advanced plaque (type Vc) is almost entirely composed of collegen and smooth muscle cells, with a trivial lipid component.
Basic Mechanisms in Plaque Formation
In experimental models and human disease, the first morphologic phenomenon observed in plaque formation is adhesion of monocytes to an intact endothelial surface. This adhesion is followed by monocyte migration into the intima. In the intima, monocytes are activated,converted to macrophages, and may divide. Lipid uptake by macrophages then leads to the formation of the foam cell. Many factors act in concert to cause monocyte migration to allow the incoming monocytes to establish themselves in the intima. The endothelial surface is intact in the initial phase of coronary atherosclerosis. There is no exposure of the subendothelial connective tissue matrix and therefore no adhesion of platelets to the vessel wall. Much of the cholesterol and esters in a lipid core is released from the cytoplasm of dying foam cells. Active plaques contain numerous macrophages clustered at the edge of the core with the expression of a range of metalloproteinases that likely are engaged in the active destruction of the collagen matrix.
Smooth muscle cell migration and proliferation as well as collagen deposition are driven by growth factors produced by virtually every cell type, including smooth muscle cells themselves.The normal media is a vascular, but once intimal thickening occurs, new vessels grow in from the adventitia and reach the base of the plaque.
The Plaque and its Complications
The presence of advanced plaques of types IV and Va allows clinical symptoms to develop.Atherosclerosis is a biphasic disease; in the first stage, advanced plaques are generated but the patient is asymptomatic; in the second stage, symptoms develop. In all geographic populations,the mean number of coronary plaques present in a large number of autopsied patients who die from all caused predicts the incidence of ischaemic heart disease in that population. Smokers will, on average, have more plaques than nonsmokers. Similar data exist for hyperlipidemia,hypertension, and diabetes. Thus risk factors operate in part by increasing the number of plaques that can potentially progress to cause symptoms. Common to all type Va plaques is the presence of a fibromuscular cap.The cap may be relatively thick and uniform, or it may vary in thickness with interspersed thin areas.
Finally, in subjects with coronary atherosclerosis, coronary vasomotor tonal responses are abnormal.
Atherosclerosis is an intimal disease of arteries ranging in size from the aorta to the epicardial coronary artery i.e. characterized by discrete intimal plaques, although at an advanced stage the lesions may coalesce. Each plaque has combinations of extracellular lipid, lipid contained within cells that have foamy cytoplasm, and connective tissue matrix proteins, such as collagen,produced by smooth muscle cells. The majority of the foam cells are derived from monocytes,which enter the plaque from the arterial lumen.
Lipid is a fundamental component of the atherosclerotic plaque, which is essentially an inflammatory/repair response in the vessel wall invoked by lipid. The intimal surface of an opened human coronary artery reveals several types of plaques. Some are flat yellow dots or lines (fatty streaks), and others are raised above the surface as oval humps, which range in color from white to yellow (raised fibrolipid plaques). In children from 5 to 10 years of age, fatty streaks are often present in the coronary arteries, suggesting that they are the initial point in a sequence of plaque development. Raised plaques appear latter in life, and, by 20 years of age, are present in areas such as the proximal left anterior descending coronary artery, where fatty streaks are most prevalent in earlier life. By middle age, most subjects will have coronary plaques initiation and this continues throughout life. The initial lesion (type I) develops when monocytes migrate from the lumen of the artery across the intact endothelium to accumulate in the intima.
The type II lesion is the fatty streak, which consists of a focal accumulation of lipid-filled foam cells immediately beneath the intact endothelium. The type III lesion also contains small pools of extracellular lipid. Stage I to stage III plaques are the precursors of more advanced lesions, and they do not cause clinical symptoms. Stage IV is characterized by two additional features.Smooth muscle cells appear within the lesion beneath the endothelium, and the pools of extracellular lipid coalesce to form a lipid core. Stage V shows significant connective tissue deposition and the formation of a fibrous capsule containing the lipid core. The portion of this capsule separating the core from the lumen is the plaque cap.
Endothelial cells have receptors for many different molecules on their surface, including receptors for low-density lipoproteins (LDL), growth factors and a number of pharmacological agents. A special capacity of endothelium that may be particularly important in atherogenesis is its ability to oxidize LDL. Oxidized LDL play an important role in initiating and in inducing increased adherence and migration of monocytes and T- lymphocytes from the lumen into the artery wall. Plaques with a lipid core and a fibrous cap are designated as type Va. Type VI plaques are those complicated by thrombosis, which predominantly develops in Va plaques.
Another development attribute of plaques is heavy calcification (type Vb). Another form of advanced plaque (type Vc) is almost entirely composed of collegen and smooth muscle cells, with a trivial lipid component.
Basic Mechanisms in Plaque Formation
In experimental models and human disease, the first morphologic phenomenon observed in plaque formation is adhesion of monocytes to an intact endothelial surface. This adhesion is followed by monocyte migration into the intima. In the intima, monocytes are activated,converted to macrophages, and may divide. Lipid uptake by macrophages then leads to the formation of the foam cell. Many factors act in concert to cause monocyte migration to allow the incoming monocytes to establish themselves in the intima. The endothelial surface is intact in the initial phase of coronary atherosclerosis. There is no exposure of the subendothelial connective tissue matrix and therefore no adhesion of platelets to the vessel wall. Much of the cholesterol and esters in a lipid core is released from the cytoplasm of dying foam cells. Active plaques contain numerous macrophages clustered at the edge of the core with the expression of a range of metalloproteinases that likely are engaged in the active destruction of the collagen matrix.
Smooth muscle cell migration and proliferation as well as collagen deposition are driven by growth factors produced by virtually every cell type, including smooth muscle cells themselves.The normal media is a vascular, but once intimal thickening occurs, new vessels grow in from the adventitia and reach the base of the plaque.
The Plaque and its Complications
The presence of advanced plaques of types IV and Va allows clinical symptoms to develop.Atherosclerosis is a biphasic disease; in the first stage, advanced plaques are generated but the patient is asymptomatic; in the second stage, symptoms develop. In all geographic populations,the mean number of coronary plaques present in a large number of autopsied patients who die from all caused predicts the incidence of ischaemic heart disease in that population. Smokers will, on average, have more plaques than nonsmokers. Similar data exist for hyperlipidemia,hypertension, and diabetes. Thus risk factors operate in part by increasing the number of plaques that can potentially progress to cause symptoms. Common to all type Va plaques is the presence of a fibromuscular cap.The cap may be relatively thick and uniform, or it may vary in thickness with interspersed thin areas.
Finally, in subjects with coronary atherosclerosis, coronary vasomotor tonal responses are abnormal.
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