Mechanisms of Atherosclerosis

Atheromatous lesions develop over decades and occur principally within the intima, the innermost layer of the arterial wall. Several paradigms exist for classification of atherosclerotic lesions based primarily on morphologic considerations. The earliest identifiable lesion, the fatty streak, is a flat, yellowish, nonobstructive accumulation of neointimal lipid that can be found in the aorta and coronary arteries of most individuals beginning in the second decade of life. The fibrous plaque is a more advanced whitish lesion containing proliferative smooth muscle cells, infiltrating macrophages and other

Handbook of Models for Human Aging

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inflammatory cells, and extracellular matrix components. Whether fibrous plaques inevitably arise from fatty streaks rather than appearing de novo is not clear. Often, a necrotic lipid core resides deep within the fibrous plaque, which contains macrophage-derived foam cells and extracellular lipids. Fibrous plaques may protrude eccentrically into the lumen, resulting in obstruction of blood flow and symptoms such as angina pectoris and claudication. However, defects of the lesion surface and accompanying thrombosis are not present, and therefore unstable coronary syndromes typically are not associated with these lesions.

Progression of fibrous plaques leads to advanced or complicated lesions, which may contain increased amounts of connective tissue around the necrotic core (fibroather-omas) and/or calcifications of the necrotic core. These components may alter the compliance of the vessel and thus have a destabilizing tendency. Neovascularization of the plaque by the process of angiogenesis may occur (O'Brien et al., 1994), and the presence of these vessels may lead to intraplaque hemorrhage, which is an important source of plaque instability and intraplaque hematoma formation. The intimal surface of advanced lesions may have minor disruptions (fissures) or suffer gross denudation (the ulcerative plaque), which can serve as a nidus for acute thrombosis directly. Surface disruption may also lead to plaque rupture with extrusion of lipid core components and activation of the coagulation cascade within the intralumenal compartment. Advanced lesions encompass a variety of pathologic components in varying mixtures, but they share two ominous characteristics: They may progress rapidly, owing to features such as intraplaque hemorrhage, leading to rapid progression of obstructive symptoms such as angina. By virtue of their tendency to rupture and thrombus formation, they may also cause acute occlusion of coronary and cerebral vessels, resulting in myocardial infarction and stroke, the most deadly consequences of atherosclerotic disease.

The framework for understanding how atherosclerotic lesions form and progress was provided by Russell Ross (Ross, 1993). Dr. Ross proposed the "response-to-injury" hypothesis, which argues that the initiating event in lesion formation is some form of "injury" to the endo-thelium, the cell layer that forms the lumenal barrier of all blood vessels. Although modifications of this initial hypothesis have been made to incorporate subsequent observations, it still provides a useful framework for understanding how lesions form. Endothelial injury in this model may take the form of mechanical forces such as high blood pressure or changes in shear stress and cyclic strain that can occur at vessel bifurcations; metabolic conditions such as diabetes mellitus, hyperhomocysteine-mia, or hyperlipidemia that produce substances that directly injure the endothelium; or environmental agents such as the products of tobacco smoke or even infectious agents that also impair endothelial cell function. It is important to note the close correlation between the factors that may cause endothelial injury and the known risk factors for atherosclerosis.

Regardless of the cause, injured endothelium has several proatherogenic properties. Normal adaptive vascular responses, such as the release of endothelium-derived nitric oxide, are impaired. Endothelial denudation or activation leads to adhesion of platelets and inflammatory cells that can release proatherogenic growth factors. Adherent monocytes and lymphocytes may also directly invade the vessel wall, where they participate directly in lesion formation. Low-density lipoprotein cholesterol may be taken up by macrophages and other vascular cells after injury, leading to foam cell formation and lipid accumulation in necrotic areas. Intraplaque macrophages may be particularly destabilizing within advanced plaques by releasing factors such as matrix metalloproteinases that degrade the extracellular matrix and impair the integrity of the atherosclerotic lesion. Lesion stability can also be triggered by apoptosis of the endothelium, which removes the vessel barrier to thrombus formation, and also by apoptosis of intraplaque smooth muscle cells, which may serve as a stabilizing function in complicated lesions (Ferguson and Patterson, 2003). It is clear that the evolution of atherosclerotic lesions is incredibly complex, involving a large number of events and many cell types, some of which participate in both detrimental and protective processes within the lesion, depending on the stage of the lesion and the location of the cell. This enormous complexity explains in part why the genetics of atherosclerosis is still so poorly understood at the present time.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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