A recent major theory of atherosclerosis recognizes that the very high LDL content of the arterial intima sets the stage both for cholesterol build-up and for cell responses of atherosclerosis. It is called the Response to Retention Theory, referring to retention of LDL as the driving force in atherosclerosis. Lack of lymph vessels explains much of the retention of LDL, but researchers have also found that collagen, elastin, and proteoglycans - that is, the fibrous matrix between the intimal cells - attract and retain LDL particles. The LDL particles stick to these fibrous tissue components.
The LDL particles enter the arterial intima very slowly across the endothelial cells, and some LDL particles leave the arterial intima very slowly in the same way, crossing the endothelial cell barrier in the reverse direction. However, the slowness of these processes means that LDL particles may remain in the arterial intima for weeks to months. During this time, the particles are subject to chemical attack by various enzymes and even by oxygen. Two bad things happen when LDL particles become chemically altered. First, two or more LDL particles can fuse or coalesce. To understand this, think about what happens when you mix oil and water, than shake the mixture.
Initially, you will see small droplets of oil throughout the water, but then the small droplets will coalesce, forming successively larger droplets until all the oil is floating on top. Normal LDL particles are assembled from various lipids and one protein molecule in a way that resists coalescence. In the arterial intima, oxidation and enzymatic attack break the resistance of the LDL particles to coalescence. Large droplets and even "lakes" of oily LDL cholesterol ester lipid begin to form in the intimal tissue spaces. A second bad thing that happens to chemically altered LDL is that they are taken up into inflammatory or scavenger cells called macrophages.
Inflammation and white blood cells in atherosclerosis
Inflammation is a name for the defensive actions taken by various cells of the body to repel foreign invaders such as bacteria and viruses. Some of the same actions help the body to heal wounds, so inflammation has a role in wound healing as well. Finally, inflammatory actions are used to clean up or scavenge damaged protein or lipid molecules, which have been attacked by oxygen, by other reactive chemicals such as glucose, or by enzymes.
As far as we know, atherosclerosis is not caused directly by any bacteria or virus. Certain viruses have occasionally been found in atherosclerotic lesions, but they are thought to be bystanders, not actors. Clinical trials of antibiotics have not been effective in improving outcomes in patients with atherosclerosis.
Nevertheless, inflammation plays a major role in atherosclerosis. Certain tissue clean-up, scavenging, and healing aspects of inflammation have been identified in atherosclerotic lesions. Almost all cells of the body can participate in inflammation, but white blood cells are designed only for inflammation. Two kinds of white blood cells, monocytes and lymphocytes, are attracted into atherosclerotic lesions from the bloodstream. Both of these cell types can be seen in large numbers sticking to the endothelial cells overlying cholesterol deposits. The white blood cells squeeze between the endothelial cells to enter the arterial intima. In the arterial intima, lymphocytes make signaling molecules that can stimulate or activate monocytes, smooth muscle cells, and even endothelial cells, promoting inflammation. However, exactly what "turns on" the lymphocytes in atherosclerosis and how big a part they play are still unknown.
Monocytes have a major role in atherosclerosis, and much has been learned about what they do. Soon after monocytes enter the arterial intima, they become larger, they send out ruffles and extensions, and they develop receptors (or sticky sites) for many of the chemically altered proteins and lipids commonly found in tissues. When these changes occur, the monocytes become macrophages, the most important scavenger or clean-up cells in tissues.
What is it in atherosclerotic lesions that needs cleaning up? One obvious answer is damaged, oxidized, disrupted, and coalesced LDL particles. Macrophages engulf and ingest these LDL particles in large numbers. Each macrophage has its own digestive enzymes that further disrupt the LDL, leading to the formation of pure cholesterol ester droplets inside the macrophages. Many macrophages have so many cholesterol ester droplets inside that the cells appear bubbly or foamy in the light microscope. These are called foam cells. More about foam cells below.
One of the most interesting aspects of inflammation in atherosclerosis is the recently discovered relationship between C-reactive protein and the risk of heart attacks and stroke. Simply put, by measuring the level of C-reactive protein (often called CRP) in the blood, you can predict a person's risk of having a heart attack or stroke more accurately than by measuring either LDL or HDL cholesterol. The predictive power of CRP is surprisingly good, about as accurate as that of the ratio of LDL cholesterol divided by HDL cholesterol. Please note that CRP is not considered to cause atherosclerosis. Instead, the liver makes more CRP, whenever molecular signals tell the liver that inflammation is occurring anywhere in the body.
This leads to a question: Does a high CRP level in a person with atherosclerosis simply mean that inflammation in the arterial intima is generating molecular signals for the liver? Or alternatively, do some people have a tendency to get tissue inflammation more easily (anywhere in the body), to make more CRP and at the same time to develop more atherosclerosis (that is, inflammation in the arterial wall)? Research studies are trying to answer these questions. In any case, high CRP levels are very predictive of atherosclerosis.
John R. Guyton, MD