Study questions widespread use of C-reactive protein test to assess cardiovascular risk

October 10, 2005

A new study concludes that widespread screening for cardiovascular risk by measuring blood levels of C-reactive protein (CRP), a protein produced by the liver, should not be advocated. Researchers at the University of Maryland School of Medicine in Baltimore analyzed data from more than 15,000 adult men and women and found that CRP appears to be tightly linked to traditional risk factors for heart disease rather than being an independent risk factor. The study is published in the October 10, 2005, Archives of Internal Medicine.

C-reactive protein (CRP) is released by the liver in response to inflammation related to an infection, injury, or conditions such as arthritis. Inflammation also has been associated with the cause and progression of cardiovascular disease, particularly in the build up of fatty deposits in the lining of arteries.

The researchers found that elevated CRP goes hand in hand with traditional risk factors for heart disease, such as smoking, obesity, high blood pressure or elevated cholesterol, and rarely occurs in their absence. CRP levels are defined as normal (less than 1 milligram per liter (mg/L), borderline-high (1-3 mg/L) and high (greater than 3 mg/L).

"We believe that high C-reactive protein is truly related to the company it keeps," says principal investigator Michael Miller, M.D., director of preventive cardiology at the University of Maryland Medical Center and associate professor of medicine at the University of Maryland School of Medicine. "The CRP test gained popularity in the late 1990's when it was believed that only 50 percent of heart attacks could be explained by traditional risk factors," says Dr. Miller. "However, this turned out to be one of the greatest myths in cardiovascular medicine as recent studies have affirmed that more than 90 percent of heart attacks can be accounted for by traditional risk factors, as well as poor diet, sedentary lifestyle and mental stress."

Dr. Miller and his team examined data from the third National Health and Nutrition Examination Survey (NHANES III) conducted between 1988 and 1994. NHANES III measured CRP levels and heart disease risk factors including smoking, elevated blood pressure and cholesterol levels, diabetes, body mass index and physical activity.

"We looked at high CRP and compared its prevalence with and without other risk factors for heart disease," says Dr. Miller. Overall, 25.7 percent of the people in the study had elevated CRP, including 8.7 percent who had no other risk factors. African-Americans had higher CRP levels than Caucasians. The analysis found a high CRP level in 77.8 percent of men and 66.7 percent of women who had at least one risk factor for heart disease.

The presence of at least one of those risk factors, either in the borderline or abnormal range, resulted in a nearly three-fold higher prevalence of CRP compared to people in the study who never smoked, were not overweight and had normal blood pressure, cholesterol and blood sugar levels. "The surprising finding in our analysis was the very high percentage of elevated CRP that was directly attributable to conventional risk factors," says Dr. Miller.

A look at body mass index in the NHANES III survey illustrates how risk factors can influence CRP levels. The index can indicate whether a person is obese, overweight, underweight or normal. CRP levels were prevalent in 14.7 percent of people with a normal body mass index, but were found in 26 percent of people who were categorized as overweight. The percentage jumped to 46.6 percent among people whose body mass index put them in the obese range.

Numerous experts have been debating the use of the relatively inexpensive CRP blood test as a general screening tool for coronary heart disease, both pro and con. Some say CRP can help identify certain patients at risk for heart disease that other measurements, such as cholesterol, may miss, so they recommend that the test be given to people even if they are at low risk for cardiovascular disease.

However, in 2003, the American Heart Association and the Centers for Disease Control and Prevention issued a joint scientific statement that recommended against the general screening of the adult population for CRP. Instead, the statement said that CRP measurements should be reserved for patients at intermediate risk for heart disease, who have a 10 to 20 percent risk of developing the disease over ten years. The statement also called for additional studies of the CRP test.

Dr. Miller believes that CRP screening is unlikely to contribute sufficient insight beyond traditional risk factors and may even be counterproductive. "The great concern of CRP screening is that it may provide false assurance to men and women who may be at increased risk of a heart attack despite normal CRP levels," says Dr. Miller. "Because the majority of people at risk for a heart attack do not have high CRP, normal levels at screening may make obese patients or smokers, for example, less motivated to lose weight or kick the habit." On the other hand, according to Dr. Miller, if a high CRP is found on routine screening, then therapies that reduce high blood pressure, glucose, cholesterol and triglycerides will also lower CRP. "We should be making these adjustments anyway, regardless of CRP levels," he adds.

Dr. Miller says the good news is that in the absence of risk factors, high CRP is very rare. "If you exercise, don't smoke, have normal levels of blood pressure, cholesterol and glucose and are not overweight, the likelihood of having a high CRP is only one in 2,000," he says. Rather than screening for CRP, Dr. Miller says "Let's work more intensively to reduce the known culprits, such as obesity and diabetes, which are growing to epidemic proportions and have become a major public health concern in the U.S. Otherwise, we run the risk of erasing the great advances that have contributed to the reduction in cardiovascular disease during the past 40 years."
-end-
The research team also included Min Zhan, Ph.D. and Stephen Havas, M.D., M.P.H., M.S., both of the University of Maryland School of Medicine. The study was supported in part by a National Institutes of Health grant and a Veterans Affairs Merit Award to Dr. Miller.

University of Maryland Medical Center

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