Published Online
on October 1, 2007

A more recent version of this article appeared on October 23, 2007

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Submitted on April 24, 2007
Accepted on August 8, 2007

CC Chemokine Ligand-5 (CCL5/RANTES) and CC Chemokine Ligand-18 (CCL18/PARC) Are Specific Markers of Refractory Unstable Angina Pectoris and Are Transiently Raised During Severe Ischemic Symptoms

A. O. Kraaijeveld MD, S. C.A. de Jager BSc, W. J. de Jager BSc, B. J. Prakken MD, PhD, S. R. McColl PhD, I. Haspels BSc, H. Putter PhD, T. J.C. van Berkel PhD, L. Nagelkerken PhD, J. W. Jukema MD, PhD^*, and E. A.L. Biessen PhD

From the Department of Cardiology and Einthoven Laboratory of Experimental Vascular Medicine (A.O.K., J.W.J.) and Department of Medical Statistics and Bioinformatics (H.P.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (A.O.K., S.C.A.d.J., T.J.C.v.B., E.A.L.B.), Leiden University, Leiden, The Netherlands; Department of Paediatric Immunology, University Medical Center Utrecht, Wilhelmina Children’s Hospital (W.J.d.J., B.J.P.), Utrecht, The Netherlands; School of Molecular and Biomedical Science (S.R.M.), The University of Adelaide, Adelaide, Australia; Division of Immunological and Infectious Diseases (I.H., L.N.), TNO Prevention and Health, Leiden, The Netherlands; and Department of Pathology (E.A.L.B.), Academic University Hospital Maastricht, Maastricht, The Netherlands

^* To whom correspondence should be addressed. E-mail: j.w.jukema{at}lumc.nl.

Background—Chemokines play an important role in atherogenesis and in ischemic injury and repair; however, prospective data on individual chemokines in unstable angina pectoris (UAP) are scarce. Therefore, we assessed chemokine patterns in a prospective cohort of patients with UAP.

Methods and Results—Plasma samples of 54 patients with Braunwald class IIIB UAP were examined at baseline for 11 chemokines and 5 inflammatory mediators via multiplex analysis. Levels of CC chemokine ligand (CCL)-5 (also known as RANTES [regulated on activation, normally T-cell expressed, and secreted]; 32.7 versus 23.1 ng/mL, P=0.018) and CCL18 (also known as PARC [pulmonary and activation-regulated chemokine]; 104.4 versus 53.7 ng/mL, P=0.011) were significantly elevated in patients with refractory ischemic symptoms versus stabilized patients. Temporal monitoring by ELISA of CCL5, CCL18, and soluble CD40 ligand (sCD40) levels revealed a drop in CCL5 and sCD40L levels in all UAP patients from day 2 onward (CCL5 12.1 ng/mL, P<0.001; sCD40L 1.35 ng/mL, P<0.05), whereas elevated CCL18 levels were sustained for at least 2 days, then were decreased at 180 days after inclusion (34.5 ng/mL, P<0.001). Peripheral blood mononuclear cells showed increased protein expression of chemokine receptors CCR3 and CCR5 in CD3⁺ and CD14⁺ cells at baseline compared with 180 days after inclusion, whereas mRNA levels were downregulated, which was attributable in part to a postischemic release of human neutrophil peptide-3–positive neutrophils and in part to negative feedback. Finally, elevated CCL5 and CCL18 levels predicted future cardiovascular adverse events, whereas C-reactive protein and sCD40L levels did not.

Conclusions—We are the first to report that CCL18 and CCL5 are transiently raised during episodes of UAP, and peak levels of both chemokines are indicative of refractory symptoms. Because levels of both chemokines, as well as of cognate receptor expression by circulating peripheral blood mononuclear cells, are increased during cardiac ischemia, this may point to an involvement of CCL5/CCL18 in the pathophysiology of UAP and/or post-UAP responses.

Key words: atherosclerosis • chemokines • ligands • ischemia • leukocytes

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