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Atherosclerosis ˌath-ə-rō-sklə-ˈrō-səs

by Jules Y. T. Lam, MD, FRCP(C)

Atherosclerosis is a condition in which patchy deposits of fatty material (atheromas or atherosclerotic plaques) develop in the walls of medium-sized and large arteries, leading to reduced or blocked blood flow.

  • Atherosclerosis is caused by repeated injury to the walls of arteries.

  • Many factors contribute to this injury, including high blood pressure, tobacco smoke, diabetes, and high levels of cholesterol in the blood.

  • Often, the first symptom is pain or cramps at times when blood flow cannot keep up with the tissues‘ need for oxygen.

  • To prevent atherosclerosis, people need to stop using tobacco, improve their diet, exercise regularly, and maintain control of their blood pressure, cholesterol level, and diabetes.

  • Progression of atherosclerosis to such life-threatening complications as a heart attack or stroke requires emergency treatment.

In the United States and most other developed countries, atherosclerosis is the leading cause of illness and death. Estimates for 2008 in the United States alone are that about 16 million people have atherosclerotic heart disease and 5.8 million have stroke. Cardiovascular disease, primarily coronary and cerebrovascular atherosclerosis, caused almost 812,000 deaths in 2008—more than cancer caused and 7 times as many as injuries caused. This year an estimated 1.2 million Americans will have a heart attack. Despite significant medical advances, heart attacks due to coronary artery disease (atherosclerosis that affects the arteries supplying blood to the heart—see Overview of Coronary Artery Disease) and stroke (due to atherosclerosis that affects the arteries to the brain—see see Figure: Supplying the Brain with Blood) are responsible for more deaths than all other causes combined.

Atherosclerosis can affect the medium-sized and large arteries of the brain, heart, kidneys, other vital organs, and legs. It is the most important and most common type of arteriosclerosis, a general term for several diseases in which the wall of an artery becomes thicker and less elastic.

Causes

The development of atherosclerosis is complicated, but the primary event seems to be repeated, subtle injury to the artery‘s inner lining (endothelium), through various mechanisms. These mechanisms include physical stresses from turbulent blood flow (such as occurs where arteries branch, particularly in people who have high blood pressure) and inflammatory stresses involving the immune system, certain infections, or chemical abnormalities in the bloodstream (such as high cholesterol or high blood sugar as occurs in diabetes). The infections may be due to bacteria ( Chlamydia pneumoniae or Helicobacter pylori) or to viruses (cytomegalovirus and others).

Atherosclerosis begins when the injured artery wall creates chemical signals that cause certain types of white blood cells (monocytes and T cells) to attach to the wall of the artery. These cells move into the wall of the artery. There, they are transformed into foam cells, which collect cholesterol and other fatty materials, and trigger growth of smooth muscle cells in the artery wall. In time, these fat-laden foam cells accumulate. They form patchy deposits (atheromas, also called plaques) covered with a fibrous cap in the lining of the artery wall. With time, calcium accumulates in the plaques. Plaques may be scattered throughout medium-sized and large arteries, but they usually start where the arteries branch.

How Atherosclerosis Develops

The wall of an artery is composed of several layers. The lining or inner layer (endothelium) is usually smooth and unbroken. Atherosclerosis begins when the lining is injured or diseased. Then certain white blood cells called monocytes and T cells are activated and move out of the bloodstream and through the lining of an artery into the artery’s wall. Inside the lining, they are transformed into foam cells, which are cells that collect fatty materials, mainly cholesterol.

In time, smooth muscle cells move from the middle layer into the lining of the artery’s wall and multiply there. Connective and elastic tissue materials also accumulate there, as may cell debris, cholesterol crystals, and calcium. This accumulation of fat-laden cells, smooth muscle cells, and other materials forms a patchy deposit called an atheroma or atherosclerotic plaque. As they grow, some plaques thicken the artery’s wall and bulge into the channel of the artery. These plaques may narrow or block an artery, reducing or stopping blood flow. Other plaques do not block the artery very much but may split open, triggering a blood clot that suddenly blocks the artery.

Plaques can grow into the opening (lumen) of the artery, gradually causing it to narrow. When atherosclerosis narrows an artery, tissues supplied by the artery may not receive enough blood and oxygen. Plaques also can grow into the wall of the artery, where they do not block blood flow. Both kinds of plaques can split open (rupture), exposing the material within to the bloodstream. This material triggers blood clot formation. These blood clots can suddenly block all blood flow through the artery, which is the main cause of a heart attack or stroke. Sometimes these blood clots break off, travel through the bloodstream, and block an artery elsewhere in the body. Similarly, pieces of the plaque can break off and travel through the bloodstream and block an artery elsewhere.

Risk Factors

Some risk factors for atherosclerosis can be modified (see Overview of Coronary Artery Disease : Prevention). These factors include tobacco use, high levels of cholesterol in the blood, high blood pressure, diabetes, obesity, physical inactivity, and diet. Dietary factors include low daily consumption of fruits and vegetables and other than moderate alcohol consumption (that is, none or too much).

Risk factors that cannot be modified include having a family history of early atherosclerosis (that is, having a close relative who developed the disease before age 55 for men and before age 65 for women), advancing age, and male sex. Men have a higher risk than women, although women who have coronary artery disease are more likely to die than men who have the disease.

Smoking

One of the most important modifiable risk factors is smoking. (Using other forms of tobacco, such as snuff and chewing tobacco, also increases risk.) A smoker‘s risk of developing coronary artery disease is directly related to the amount of tobacco smoked daily. The risk of a heart attack is increased threefold in men and sixfold in women who smoked 20 or more cigarettes per day compared with nonsmokers. In people who already have a high risk of heart disease, tobacco use is particularly dangerous.

Tobacco use decreases the level of high-density lipoprotein (HDL) cholesterol—the “good” cholesterol—and increases the level of low-density lipoprotein (LDL) cholesterol—the “bad” cholesterol. Smoking increases the level of carbon monoxide in the blood, which may increase the risk of injury to the lining of the artery‘s wall. Tobacco use causes arteries already narrowed by atherosclerosis to constrict, further decreasing the amount of blood reaching the tissues. In addition, tobacco use increases the blood‘s tendency to clot (by making platelets stickier), so that it increases the risk of peripheral arterial disease (atherosclerosis affecting arteries other than those that supply the heart and brain—see Overview of Peripheral Arterial Disease), coronary artery disease (see Overview of Coronary Artery Disease), stroke (see Overview of Stroke), and blockage of an arterial graft placed during bypass surgery (see Coronary Artery Bypass Grafting and see ).

People who quit using tobacco have only half the risk of those who continue to use tobacco—regardless of how long they smoked before quitting. Quitting also decreases the risk of death after coronary artery bypass surgery or a heart attack and the risk of illness and death in people who have peripheral arterial disease. The benefits of quitting tobacco use begin immediately and increase with time.

Secondhand smoke (smoke breathed in from someone else‘s smoking) appears to increase risk also. It should be avoided.

Did You Know...

  • Smoking is an important risk factor for atherosclerosis.

Cholesterol levels

A high level of LDL cholesterol level is another important modifiable risk factor. A diet that is high in saturated fats causes LDL cholesterol levels to increase in susceptible people. Cholesterol levels also increase as people age and are normally higher in men than in women, although levels increase in women after menopause. Several hereditary disorders result in high levels of cholesterol or other fats. People with these hereditary disorders can have extremely high levels of cholesterol and (if untreated) die of coronary artery disease at an early age.

Lowering high LDL cholesterol levels through the use of drugs called statins (see Table: Lipid-Lowering Drugs) can significantly reduce the risk of heart attacks, strokes, and death.

Not all types of cholesterol increase the risk of atherosclerosis. A high level of HDL (good) cholesterol decreases the risk of atherosclerosis, and a low level increases the risk.

The desired level of total cholesterol, which includes LDL and HDL cholesterol and triglycerides, is 140 to 200 mg/dL (3.6 to 5.2 mmol/L). Risk of a heart attack more than doubles when the total cholesterol level approaches 300 mg/dL (7.8 mmol/L). The risk is decreased when the LDL cholesterol level is below 130 mg/dL (3.4 mmol/L), and the HDL cholesterol level is above 40 mg/dL (1 mmol/L). In high-risk people, such as those who have diabetes or who already have atherosclerotic heart disease, heart attacks, stroke, or bypass surgery, LDL cholesterol should be below 70 mg/dL (1.8 mmol/L—see Overview of Cholesterol and Lipid Disorders). However, the percentage of HDL cholesterol in relation to total cholesterol is a more reliable measure of risk than is the total or LDL cholesterol level. HDL cholesterol should account for more than 25% of total cholesterol. High triglyceride levels are often associated with low HDL cholesterol levels. However, evidence suggests that high triglyceride levels alone may also slightly increase the risk of atherosclerosis.

High blood pressure

Uncontrolled high diastolic or systolic blood pressure is a risk factor for heart attack and stroke, which are caused by atherosclerosis. The risk of cardiovascular disease starts increasing when blood pressure levels are above 110/75 mm Hg. Reducing high blood pressure clearly lowers risk. Doctors usually try to achieve a blood pressure of less than 140/90 mm Hg, and often less than 130/80 mm Hg in people with diabetes or kidney disease.

Diabetes mellitus

People who have type 1 diabetes (see Diabetes Mellitus) tend to develop disease that affects small arteries, such as those in the eyes, nerves, and kidneys, leading to vision loss, nerve damage, and kidney failure. Some people with type 1 diabetes and most people with type 2 diabetes tend to develop atherosclerosis in large arteries. These people also tend to develop atherosclerosis at an earlier age and more extensively than do people who do not have diabetes. The risk of developing atherosclerosis is 2 to 6 times higher for people with diabetes, particularly women. Women who have diabetes, unlike those who do not, are not protected from atherosclerosis before menopause. People who have diabetes have the same risk of death as someone who has had a prior heart attack, and doctors usually try to help these people keep other risk factors (such as high cholesterol levels and high blood pressure) under careful control.

Obesity

Obesity, particularly abdominal (truncal) obesity, increases the risk of coronary artery disease (atherosclerosis of the arteries that supply blood to the heart). Abdominal obesity increases the risk of other risk factors for atherosclerosis: high blood pressure, type 2 diabetes, and high cholesterol levels. Losing weight reduces the risk of all these disorders.

Physical inactivity

Physical inactivity appears to increase the risk of developing coronary artery disease, and much evidence suggests that regular exercise even to a moderate degree reduces this risk and decreases mortality. Exercise can also help modify other risk factors for atherosclerosis—by lowering blood pressure and cholesterol levels and by helping with weight loss and decreasing insulin resistance.

Diet

There is substantial evidence that regular vegetable and fruit consumption can decrease coronary artery disease risk. It is unclear whether fruits and vegetables appear beneficial due to the substances (phytochemicals) they contain, or whether people who eat a lot of fruits and vegetables also eat less saturated fat and are more likely to take fiber and vitamins. However, phytochemicals called flavonoids (in red and purple grapes, red wine, black teas, and dark beers) appear especially protective. High concentrations in red wine may help explain why the French have a relatively low incidence of coronary artery disease, even though they use more tobacco and consume more fat than Americans do. But no studies prove that eating flavonoid-rich foods or using supplements instead of foods prevents atherosclerosis. Increased fiber content in certain vegetables may decrease total cholesterol and may decrease blood glucose and insulin levels. However, excessive fiber interferes with the absorption of certain minerals and vitamins. In general, foods rich in phytochemicals and vitamins are also rich in fiber.

Fat is an essential part of the diet. The notion that eating less fat is important to a healthy diet is only partly true because the type of fat also matters. The main types of fats are

  • Saturated and trans fats

  • Unsaturated fats (polyunsaturated and monounsaturated—see Types of Fat)

Fats may be soft (or liquid) or firm at room temperature. Soft fats, such as oils and some margarines, tend to be higher in polyunsaturated and monounsaturated fats. Hard fats, such as butter and shortening, tend to be higher in saturated and trans fats. Saturated and trans fats are more likely to cause atherosclerosis. Thus, whenever possible, people should limit the amount of saturated and trans fats in their diet and choose foods with monounsaturated or polyunsaturated fats instead. Saturated and trans fats are found in red meat, many fast food and junk food items, full-fat dairy products (such as cheese, butter, and cream), and hard (stick) margarines. Monounsaturated fats are found in canola and olive oil, soft margarines with no trans fat, nuts, and olives. Polyunsaturated fats are found in nuts, seeds, oils, and mayonnaise.

Two types of polyunsaturated fats—omega-3 and omega-6 fats—are essential to a healthy diet. Omega-3 fats are found in fatty fish such as salmon, omega-3 eggs, canola oil, and walnuts. Omega-6 fats are found in some nuts and seeds and in safflower, sunflower, and corn oils.

Eating a healthy diet can help decrease the risk of atherosclerosis. However, it is less clear whether supplementing the diet with vitamins, phytochemicals, trace minerals, or coenzyme Q10 also helps reduce the risk.

Alcohol intake

People who drink a moderate amount of alcohol seem to have a lower risk of coronary artery disease than do people who drink too much or do not drink at all. Alcohol increases the level of HDL cholesterol (good cholesterol) and it also decreases the risk of blood clots and inflammation and helps protect the body from the by-products of cell activity. However, more than moderate alcohol consumption (more than 14 drinks per week for men and more than 9 drinks per week for women) can cause significant health problems and increase the risk of death. People who drink greater amounts of alcohol should cut back. However, people who do not drink alcohol should not start.

High blood levels of homocysteine (hyperhomocysteinemia)

People who have very high levels of homocysteine (an amino acid) in their blood, usually because of a hereditary disorder, have an increased risk of coronary artery disease, usually at a young age. High levels of homocysteine may directly injure the lining of arteries, making the formation of plaques more likely. High homocysteine levels may also promote the formation of blood clots. However, giving people drugs that lower homocysteine levels does not seem to reduce risk of death.

Symptoms

Symptoms depend on where the affected artery is located and whether it is gradually narrowed or suddenly blocked.

With gradual narrowing, atherosclerosis usually does not cause symptoms until the interior of an artery is narrowed by more than 70%. The first symptom of a narrowed artery may be pain or cramps at times when blood flow cannot keep up with the tissues’ need for oxygen. For instance, during exercise, a person may feel chest pain or discomfort because the oxygen supply to the heart is inadequate. This chest pain (angina) goes away within minutes after the person stops exertion. While walking, a person may feel leg cramps (intermittent claudication—see Peripheral Arterial Disease:Arteries of the Legs and Arms) because the oxygen supply to the leg muscles is inadequate. If the arteries supplying one or both kidneys become narrowed, kidney failure or dangerously high blood pressure can result.

If the arteries supplying the heart (coronary arteries) are blocked suddenly, a heart attack can result. Blockage in the arteries supplying the brain can cause a stroke. Blockage of the arteries in the legs can cause gangrene of a toe, foot, or leg.

Diagnosis

People who have symptoms that suggest a blocked artery have tests to look for the location and extent of the blockage. Different tests are used depending on what organ seems to be involved. For example, if doctors suspect blockage of an artery in the heart, they typically do electrocardiography (ECG), blood tests for substances (cardiac markers) that indicate heart damage, and sometimes a stress test or heart catheterization (see Acute Coronary Syndromes (Heart Attack).

People with atherosclerotic arteries in one organ often have atherosclerosis in other arteries. Therefore, when doctors find atherosclerotic blockage in one artery, for example in the leg, they usually do tests to look for blockage in other arteries, such as those in the heart. Doctors also test for certain risk factors in people who have an atherosclerotic blockage. For example, they measure the levels of glucose, cholesterol, and triglycerides in the blood after the person has fasted. Doctors usually also do these tests as part of the routine yearly examination in adults.

Because some plaques in arteries are more likely to break open and trigger a clot than others, doctors sometimes do tests to look for such dangerous plaques. No test is definitive, but doctors are using computed tomography (CT) angiography, intravscular ultrasonography (which uses an ultrasound probe on the tip of a catheter placed inside of an artery) during heart catheterization and coronary angiography, and a number of other imaging tests and blood tests.

Some doctors recommend tests to look for atherosclerotic blockage in people who have risk factors but no symptoms as part of a prevention strategy. Such tests include an electron beam CT or magnetic resonance imaging (MRI) of the heart and ultrasonography of the arteries in the neck (carotid arteries). Electron beam CT and MRI can detect hardened (calcified) plaque in the coronary arteries. Ultrasonography of the carotid arteries can detect thickening of the artery wall, which suggests atherosclerosis. However, many doctors think that these tests rarely change the advice they would give based on the person‘s other, more easily recognized, risk factors.

Prevention and Treatment

To help prevent atherosclerosis, people need to stop tobacco use (see Coronary Artery Disease:Smoking), lower LDL cholesterol levels (see Desirable Lipid Levels in Adults), lower blood pressure (see High Blood Pressure:Drug therapy), lose weight (see Obesity and the Metabolic Syndrome), and exercise (see Starting an Exercise Program). People who have diabetes must maintain strict control of their blood sugar (glucose).

People who are at high risk for atherosclerosis also may benefit from taking certain drugs. Helpful drugs include the statins (even if cholesterol levels are normal or only slightly high) and aspirin or other antiplatelet drugs (see Pain:Aspirin).

Some drugs used to treat high blood pressure and some drugs used to treat diabetes also help reduce risk of atherosclerosis.

When atherosclerosis becomes severe enough to cause complications, the complications themselves must be treated. Complications include

  • Angina

  • Heart attack

  • Abnormal heart rhythms

  • Heart failure

  • Kidney failure

  • Stroke

  • Leg cramps (intermittent claudication)

  • Gangrene

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