C Reactive Protein: The Next Big Thing?

Editor’s Note:  This story, first published in 2004, has been updated.

Harold Olivey
Published: December, 2004

A 70-year-old diagnostic test has become the latest tool for predicting a person’s future risk of developing cardiovascular disease. It measures levels of C-reactive protein (CRP), which is made by the liver during periods of inflammatory activity in the body.

Atherosclerosis is thought to raise the plasma levels of CRP as any other inflammatory process would. Until recently, however, the relatively small increase in CRP resulting from vessel disease was below the detection range of the standard test method.

A method was developed in the late 1990s to increase the sensitivity of the CRP assay. This new diagnostic tool, called the high-sensitivity CRP test (hsCRP), has become a recommended standard for the care of individuals at risk for developing coronary artery disease.

Cardiologist Paul Ridker, M.D., Eugene Braunwald Professor of Medicine at Harvard University, helped develop the hsCRP test and has been its main champion.

Ridker and colleagues measured CRP levels in blood samples from a subset of participants in the Physicians’ Health Study, which assessed the benefits of aspirin and beta-carotene in reducing the risk of adverse cardiovascular events in several thousand male physicians. They found that participants with elevated CRP, as detected by the hsCRP assay, were at increased risk for heart attack and stroke.

Intriguingly, the elevated risk was independent of other known risk factors like serum LDL cholesterol concentration and smoking. Subsequent studies have largely supported this finding.

In 2003 the American Heart Association and U.S. Centers for Disease Control and Prevention (CDC) published a scientific statement suggesting that physicians could reasonably test for CRP in patients considered to be at moderate risk for developing cardiovascular disease.

A meta-analysis of prospective studies of coronary artery disease, however, found that CRP concentration “added only marginally” to the predictive value of established risk factors like smoking and serum LDL concentration.

“Recent recommendations regarding the use of measurements of C-reactive protein in the prediction of coronary heart disease may need to be reviewed,” researchers led by John Danesh, M.B., Ch.B., of Cambridge University reported in 2004 in The New England Journal of Medicine.

Sergio Fazio, M.D., Ph.D., professor of Medicine and Pathology at Vanderbilt University Medical Center, does not believe that current data conclusively support a causal link between CRP and atherosclerosis. In comparison, LDL cholesterol is both a circulating marker and causative agent of atherosclerosis. CRP is, however, the best of several diagnostic tools available to detect inflammation, a recognized component of atherosclerosis, he says.

CRP also may be useful in the diagnosis of metabolic syndrome, a clustering of risk factors related to insulin resistance that is recognized as a predictor of future risk for developing cardiovascular disease and diabetes.

People diagnosed with metabolic syndrome possess at least three of the following conditions: elevated serum triglycerides, low HDL (often called the “good” cholesterol), visceral obesity, elevated blood pressure, and insulin resistance or glucose intolerance (see table).

Obesity may help tie inflammation to heart disease and diabetes.

Adipose (fat) tissue releases pro-inflammatory cytokines such as interleukin-6 (IL-6), which may contribute to the development of atherosclerosis and heart disease. IL-6 also may interfere with the body’s ability to respond to insulin, a hormone that regulates glucose metabolism. Resistance to insulin signaling is a hallmark of metabolic syndrome, and can eventually lead to type 2 diabetes.

“As a relatively specific marker of inflammation, (CRP) does help identify people” at elevated risk of cardiovascular disease, says Doug Vaughan, M.D., chair of Medicine at Northwestern University Feinberg School of Medicine and former chief of Cardiovascular Medicine at Vanderbilt.

“It helps you change your perceptions about a given patient and perhaps move them from a moderate risk category to a higher risk category. And that in turn precipitates a more aggressive intervention to reduce risk. That’s the value of it.”

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