4.8: Atherosclerosis- An Arterial Disease

By far the most common arterial disease is atherosclerosis, which is one of a group of arterial diseases called arteriosclerosis. Because atherosclerosis is very common, some people mistakenly use these two terms interchangeably. The incidence of atherosclerosis and the serious difficulties it causes rise with age for the same reasons that cause the age‑related increase in heart disease.

Importance

Some statistics on the importance of atherosclerosis were presented earlier in this chapter. In addition to causing most heart attacks, atherosclerosis causes most strokes. A stroke is injury to or death of brain cells caused by low blood flow or bleeding in the brain (Chapter 6). For those over age 65, strokes are now the fourth leading cause of death, days in the hospital, and days in bed. Strokes also cause many cases of dementia and other forms of disability.

Atherosclerosis is also a major contributor to kidney disease, problems in the legs (e.g., weakening of muscles and skin, pain during exertion), and male impotence. Such outcomes not only affect an individual's health and survival, but also have an impact on all other aspects of life. For example, dietary restrictions may become necessary, demanding that occupational or recreational activities may have to be curtailed, and interpersonal relations between affected men and their spouses/partners can suffer dramatically.

Development and Effects

Atherosclerosis begins as small streaks of fatty tissue within the inner layer of arteries. Gradually, the streaks widen and thicken as they accumulate a variety of other materials, including smooth muscle cells, collagen fibers, cholesterol, and calcium deposits. The resulting masses – plaques - protrude inward and narrow the passageway in the artery (Figure 4.7). The plaques often grow completely through the endothelium and replace regions of it. Both the roughness and the collagen fibers of the plaques cause the blood to form clots. As a result, the narrowing of the artery leads to reductions in or complete blockage of blood flow. In addition, pieces of the plaque sometimes break off, move down the artery, and block the artery where it branches to form smaller arteries.

These plaques usually grow outward and infiltrate the middle layer of the artery, causing it to stiffen. When this occurs in larger arteries, they are less able to be stretched outward to accommodate pulses of blood from the heart, and systolic pressure can skyrocket. Since the arteries are also less able to spring back when the heart relaxes, diastolic pressure drops and the flow of blood becomes less regular. When plaque grows outward in smaller arteries, the stiffening and replacement of the smooth muscle prevent them from adjusting blood pressure and blood flow to suit body needs. The cells do not receive adequate oxygen and nutrients, and waste materials accumulate. The resulting loss of homeostasis injures or kills cells, and the organs they compose malfunction.

The outward growth of plaque also causes weakening of the middle layer, and affected arteries begin to bulge outward from blood pressure. The outpocketings, called aneurysms, can disturb nearby structures by pressing on them (Figure 4.10a). Additionally, blood flowing past aneurysms tends to swirl and form clots (Figure 4.10b). Some arteries become so weak that they rupture, causing severe internal bleeding that can lead to the most serious strokes (Figure 4.10c).

Figure 4.10a Aneurysms – (a) Pressure on structures. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

Figure 4.10b Aneurysms – (b) Clot formation. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission).

Figure 4.10c Aneurysms – (c) Bleeding. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission).

Mechanism promoting atherosclerosis

Several factors seem to cause atherosclerosis or to promote its development. These include endothelial dysfunction, free radicals, blood lipoproteins, elastase, glycation, heat shock proteins, and insulin-like growth factors (IGFs). Some of these may interact synergistically.

Endothelial dysfunction

Endothelial dysfunction may cause or result from endothelial aging, high blood pressure, or atherosclerosis. Endothelial dysfunction increases the adverse effects from high BP and from atherosclerosis. Part of the effect may be from an age-related increase in *O₂^-, which reduces *NO by reacting with it to form ONOO^-. With less *NO, vessel dilation is reduced and vessel smooth muscle growth and clot formation increase. At the same time, ONOO^- may initiate or promote plaque formation by injuring the vessel wall.

Free radicals

Free radicals may also contribute to atherosclerosis by increasing the formation of lipid peroxides (LPs) from blood lipoproteins. Blood LPs increase with age and after menopause, and also with increases in blood LDLs, blood pressure, stress, diabetes mellitus, and smoking. Lipid peroxides may promote atherosclerosis in several ways. Examples include increasing the absorption of LDLs by vessel macrophages, converting them to cholesterol-filled foam cells; injuring vessel cells directly; attracting monocytes and macrophages into vessel walls, which promote inflammation and cell damage; promoting vessel constriction; and promoting blood clot formation.

Blood LDLs

Blood LDLs may promote atherosclerosis by increasing LPs and by increasing elastase.

Elastase

Elastase is an enzyme that breaks down elastic fibers into elastin peptides. Elastin peptides are also formed during elastin synthesis. Elastase increases with age and with higher LDL levels. Elevated levels of elastin peptides seem to promote more elastase production by promoting the binding of calcium and lipids to elastin fibers.

Elastase may increase atherosclerosis by reducing elastic fibers in arteries, making vessels more susceptible to damage by blood pressure. The effects from the elastin peptides produced seem to increase *NO. Results include benefits such as vasodilation, and drawbacks such as vessel damage by stimulated monocytes. Research has provided contradictory results regarding the effects from elevated elastin peptides on promoting or reducing atherosclerosis.

Glycation

Glycation of proteins in arteries produces age-related glycation end-products (AGEs) and *FRs. The *FRs may promote atherosclerosis directly. The AGEs bind to fatty streaks and stimulate inflammation and *FR formation by macrophages. Glycated collagen in arteries is distorted and stiffer, causing adverse effects. These include reduced effectiveness of nitric oxide as a vasodilator; detachments of endothelium from the vessel wall; and increased clot formation.

Heat shock proteins

Heat shock proteins are produced when cells are stressed or injured. These proteins received their name because they were first discovered in cells subjected to abnormally high temperatures. Heat shock proteins seem to protect cells from a variety harmful environmental factors. An immune response to heat shock protein in damaged arteries may be the initial event in atherosclerosis.

Insulin-like growth factors

Insulin-like growth factors (IGFs) from cells stimulate growth and regulate other cell activities. The distribution and effectiveness of IGFs are altered when they bind to insulin-like growth factor binding proteins (IGFBPs). Research suggests that different ratios of IGFs and IGFBPs influence the development of atherosclerosis, possible by altering blood levels of lipoproteins and *NO and by affecting the growth of vessel smooth muscle.

Prevention

The incidence and seriousness of atherosclerosis can be greatly lowered by avoiding or reducing the known risk factors, which were discussed in the section on coronary artery disease.