Clinical Laboratory Strategies: February 14, 2008

Searching for New Cardiac Markers: Will MCP-1 Prove Useful?
By Deborah Levenson

Researchers have identified several promising cardiac biomarkers in recent years. While most of these novel markers rise during the acute phase of ACS, one new biomarker—monocyte chemoattractant protein-1 (MCP-1)—has been shown in a recent study to remain stable during this phase. The study raises the possibility that MCP-1 might someday provide valuable prognostic information as part of a panel of cardiac markers that predicts risk. This issue of Strategies examines these findings.

A member of the chemokine family of small cytokines, or proteins secreted by cells, monocyte chemoattractant protein-1 (MCP-1) recruits monocytes to the site of inflammation, spurring a cascade of events that may be linked to atherosclerosis and ACS. While it’s not near ready for clinical use, lab directors may soon be hearing more about this protein. Results from a recent trial show that unlike most cardiac markers proven to have prognostic value— such as CRP and BNP —MCP-1 does not rise during the acute phase of ACS and its elevation is associated with increased risk for long-term death and major adverse cardiac events. These findings are independent of standard risk factors, according to a team of researchers from UT Southwestern Medical Center in Dallas, Texas, Brigham and Women’s Hospital in Boston, Mass., and Duke Clinical Research Institute in Durham, N.C. (Journal of the American College of Cardiology 2007; 50: 2117–2124).

The team measured MCP-1 at baseline in 4,244 ACS patients, at 4 months in 3,603 of them, and at 12 months in 2,950. The researchers correlated MCP-1 levels with clinical events in the “Z” phase of the A to Z (Agrastat to Zocor) trial, which compared early intensive statin therapy versus delayed and less intensive treatment with these drugs after ACS. The trial was sponsored by Merck and Co. (Whitehouse Station, N.J.)

While researchers found that statins had only modest influence on MCP-1 levels and that the marker was not useful for identifying patients who might benefit from the drugs, they also observed that higher MCP-1 levels at both baseline and 4 months were associated with an increased risk for mortality in the long term and major adverse cardiovascular events. Rates of death and major adverse cardiac events including myocardial infarction (MI), death, heart failure, and stroke increased across baseline quartiles of MCP-1 and among patients with MCP-1 levels greater than 238 pg/mL, versus those patients with levels less than or equal to that pre-specified threshold. After adjustment for standard risk predictors and levels of CRP and BNP, MCP-1 levels greater than 238 pg/mL remained independently associated with mortality (HR 2.16, 95% CI, 1.54—3.02) and with each composite end point. A MCP-1 value greater than 238 pg/dL at 4 months was also independently associated with mortality (HR 1.76, 95% CI, 1.12—2.76).

MCP-1: Something to Watch

“This research shows that CRP doesn’t tell the whole inflammation story. But MCP-1 isn’t anywhere near ready for clinical use,” said lead researcher James de Lemos, MD, Associate Professor of Medicine and UT Southwestern University and Director of the Coronary Care Unit at UT Southwestern Medical School. “These findings are significant in part because of the size of the study. Labs should keep an eye on how the research on MCP-1 plays out.”

But could MCP-1 add to the information labs and physicians now get from established markers? According to de Lemos, MCP-1 adds some information, but its value “isn’t anywhere near what we learn from troponin, and MCP-1 doesn’t give as much information as BNP does.” While his results are promising, de Lemos urged researchers to be very critical and selective about research on MCP-1 before putting it on a cardiac panel.

“The study extends previous investigations suggesting that MCP-1 may be valuable for risk stratification of patients in both the early and late stage after an acute coronary event. In addition, the findings raise an intriguing question regarding the potential role of MCP-1 in patients with coronary disease,” notes an accompanying editorial by Nikolaos G. Frangogiannis, MD, of Baylor College of Medicine in Houston, Texas. “Why do patients with persistently MCP-1 plasma levels have adverse outcomes after an ACS event?”

The View from the Lab

The A to Z Trial findings attracted the interest of laboratorian experts on cardiac markers, but they are taking a wait-and-see attitude on MCP-1. “This paper does stand out because it shows that MCP-1 adds prognostic benefit independent of traditional risk factors. But I would call this paper a proof of principle study,” remarked Fred Apple, PhD, an author of the National Academy for Clinical Biochemistry’s guidelines on cardiac markers, Professor of Laboratory Medicine and Pathology at University of Minnesota School of Medicine in Minneapolis, and Medical Director of Clinical Laboratories at Hennepin County Medical Center in Minneapolis. “MCP-1 still needs a lot more study before anyone can say if it will be useful in clinical practice.”

“MCP-1 is nowhere near ready,” agreed Alan Wu, PhD, Director of Clinical Chemistry and Toxicology at San Francisco General Hospital and Professor of Laboratory Medicine at University of California-San Francisco. “But the study data is interesting because it indicates inflammation of lesions versus infiltration. It’s another marker showing a different aspect of the disease process.”

The Need for Standards

While considering the growing body of research on novel cardiac biomarkers, Apple identified a problem in many papers about them. “There’s a lack of uniformity in how we define cutoffs,” he said, pointing to the MCP-1 article as an example. While clinical chemists use the 97.5th percentile of a healthy reference populations as the cutoff for most assays and the 99th percentile for troponin, this paper’s cutoff of 238 pg/mL is based on the authors’ previous finding from OPUS- -TIMI Trial that found that MCP-1 levels more than 238 pg/mL were independently associated with death and myocardial infarction after ACS. That earlier study used the 90th percentile as a cutoff, Apple pointed out. Noting that this cutoff isn’t used in clinical practice, he suggested that cardiologist and clinical chemist researchers establish common rules regarding cutoffs for cardiac markers.

Dr. Apple has received research funding from several companies involved in cardiac biomarker research and sales, including Abbott Diagnostics (Abbott Park, Ill.), Biosite (San Diego, Calif.), Beckman Coulter (Fullerton, Calif.), Ortho Clinical Diagnostics (Raritan, N.J.), and Sensera (Chelmsford, Mass.)

Dr. de Lemos consults for several companies involved in cardiac biomarker research and sales, including Biosite, Roche Diagnostics, Inverness Medical Innovations (Waltham, Mass.), and Tethys Bioscience (Emeryville, Calif.).

Dr. Wu has received research grants to study cardiac biomarkers from Abbott Diagnostics, Nanosphere (Northbrook, Ill.), Response Biomedical (Vancouver, British Columbia, Canada), and Singulex Corporation, (Hayward, Calif.), but the support does not include MCP-1 studies.

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