In the normal arterial intima, the stage is already set for the beginning of cholesterol deposition and atherosclerosis. The normal arterial intima is loaded with low density lipoproteins (also called LDL, the "bad cholesterol"). The amount, or concentration, of LDL in the arterial intima is about 10 times higher than in any other connective tissue in the body. We will see below why this is so. Except for this high concentration of LDL, the normal arterial intima looks and acts like most other connective tissues.
Unless special tricks are used to detect LDL in the arterial wall, LDL are not visible even with electron microscopy. The earliest abnormal appearance in the arterial intima comes when the LDL particles change and form deposits of cholesterol and other lipids (lipids are fatty substances) outside of cells. These early cholesterol deposits are not usually visible in ordinary light microscopes, but can be seen when new lipid-stabilizing techniques are used with powerful electron microscopes.
Historically, the first lesion of atherosclerosis (a "lesion" simply means an abnormality in the tissue) is considered to be the fatty streak. Cells identified as macrophages become filled with oily cholesterol esters. Some smooth muscle cells also develop the same type of cholesterol ester deposits. If you look at the inner surface of an arterial specimen, fatty streaks appear as flat, yellowish streaks or dots to the naked eye. The larger dots will include hundreds of macrophages filled with cholesterol, many of them just beneath the endothelial surface. Fatty streaks are harmless early lesions, never causing arterial clots or damage.
When a person reaches about age 20, some fatty streaks develop a more troubling kind of cholesterol deposit. This is a kind of cholesterol-loaded membranous debris, which first appears deep in the arterial intima, close to the boundary between intima and media. Solid crystals of pure cholesterol may be found among the membranous debris. Why are these deposits worrisome? Cells sitting close to these deposits begin to die. Too much cholesterol is harmful to cells, and the intense cholesterol deposition is probably the reason for death of nearby cells. The fatty streak with deep cholesterol/membranous debris and early cell dropout is a transitional, or in-between, lesion of atherosclerosis. This transitional lesion was first clearly described in 1994 - not very long ago.
It is interesting to note that cells can happily stay alive with enormous amounts of cholesterol ester inside, but not cholesterol itself. However, we haven't figured out how to shift all the cholesterol into the esterified form to prevent atherosclerosis progression. It seems likely that cholesterol kills smooth muscle cells and macrophages in therosclerotic lesions. However, I should mention an alternative idea about how these cells die. The alternative suggestion is that only oxidized cholesterol and other oxidized lipids, but not plain cholesterol, kill cells. We'll discuss this more later.
There is also a debate about where the membranous debris in the deep intima comes from. I and a few other researchers have suggested that it comes from LDL, more or less directly. Most researchers seem to think that it comes from dead cells, but we think they are weak on the details!
The next routinely identified lesion is the atherosclerotic fibrous plaque. The word "plaque," as we shall use it, means a thickened area on an otherwise smooth surface. An atherosclerotic plaque, therefore, is a thickening of cholesterol-loaded arterial intima. Note that the fatty streak, described above, is a flat and not a thickened lesion. Since the atherosclerotic plaque contains a large amount of fibrous protein, it can also be called a fibrous plaque.
Fibrous plaques contain an increased number of cells and an increased amount of fibrous protein, largely collagen. Almost all fibrous plaques also contain a central, cholesterol-rich core. In the core region, the cells are mostly dead or all dead, and the tissue is weakened because much of the fibrous protein has disappeared.
As time passes, the cholesterol-rich core may expand within an atherosclerotic plaque. The healthy intimal tissue between the core and the endothelial surface, called the fibrous cap, can be eroded from below by the twin processes of cholesterol deposition and cell death. The fibrous cap may become so thin that it finally breaks or ruptures. When this happens, the endothelial surface is also torn apart, and blood inside the artery comes into direct contact with the contents of the cholesterol-rich core. This contact makes the blood rapidly form a clot. The ruptured plaque with a blood clot is the final stage of atherosclerosis. By the time it is detected, the unfortunate person may be dead or may have suffered severe heart damage or a stroke.
John R. Guyton, MD