The core of the atherosclerotic plaque is an area packed with cholesterol, cholesterol esters, and other lipids. The core is often a distinct region in the arterial intima, and it may occupy as much as 70-80% of intimal area. In other places, the core is recognized only as an area of increased lipid deposits. In a developed atherosclerotic core, most of the cells have died and disappeared. It is sometimes called the necrotic core to indicate cell death.
(Cell biologists make a distinction between "necrosis," which is a rapid, bursting type of cell death, and "apoptosis," which is a slower, controlled process of cell death. Apoptosis seems to be the way most cells die in atherosclerosis, despite historical use of the term "necrotic core.")
In addition to cell death, fibrous tissue proteins such as collagen and elastin are eroded away in the atherosclerotic core. The erosion of these proteins is the result of enzymes that lyse, or break apart, the protein chains. The components of the protein chains then dissolve in the tissue fluid and float away. Loss of collagen and elastin leads to serious weakening of the inner arterial wall. Since no living cells are present to make new collagen and elastin, the weakening of the tissue is permanent and progressive.
The lipid-rich core is part of the essential description of atherosclerosis, since the Greek "athero"signifies "gruel" or "thick porridge." If you cut into an atherosclerotic plaque and then squeeze it, the core contents may be extruded like toothpaste. It is not certain how the processes of lipid deposition, cell death, and lysis of fibrous tissue work together to produce the atherosclerotic core. This is an important question, since the growth of the core eventually leads to complete breakdown of intimal tissue strength, plaque rupture, and blood clot formation in the artery. There are two main theories about how the core originates and grows.
The first theory states that cells in the plaque, especially macrophages, accumulate large amounts of cholesterol, which they store as oily droplets of cholesterol ester. These cells are then called foam cells. The cells also make and secrete enzymes that digest away the surrounding collagen and elastin. Foam cells can grow to enormous size. The foam cells eventually die, leaving behind lipid deposits in an area with little collagen and lastin.
That's a neat, fairly simple story. In fact, a great deal has been learned in cell culture dishes about foam cell accumulation of cholesterol, foam cell death, and macrophage production of enzymes. However, certain details about atherosclerotic core development observed in human arteries, rather than culture dishes, argue for a different understanding with less of a role for foam cells. Some of the details are as follows: The smallest, earliest core regions in atherosclerotic lesions are found in the deeper part of the arterial intima, while macrophage foam cells are largely confined to the shallower part of the intima. Intensive lipid deposits are observed within fibers of elastin and within bundles of collagen fibrils, suggesting a direct interaction between these fibers and lipids such as cholesterol. The characteristic lipid deposits of the early atherosclerotic core have a high concentration of cholesterol and a low concentration of cholesterol ester, just the opposite of what one finds in foam cells. Finally, the exact pattern of cholesterol esters found in the atherosclerotic core tends to match the pattern seen in blood lipoproteins (high in cholesterol linoleate), rather than the pattern found in foam cells (high in cholesterol oleate).
These observations lead to a theory of core development than begins with deposition of cholesterol and other lipids in the fibrous tissue matrix between intimal cells. Exactly how this deposition occurs remains unknown. There is a very high content of cholesterol in the lipid deposits. The cholesterol may diffuse through the tissue fluid, perhaps aided by lipoproteins, to the membranes of nearby cells. When the cells acquire an excessive amount of cholesterol in their membranes, the membranes can no longer function properly, and the cells die.
Which of these theories is correct? How does the atherosclerotic core develop? The answer may be that both theories have something to tell us about the atherosclerotic core. Like detectives at the site of a crime, researchers examining the atherosclerotic core must ask critical questions to evaluate the evidence left behind.
John R. Guyton, MD