Getting a Handle on Heart Disease

How do you know if you're at risk for a heart attack? When it comes to risk factors, the "big four"-high cholesterol, high blood pressure, smoking, and diabetes-pose the greatest threat to heart health. Add two major contributing factors-obesity and lack of exercise-and most of us have some warning if we're in the danger zone.

But some people fall through the cracks of traditional testing methods-say, someone who is healthy and fit but whose father or mother died of heart disease, or someone who has marginally high cholesterol or triglycerides but no other obvious risk factors (see "Who's at Risk for Heart Disease?" page 4). And despite the fact that the blood cholesterol test has remained the "gold standard" of heart-disease risk testing for three decades, an estimated 50 percent of all people who suffer a heart attack have normal or near-normal cholesterol. This has prompted researchers to look past traditional cholesterol testing to other blood tests that could pinpoint heart disease in its earliest, most treatable stages, before signs of disease become apparent.

They haven't yet found one such test that completely fills the bill. But there are several in the works that might give doctors a more comprehensive picture of their patients' heart health, which may, in turn, lead them to consider options such as changes in diet and exercise, drug therapy, or more aggressive tests. Several of these blood tests analyze the fats and proteins that make up "bad" LDL-cholesterol, zooming in on the molecules' makeup to see if they fit particular patterns. Others look for substances that may be byproducts of a poorly running circulatory system.

Of course, nobody's calling for an end to routine cholesterol testing. But advocates of several of these tests feel that they would make good additions to what's already available-thus giving physicians more information that can help head off artery damage before it turns deadly. With this in mind, we took a look at some of these tests, keeping an eye out for what's available right now-and what may be "coming down the road."

An accumulating body of evidence suggests that high blood levels of homocysteine, an amino acid released into the blood from body tissues, may greatly increase the risk of heart disease. Scientists aren't sure, but they suspect that excess homocysteine may damage the lining of blood vessels or trigger the growth of cells that form the framework of fatty deposits, or plaque, that builds up on artery walls. It may also hasten artery damage by promoting the breakdown of "bad" LDL-cholesterol within the plaque, adding to the progressive damage that results in hardening of the arteries. (And it may affect more than just the arteries of the heart: some studies suggest that high homocysteine may be associated with the vascular problems that increase the risk of Alzheimer's disease.)

But the exact connection between homocysteine and diseased arteries has been hard to pin down. Some re-searchers speculate that high homocysteine may not be the cause of artery damage, but instead the result of damage already done. If this is the case, then lowering homocysteine levels in the blood won't actually reduce a person's risk of heart disease.

Given the uncertainty, doctors are divided on whether they should routinely test for homocysteine. Those in favor of testing say that the test is relatively inexpensive (as is the treatment for high homocysteine levels-getting more B vitamins). And testing may provide more information about the state of their patients' heart health than they can get from cholesterol testing alone. But there are currently no professional guidelines that outline the cases in which the test should be obtained, so it's left to individual physicians to decide. Robert H. Eckel, MD, a professor of medicine at the University of Colorado Health Sciences Center, admits that he hasn't fully determined when to test for homocysteine, although he says, "I find myself measuring it more frequently all the time."

The cost of a homocysteine test varies from lab to lab, but usually runs somewhere between $25 and $50. Some insurance companies and HMOs will cover the cost of the test when ordered by a physician. Values will vary with each lab doing the testing, but generally a high reading (and the cut-off point used in research studies) is anything above 12 micromoles per liter of blood.

High-Sensitivity C-Reactive Protein (hs-CRP or cardio-CRP)
This test measures levels of a protein called C-reactive protein (CRP) that is produced by the liver in response to inflammation somewhere in the body-important because scientists believe that hardening of the arteries is an inflammatory process. In theory, arteries damaged by plaque buildup would trigger a rise in the level of CRP in the bloodstream.

The hs-CRP has generated some significant buzz among scientists in recent months, especially since studies published in two prestigious medical journals showed that it was able to predict heart disease in people with normal and near-normal cholesterol levels. And the American Heart Association says that it has the potential to be a new marker of coronary artery disease risk, although more studies are needed before it could ever be part of a routine risk assessment.

It's not yet clear who would get the most out of the hs-CRP test. Harvard researcher Paul Ridker, MD, who helped to develop it, feels that the test is best used in the setting of primary care, where health screening might include both cholesterol and hs-CRP tests, because they measure different things. Cholesterol tests indicate the level of risk that fatty deposits are contributing to plaque buildup in the arteries. On the other hand, the hs-CRP, because it measures inflammation, can tell doctors how likely any existing plaque is to rupture-the 'flash point' that triggers a heart attack.

Others, including Tufts scientist Ernst Schaefer, MD, believe that testing for the presence of CRP may prove to be useful, but for smaller groups of people. It might, for instance, help doctors to gauge the amount of inflammation in the arteries of someone who's already being treated for heart disease or has evidence of vascular disease elsewhere, in order to assess how aggressive they should be with risk factor modification.

The hs-CRP test is relatively inexpensive (about $50) and has been cleared by the FDA for use in the diagnosis of heart disease for more than a year; some insurance companies and HMOs will cover the cost. If you plan to discuss with your physician whether or not you'd be a good candidate for this test, it's important to make sure you're getting the "high-sensitivity" or "hs" version. (There's an older test, called simply the "CRP," that doesn't measure levels of the protein as precisely as the high-sensitivity one.) Labs will vary slightly in what they consider "normal," but the lab we consulted for this story considers an hs-CRP reading lower than 2 milligrams per liter as normal. A higher number would indicate the need for further testing.

Small Particle LDL
Garden-variety cholesterol tests just reveal the total amounts of different cholesterol particles in the blood. But doctors at the Berkeley Heart Lab, a commercial blood testing lab in California, say that knowing the size of the particles is important, too. Cholesterol and fat particles are trans-ported through the bloodstream bound to proteins-the whole "package" is called a lipoprotein. These vary in composition, as with "good" HDL-cholesterol and "bad" LDL-cholesterol. But each type also varies in size-and with LDL-cholesterol, the range of sizes affects how they're handled by the body. So the best informed individuals, the Berkeley Heart Lab doctors say, are the ones armed with the knowledge of exactly how much of each different size of LDL-cholesterol is floating in their bloodstream.

They've developed a test called "LDL segmented gradient gel electrophoresis" that provides this information. To do the test, clinicians run a mild electrical current through a blood sample. This causes the cholesterol particles to sort themselves by size and by weight-smaller, lighter particles rise to the top, while larger, heavier particles sink to the bottom. (The eventual reading looks something like a line graph on a strip of paper.)

What the doctors are looking for, specifically, is a pattern toward large numbers of very small LDL-cholesterol particles, which some research suggests may be even more unhealthful than "regular size" LDL. About 30 percent of the American public tends to have higher-than-normal levels of these small cholesterol particles, a condition called LDL pattern B. It tends to run in families who have a medical history of heart disease and may also include slightly elevated triglycerides and lower-than-normal levels of "good" HDL-cholesterol.

Who should be tested? The best candidates, according to Ronald Krauss, MD, a researcher with the Lawrence Berkeley Laboratory in California who helped develop the test, "are those individuals who have 'borderline' lipid levels" (meaning their cholesterol values are in the murky range between normal and risky), especially those "with family history of premature coronary disease, diabetes, or hypertension." The test could warn such folks, if they fit the pattern, to get further medical help. And because LDL pattern B is associated with elevated triglycerides, Dr. Krauss notes that treatments that improve both cholesterol and triglycerides "could be more beneficial to pattern B subjects."

But the test is a fairly new procedure, so not all physicians will be familiar with when to order it-or even how to interpret the results. It's expensive (about $225) and few labs can do it in-house. Before it can be useful to most people, comments Dr. Krauss, it will need to become less expensive and easier to do-and doctors will need to have a clearer idea of when the test is called for. The American Heart Association takes a cautious approach as well, saying that more research is needed before doctors know exactly how small LDL contributes to overall heart-disease risk.

Further down the road
There are several other promising tests available through specialized labs, and some doctors may be inclined to give them a try. For the most part, though, they're still firmly within the realm of research. How well they work-and whether they measure something that truly needs to be measured-is still very much up in the air.

Lipoprotein(a), or Lp(a), is a type of LDL-cholesterol that tends to run in families. Researchers have suspected for years that higher levels of this particular kind of cholesterol particle may significantly increase a person's risk for heart disease, but they don't yet know exactly why. It's possible, but still speculative, that something in Lp(a) aggravates lesions on artery walls and leads to more plaque buildup.

Apolipoprotein B (Apo B)
Apolipoprotein B is the main protein component of LDL-cholesterol, and it is also present in another unhealthful kind of cholesterol called very low density, or VLDL-cholesterol. Because it's found in both "bad" types, some scientists think that Apo B provides an accurate measurement of heart-disease risk, especially in people who tend to have small LDL particles. But there are currently few reliable Apo B tests available to the general public, and even fewer health professionals outside of a research setting who can accurately interpret the test results.

Fibrinogen is a protein particle that must be present in blood in order for it to clot. Higher-than-normal levels, though, could indicate inflammation somewhere in the blood vessels, a sign that arteries damaged by plaque may have ruptured and then formed a clot. Such a clot could block an artery, which would trigger a heart attack.

Some researchers think that it would be a good idea for physicians to test for fibrinogen levels when they test for cholesterol. But at the moment, there isn't a reliable way to test for it outside of the research laboratory.

Who's at Risk for Heart Disease?
The following factors play an important role in determining who may be at greater risk for developing heart disease.

Factors you can control or change:
High cholesterol (and low "good" HDL-cholesterol)
High blood pressure
Sedentary lifestyle
Factors you can't control:
Age and gender (men over age 45 and postmenopausal women are at the greatest risk)

Family history of heart disease
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