Atherosclerosis: Difference between revisions

The atherosclerotic plaque at this stage is called fibrous cap atheroma featuring two characteristics, which are lipid-rich necrotic core and encapsulation by fibrous cap (Figure 9). The fibrous cap is an area between the vessel lumen and the core of the plaque, which contains dead foam cells, macrophages, smooth muscle cells, lymphocytes and extracellular matrix. A distinctive hallmark of this phase is necrosis with macrophage infiltration around a lipid pool and loss of proteoglycans or collagen. At this point, the deposition of free cholesterol is not easily visible and the plaque does not always cause luminal restriction of blood flow due to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may evade detection by angiography. Continuous plaque growth at a later stage contains cellular debris, higher free cholesterol and results into complete depletion of extracellular matrix. From this stage, the fibrous cap atheroma may go through episodes of hemorrhage with or without calcification and even fibrous cap disruption. Progressive vessel narrowing may result in ischemia and can cause ischemic symptoms such as angina pectoris or intermittent claudication.<br />

Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induce the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion. Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthrombus contains activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparin sulfate, which normally counteracts this process.<br />

Metabolic process in extracellular matrix plays a central role in bridging the plaque progression to plaque rupture. Ultimately, this process weakens the fibrous cap, predisposing it to rupture. This process is influenced by the balance of matrix deposition synthesis by smooth muscle cells and degradation by matrix metalloproteinases (MMP), a class of proteolytic enzymes. For example, PDGF and TGF-β stimulate interstitial collagen production, while inflammatory cytokines such as IFN-γ inhibits collagen synthesis. TGF-β also induces formation of fibronectin and proteoglycans. It is an important regulator since it enhances the expression of protease inhibitors, leading to the inhibition of proteolytic enzymes that promote matrix degradation. On the other hand, inflammatory cytokines weaken the fibrous cap by stimulating local foam cells to secrete MMP that degrades collagen and elastin of the fibrous cap. Furthermore, the deeper parts of the thickened intima undergo necrosis due to poor nourishment.<br />