Development of atherosclerotic plaque. A, Attachment of a monocyte to an adhesion molecule on a damaged endothelial cell of an artery. The monocyte then migrates through the endothelium into the intimal layer of the arterial wall and is transformed into a macrophage. The macrophage then ingests and oxidizes lipoprotein molecules, becoming a macrophage foam cell. The foam cells release substances that cause inflammation and growth of the intimal layer. B, Additional accumulation of macrophages and growth of the intima cause the plaque to grow larger and accumulate lipids. Eventually, the plaque could occlude the vessel or rupture, causing the blood in the artery to coagulate and form a thrombus. (Modified from Libby P: Inflammation in atherosclerosis. Nature 420:868, 2002.)
differentiate to become macrophages, which then ingest and oxidize the accumulated lipoproteins, giving the macrophages a foamlike appearance. These macrophage foam cells then aggregate on the blood vessel and form a visible fatty streak.
With time, the fatty streaks grow larger and coalesce, and the surrounding fibrous and smooth muscle tissues proliferate to form larger and larger plaques (see Figure 68-6B). Also, the macrophages release substances that cause inflammation and further proliferation of smooth muscle and fibrous tissue on the inside surfaces of the arterial wall. The lipid deposits plus the cellular proliferation can become so large that the plaque bulges into the lumen of the artery and greatly reduces blood flow, sometimes completely occluding the vessel. Even without occlusion, the fibroblasts of the plaque eventually deposit extensive amounts of dense connective tissue; sclerosis (fibrosis) becomes so great that the arteries become stiff and unyielding. Still later, calcium salts often precipitate with the cholesterol and other lipids of the plaques, leading to bony-hard calcifications that can make the arteries rigid tubes. Both of these later stages of the disease are called "hardening of the arteries."
Atherosclerotic arteries lose most of their distensi-bility, and because of the degenerative areas in their walls, they are easily ruptured. Also, where the plaques protrude into the flowing blood, their rough surfaces can cause blood clots to develop, with resultant thrombus or embolus formation (see Chapter 36), leading to a sudden blockage of all blood flow in the artery.
Almost half of all deaths in the United States and Europe are due to vascular disease. About two thirds of these deaths are caused by thrombosis of one or more coronary arteries. The remaining one third are caused by thrombosis or hemorrhage of vessels in other organs of the body, especially the brain (causing strokes), but also the kidneys, liver, gastrointestinal tract, limbs, and so forth.
Basic Causes of Atherosclerosis— The Roles of Cholesterol and Lipoproteins
Increased Low-Density Lipoproteins. An important factor in causing atherosclerosis is a high blood plasma concentration of cholesterol in the form of low-density lipoproteins. The plasma concentration of these high-cholesterol low-density lipoproteins is increased by several factors, including eating highly saturated fat in the daily diet, obesity, and physical inactivity. To a lesser extent, eating excess cholesterol may also raise plasma levels of low-density lipoproteins.
An interesting example occurs in rabbits, which normally have low plasma cholesterol concentrations because of their vegetarian diet. Simply feeding these animals large quantities of cholesterol as part of their daily diet leads to serious atherosclerotic plaques throughout their arterial systems.
Familial Hypercholesterolemia. This is a disease in which the person inherits defective genes for the formation of low-density lipoprotein receptors on the membrane surfaces of the body's cells. In the absence of these receptors, the liver cannot absorb either intermediate-density or low-density lipoproteins. Without this absorption, the cholesterol machinery of the liver cells goes on a rampage, producing new cholesterol; it is no longer responsive to the feedback inhibition of too much plasma cholesterol. As a result, the number of very low density lipoproteins released by the liver into the plasma increases immensely.
Patients with full-blown familial hypercholes-terolemia have blood cholesterol concentrations of 600 to 1000 mg/dl, levels that are four to six times normal. Many of these people die before age 20 because of myocardial infarction or other sequelae of atherosclerotic blockage of blood vessels throughout the body.
Role of High-Density Lipoproteins in Preventing Atherosclerosis.
Much less is known about the function of high-density lipoproteins compared with that of low-density lipopro-teins. It is believed that high-density lipoproteins can actually absorb cholesterol crystals that are beginning to be deposited in arterial walls. Whether this mechanism is true or not, high-density lipoproteins do help protect against the development of atherosclerosis. Consequently, when a person has a high ratio of high-density to low-density lipoproteins, the likelihood of developing atherosclerosis is greatly reduced.
In some people with perfectly normal levels of cholesterol and lipoproteins, atherosclerosis still develops. Some of the factors that are known to predispose to atherosclerosis are (1) physical inactivity and obesity, (2) diabetes mellitus, (3) hypertension, (4) hyperlipidemia, and (5) cigarette smoking.
Hypertension, for example, increases the risk for atherosclerotic coronary artery disease by at least twofold. Likewise, a person with diabetes mellitus has, on average, more than a twofold increased risk of developing coronary artery disease. When hypertension and diabetes mellitus occur together, the risk for coronary artery disease is increased by more than eightfold. And when hypertension, diabetes mellitus, and hyperlipemia are all present, the risk for atherosclerotic coronary artery disease is increased almost 20-fold, suggesting that these factors interact in a synergistic manner to increase the risk of developing atherosclerosis. In many overweight and obese patients, these three risk factors do occur together, greatly increasing their risk for atherosclerosis, which in turn may lead to heart attack, stroke, and kidney disease.
In early and middle adulthood, men are more likely to develop atherosclerosis than are women of comparable age, suggesting that male sex hormones might be atherogenic or, conversely, that female sex hormones might be protective.
Some of these factors cause atherosclerosis by increasing the concentration of low-density lipoproteins in the plasma. Others, such as hypertension, lead to atherosclerosis by causing damage to the vascular en-dothelium and other changes in the vascular tissues that predispose to cholesterol deposition.
To add to the complexity of atherosclerosis, experimental studies suggest that excess blood levels of iron can lead to atherosclerosis, perhaps by forming free radicals in the blood that damage the vessel walls. About one quarter of all people have a special type of low-density lipoprotein called lipoprotein(a), containing an additional protein, apoprotein(a), that almost doubles the incidence of atherosclerosis. The precise mechanisms of these atherogenic effects have yet to be discovered.
The most important measures to protect against the development of atherosclerosis and its progression to serious vascular disease are (1) maintaining a healthy weight, being physically active, and eating a diet that contains mainly unsaturated fat with a low cholesterol content; (2) preventing hypertension by maintaining a healthy diet and being physically active, or effectively controlling blood pressure with antihypertensive drugs if hypertension does develop; (3) effectively controlling blood glucose with insulin treatment or other drugs if diabetes develops; and (4) avoiding cigarette smoking.
Several types of drugs that lower plasma lipids and cholesterol have proved to be valuable in preventing atherosclerosis. Most of the cholesterol formed in the liver is converted into bile acids and secreted in this form into the duodenum; then, more than 90 per cent of these same bile acids is reabsorbed in the terminal ileum and used over and over again in the bile. Therefore, any agent that combines with the bile acids in the gastrointestinal tract and prevents their reabsorption into the circulation can decrease the total bile acid pool in the circulating blood. This causes far more of the liver cholesterol to be converted into new bile acids. Thus, simply eating oat bran, which binds bile acids and is a constituent of many breakfast cereals, increases the proportion of liver cholesterol that forms new bile acids rather than forming new low-density lipoproteins and atherogenic plaques. Resin agents can also be used to bind bile acids in the gut and increase their fecal excretion, thereby reducing cholesterol synthesis by the liver.
Another group of drugs called statins competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the synthesis of cholesterol. This inhibition decreases cholesterol synthesis and increases low-density lipoprotein receptors in the liver, usually causing a 25 to 50 per cent reduction in plasma levels of low-density lipoproteins. The statins may also have other beneficial effects that help prevent atherosclerosis, such as attenuating vascular inflammation. These drugs are now widely used to treat patients who have increased plasma cholesterol levels.
In general, studies show that for each 1 mg/dl decrease in low-density lipoprotein cholesterol in the plasma, there is about a 2 per cent decrease in mortality from atherosclerotic heart disease. Therefore, appropriate preventive measures are valuable in decreasing heart attacks.
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