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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Serial Measurement of Monocyte Chemoattractant Protein-1 After Acute Coronary Syndromes

Results From the A to Z Trial

James A. de Lemos, MD, FACC^_*,_*, David A. Morrow, MD, MPH, FACC, Michael A. Blazing, MD, FACC, Petr Jarolim, MD, PhD, Stephen D. Wiviott, MD, FACC, Marc S. Sabatine, MD, MPH, FACC, Robert M. Califf, MD, MACC and Eugene Braunwald, MD, MACC

^_* Donald W. Reynolds Cardiovascular Clinical Research Center, UT Southwestern Medical Center, Dallas, Texas
TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
Duke Clinical Research Institute, Durham, North Carolina. The A to Z trial was sponsored by Merck and Co. Dr. de Lemos has received grant support from Biosite and Merck, and honoraria or consulting fees from Biosite, Roche Diagnostics, Bayer Diagnostics, Inverness, GlaxoSmithKline, Merck/Schering, and Pfizer. The TIMI Study Group (Drs. Morrow, Wiviott, Sabatine, and Braunwald) has received grant support from Beckman Coulter, Biosite, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck/Schering, Ortho-Clinical Diagnostics, Pfizer, and Roche Diagnostics. Dr. Morrow has received honoraria or consulting fees from Bayer Diagnostics, Beckman Coulter, Critical Diagnostics, Dade-Behring, GlaxoSmithKline, OrthoClinical Diagnostics, and Roche Diagnostics. Dr. Jarolim has received consulting fees from Bayer Diagnostics. Dr. Blazing has received grant support from Merck and honoraria from Merck/Schering and Pfizer. Dr. Wiviott has received honoraria from Pfizer and Merck. Dr. Sabatine has consulting fees from Bristol-Myers Squibb. Dr. Califf has received grant support through the Duke Clinical Research Institute from Merck and Merck/Schering and serves as a consultant to Merck/Schering, with the proceeds donated to charity. Dr. Braunwald has received honoraria and consulting fees from Merck

Manuscript received March 29, 2007; revised manuscript received May 29, 2007, accepted June 12, 2007.

^_* Reprint requests and correspondence: Dr. James A. de Lemos, MD, UT Southwestern Medical Center, 5909 Harry Hines Boulevard, HA 9.108, Dallas, Texas 75390-9047. (Email: james.delemos{at}utsouthwestern.edu).

Objectives: This study sought to determine whether the novel biomarker monocyte chemoattractant protein (MCP)-1 adds prognostic value to standard risk assessment tools and biomarkers after acute coronary syndromes (ACS).

Background: Monocyte chemoattractant protein-1 is a chemokine recruiting signal for monocytes that may function as both a mediator and biomarker of ACS.

Methods: Monocyte chemoattractant protein-1 was measured at baseline (n = 4,244), 4 months (n = 3,603), and 12 months (n = 2,950), and correlated with clinical events in the Z phase of the A to Z (Aggrastat to Zocor) trial, which compared early intensive versus delayed and less intensive statin therapy after ACS.

Results: Rates of death and the composite end points of death or myocardial infarction (MI); death, MI, or heart failure; and cardiovascular death, MI, readmission for ACS, or stroke increased across baseline quartiles of MCP-1 and among patients with MCP-1 greater than versus less than or equal to the pre-specified threshold of 238 pg/ml (p < 0.01 for each). After adjustment for standard risk predictors and levels of C-reactive protein and B-type natriuretic peptide, MCP-1 >238 pg/ml remained independently associated with mortality (hazard ratio 2.16; 95% confidence interval 1.54 to 3.02) and with each composite end point, and increased the C-statistic of the fully adjusted mortality model from 0.76 to 0.78 (p < 0.0001). A value of MCP-1 >238 pg/ml at the 4-month follow-up visit was also independently associated with mortality after 4 months (hazard ratio 1.76; 95% confidence interval 1.12 to 2.76). Elevated MCP-1 levels did not identify patients who derived incremental benefit from intensive statin therapy.

Conclusions: Monocyte chemoattractant protein-1 provides independent prognostic value in the acute and chronic phases after ACS and merits further evaluation as a prognostic marker and potential therapeutic target.

Abbreviations and Acronyms   ACS = acute coronary syndrome   BNP = B-type natriuretic peptide   CRP = C-reactive protein   LDL-C = low-density lipoprotein cholesterol   MCP = monocyte chemoattractant protein   MI = myocardial infarction   ULN = upper limit of normal

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