Stage 1: Abnormalities in blood cholesterol

Cholesterol belongs to the class of chemicals known as lipids. Cholesterol performs a number of vital functions in your body: It helps maintain cell membranes, is the backbone for the bile acids that are essential for digestion, and is an important precursor to vitamin D and a number of hormones. In fact, this substance is so important that the body can produce its own supply from raw materials such as fat, glucose, and protein when diet alone does not supply enough. The health problems begin when blood levels of cholesterol become abnormal, initiating the first event in the coronary cascade.

Cholesterol travels in the bloodstream within spherical particles called lipoproteins. There are five major classes of lipoproteins: chylomicrons (the largest and least dense), very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL, the smallest, heaviest, and least fatty).

On average, about two-thirds of blood cholesterol is in the form of LDL. The higher the level of LDL cholesterol, the greater the risk for atherosclerosis, coronary artery disease, and heart attack. That's because excess LDL cholesterol leaves the blood and lodges in the artery walls, initiating the inflammatory response that is central to coronary artery disease.

Where a villain lurks, a hero can often be found. When it comes to cholesterol, HDL is the hero. Whereas LDL deposits cholesterol in the blood vessel walls, HDL carries cholesterol away from the arteries to the liver, where it's metabolized into bile salts that are eliminated harmlessly from the body via the intestinal tract.

Stage 2: Changes in the artery wall

Once LDL penetrates the artery walls, the next step in the coronary cascade begins. Every artery wall has three layers; two are involved in atherosclerosis.

The inner layer, or intima, consists of a delicate layer of cells known as endothelial cells. Normally the endothelial cells secrete many molecules that keep blood flowing smoothly and keep just the right amount of flow headed to tissue downstream. These cells produce nitric oxide, a tiny molecule that widens the artery to allow more blood to pass through. Nitric oxide also helps keep the artery's inner lining smooth and slippery so that white blood cells and platelets, the fragmentary blood cells that initiate the clotting process, can't latch on. Endothelial cells also produce substances like endothelin, a chemical that narrows arteries, to adjust blood flow.

The middle layer of the artery wall, or the media, is where the cholesterol-laden deposits of atherosclerosis develop. Composed chiefly of smooth muscle cells, the media can increase or restrict the flow of blood in an artery. When the cells of the media relax, the artery widens. When those cells contract, the artery narrows. Nitric oxide and endothelin are among the messengers that tell the smooth muscle cells to relax or constrict. But when the arterial wall is injured by cholesterol, the smooth muscle cells enlarge, contributing to the development of plaque.

Stage 3: Adding inflammation to injury

Although endothelial cells play a role in keeping arteries healthy, they can't prevent LDL cholesterol from passing out of the blood and into the artery wall. Making matters worse, any injury to the endothelial layer (caused by high blood pressure, smoking, or diabetes, for example) speeds this process. Once in the arterial wall, the LDL triggers a harmful sequence of events.

After the LDL particles lodge in the artery wall, inflammation and injury result. Injured endothelial cells can't produce nitric oxide normally. They also send out distress signals, in the form of cytokines, which draw white blood cells to the scene. These cells, called monocytes and macrophages, gobble up the LDL cholesterol in the artery wall. In the process, they enlarge and transform into fat-laden foam cells.

The foam cells can't dispose of all the toxic LDL. Instead, the LDL injures the foam cells that ingest it, and many die, releasing a soft, fatty gruel that causes advanced atherosclerosis and provokes further inflammation. In an apparent attempt to seal off the inflammation, smooth muscle cells in the artery wall enlarge and proliferate, forming a fibrous cap over the whole mess and adding to the bulk of the plaque.

Stage 4: Pulling the trigger

Large plaques, of course, can block blood flow more than small plaques, but some smaller plaques can be the most dangerous. This is because atherosclerotic plaques are not just passive plugs that block arteries like a cork in a bottle. They are active, dynamic lesions teeming with inflammatory T cells (another type of white blood cell) and macrophages, as well as cholesterol. Large plaques tend to be covered by thick, fibrous caps that can resist breaking apart even though they are holding a fatty core in place. Smaller plaques sometimes have very thin, underdeveloped fibrous caps that rupture easily and start blood clotting, even though the plaque itself is too small to block blood flow.

About three-quarters of all heart attacks result when plaques rupture. This occurs after a two-pronged attack on collagen that degrades the fibrous cap until it breaks. First T cells tell smooth muscle cells in the fibrous caps to stop producing collagen, and then macrophages produce enzymes that degrade collagen.

Stage 5: The final insult

Once a plaque ruptures, the T cells send a signal that provokes the macrophages to release a protein called tissue factor. As tissue factor spills out and encounters circulating blood, it attracts platelets. The platelets adhere to the surface of the disrupted plaque. Once activated, the platelets trigger an interaction of the blood proteins that help create clots. The result is a thrombus — a clot of red blood cells, platelets, and other material — that completes the blockage (see Figure 5) and prevents blood from reaching the heart cells downstream. Deprived of blood and oxygen, a portion of the heart muscle dies.

Age

Heart disease becomes more prevalent with age in both men and women. Simply put, older people have more heart attacks than younger people do. More than four in five people who die from heart attacks are over age 65. Men over age 45 and women over age 55 are most at risk of having a heart attack.

Sex

Although heart disease remains the leading killer of both American women and men, there are significant differences between the sexes when it comes to symptoms and prognosis. On the other hand, the death rate from heart disease has declined for both men and women because more people are taking preventive measures, such as avoiding smoking and cutting saturated and trans fats from their diets.

Men are more at risk. Men are more likely than women to develop coronary artery disease, and usually at younger ages. After age 40, half of all men can expect to develop coronary artery disease, compared with one-third of all women. Moreover, the average age for a first heart attack in men is 65; for women, it is 70.

The prevailing wisdom for a long time has been that hormones explain much of this disparity. Estrogen appears to provide some heart-protective benefits to women until menopause, and researchers have long suspected that male hormones may contribute to heart disease in various ways. After all, athletes who abuse testosterone and other male hormones have a clearly increased risk for high blood pressure, heart attack, and stroke.

Yet studies examining testosterone's effects on the heart have produced mixed results. So the jury is still out when it comes to testosterone (not only in terms of its impact on the heart, but also on muscles, bones, and the prostate). It will take time for scientists to sort out the answers. In the meantime, men can reduce their risk by eliminating some of the bad habits that increase risk for heart disease.

Women have poorer outcomes. Women tend to develop heart disease 10 years later than men, probably because of the protective effects of estrogen. This hormone not only helps regulate the monthly menstrual cycle, but also has a beneficial effect on blood cholesterol levels, by raising HDL (good) cholesterol and lowering LDL (bad) cholesterol.

But when estrogen declines at menopause, so do its protective effects, causing a sharp increase in the risk for heart disease. Women who have gone through menopause are two to three times as likely to develop heart disease as women the same age who are still menstruating. For that reason, for many years doctors recommended hormone replacement therapy (HRT) to women who were entering menopause. But in 2002 and 2004, the heart-protective benefits of HRT came under fire when two major studies funded by the Women's Health Initiative found that HRT does not prevent heart disease, and in some cases increases the risk for heart attack. The consensus now is that hormone therapy should not be used to prevent heart disease in women. (For more details, see "Hormone replacement therapy.")

Women also differ from men in terms of cardiac health outcomes. Although women tend to be better than men at describing medical symptoms and seeking help, women have a 50% greater chance of dying from heart disease than men do. About 38% of women who've had heart attacks die within a year, compared with 25% of men. What's more, women are almost twice as likely as men to have a second heart attack within six years of the first. Women are also more likely to die in the hospital after coronary artery bypass surgery or angioplasty.

It is not clear why these disparities exist. A leading theory is that women are more likely to die because they tend to develop heart disease and have heart attacks later than men do. Another problem is anatomy: Women's hearts tend to be smaller than men's, making it more difficult for surgeons to stitch arteries together during surgery or keep them open after angioplasty. Women also are more likely than men to have coexisting chronic diseases, such as diabetes, by the time they undergo heart surgery.

However, some research has found that women may not be diagnosed as early or treated as aggressively as men. For instance, women who are having the symptoms of a heart attack are less likely than men to be admitted to the intensive- or cardiac-care unit and to get electrocardiograms, clot-busting drugs, or cardiac catheterization. After discharge from the hospital, they are less likely to be directed to a cardiac rehabilitation program (or to finish one), or to get counseling about nutrition, exercise, and weight loss.

The classic symptoms of a heart attack were identified largely in studies of white, middle-aged men; these symptoms do not always occur in women, which may contribute to delays in diagnosis and treatment. For instance, a 2003 paper that sought to better define heart attack symptoms reported that an astounding 43% of women who had heart attacks did not recall any type of chest pain, usually considered the hallmark symptom. Instead, the women reported shortness of breath, weakness, unusual fatigue, cold sweat, and dizziness.

What should you do if you're a woman? Perhaps most important, focus on steps you can take to prevent heart disease, and take medications if necessary to lower blood pressure and cholesterol (see "Medications for heart disease"). Second, learn more about what types of symptoms indicate you may be having a heart attack (see Table 9).

Family history and ethnicity

Coronary artery disease runs in families, and certain ethnic groups are more at risk than others. African Americans, Mexican Americans, Native Americans, and native Hawaiians, for instance, are all more likely than white people of European descent to develop heart disease. But are certain families and ethnic groups more at risk because of shared lifestyles such as smoking, diet, inactivity, or stress? Or does this situation reflect genetics, which may underlie risk factors such as high cholesterol, blood pressure, and blood sugar? The answer is both.

The genes an individual inherits are certainly important. Multiple epidemiologic studies have shown that people with a parent who developed coronary artery disease before age 55 are significantly more at risk than others for developing heart disease themselves. How great is the risk? Estimates vary, but this type of family history is clearly on a par with other major risk factors such as high blood pressure and cholesterol.

However, it's important to keep two things in mind. First, not every family history is equally worrisome; it takes a strong history (for example, a father or brother afflicted before age 55 or a mother or sister stricken before age 65) to increase your risk. Second, genetic research into heart disease remains in its infancy and many questions remain, particularly about what genes are most important in making people susceptible to heart disease and how these genes interact with other genes and environmental factors to increase or decrease risk.

Many studies are now under way to better understand the genetics of heart disease. The hope is that genetic testing will one day enable doctors to identify people at high risk for heart problems and perhaps help them avoid those problems with preventive treatment. In the meantime, if you have a family history of heart disease, it's vital for you to address risk factors like high blood pressure and elevated cholesterol, and adopt a heart-healthy lifestyle in your youth.

Total cholesterol

This number is the sum of cholesterol carried in all cholesterol-bearing particles in the blood, including HDL, LDL, and VLDL. Although the total cholesterol level closely parallels the LDL level in most people, there are enough exceptions to that rule to make it useful to test separately for LDL, HDL, and triglycerides. The NCEP guidelines advise aiming for a total cholesterol level below 200 mg/dL.

LDL

No specific cholesterol level guarantees that you will, or won't, develop heart disease. However, LDL is clearly the most significant of the blood lipids in terms of raising your risk for heart disease, so lowering elevated LDL should be the primary target of therapy. In making its July 2004 recommendations, the NCEP cited data from clinical studies that indicate that, for every 1% reduction in LDL levels, there is a corresponding 1% decrease in the chance of being stricken with a heart attack, stroke, or some other type of cardiac event. This is significant given that the proper combination of lifestyle changes and heart medications can help lower LDL levels by 30%–40% in many people at risk for heart disease (and in some people, lower it even further), creating a corresponding drop in cardiac events.

So how low do you go? One series of studies changed the thinking in this area. In a nutshell, if you have had a heart attack or are at very high risk of having one, the answer is lower than before, and probably as low as possible (see "The lower the cholesterol, the better," below). Your particular LDL target depends on your cardiovascular health and your odds of having a heart attack in the next 10 years (see Table 6 or 7 to calculate your own heart attack risk). Levels range from below 70 mg/dL or lower for those at very high risk to less than 160 mg/dL for people at lowest overall risk.

You can lower LDL levels by reducing the amount of saturated fat, trans fat, and cholesterol in your diet; eating more complex carbohydrates, such as fruits and vegetables; eating more fiber; reducing body fat; and exercising regularly (see "Lifestyle changes to protect yourself"). When these good habits aren't sufficient to reach your cholesterol goal, cholesterol-lowering medications are recommended.

HDL

The more HDL in your bloodstream, the lower your chances of having a heart attack. Studies from the Framingham Heart Study and elsewhere suggest that every one-point rise in HDL results in a 2%–3% reduction in the risk for heart attack. The NCEP guidelines consider levels of 60 mg/dL or above protective against heart disease, while levels of less than 40 mg/dL are regarded as too low and increase your risk. However, some clinicians use the ratio of total cholesterol to HDL cholesterol to help identify people who need cholesterol-lowering therapy. The less HDL you have relative to total cholesterol, the greater your risk for heart disease. To boost your HDL, your best bets are to lose weight, eat well, engage in more physical activity, and stop smoking.

Triglycerides

The main form of stored fat — both in the food we eat and in the body's adipose (fat) tissue — is triglycerides. The chylomicron, the largest and least dense of the lipoprotein particles, carries most of the triglycerides in the bloodstream. In general, triglyceride levels have less of an impact on heart disease risk than LDL or HDL levels. However, when triglyceride levels are very high, risk for heart disease does increase. Often people with low HDL cholesterol levels also have high triglycerides, and this combination seems an especially important predictor of heart disease risk.

The NCEP guidelines define normal triglyceride levels as below 150 mg/dL. High triglyceride levels can result from obesity, physical inactivity, cigarette smoking, alcohol abuse, uncontrolled diabetes, and even certain medications, as well as some genetic disorders. Often, triglycerides can be lowered using the same steps that help bring down LDL cholesterol: eating a healthier diet, exercising more often, losing weight, and, if necessary, taking medications to lower LDL, triglycerides, or both.

Updated blood pressure goals

Given the evidence, the JNC7 guidelines not only redefined normal (meaning "optimal") blood pressure as anything under 120/80 mm Hg, but also introduced a new category, prehypertension, to identify people who might prevent or at least slow the onset of hypertension by adopting a healthier lifestyle (see Table 3).

So who is at risk? Almost everyone will be at some point. About 60% of American adults currently have high blood pressure (either prehypertension or hypertension). And data from the Framingham Heart Study indicate that people who are 55 years old and have normal blood pressure face a 90% chance of developing high blood pressure as they get older, unless they take preventive steps.

When to be tested. Because hypertension usually begins gradually between ages 20 and 50, all adults should have their blood pressure checked regularly. Blood pressure checks every two years might suffice for people with normal levels. But people with elevated blood pressure need more frequent measurement — once a year for those with prehypertension, and sometimes even more frequently in people with hypertension.

How low to go. For people with hypertension, JNC7 defines good control as getting your blood pressure under 140/90 mm Hg. But people with diabetes or chronic kidney disease should aim for an even lower level, below 130/80 mm Hg.

To prevent or treat hypertension, the first step is to adopt healthier habits (see "Lifestyle changes to protect yourself"). Even with lifestyle changes, however, many people with hypertension also need medications to treat the disorder (see "Blood pressure medications").

C-reactive protein

C-reactive protein (CRP) is a by-product of inflammation that shows up in a simple yet highly sensitive blood test. Although the protein's exact function is still something of a mystery, doctors have used it for years to monitor diseases such as pneumonia, rheumatoid arthritis, and lupus. After researchers realized that inflammation is central to the development of coronary artery disease, they began taking a closer look at how small but persistent elevations in CRP levels might be used to predict the risk for heart attacks.

A number of major epidemiologic studies report that as CRP level rises, so does the risk of having, or dying from, a heart attack, stroke, or other cardiovascular problem. These studies have consistently shown that people with the highest C-reactive protein levels are about twice as likely to develop coronary artery disease and suffer a heart attack or other cardiac event as people with the lowest levels. (The studies included men and women of various ages, but mostly involved white people of European descent; it is not yet clear if the data apply to all ethnic and racial groups.) The evidence is so strong, in fact, that CRP is now widely accepted as an independent risk factor for heart disease that can be considered in addition to more established risk factors such as abnormal cholesterol and high blood pressure.

There is an important caveat to keep in mind, however. No one knows whether lowering CRP levels actually reduces the risk of having a heart attack, stroke, or dying from heart disease. This may seem puzzling, given the strong evidence that CRP levels can be used to assess risk. But it is not clear whether the protein actually contributes to the coronary cascade (see "The coronary cascade") or is merely a sign that cardiovascular damage has already taken place. And if CRP is just a marker or stand-in for one of the real culprits behind heart disease, then taking steps to lower it could be like treating measles by covering the rash with makeup.

Studies are now under way to determine whether lowering CRP actually helps long-term health outcomes and, if so, what type of treatment to recommend and when to initiate it. Two studies reported in January 2005 provided at least part of the answer: Both found that using statins to lower cholesterol levels in people with heart disease reduced the risk of having a heart attack or other cardiac event. But as they lowered cholesterol levels, the statins also reduced CRP levels; for a given cholesterol level, people with the lowest CRP enjoyed the greatest protection. Although the reports sparked a spirited debate over whether it was time to call for routine testing and treatment of elevated CRP — as is currently the case for cholesterol — it remains unclear whether people who are healthy or at low or moderate risk for heart disease would benefit from such testing and treatment.

Should you be tested? An expert panel convened by the Centers for Disease Control and Prevention and the American Heart Association released updated recommendations about CRP testing in 2004. The experts do not yet recommend widespread screening for elevated CRP, because it is not yet clear what CRP target levels should be for healthy men and women of different ages and ethnic groups. Moreover, most coronary artery disease develops as a result of the more conventional risk factors, which are much better understood than CRP.

Even so, the experts decided that CRP testing may provide a way to identify individuals who might benefit from a more aggressive effort to prevent or treat heart disease. Risk assessment is based on three levels of CRP (see Table 5). So what should you do?

If you are already being treated for heart disease or are considered at high risk for a heart attack (more than 20% in the next 10 years, based on the calculations in Table 6 or 7), a CRP test is not necessary. The results won't change how you and your doctor manage your condition (see "Dealing with high CRP," below).

If you have a moderate risk of having a heart attack (10%–20% in the next 10 years), ask your doctor whether he or she recommends a CRP test. Studies indicate that people at moderate risk based on the conventional risk factors might move into the high-risk category if they also have elevated CRP. Such people might need more aggressive treatment to prevent a heart attack. In particular, your doctor may recommend a lower LDL goal — under 100 mg/dL rather than under 130 mg/dL.

If your cholesterol levels are fine but you have other risk factors (such as diabetes, high blood pressure, or a family history of heart disease), ask your doctor whether a