Theories of Atherosclerosis − Rakyat Biologi

Several theories advanced by eminent pathologists working in the field of cardiovascular pathology have been proposed to explain the initiation and growth of atherosclerotic plaques. As our knowledge increases it appears that these theories are not mutually exclusive, and are indeed linked to each other.

Insudation Theory: Proponents of this widely accepted theory proposed that the critical events in atherosclerosis center on the focal accumulation of fat in the vessel wall. It is believed that the lipid in these lesions is derived from plasma lipoproteins, a view consistent with the role of blood lipids as risk factors for myocardial infarction. Although there is still controversy over how the lipid accumulates in the vessel wall, the hypothesis is widely accepted. Whereas this hypothesis explains the source of plaque lipid, it does not provide a complete explanation for the pathogenesis of the atherosclerotic lesion. Since many other clinically important features of the plaque, such as smooth muscle proliferation and thrombosis, remain unexplained, lipid deposition appears to be necessary but not sufficient to explain plaque development and growth.

Low-density lipoprotein (LDL) is the form of lipid in the plasma that has been most closely associated with accelerated atherosclerosis. The LDL particle is too large to penetrate the tightly closed junctions between adjacent endothelial cell. However, endothelial cells have receptors for both LDL and modified forms of LDL. Transport can occur across an intact endothelium either by receptor-mediated uptake of lipoproteins or by nonspecific uptake into micropinocytic channels. Alternatively, lipid may be engulfed by monocytes in the blood and then transported into the vascular wall inside these cells as they transmigrate into the wall between dysfunctional endothelial cells. Lipid that becomes extracellular may be trapped in the wall by altered components of the intimal matrix.

Encrustation Theory: Initially supporters of this theory asserted that material from the blood was deposited on the inner surface of arteries and lead to thickening of the inner lining. Later it was thought to be the platelets and fibrin of thrombi that initiated atherosclerosis. Mural thrombosis is not the initial event in atherogenesis. However, mural thrombosis is a likely to promote the later progression of the atherosclerotic lesion and is the major event leading to vascular occlusion, especially in coronary arteries.

Inflammation and Repair; A Reaction to Injury Theory: This theory was originally proposed to explain the mechanisms that lead to the accumulation of smooth muscle cells in atherosclerotic lesions. It was suggested that smooth muscle cell proliferation depends on the release of polypeptide growth factors by endothelial cells, macrophages, and smooth muscle cells themselves at sites of injury. The nature of the injury is not well understood. This theory has been broadened to focus on the role of all the cell types found in the artery wall in the initiation and growth of an atherosclerotic lesion, including dysfunctional endothelial cells and inflammatory cells; both macrophages and lymphocytes. It is suggested that the cellular responses that occur during the pathogenesis of the lesion constitute an inflammatory and a fibroproliferative response to injury. In this theory, endothelial dysfunction compromises the integrity of the endothelial barrier to macromolecules and leukocyte adhesion molecules on the surface endothelial cells are activated to promote the infiltration of macrophages into the subendothelium. The nature of the injury is likely to involve numerous factors and is different in different people depending on genetic and environmental conditions.

The “reaction to injury” hypothesis evolved from the discovery that the growth of smooth muscle cells in cell culture requires one or more platelet-derived polypeptides. The best known of these is platelet-derived growth factor (PDGF), which is also secreted by both macrophages and vascular wall cells. PDGF is not only mitogenic for smooth muscle cells in vitro, but is also chemotactic for them. Thus, in addition to stimulating the proliferation of cells already located in the intima, PDGF may recruit smooth muscle cells from the media. The number of growth promoters that can potentially induce proliferation of cells include fibroblast growth factor (FGF), PDGF, transforming growth factor-b (TGF-b), thrombin, LDL, endothelin, and others. There are also growth inhibitors, such as heparin and nitric oxide (NO). Another suggestion was that smooth muscle proliferation might be due to an aberration of growth control in one, or at most a few cells, in a manner similar to the process in a benign smooth muscle tumor. It has been established that some plaques are monoclonal; that is, they originate from one or very few smooth muscle cells. This suggests that some unknown factor, might induce fibrous cap formation by altering growth control in the smooth muscle cells of the arterial wall. Research has yet to identify possible mechanisms of monoclonality.