Biomarkers Under Investigation - Recognizing And Reducing Risk Factors: Heart Disease

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Biomarkers under investigation

As researchers have learned more about how coronary artery disease develops, they have also searched for early biological signs in the blood — known as biomarkers — that can better define who is at risk.

Scientists are currently investigating dozens of possible biomarkers for coronary artery disease, but for most of them, it still isn't clear what level puts you at risk or whether controlling your levels will help prevent heart disease. As science has progressed, some previously suspected culprits — such as the bacterium Chlamydia pneumoniae — have now fallen out of contention. Other biomarkers have emerged, such as myeloperoxidase (MPO), a marker of inflammation that may be useful in evaluating unstable angina that has not yet produced a full-blown heart attack. Many of these biomarkers look interesting, but levels vary so widely among people that it is hard to determine whether they indicate a risk. Currently the evidence is strong that elevated levels of four biomarkers represent an increased risk for heart disease: C-reactive protein, fibrinogen, homocysteine, and lipoprotein(a).

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 CRP test is in order to better assess your risk and decide how to reduce it.

Dealing with high CRP. A high CRP isn't a disease. Think of it as a symptom, like a fever, that signals that something is amiss and needs tending. Fortunately it is possible to reduce your CRP levels by following the same advice recommended for general cardiovascular health: Lose weight, stop smoking, and exercise regularly. If you have a high CRP and you have other risk factors for heart disease, your doctor may suggest that you take a daily aspirin, since this drug offers the greatest protection against heart attack in people with high CRP. A statin may also be in order, even if your cholesterol is in the normal range. These drugs can cool inflammation and stabilize plaque. Studies are currently under way to better understand how to lower CRP in a way that improves health outcomes.

Fibrinogen

Fibrinogen is a blood protein that's crucial to the clotting process and, as such, is essential to health. Because in many cases blood clotting is the final event that blocks the coronary arteries, it's not surprising that studies have implicated elevated fibrinogen levels as a cardiac risk factor. However, fibrinogen levels also increase as a result of inflammation, just as CRP levels do. So it remains unclear whether fibrinogen actually promotes coronary artery disease or simply indicates that blood vessel damage has already taken place for some other reason. Currently fibrinogen levels aren't routinely measured. First of all, a variety of tests exist, but not all are reliable, and there is no agreed-upon standard for how to measure fibrinogen in the most commonly used tests. Second, there's no medical treatment to reduce high fibrinogen levels. In some cases, however, regular exercise and weight loss can lower fibrinogen levels. Other preventive interventions that inhibit excessive blood clotting include low-dose aspirin, low alcohol intake, and ample fish in your diet.

Homocysteine

Homocysteine is a highly reactive amino acid that first came to the attention of heart researchers in the 1960s and 1970s, when studies revealed that about half of the people born with genetic disorders that resulted in very high blood levels of homocysteine developed blood vessel clots by the time they were 30. This raised the question of whether elevated homocysteine might also pose a cardiac risk to other people.

Since 1984, dozens of studies have reported a link between high levels of homocysteine and severe atherosclerosis involving arteries of the heart, brain, or legs. Although details vary, most studies show a dose-response relationship: The higher the homocysteine levels, the greater the risk of developing coronary artery disease.

It appears that excessive concentrations of homocysteine in the blood may harm an artery by damaging the endothelial cells that line its inner layer or by stimulating abnormal growth of smooth muscle cells in its middle layer, either of which could contribute to coronary artery disease. Homocysteine may also activate the clotting system, thereby promoting formation of the clots that serve as the immediate trigger for most heart attacks.

But here's the rub: It has not yet been proved that testing people for homocysteine and decreasing their levels will actually reduce their risk for coronary artery disease. That's why a blood test that measures homocysteine levels is not recommended for routine heart disease screening. Although researchers consider a healthy homocysteine level to be about 12 µmol/L, they don't know whether reducing those levels would actually lower the risk for atherosclerosis.

Many studies reveal that people with high homocysteine levels are deficient in the B vitamins: folic acid, B₆, and B₁₂. Vitamin supplements can reduce homocysteine levels within weeks. Until research provides more specific recommendations, a reasonable approach to take — regardless of whether you have had homocysteine screening — is to take a multivitamin each day and do your best to control other heart disease risk factors. If you do get tested and have a high homocysteine level, your doctor may recommend that you take a bit more folic acid and B₁₂ than the amounts found in many multivitamin pills.

Lipoprotein(a)

Lipoprotein(a) is a type of lipid that is similar in structure to LDL ("bad") cholesterol. Studies indicate that it may damage blood vessel walls and help promote the formation of blood clots, thereby contributing to heart disease. An analysis of more than two dozen studies has shown that people with the highest blood levels of lipoprotein(a) are about 1.5 times as likely to develop atherosclerosis as those with the lowest levels. The risk is especially pronounced in people who have other risk factors, such as high LDL or diabetes.

But while the scientific evidence indicates lipoprotein(a) may be a viable biomarker for heart disease, in practical terms it is not yet of much use. There is currently no standardized way to test and measure blood levels of lipoprotein(a). And even if there were, there is not much you can do to lower your level of this substance. Blood levels of lipoprotein(a) are mostly determined by genes — not by what you eat or how often you exercise. And most medications used to treat high cholesterol do not affect levels of lipoprotein(a), although there is some evidence that niacin may lower it a small amount. For now, at least, this biomarker is more of interest to scientists trying to understand the process of coronary artery disease than to people trying to prevent it.

Last updated:	May 03, 2007