Atherosclerosis is the most common form of arteriosclerosis (hardening of the arteries) and, through its contribution to heart disease and stroke, is responsible for about 50% of the deaths in the United States, Europe, and Japan. In atherosclerosis, localized plaques, or atheromas, protrude into the lumen of the artery and thus reduce blood flow. The atheromas additionally serve as sites for thrombus (blood clot) formation, which can further occlude the blood supply to an organ (fig. 13.30).
Lumen of vessel
Smooth muscle cells
■ Figure 13.30 Atherosclerosis. (a) A photograph of the lumen (cavity) of a human' coronary artery that is partially occluded by an atherosclerotic plaque and a thrombus. (b) A diagram of the structure of an atherosclerotic plaque.
It is currently believed that the process of atherosclerosis begins as a result of damage, or "insult," to the endothelium. Such insults are produced by smoking, hypertension (high blood pressure), high blood cholesterol, and diabetes. The first anatomically recognized change is the appearance of "fatty streaks," which are gray-white areas that protrude into the lumen of arteries, particularly at arterial branch points. These are aggregations of lipid-filled macrophages and lymphocytes within the tunica interna. They are present to a small degree in the aorta and coronary arteries of children aged 10 to 14, but progress to more advanced stages at different rates in different people. In the intermediate stage, the area contains layers of macrophages and smooth muscle cells. The more advanced lesions, called fibrous plaques, consist of a cap of connective tissue with smooth muscle cells over accumulated lipid and debris, macrophages that have been derived from monocytes (see chapter 15), and lymphocytes.
The disease process may be instigated by damage to the endothelium, but its progression appears to result from the action of a wide variety of cytokines and other paracrine regulators secreted by the endothelium and by the other participating cells, including platelets, macrophages, and lymphocytes. Some of these regulators attract monocytes and lymphocytes to the damaged endothelium and cause them to penetrate into the tunica interna. The monocytes then become macrophages, engulf lipids, and take on the appearance of "foamy cells." Smooth muscle cells change from a contractile state to a "synthetic" state, in which they produce and secrete connective tissue matrix proteins. (This is unique; in other tissues, connective tissue matrix is secreted by cells called fibroblasts.) The changed smooth muscle cells respond to chemical attractants and migrate from the tunica media to the tunica interna, where they can proliferate.
Endothelial cells normally prevent the progression just described by presenting a physical barrier to the penetration of monocytes and lymphocytes and by producing paracrine regulators such as nitric oxide. The vasodilator action of nitric oxide helps to counter the vasoconstrictor effects of another paracrine regulator, endothelin-1, which is increased in atherosclerosis. Hypertension, smoking, and high blood cholesterol, among other risk factors, interfere with this protective function.
There is considerable evidence that high blood cholesterol is associated with an increased risk of atherosclerosis. This high blood cholesterol can be produced by a diet rich in cholesterol and saturated fat, or it may be the result of an inherited condition known as familial hypercholesteremia. This condition is inherited as a single dominant gene; individuals who inherit two of these genes have extremely high cholesterol concentrations (regardless of diet) and usually suffer heart attacks during childhood.
Lipids, including cholesterol, are carried in the blood attached to protein carriers (this topic is covered in detail in chapter 18). Cholesterol is carried to the arteries by plasma proteins called low-density lipoproteins (LDLs). LDLs, produced by the liver, are small protein-coated droplets of cholesterol, neutral fat, free fatty acids, and phospholipids. Cells in various organs contain receptors for the proteins in LDLs; when LDL proteins attach to their receptors, the cell engulfs the LDL by receptor-mediated endocytosis (chapter 3; see fig. 3.4) and utilizes the cholesterol for different purposes. Most of the LDL particles in the blood are removed in this way by the liver.
People who eat a diet high in cholesterol and saturated fat, and people with familial hypercholesteremia, have a high blood LDL concentration because their livers have a low number of LDL receptors. With fewer LDL receptors, the liver is less able to remove the LDL from the blood, and thus more LDL is available to enter the endothelial cells of arteries.
When endothelial cells engulf LDL, they oxidize it to a product called oxidized LDL. Recent evidence suggests that oxidized LDL contributes to endothelial cell injury, migration of monocytes and lymphocytes into the tunica interna, conversion of monocytes into macrophages, and other events that occur in the progression of atherosclerosis.
Since oxidized LDL seems to be so important in the progression of atherosclerosis, it would appear that antioxidant compounds could be used to treat this condition or help to prevent it. The antioxidant drug probucol, as well as vitamin C, vitamin E, and beta-carotene, which are antioxidants (see chapter 19), have been shown to be effective in this regard.
Excessive cholesterol may be released from cells and travel in the blood as high-density lipoproteins (HDLs), which are removed by the liver. The cholesterol in HDL is not taken into the artery wall because these cells lack the membrane receptor required for endocytosis of the HDL particles. For this reason, HDL-cholesterol does not contribute to atherosclerosis. Indeed, a high proportion of HDL-cholesterol as compared to LDL-cholesterol is beneficial, since it indicates that cholesterol may be traveling away from the blood vessels to the liver. The concentration of HDL-cholesterol appears to be higher and the risk of atherosclerosis lower in people who exercise regularly. The HDL-cholesterol concentration, for example, is higher in marathon runners than in joggers and is higher in joggers than in sedentary individuals. Women in general have higher HDL-cholesterol concentrations and a lower risk of atherosclerosis than men.
Many people with dangerously high LDL-cholesterol concentrations take drugs known as statins. These drugs function as inhibitors of the enzyme HMG-coenzyme A reductase, which catalyzes the rate-limiting step in cholesterol synthesis. The statins therefore decrease the ability of the liver to produce its own cholesterol. The lowered intracel-lular cholesterol then stimulates the production of LDL receptors, allowing the liver cells to engulf more LDL-cholesterol. When a person takes a statin drug, therefore, the liver cells remove more LDL-cholesterol from the blood and thus decrease the amount of blood LDL-cholesterol that can enter the endothelial cells of arteries.
Many people can significantly lower their blood cholesterol concentration through a regimen of exercise and diet. Since saturated fat in the diet raises blood cholesterol, such foods as fatty meat, egg yolks, and internal animal organs (liver, brain, etc.) should be eaten only sparingly. The American Heart Association recommends that fat contributes less than 30% to the total calories of a diet. By way of comparison, 40% to 50% of the calories in a fast-food meal are derived from fat. The single most effective action that smokers can take to lower their risk of atherosclerosis, however, is to stop smoking.
Clinical Investigation Clues
Remember that Jason had a high blood cholesterol and a high LDL/HDL ratio.
What dangers are indicated by the lab results? What can Jason do about reducing these dangers?
A tissue is said to be ischemic when its oxygen supply is deficient because of inadequate blood flow. The most common cause of myocardial ischemia is atherosclerosis of the coronary arteries. The adequacy of blood flow is relative—it depends on the tissue's metabolic requirements for oxygen. An obstruction in a coronary artery, for example, may allow sufficient coronary blood flow at rest but not when the heart is stressed by exercise or emotional conditions. In these cases, the increased activity of the sympathoadrenal system causes the heart rate and blood pressure to rise, increasing the work of the heart and raising its oxygen requirements. Recent evidence also suggests that mental stress can cause constriction of atherosclerotic coronary arteries, leading to ischemia of the heart muscle. The vasoconstriction is believed to result from abnormal function of a damaged endothelium, which normally prevents constriction (through secretion of paracrine regulators) in response to mental stress. The control of vasoconstriction and vasodilation is discussed more fully in chapter 14.
Myocardial ischemia is associated with increased concentrations of blood lactic acid produced by anaerobic respiration of the ischemic tissue. This condition often causes substernal pain, which may also be referred to the left shoulder and arm, as well as to other areas. This referred pain is called angina pectoris. People with angina frequently take nitroglycerin or related drugs that help to relieve the ischemia and pain. These drugs are effective because they produce vasodilation, which improves circulation to the heart and decreases the work that the ventricles must perform to eject blood into the arteries.
Myocardial cells are adapted to respire aerobically and cannot respire anaerobically for more than a few minutes. If ischemia and anaerobic respiration are prolonged, necrosis (cellular death) may occur in the areas most deprived of oxygen. A
■ Figure 13.31 Depression of the S-T segment as a result of myocardial ischemia. This is but one of many ECG changes that alert trained personnel to the existence of heart problems.
sudden, irreversible injury of this kind is called a myocardial infarction, or MI. The lay term "heart attack," though imprecise, usually refers to a myocardial infarction.
Myocardial ischemia may be detected by changes in the ST segment of the electrocardiogram (fig. 13.31). The diagnosis of myocardial infarction is aided by measurement of the blood levels of enzymes released by the infarcted tissue. Plasma concentrations of creatine phosphokinase (CPK), for example, increase within 3 to 6 hours after the onset of symptoms and return to normal after 3 days. Plasma levels of lactate dehydro-genase (LDH) reach a peak within 48 to 72 hours after the onset of symptoms and remain elevated for about 11 days. Plasma concentrations of troponins T and I (regulatory muscle proteins released by damaged myocardial cells; see p. 354) are also now important for the diagnosis of myocardial infarction.
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