Development of Atherosclerotic Plaques

Ø Although the following discussion applies to coronary arteries, the process can also occur in arteries outside the heart. Thickening of the walls of arteries and loss of elasticity are the main characteristics of a group of diseases called arteriosclerosis (ar-te¯ -re¯ -o¯ -skle-RO¯ -sis; sclero- hardening). One form of arteriosclerosis is atherosclerosis (ath-er-o¯ -skle-RO ¯ -sis), a progressive disease characterized by the formation in the walls of large and medium-sized arteries of lesions called atherosclerotic plaques.

Ø To understand how atherosclerotic plaques develop, you will need to learn about the role of molecules produced by the liver and small intestine called lipoproteins. These spherical particles consist of an inner core of triglycerides and other lipids and an outer shell of proteins, phospholipids, and cholesterol.

Ø Like most lipids, cholesterol does not dissolve in water and must be made water-soluble in order to be transported in the blood. This is accomplished by combining it with lipoproteins. Two major lipoproteins are low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). LDLs transport cholesterol from the liver to body cells for use in cell membrane repair and the production of steroid hormones and bile salts.

Ø However, excessive amounts of LDLs promote atherosclerosis, so the cholesterol in these particles is commonly known as “bad cholesterol.” HDLs, on the other hand, remove excess cholesterol from body cells and transport it to the liver for elimination. Because HDLs decrease blood cholesterol level, the cholesterol in HDLs is commonly referred to as “good cholesterol.” Basically, you want your LDL concentration to be low and your HDL concentration to be high.

Ø It has been learned recently that inflammation, a defensive response of the body to tissue damage, plays a key role in the development of atherosclerotic plaques. As a result of tissue damage, blood vessels dilate and increase their permeability, and phagocytes, including macrophages, appear in large numbers.

Ø The formation of atherosclerotic plaques begins when excess LDLs from the blood accumulate in the inner layer of an artery wall (layer closest to the bloodstream) and the lipids and proteins in the LDLs undergo oxidation and the proteins also bind to sugars. In response, endothelial and smooth muscle cells of the artery secrete substances that attract monocytes from the blood and convert them into macrophages.

Ø The macrophages then ingest and become so filled with oxidized LDL particles that they have a foamy appearance when viewed microscopically (foam cells). T cells (lymphocytes) follow monocytes into the inner lining of an artery where they release chemicals that intensify the inflammatory response. Together, the foam cells, macrophages, and T cells form a fatty streak, the beginning of an atherosclerotic plaque.

Ø Macrophages secrete chemicals that cause smooth muscle cells of the middle layer of an artery to migrate to the top of the atherosclerotic plaque, forming a cap over it and thus walling it off from the blood.

Ø Because most atherosclerotic plaques expand away from the bloodstream rather than into it, blood can still flow through the affected artery with relative ease, often for decades. Relatively few heart attacks occur when plaque in a coronary artery expands into the bloodstream and restricts blood flow. Most heart attacks occur when the cap over the plaque breaks open in response to chemicals produced by foam cells. In addition, T cells induce foam cells to produce tissue factor (TF), a chemical that begins the cascade of reactions that result in blood clot formation. If the clot in a coronary artery is large enough, it can significantly decrease or stop the flow of blood and result in a heart attack.

Ø In recent years, a number of new risk factors (all modifiable) have been identified as significant predictors of CAD. C-reactive proteins (CRPs) are proteins produced by the liver or present in blood in an inactive form that are converted to an active form during inflammation. CRPs may play a direct role in the development of atherosclerosis by promoting the uptake of LDLs by macrophages. Lipoprotein (a) is an LDL-like particle that binds to endothelial cells, macrophages, and blood platelets, may promote the proliferation of smooth muscle fibers, and inhibits the breakdown of blood clots. Fibrinogen is a glycoprotein involved in blood clotting that may help regulate cellular proliferation, vasoconstriction, and platelet aggregation. Homocysteine is an amino acid that may induce blood vessel damage by promoting platelet aggregation and smooth muscle fiber proliferation.