What causes noncoronary atherosclerosis?

Updated: Dec 23, 2019
  • Author: F Brian Boudi, MD, FACP; Chief Editor: Yasmine S Ali, MD, FACC, FACP, MSCI  more...
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The mechanisms of atherogenesis remain uncertain. An incompletely understood interaction exists between the critical cellular elements—endothelial cells, smooth muscle cells, platelets, and leucocytes—of the atherosclerotic lesion. 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 biologic processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis.

The "response-to-injury" theory is most widely accepted explanation for atherogenesis. 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 ribonucleic acid (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. (This article will focus on noncoronary sites of atherogenesis.)

One study suggested that hypercholesterolemia-induced neutrophilia develops in arteries primarily during early stages of atherosclerotic lesion formation. [2]

The earliest pathologic lesion of atherosclerosis is the fatty streak, which 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.

The fatty streak may progress to form a fibrous plaque, the result of progressive lipid accumulation and the migration and proliferation of smooth muscle cells.

Platelet-derived growth factor, insulinlike growth factor, transforming growth factors alpha and beta, thrombin, and angiotensin II are potent mitogens that are produced by the activated platelets, macrophages, and dysfunctional endothelial cells that characterize early atherogenesis, vascular inflammation, and platelet-rich thrombosis at sites of endothelial disruption. The relative deficiency of endothelium-derived nitric oxide further potentiates this proliferative stage of plaque maturation.

The proliferating smooth muscle cells are responsible for the deposition of extracellular connective tissue matrix and form a fibrous cap that overlies a core of lipid-laden foam cells, extracellular lipid, and necrotic cellular debris. Growth of the fibrous plaque results in vascular remodeling, progressive luminal narrowing, blood-flow abnormalities, and compromised oxygen supply to the target organ.

Progressive luminal narrowing of an artery due to expansion of a fibrous plaque results in impairment of flow once more than 50-70% of the lumen diameter is obstructed. Flow impairment causes symptoms of inadequate blood supply to the target organ in the event of increased metabolic activity and oxygen demand.

Developing atherosclerotic plaques acquire their own microvascular network, which consists of a collection of vessels known as the vasa vasorum. These vessels are prone to hemorrhage and contribute to the progression of atherosclerosis. [3]

Denudation of the overlying endothelium or rupture of the protective fibrous cap may result in exposure of the thrombogenic contents of the core of the plaque to the circulating blood. This exposure constitutes an advanced or complicated lesion.

The plaque rupture occurs due to weakening of the fibrous cap. Inflammatory cells localize to the shoulder region of the vulnerable plaque. T lymphocytes elaborate interferon gamma, an important cytokine that impairs vascular smooth muscle cell proliferation and collagen synthesis. In addition, activated macrophages produce matrix metalloproteinases that degrade collagen. These mechanisms explain the predisposition to plaque rupture and highlight the role of inflammation in the genesis of the complications of the fibrous atheromatous plaque.

A plaque rupture may result in thrombus formation, partial or complete occlusion of the blood vessel, and progression of the atherosclerotic lesion due to organization of the thrombus and incorporation within the plaque.

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