Circulation. 2002;106:24-30
Published online before print June 3, 2002, doi: 10.1161/01.CIR.0000020546.30940.92
Published online before print June 3, 2002, doi: 10.1161/01.CIR.0000020546.30940.92
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(Circulation. 2002;106:24.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina
From the Department of Medicine II (S.B., C.B., J.M., H.J.R.) and the Department of Clinical Chemistry (D.P.), Johannes Gutenberg-University, Mainz, Germany; and INSERM U525, Faculté de Médecine Pitié-Salpétrière (S.B., L.T., F.C.), Paris, France.
Correspondence to Stefan Blankenberg, MD, INSERM U 525, Faculté de Médecine Pitié-Salpétrière, 91 bld de l’Hôpital, 75634 Paris cedex 13, France. E-mail stefan.blankenberg{at}chups.jussieu.fr
Background— Interleukin (IL)-18 plays a central role in orchestrating the cytokine cascade and accelerates atherosclerosis and plaque vulnerability in animal models. However, epidemiological data evaluating the role of IL-18 levels in atherosclerosis are lacking.
Methods and Results— In a prospective study of 1229 patients with documented coronary artery disease, we measured baseline serum concentrations of IL-18 and other markers of inflammation. During the follow-up period (median, 3.9 years), 95 patients died of cardiovascular causes. Median serum concentrations of IL-18 were significantly higher among patients who had a fatal cardiovascular event than among those who did not (68.4 versus 58.7 pg/mL; P<0.0001). The hazard risk ratio of future cardiovascular death increased with increasing quartiles of IL-18 (hazard risk ratio, 1.46; 95% CI 1.21 to 1.76; P for trend <0.0001). After adjustment for most potential confounders, including the strong predictor ejection fraction as well as the inflammatory variables IL-6, high-sensitive C-reactive protein, and fibrinogen, this relation remained almost unchanged, such that patients within the highest quartile of IL-18 had a 3.3-fold increase in hazard risk compared with those in the first quartile (95% CI, 1.3 to 8.4, P=0.01). This relation was observed in patients with stable angina and patients with unstable angina at baseline.
Conclusions— Serum IL-18 level was identified as a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease regardless of the clinical status at admission. This result strongly supports recent experimental evidence of IL-18–mediated inflammation leading to acceleration and vulnerability of atherosclerotic plaques.
Key Words: interleukins • inflammation • prognosis • coronary disease
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E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen Atherosclerotic Plaque Rupture: Local or Systemic Process? Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2123 - 2130. [Abstract] [Full Text] [PDF]
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S. Blankenberg, G. Luc, P. Ducimetiere, D. Arveiler, J. Ferrieres, P. Amouyel, A. Evans, F. Cambien, L. Tiret, and on behalf of the PRIME Study Group Interleukin-18 and the Risk of Coronary Heart Disease in European Men: The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Circulation, November 18, 2003; 108(20): 2453 - 2459. [Abstract] [Full Text] [PDF]
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R. Marfella, M. Siniscalchi, K. Esposito, A. Sellitto, U. de Fanis, C. Romano, M. Portoghese, S. Siciliano, F. Nappo, F. C. Sasso, et al. Effects of Stress Hyperglycemia on Acute Myocardial Infarction: Role of inflammatory immune process in functional cardiac outcome Diabetes Care, November 1, 2003; 26(11): 3129 - 3135. [Abstract] [Full Text] [PDF]
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P. E. Szmitko, C.-H. Wang, R. D. Weisel, J. R. de Almeida, T. J. Anderson, and S. Verma New Markers of Inflammation and Endothelial Cell Activation: Part I Circulation, October 21, 2003; 108(16): 1917 - 1923. [Full Text] [PDF]
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Y. Aso, K.-i. Okumura, K. Takebayashi, S. Wakabayashi, and T. Inukai Relationships of Plasma Interleukin-18 Concentrations to Hyperhomocysteinemia and Carotid Intimal-Media Wall Thickness in Patients With Type 2 Diabetes Diabetes Care, September 1, 2003; 26(9): 2622 - 2627. [Abstract] [Full Text] [PDF]
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P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1927 - 1939. [Full Text] [PDF]
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 P. Reidar Woldbaek, T. Tonnessen, U. Lie Henriksen, G. Florholmen, P. Kristian Lunde, T. Lyberg, and G. Christensen Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction Cardiovasc Res, July 1, 2003; 59(1): 122 - 131. [Abstract] [Full Text] [PDF]
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A. Kretowski, I. Kinalska, K. Esposito, F. Nappo, R. Marfella, G. Giugliano, F. Giugliano, M. Ciotola, D. Giugliano, L. Quagliaro, et al. Serum Levels of Interleukin-18--a Potential Marker of Cardiovascular Death--Could Be Determined by Genetic Predisposition * Response Circulation, June 10, 2003; 107 (22): e206 - e207. [Full Text] [PDF]
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K. Esposito, F. Nappo, F. Giugliano, C. Di Palo, M. Ciotola, M. Barbieri, G. Paolisso, and D. Giugliano Cytokine Milieu Tends Toward Inflammation in Type 2 Diabetes Diabetes Care, May 1, 2003; 26(5): 1647 - 1647. [Full Text] [PDF]
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K. Esposito, A. Pontillo, C. Di Palo, G. Giugliano, M. Masella, R. Marfella, and D. Giugliano Effect of Weight Loss and Lifestyle Changes on Vascular Inflammatory Markers in Obese Women: A Randomized Trial JAMA, April 9, 2003; 289(14): 1799 - 1804. [Abstract] [Full Text] [PDF]
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S. Blankenberg, H. J. Rupprecht, O. Poirier, C. Bickel, M. Smieja, G. Hafner, J. Meyer, F. Cambien, L. Tiret, and for the AtheroGene Investigators Plasma Concentrations and Genetic Variation of Matrix Metalloproteinase 9 and Prognosis of Patients With Cardiovascular Disease Circulation, April 1, 2003; 107(12): 1579 - 1585. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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Z. Mallat, J.-S. Silvestre, S. Le Ricousse-Roussanne, L. Lecomte-Raclet, A. Corbaz, M. Clergue, M. Duriez, V. Barateau, S. Akira, A. Tedgui, et al. Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Ischemia-Induced Neovascularization in Mice Hindlimb Circ. Res., September 6, 2002; 91(5): 441 - 448. [Abstract] [Full Text] [PDF]
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