ATHEROSCLEROSIS

The most common cause of death and disability in the United States is atherosclerosis, popularly known as "hardening of the arteries."

EPIDEMIOLOGY

Every year atherosclerosis causes about 500,000 deaths nationally, most of these due to heart attack or stroke. There are about 15 million people in the United States suffering from atherosclerosis, and another 60 million are at risk. The factors that put individuals at risk of atherosclerosis include high blood levels of cholesterol and sugar, high blood pressure, and tobacco use. Another important risk factor is a family history of premature atherosclerosis (e.g., a close relative who has had a heart attack or stroke under the age of sixty). In addition to these risk factors, there is accumulating evidence that elevated plasma levels of lipoprotein (a), C-reactive peptide, asymmetric dimethylarginine, and homocysteine also accelerate atherosclerosis, as do obesity, type A personality, and sedentary lifestyle.

PATHOPHYSIOLOGY

Atherosclerosis is thought to be initiated by a "response to injury" of the endothelium (the lining of the blood vessel). Elevated blood levels of cholesterol or glucose, as well as high blood pressure and smoking, cause changes in the endothelium (normally the "teflon" coating of the vessel), which then becomes sticky. It begins to express on its surface "adhesion molecules," which are a bit like cellular velcro. It also expresses "chemokines" which are proteins that attract white blood cells into the vessel. White blood cells (specifically monocytes and T-lymphocytes) begin to stick to the lining of the vessel, and to infiltrate the vessel.

The monocytes migrate into the vessel wall, where they begin to accumulate cholesterol. They become engorged by cholesterol in the vessel wall and become foam cells. As foam cells accumulate in the vessel they distort the overlying endothelium (forming a "fatty streak" in the vessel), and they eventually may even rupture through the endothelial surface. In these areas of endothelial ulceration, platelets adhere to the vessel wall, releasing molecules that stimulate smooth-muscle migration and proliferation. Vascular smooth-muscle cells in the vessel wall proliferate and migrate into the area above the foam cells. The smooth-muscle cells may also become engorged with lipid to form foam cells, and atherosclerotic plaque begins to take form. The plaque grows with the recruitment of more cells, and with the accumulation of matrix made by the cells and cholesterol from the bloodstream. The progression of atherosclerotic plaque is also related to the growth of microscopic vessels into the plaques. The complex plaque typically is characterized by a fibrous cap that overlies a necrotic core composed of cell debris and cholesterol. This core also contains a high concentration of tissue factor, secreted by macrophages. If the plaque ruptures, the exposed tissue factor will cause a blood clot to form, which can lead to a heart attack or stroke.

CLINICAL MANIFESTATIONS

By virtue of its bulk, the complex plaque may limit blood flow. With moderate-sized lesions (e.g., occupying 50% of the cross-sectional area of the inner bore of the vessel), not enough blood can flow through the vessel during states of higher demand. With physical exertion, the inadequate supply of blood may cause chest pain (angina) if the narrowing is in a heart artery, or leg pain (claudication) if the narrowing is in a leg artery. As the lesion becomes larger (e.g., 80 to 90% of the cross-sectional area), it may limit basal blood flow, causing pain at rest (e.g., rest angina).

The complicated plaque is the major cause of acute cardiovascular events (e.g., heart attack and stroke). Hemorrhage into the plaque (secondary to spontaneous rupture of small vessels supplying the lesion) can cause rapid expansion of the plaque. Alternatively, rupture of the plaque releases the tissue factor in the necrotic core, which causes local clot formation and even occlusion of the vessel, leading to heart attack, stroke, or gangrene of the leg, depending upon what vessels are effected. Microscopic examination of the ruptured plaque generally reveals that the plaque is inflamed. Infection of the plaque by bacteria or viruses may play a role in the inflammation and rupture of plaques.

PREVENTION OF ATHEROSCLEROSIS

The best medical strategy for this disease is prevention through aggressive modification of risk factors. Regular physical activity; reduction of cholesterol, blood sugar, and blood pressure; and cessation of tobacco use are known to modify the progression of disease and reduce morbidity and mortality. In addition to removing or reducing risk factors, recent work indicates that enhancing endothelial function can also favorably influence the course of disease.

ROLE OF THE ENDOTHELIUM

The endothelium is the lining of the blood vessel. It produces a panoply of paracrine factors that effect vessel tone and structure. Possibly the most important of these is endothelium-derived nitric oxide (NO). NO is derived from the metabolism of L-arginine to L-citrulline and NO by the enzyme NO synthase. NO is the most potent endogenous vasodilator known, and it exerts its actions in the same way as nitroglycerine, a medicine taken by people to relieve angina.

NO also inhibits clot formation, and adherence of monocytes to the vessel. It also inhibits the growth of vascular smooth-muscle cells. By exerting these effects, NO, and a similarly acting molecule, prostacyclin, may be the body's self-defense against atherosclerosis.