Atherosclerosis: Difference between revisions

When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t phagocyte LDL with a classic cell surface LDL-receptor, since it does not recognize modified LDL, but with a family of ‘scavenger’ receptors that do bind and internalize modified LDL. Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells. This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however since these foam cells have impaired trafficking, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines.<br />

=== Plaque progression ===

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 />

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 />

=== Plaque rupture ===

==== ''Integrity of plaque'' ====