Emerging Heart Desease Risk Factors

You may have heard about new tests such as those that measure homocysteine or C-reactive protein levels that can estimate risk for heart disease. There are four critical questions that must be answered about any new risk factor before it can be recommended that the general population get screened for it:

  1. Is there an accurate laboratory test for the risk factor?
  1. Will measurement of the risk factor provide additional information beyond what can be obtained by measuring already established risk factors?
  1. Will treatment of the risk factor, or use of the information it provides to treat other risks, lead to a reduction in mortality, heart attacks, or strokes?
  1. Does the risk factor predict risk in the population in which it is going to be used? For example, it is possible that risk in individuals who have already had a heart attack will not prove very useful in predicting risk in individuals who have never had a heart attack.

As of this writing, the following risk factors don’t meet all four of these criteria, and so I don’t generally recommend testing for them except in these circumstances:

  • You don’t have any symptoms or high levels of conventional risk factors, but you do have a strong family history of CVD.
  • You have early CVD without high levels of conventional risk factors.
  • You have aggressive or recurrent CVD despite controlling the conventional risk factors.

Here are some of the emerging risk factors getting the most attention in the medical journals.

C-Reactive Protein (CRP)

Inflammation is the body’s protective response to injury, infection, or allergy. But when inflammation occurs in coronary arteries— in response to damage inflicted by modified LDL cholesterol—it can set the stage for atherosclerosis. C-reactive protein is a by-product of inflammation that shows up in a simple blood test.

In 1997, Harvard researchers reported in the New England Journal of Medicine that elevated levels of CRP were a predictor of heart attacks. Healthy, middle-aged men with the highest C-reactive protein levels were nearly three times as likely to have a heart attack as those with the lowest levels.

In 1998, results from the Harvard Women’s Health Study showed that CRP predicts heart disease in women as well. A study done in 2004 that looked at the CRP levels of almost 6,500 people with and without heart disease found that the level did predict coronary heart disease events, but this study found it to be a less powerful predictor than cholesterol or smoking risks.

This is a fairly common pattern in medical studies, where the initial reports suggest a very powerful effect and then later, larger studies find something a little more modest. Studies have also shown that people who are obese tend to have high levels of CRP.

Some exciting recent work suggests that as people gain weight, their fat tissue becomes infiltrated with inflammatory cells, which may be responsible for generating the signals that lead to elevated C-reactive protein levels. Fortunately, losing weight can reduce those levels.

A 2002 study in the journal Circulation followed sixty-one obese postmenopausal women, twenty-five of whom participated in a weight-loss program. After thirteen months, the women had lost an average of thirty-three pounds and reduced their C-reactive protein levels by 32 percent, from 3.06 micrograms per milliliter (mcg/mL) to 1.63 mcg/mL.

The more weight a woman lost, the more her CRP level declined. CRP has almost all the elements necessary to join the fight against heart disease. It’s effective at predicting heart disease risk. Testing for it isn’t expensive. CRP levels aren’t influenced by food, nor do they vary during the course of the day.

And they can be modified. Losing weight can lower CRP. So can taking a cholesterol- lowering statin drug. But a key piece of the puzzle is missing in our understanding of CRP. No one knows whether lowering CRP levels actually makes a difference.

It is possible that CRP is simply a marker or stand-in for one of the real culprits behind atherosclerosis. In other words, levels of CRP go up when atherosclerosis gets worse, but CRP may only go up with that worsening, not cause it. Lowering CRP levels could then be like treating measles by covering the skin rash with makeup.

While very recent scientific evidence has begun to suggest a direct role for CRP in atherosclerosis, it is still too soon to declare that relationship proved. A four-year study started in 2003 by Harvard researchers is currently under way to determine if the lowering of CRP by statins can be separated from the effect on LDL cholesterol levels.

The researchers plan to enroll fifteen thousand healthy men and women with normal LDL and high CRP. Half will take rosuvastatin and half will take a placebo. If there is a reduction in CRP levels in those with normal LDL and that is associated with a reduction in coronary events, the case for CRP will be strengthened considerably.

Another potential problem with the use of CRP levels is that they can be elevated in people with any sort of infection or other chronic inflammatory condition (such as rheumatoid arthritis), not just inflammation in the coronary arteries.

While this makes the test not useful in such a patient, the real problem would come if a doctor and patient weren’t aware of another inflammatory cause and incorrectly blamed the high CRP level on heart disease. Until we know more about what high and low CRP levels really mean, not everyone needs to have this test.

My advise according to the following guidelines for CRP testing:

  • Don’t bother if you are already being treated very aggressively for heart disease or high cholesterol. The intervention we use for elevated CRP levels currently is treatment with the statin class of drugs. If you are already receiving that treatment, the results of a CRP test aren’t likely to change how you and your doctor manage your condition.

If you have arthritis, inflammatory bowel disease, or some other condition that causes inflammation and thus elevates CRP, the test for this protein might not tell you much about your future chances of developing heart disease.

  • Think about it if your cholesterol levels are acceptable but you have other signs that heart trouble could be in your future, like a family history of heart disease, high blood pressure, or diabetes. Also, if you and your doctor are debating a change in your treatment plan, the CRP might be useful in tipping the balance in favor of moving in one direction or another.

If you get tested and find you have a high CRP level (the following chart defines what’s high), pay extra attention to hearthealthy habits. Losing weight, stopping smoking, and exercising all lower CRP—and help with many other risk factors for heart disease.

I also suggest that take a daily aspirin, because some studies have shown that this approach may offer protection against heart attack in people with high CRP, and we already know that taking aspirin can be helpful in preventing the clots that block arteries during a heart attack.


Although we talk almost exclusively about two lipoproteins, LDL and HDL, there are actually many others. Lipoprotein(a), which is often abbreviated as Lp(a) (pronounced el-pee-little-a), is a molecule of LDL cholesterol with an extra protein attached. Lp(a) consists of a molecule of LDL linked to a sugar-coated protein that may keep the body’s natural clot-busters from doing their job.

If so, high levels of Lp(a) could contribute to heart attacks. What determines your Lp(a) level? It depends far more on genetic factors than on lifestyle. Cardiologists aren’t sure what elevated Lp(a) means in terms of cardiovascular risk. Some studies show a connection between high Lp(a) and increased risk for heart disease and stroke.

Others don’t. One thing seems clear: high levels are worrisome in people with high LDL. Among those with normal cholesterol, Lp(a) might be important when HDL levels are low.

In one major study, for example, the risk for a heart attack or sudden death was almost three times higher among men with Lp(a) levels of 20 mg/dL and above compared with those whose levels were below 20. Among men with low HDL (less than 35 mg/dL) and high Lp(a), the risk was eight times higher.

One problem with interpreting Lp(a) values is that different ethnic populations vary widely in their normal ranges. Most experts don’t recommend “treating” high Lp(a).

However, when it occurs in people who have a very strong family history for heart disease but no other cholesterol problems, high total cholesterol, coronary artery disease, or damage to organs caused by high blood pressure, then it makes sense to intensify protective strategies, including diet, exercise, and drug therapy.

Lifestyle changes don’t appear to lower Lp(a) levels, and neither do most medications. The one exception to this is high-dose niacin, which isn’t always well tolerated by patients. Finally, for the majority of people, we just don’t know whether lowering Lp(a) is beneficial.