The Three Stages of Atherosclerosis − Rakyat Biologi

The precursor lesions to atherosclerosis may appear as early as the fetal stage, with the formation of intimal cell masses, or perhaps shortly after birth, when fatty streaks begin to evolve. However, the characteristic fibroinflammatory lipid plaque, which is initially sub-clinical, usually requires 20 to 30 years to form. Once formed, serious acute complications may occur and/or complicated lesions may emerge after several more years.

We can construct a hypothetical sequence divided into three stages: an initiation and formation stage, an adaptation stage and a clinical stage. The first two stages are sub-clinical so that the disease is present but does not usually produce signs or symptoms of disease. Biologically active molecules regulate a number of dynamic cellular functions. It is imbalance between proatherogenic and antiatherogenic factors and processes that leads to initiation and growth of the atherosclerotic plaque. At present, it is unlikely to identify a single atherogenic gene that explains pathogenesis. Instead multiple genes (polygenic) interacting with the environment and with each other need to be considered to understand atherogenesis. In persons at increased risk of atherosclerosis, lesions also occur in areas that are not predisposed to the disease.

Stage I: Initiation and Formation

The intimal lesion initially occurs at sites that are predisposed to lesion formation, owing to hemodynamic shear stress, endothelial dysfunction or the accumulation of subendothelial smooth muscle cells, as occurs in an intimal cell mass at branch points. This cell mass is considered a predisposing condition for plaque formation. The distribution of atherosclerotic lesions in large vessels, and the differences in location and frequency of lesions in different vascular beds, has supported the role of hemodynamic factors. In humans, atherosclerotic lesions tend to occur at sites where shear stresses are low but fluctuate rapidly, such as at branch points and. Hemodynamic forces induce gene expression of several factors in endothelial cells that are likely to promote atherosclerosis, including FGF-2, TF, plasminogen activator, and endothelin. However, shear stress also induces gene expression of agents that may be antiatherogenic, including nitric oxide synthase (NOS) and plasminogen activator inhibitor-1 (PAI-1).

Lipid accumulation initially as a fatty streak depends on disruption of the integrity of the endothelial barrier through cell loss and/or cell dysfunction. Risk factors (see below), micro-organisms, oxidized low density lipoproteins promote endothelial injury. Low density lipoproteins carry lipids into the intima. Macrophages adhere to activated endothelial cells and transmigrate into the intima bringing in lipids. Some of these macrophage foam cells, undergo necrosis and release lipids. The types of connective tissue, glycosaminoglycans and proteoglycans synthesized by the smooth muscle cells in the intima also render these sites prone to lipid accumulation due to capacity of these macromolecules to trap lipids in the intima. Oxidative stress leads to cellular dysfunction and damage due to oxaclative changes in LDL in endothelial cells and macrophages.

As proposed in the “reaction to injury” hypothesis, mononuclear macrophages in addition to playing a central role by participating in lipid accumulation, release growth factors, thereby stimulating further accumulation of smooth muscle cells. Oxidized lipoproteins induce tissue damage and further macrophage accumulation. Monocyte/ macrophages synthesize PDGF, FGF, TNF, IL-1, interferon-µ (IFN-µ), and TGF-b, each of which can modulate the growth of smooth muscle or endothelial cells, either positively or negatively. For example, IFN-µ and TGF-b inhibit cell proliferation and could account for the failure of endothelial cells to maintain continuity over the lesion. Alternatively, such molecules could inhibit growth-stimulatory peptides. Interlukin-1 (IL-1) and TNF stimulate endothelial cells to produce platelet-activating factor (PAF), tissue factor (TF), and PAI. Thus, the combination of macrophages and endothelial cells may transform the normal anticoagulant vascular surface to a procoagulant one.

As the lesion progresses, mural thrombosis may occur on the disrupted an/or dysfunctional intimal surface. This stimulates the release of PDGF, which accelerates smooth muscle proliferation and the secretion of matrix components. The thrombus itself may grow in size, lyse, embolize or become organized and incorporated into the plaque.

The deeper areas of the thickened intima are now poorly nourished by diffusion of oxygen and nutrients from the lumen and undergo necrosis, which is augmented by proteolytic enzymes released by macrophages and tissue damage caused by oxidized LDL, reactive oxygen species and other agents. This initiates neovascularization (angiogenesis) with new vessels forming in the plaque derived from the vasa vasorum.

The fibroinflammatory lipid plaque is formed, with a central necrotic core and a fibrous cap which separates the core from the blood in the lumen. The plaque becomes heterogeneous with respect to inflammatory cell infiltration, lipid deposition and matrix organization. TGFb is an important regulator of extracellular matrix deposition. TGFb increases several types of collagen, fibronectin and proteoglycans. It inhibits proteolytic enzymes that promote matrix degradation and enhances expression of protease inhibitors.

Stage II: Adaptation

As the lumen is encroached upon by the extension of the plaque into the lumen. This is best seen in the coronary arteries, the wall of the artery undergoes remodeling to maintain the lumen size. Once a plaque encroaches upon half the lumen, compensatory remodeling can no longer maintain normal patency, and the lumen of the artery becomes narrowed (stenosis). Hemodynamic shear stress is an important regulator of vessel wall remodeling acting through the mechanotransduction properties of the endothelial cells. It is likely that smooth muscle cell turnover, proliferation and apoptosis, and matrix synthesis and degradation modulate remodeling of the vessel wall and the plaque. Matrix metalloproteinases (MMP) and their inhibitors, tissue inhibitors of metaloproteinases (TIMP) play important roles in this remodeling. This remodeling is useful because it maintains patency of the lumen preventing ischemia, however it may delay clinical diagnosis of the presence of atherosclerosis since the plaque may be clinically silent if that there are no symptoms reported by the individual. Even though the plaque is small, plaque rupture with catastrophic results may occur at this stage, as noted below resulting in sudden death and/or acute myocardial infarction.

Stage III: Clinical

Plaque progression continues as the plaque protrudes into the lumen. Hemorrhage into a plaque without rupture may increase its size. The expression of HLA-DR antigens on both endothelial cells and smooth muscle cells in plaques implies that these cells have undergone some type of immunological activation, perhaps in response to IFN-µ released by activated T cells in the plaque. In this scenario, the presence of T cells reflects an autoimmune response that is important for the progression of atherosclerotic lesions. The antigens may include oxidized LDL to which antibodies have been identified in the plaque.

Complications develop in the plaque, including surface ulceration, fissure formation, calcification, and aneurysm formation. Activated mast cells are found at sites of erosion and may release proinflammatory mediators and cytokines. Continued plaque growth leads to severe stenosis and even occlusion of the lumen. Plaque rupture, involving the fibrous cap, and ensuing thrombosis and occlusion of the lumen may precipitate acute catastrophic events in these advanced plaques. However, an important observation in angiographic studies shows that even plaques causing less than 50% stenosis may suddenly rupture, occlude the lumen and result in acute myocardial infarction and/or sudden death.