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Atherosclerosis Empty
PostSubject: Atherosclerosis   Atherosclerosis Icon_minitimeMon Mar 28, 2011 9:05 am



Atherosclerosis is a disease of large and medium-sized muscular
arteries and is characterized by endothelial dysfunction, vascular
inflammation, and the buildup of lipids, cholesterol, calcium, and
cellular debris within the intima of the vessel wall. This buildup
results in plaque formation, vascular remodeling, acute and chronic
luminal obstruction, abnormalities of blood flow, and diminished oxygen
supply to target organs.

A complex and incompletely understood interaction exists between the
critical cellular elements of the atherosclerotic lesion. These cellular
elements are endothelial cells, smooth muscle cells, platelets, and
leucocytes. Vasomotor function, the thrombogenicity of the blood vessel
wall, the state of activation of the coagulation cascade, the
fibrinolytic system, smooth muscle cell migration and proliferation, and
cellular inflammation are complex and interrelated biological
processes that contribute to atherogenesis and the clinical
manifestations of atherosclerosis.
The mechanisms of atherogenesis remain uncertain. The
"response-to-injury" theory is most widely accepted. Endothelial injury
causes vascular inflammation and a fibroproliferative response ensues.
Probable causes of endothelial injury include oxidized low-density
lipoprotein (LDL) cholesterol; infectious agents; toxins, including the
byproducts of cigarette smoking; hyperglycemia; and
hyperhomocystinemia. Circulating monocytes infiltrate the intima of the
vessel wall, and these tissue macrophages act as scavenger cells,
taking up LDL cholesterol and forming the characteristic foam cell of
early atherosclerosis. These activated macrophages produce numerous
factors that are injurious to the endothelium.
Elevated serum levels of LDL cholesterol overwhelm the antioxidant
properties of the healthy endothelium and result in abnormal
endothelial metabolism of this lipid moiety. Oxidized LDL is capable of
a wide range of toxic effects and cell/vessel wall dysfunctions that
are characteristically and consistently associated with the development
of atherosclerosis. These dysfunctions include impaired
endothelium-dependent dilation and paradoxical vasoconstriction. These
dysfunctions are the result of direct inactivation of nitric oxide by
the excess production of free radicals, reduced transcription of nitric
oxide synthase messenger RNA (mRNA), and posttranscriptional
destabilization of mRNA.
The decrease in the availability of nitric oxide also is associated
with increased platelet adhesion, increased plasminogen activator
inhibitor, decreased plasminogen activator, increased tissue factor,
decreased thrombomodulin, and alterations in heparin sulfate
proteoglycans. The consequences include a procoagulant milieu and
enhanced platelet thrombus formation. Furthermore, oxidized LDL
activates inflammatory processes at the level of gene transcription by
up-regulation of nuclear factor kappa-B, expression of adhesion
molecules, and recruitment of monocytes/macrophages.
The lesions of atherosclerosis do not occur in a random fashion.
Hemodynamic factors interact with the activated vascular endothelium.
Fluid shear stresses generated by blood flow influence the phenotype of
the endothelial cells by modulation of gene expression and regulation
of the activity of flow-sensitive proteins. Atherosclerotic plaques
characteristically occur in regions of branching and marked curvature
at areas of geometric irregularity and where blood undergoes sudden
changes in velocity and direction of flow. Decreased shear stress and
turbulence may promote atherogenesis at these important sites within
the coronary arteries, the major branches of the thoracic and abdominal
aorta, and the large conduit vessels of the lower extremities.

One study suggests that hypercholesterolemia-induced neutrophilia
infiltrate arteries primarily during early stages of atherosclerotic
lesion formation.1
The earliest pathologic lesion of atherosclerosis is the fatty streak.
The fatty streak is observed in the aorta and coronary arteries of most
individuals by age 20 years. The fatty streak is the result of focal
accumulation of serum lipoproteins within the intima of the vessel wall.
Microscopy reveals lipid-laden macrophages, T lymphocytes, and smooth
muscle cells in varying proportions.

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