Thromb Haemost 2007; 97(05): 748-754
DOI: 10.1160/TH07-01-0029
Theme Issue Article
Schattauer GmbH

Chemokines in cardiovascular risk prediction

Pål Aukrust
1   Research Institute for Internal Medicine
2   Section of Clinical Immunology and Infectious Diseases
,
Arne Yndestad
1   Research Institute for Internal Medicine
,
Camilla Smith
1   Research Institute for Internal Medicine
,
Thor Ueland
1   Research Institute for Internal Medicine
3   Section of Endocrinology
,
Lars Gullesta
4   Department of Cardiology, Rikshospitalet-Radiumhospitalet, Medical Center, University of Oslo, Oslo, Norway
,
Jan K. Damås
1   Research Institute for Internal Medicine
2   Section of Clinical Immunology and Infectious Diseases
› Author Affiliations
Financial support: This work was supported by grants from the Norwegian Council of Cardiovascular Research, Research Council of Norway, the University of Oslo, Medinnova Foundation, Rikshospitalet-Radiumhospitalet Medical Center, and Helse Sør.
Further Information

Publication History

Received 16 January 2007

Accepted after revision 15 February 2007

Publication Date:
24 November 2017 (online)

Summary

In consideration of the important role of inflammation in plaque progression and stability, recent work has focused on whether plasma markers of inflammation can non-invasively diagnose and predict coronary artery disease (CAD) and other forms of atherosclerotic disorders. Although several studies support an important pathogenic role of chemokines in atherogenesis and plaque destabilization, potentially representing attractive therapeutic targets in atherosclerotic disorders,this does not necessarily mean that chemokines are suitable parameters for risk prediction. In fact, the ability to reflect up-stream inflammatory activity, stable levels in individuals and high stability of the actual protein (e.g. long half-life and negligible circadian variation), are additional important criteria for an ideal biomarker in cardiovascular disease. Although plasma/serum levels of certain chemokines (e.g. interleukin 8 and monocyte chemoattractant protein- 1) have been shown to be predictive for future cardiac events in some studies, independent of traditional cardiovascular risk factors and C-reactive protein,and although certain gene polymorphisms of chemokines/chemokine receptors (e.g. fractalkine receptor) have been shown to be predictive of future atherosclerotic disease, further prospective studies, including a larger number patients,are needed to make any firm conclusion. While the demonstrations of an association between chemokines and CAD are a necessary first step, such studies do not establish the full clinical utility of a biomarker, which is a more demanding process that requires validation in multiple cohorts, and clear demonstration of incremental prognostic value over traditional risk models. If successful, such new biomarker will be a useful indicator for better risk assessment,diagnosis,and prognosis, as well as monitoring pharmacological treatments for atherosclerosis.

 
  • References

  • 1 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
  • 2 Fichtlscherer S, Heeschen C, Zeiher AM. Inflammatory markers and coronary artery disease. Curr Opin Pharmacol 2004; 04: 124-131.
  • 3 Tsimikas S, Wilerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol 2006; 47 (Suppl. 08) (Suppl) C19-31.
  • 4 Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: 363-369.
  • 5 Morrow DA, Rifai N, Antman EM. et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998; 31: 1460-1465.
  • 6 Morrow DA, de Lemos JA, Sabatine MS. et al. Clinical relevance of C-reactive protein during followup of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation 2006; 114: 281-288.
  • 7 Ridker PM, Hennekens CH, Buring JE. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843.
  • 8 Biasucci LM, Liuzzo G, Fantuzzi G. et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 1999; 99: 2079-2084.
  • 9 Ridker PM, Hennekens CH, Roitman-Johnson B. et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351: 88-92.
  • 10 Ueland T, Jemtland R, Godang K. et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol 2004; 44: 1970-1976.
  • 11 Heeschen C, Dimmeler S, Hamm CW. et al. CAPTURE Study Investigators. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 1104-1111.
  • 12 Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006; 354: 610-621.
  • 13 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86: 515-581.
  • 14 Smith C, Damås JK, Otterdal K. et al. Increased levels of Neutrophil-activating peptide-2 in acute coronary syndromes. Possible role of platelet-mediated vascular inflammation. J Am Coll Cardiol 2006; 48: 1591-1599.
  • 15 Lee WH, Kim SH, Jeong EM. et al. A novel chemokine, Leukotactin-1, induces chemotaxis, pro-atherogenic cytokines, and tissue factor expression in atherosclerosis. Atherosclerosis 2002; 161: 255-260.
  • 16 Schecter AD, Berman AB, Taubman MB. Chemokine receptors in vascular smooth muscle. Microcirculation 2003; 10: 265-272.
  • 17 Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 2005; 96: 612-616.
  • 18 Gu L, Okada Y, Clinton SK. et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998; 02: 275-281.
  • 19 Boring L, Gosling J, Clearl M. et al. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394: 894-897.
  • 20 Boisvert WA, Santiago R, Curtiss LK. et al. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998; 101: 353-361.
  • 21 Combadiere C, Potteaux S, Gao JL. et al. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 2003; 107: 1009-1016.
  • 22 Lesnik P, Haskell CA, Charo IF. Deceased atherosclerosis in CX3CR1 -/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003; 111: 333-340.
  • 23 Libby P. Current consepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 104: 365-372.
  • 24 Moreau M, Brocheriou I, Petit L. et al. Interleukin- 8 mediates downregulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages: relevance to stability of atherosclerotic plaque. Circulation 1999; 99: 420-426.
  • 25 Schecter AD, Rollins BJ, Zhang YJ. et al. Tissue factor is induced by monocyte chemoattractant protein- 1 in human aortic smooth muscle and THP-1 cells. J Biol Chem 1997; 272: 28568-28573.
  • 26 Haque Fallon JT, Pan JJ. et al. Chemokine receptor- 8 (CCR8) mediates human vascular smooth muscle cell chemotaxis and metalloproteinase-2 secretion. Blood 2004; 103: 1296-1304.
  • 27 Kodali R, Hajjou M, Berman A. et al. Chemokines induce matrix metalloproteinase-2 through activation of epidermal growth factor receptor in arterial smooth muscle cells. Cardiovasc Res 2006; 69: 706-715.
  • 28 Moulton KS, Vakili K, Zurakowski D. et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA 2003; 100: 4736-4741.
  • 29 Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res 2004; 95: 858-866.
  • 30 Aukrust P, Berge RK, Ueland T. et al. Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes. J Am Coll Cardiol 2001; 37: 485-491.
  • 31 Lutgens E, Faber B, Schapira K. et al. Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody. Circulation 2005; 111: 3443-3452.
  • 32 Ockene IS, Matthews CE, Rifai N. et al. Variability and classification accuracy of serial high-sensitivity C-reactive protein measurements in healthy adults. Clin Chem 2001; 47: 444-450.
  • 33 Meier-Ewert HK, Ridker PM, Rifai N. et al. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem 2001; 47: 426-430.
  • 34 Weyrich AS, Zimmerman GA. Platelets: signaling cells in the immune continuum. Trends Immunol 2004; 25: 489-495.
  • 35 Ranjbaran H, Wang Y, Manes TD. et al. Heparin displaces interferon-gamma-inducible chemokines (IP-10, I-TAC, and Mig) sequestered in the vasculature and inhibits the transendothelial migration and arterial recruitment of T cells. Circulation 2006; 114: 1293-1300.
  • 36 Boekholdt SM, Peters RJ, Hack CE. et al. IL-8 plasma concentrations and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 2004; 24: 1503-1508.
  • 37 Deo R, Khera A, McGuire DK. et al. Association among plasma levels of monocyte chemoattractant protein- 1, traditional cardiovascular risk factors, and subclinical atherosclerosis. J Am Coll Cardiol 2004; 44: 1812-1818.
  • 38 Hoogeveen RC, Morrison A, Boerwinkle E. et al. Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: Atherosclerosis Risk in Communities study. Atherosclerosis 2005; 183: 301-307.
  • 39 Rothenbacher D, Muller-Scholze S, Herder C. et al. Differential expression of chemokines, risk of stable coronary heart disease, and correlation with established cardiovascular risk markers. Arterioscler Thromb Vasc Biol 2006; 26: 194-199.
  • 40 de Lemos JA, Morrow DA, Sabatine MS. et al. Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 2003; 107: 690-695.
  • 41 Kervinen H, Manttari M, Kaartinen M. et al. Prognostic usefulness of plasma monocyte/macrophage and T-lymphocyte activation markers in patients with acute coronary syndromes. Am J Cardiol 2004; 94: 993-996.
  • 42 Falcone C, Minoretti P, D'Angelo A. et al. Markers of eosinophilic inflammation and risk prediction in patients with coronary artery disease. Eur J Clin Invest 2006; 36: 211-217.
  • 43 Emanuele E, Falcone C, D'Angelo A. et al. Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease. Atherosclerosis 2006; 186: 140-145.
  • 44 Bursill CA, Channon KM, Greaves DR. The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics. Curr Opin Lipidol 2004; 15: 145-149.
  • 45 Szalai C, Duba J, Prohaszka Z. et al. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 –2518 G/G genotype in CAD patients. Atherosclerosis 2001; 158: 233-239.
  • 46 Kim MP, Wahl LM, Yanek LR. et al. A monocyte chemoattractant protein-1 gene polymorphism is associated with occult ischemia in a high-risk asymptomatic population. Atherosclerosis. 2006 epub ahead of print
  • 47 Alonso-Villaverde C, Coll B, Parra S. et al. Atherosclerosis in patients infected with HIV is influenced by a mutant monocyte chemoattractant protein-1 allele. Circulation 2004; 110: 2204-2209.
  • 48 Brenner D, Labreuche J, Touboul PJ. et al. GENIC Investigators. Cytokine polymorphisms associated with carotid intima-media thickness in stroke patients. Stroke 2006; 37: 1691-1696.
  • 49 McDermott DH, Yang Q, Kathiresan S. et al. CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study. Circulation 2005; 112: 1113-1120.
  • 50 Ortlepp JR, Vesper K, Mevissen V. et al. Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age. J Mol Med 2003; 81: 363-367.
  • 51 Gonzalez P, Alvarez R, Batalla A. et al. Genetic variation at the chemokine receptors CCR5/CCR2 in myocardial infarction. Genes Immun 2001; 02: 191-195.
  • 52 Benkirane M, Jin DY, Chun RF. et al. Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ 32. J Biol Chem 1997; 272: 30603-30606.
  • 53 Pai JK, Kraft P, Cannuscio CC. et al. Polymorphisms in the CC-chemokine receptor-2 (CCR2) and –5 (CCR5) genes and risk of coronary heart disease among US women. Atherosclerosis 2006; 186: 132-139.
  • 54 Simeoni E, Winkelmann BR, Hoffmann MM. et al. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 –2518 G/G genotype in CAD patients. Eur Heart J 2004; 25: 1438-1446.
  • 55 Boger CA, Fischereder M, Deinzer M. et al. RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients. Atherosclerosis 2005; 183: 121-129.
  • 56 Cybulsky MI, Hegele RA. The fractalkine receptor CX3CR1 is a key mediator of atherogenesis. J Clin Invest 2003; 111: 1118-1120.
  • 57 Moatti D, Faure S, Fumeron F. et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 2001; 97: 1925-1928.
  • 58 McDermott DH, Halcox JP, Schenke WH. et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-407.
  • 59 McDermott DH, Fong AM, Yang Q. et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest 2003; 111: 1241-1250.
  • 60 Niessner A, Marculescu R, Haschemi A. et al. Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome. A possible implication of fractalkine in inflammatory activation. Thromb Haemost 2005; 93: 949-954.
  • 61 Hegele RA. SNP judgments and freedom of association. Arterioscler Thromb Vasc Biol 2002; 22