Dallas, TX - A new potential risk marker—monocyte chemoattractant protein-1 (MCP-1)—has been shown to provide independent prognostic value in ACS patients and might also be a good therapeutic target, researchers suggest [1].

The latest study of this marker, an analysis from the A to Z study, published online before its appearance in the November 27 issue of the Journal of the American College of Cardiology, found that plasma levels of MCP-1 provided prognostic value in both the acute and chronic periods after ACS that is complementary to that of standard clinical variables and emerging biomarkers, such as C-reactive protein (CRP) and brain natriuretic peptide (BNP).

But the study authors, led by Dr James de Lemos (UT Southwestern Medical Center, Dallas, TX), report that the influence of statins on MCP-1 is modest and that MCP-1 is not useful in identifying patients who benefit from aggressive statin regimens after ACS. They conclude that future studies are needed to evaluate whether MCP-1 should be included in multiple-biomarker panels for risk stratification and whether this biomarker can be used as a measurable target for antiatherosclerosis therapies.

de Lemos commented to heartwire: "Our study shows that if MCP-1 is raised after ACS, the adverse-event rate is higher, so it is a marker of risk. This analysis also included BNP and CRP, and we found that if we add in MCP-1 it increases the predictive value. This marker provides modest additional information, but whether it provides enough to be meaningful is still debatable. It provides some support for the use of multiple markers, but I don't know yet if it will make it to routine use. It is one of several markers that could be considered to give us a bit more information. It has been validated now, but there is still a long road ahead until we will know where this marker will fit in."

de Lemos explained that the major stumbling block in the biomarker field is knowing what to do with a positive result. "We know that several of these markers predict a higher risk of clinical events, but what we don't know is what exactly we should do differently in these particular patients." He added: "We wondered whether MCP-1 could be used as a way of stratifying aggressive lipid-lowering treatment (ie, identifying a high-risk group that needs more aggressive lipid-lowering treatment than other ACS patients), but from our results in the A to Z study, that doesn't seem to be the case."

He pointed out that MCP-1 is different from other markers in that it is strikingly associated with risk markers for atherosclerosis. "MCP-1 is involved in the pathological process of atherosclerosis. In many ways it looks like LDL cholesterol, which is also a modest predictor of CHD events." de Lemos suggested that MCP-1 could be a new target for therapy. Noting that inhibitors of MCP-1 are being developed but are being tested first in inflammatory diseases, such as rheumatoid arthritis, he suggested that these compounds should be tested as antiatherosclerosis agents as well.

de Lemos says that MCP-1 is a different type of marker from CRP. "It is reflecting a different biology. In many ways it is more attractive as a marker of increased heart-disease risk, as it is not so influenced by obesity parameters and it appears to have a more definite role in the biology of atherosclerosis. MCP-1 identifies a different group of patients than CRP or BNP. I don't measure CRP in ACS patients, but I do tend to measure BNP, and those who have high levels, I would treat more aggressively. That practice is not fully supported by evidence, but that is my interpretation of the evidence. Maybe MCP will be used in a similar way one day. My hope, however, is that MCP may be a little smarter than this—that one day we might have more target-specific pathways for treatments. For example, we will use a therapy that targets monocytes in patients with raised MCP-1. The idea of using specific markers to guide specific treatments in different groups of patients is what we're looking for. This is still somewhat of a pipe dream, but we've got to start somewhere."

In the paper, de Lemos and his colleagues explain that MCP-1 is a chemokine produced by monocytes, macrophages, smooth-muscle cells, and endothelial cells within atherosclerotic plaques. It serves as a chemotactic agent to recruit monocytes into the vascular wall and, in animal models, atherosclerosis is promoted when MCP-1 expression is increased and is inhibited when the gene for MCP-1 is deleted. Clinical trials have shown plasma levels of MCP-1 to be correlated with most cardiovascular risk factors, with measures of coronary atherosclerosis burden, and with incident coronary and peripheral artery disease.

In this study, researchers measured MCP-1 in a large population of patients stabilized after ACS in the A to Z trial of early intensive vs delayed and less-intensive statin therapy. Measurements were taken at baseline, at four months, and at 12 months. Results showed that rates of death and cardiovascular events increased across baseline quartiles of MCP-1 and among patients with MCP-1 greater than the prespecified threshold of 238 pg/mL, and this increase remained after adjustment for standard risk predictors and levels of CRP and BNP, increasing the C-statistic of the fully adjusted mortality model from 0.76 to 0.78. In addition, MCP-1 levels measured four months after the coronary event also provided independent prognostic information. However, elevated MCP-1 levels did not identify patients who derived incremental benefit from intensive statin therapy.

"These findings suggest that MCP-1 measurement will not be useful as a tool for monitoring statin therapy or for identifying patients for more aggressive statin treatment. However, given the clear pathogenic role for MCP-1 in atherosclerosis and its complications and the association of plasma levels of MCP-1 with coronary risk factors, atherosclerosis burden, and clinical events, MCP-1 should be further studied as a biomarker 'target' for novel atherosclerosis therapies," the authors conclude.

In an accompanying editorial [2], Dr Nikolaos Frangogiannis (Baylor College of Medicine, Houston, TX) says the study extends previous investigations suggesting that MCP-1 is valuable for the risk stratification of patients in both the early and late stages after an acute coronary event.

He also agrees that MCP-1 might be an attractive therapeutic target. Noting that the beneficial effects of statins might be mediated through decreased MCP-1 expression, he suggests that therapeutic interventions aimed at further reducing MCP-1 levels might provide additional benefit, adding that experimental studies have shown that disruption of the MCP-1 signaling pathway reduces remodeling after MI. But he warns that the absence of MCP-1 results in delayed phagocytosis of injured cardiomyocytes, which can increase the arrhythmogenic potential or predispose to mechanical complications in patients with MI, which should be taken as a note of caution regarding the potential consequences of overly aggressive suppression of MCP-1.