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227 which serum should be used

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227 which serum should be used

  1. 1. Editorial Slides VP Watch –June 12, 2002 - Volume 2, Issue 23 CRP, IL-6, CD-40, PAPP-a, CTX-3, IL-18,… Which One?
  2. 2.  Atherosclerosis is an inflammatory disease. 1  Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development from leukocyte recruitment to eventual rupture of the vulnerable plaque. 1  Elevated levels of P-selectin, ICAM-1, IL-6, TNF-α , and CRP have been shown to predict future vascular risk in a variety of clinical settings.
  3. 3.  A previously unknown inducer of interferon- gamma (IFN-γ) was discovered and named interleukin-18 (IL-18) in 1989.  IL-18 stimulates IFN-γ production by initiating IFN- γ gene transcription via activation of the IFN-γ promoter.  Cells known to express IL-18 include macrophages, keratinocytes, glucocorticoid- secreting adrenal cortex cells, and osteoblasts.
  4. 4.  Studies showed that IL-18 induces IFN-γ expression not only in macrophages, but also in vascular SMCs.  Both IL-18 and IL-18R (receptor) /ß are over -expressed within human atheroma in situ compared with non-diseased arterial tissue.4  Whitman and colleagues showed that exogenous IL-18 increases atherosclerotic plaque development in ApoE deficient mice through enhancement of an inflammatory response via an IFN-γ dependent mechanism.6  Mallat et al. found that exogenous expression of the murine IL-18 binding protein (the endogenous inhibitor of IL-18) reduced plaque development in ApoE-KO mice. 7
  5. 5.  Mallat and colleagues also showed that IL- 18 levels are related to pathological and clinical signs of plaque instability.3  Their results suggest an important role for IL-18 in ischemic myocardial dysfunction leading to severe clinical events and eventually to death.3
  6. 6. IL-18/IL-18BP in Atherosclerosis IL-18mRNA and Plaque Stability mRNA expression (relative to GAPDH) ** p < 0.0074 Symptomatic Asymptomatic 1 0 2 3 4 * p < 0.018 Ulceration No Ulceration mRNA expression (relative to GAPDH) 1 0 2 3 4 Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y, Tedgui A. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. . 2001; 104: 1598–1603. Quantitative data for IL-18 mRNA expression according to clinical (A) or pathological (B) signs of plaque instability were displayed graphically. A B
  7. 7.  As reported in VP Watch of this week, Blankenberg and colleagues showed that median serum concentration of IL-18 was significantly higher among CAD patients who had a fatal cardiovascular event than among those who did not have fatal events.8
  8. 8.  They showed that the hazard risk ratio of future cardiovascular death increased with increasing quartiles of IL-18. 8  After adjustment for most potential confounders, including ejection fraction as well as IL-6, hsCRP, 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.8
  9. 9. HRR Lower CI Upper CI P value Age, Y 1.05 1.02 1.09 0.002 Diabetes 1.77 1.00 3012 0.05 Hypertention 1.10 0.64 2.18 0.6 HDL 1.01 0.78 1.31 0.9 Trigelyceride 1.9 0.85 1.40 0.5 Number of vessel disease 0.53 0.66 1.24 0.5 Β-Blocker 0.74 0.44 1.25 0.3 Statin therapy 0.73 0.39 1.36 0.3 Ejection fraction 0.97 0.96 0.98 <0.0001 hs-CRP 0.94 0.70 1.25 0.7 Fibrinogen 1.19 0.88 1.50 0.2 IL-6 1.15 0.90 1.49 0.3 IL-18 1.50 1.17 1.92 0.001 Independent predictors of death from cardiovascular causes after a median follow-up of 3.9 years in cox regression model when all variables presented simultaneously in 1229 patients with CAD Stefan Blankenberg, Laurence Tiret, Christoph Bickel, Dirk Peetz, François Cambien, Jürgen Meyer, and Hans J. Rupprecht; Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina; Circulation published June 3, 2002 HRR=Hazard Risk Ratios
  10. 10. Conclusion • Expression of IL-18 is associated with the presence of both clinical (unstable symptomatic plaque) and pathological (ulcerated plaque) signs of plaque vulnerability. • Serum IL-18 is a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease regardless of the clinical status at admission.
  11. 11. Questions: • Surprisingly in this study a number of well known predictors of outcome such as lipid- lowering therapy did not correlate with the outcome. How representative is the study population? • Is IL-18 an independent predictor of future coronary events in healthy population as well as symptomatic patients?
  12. 12. Questions: • Is the effect of IL-18 on plaque inflammation / vulnerability mediated only by INF-γ? If so, does blocking INF-γ (INF-KO mice) prevent the effect of IL-18 on atherosclerotic plaque? • Since IL-18 is a non-specific proinflammatory cytokine, does serum IL-18 increase in response to common infections? If so would that be significant enough to affect the plaque stability?
  13. 13. 1) Ross, R. 1999. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340:115–126. 2) Dinarello CA. Interleukin-18: a proinflammatory cytokine. Eur Cytokine Netw. . 2000; 11: 483–486. 3) Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y, Tedgui A. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. . 2001; 104: 1598–1603. 4) Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U.; Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis.; J Exp Med. 2002 Jan 21;195(2):245-57. 5) Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001; 89: 763–771. 6) Whitman SC, Ravisankar P, Daugherty A.; Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma.; Circ Res 2002 Feb 8;90(2):E34-8 7) Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B, Humbert Y, Chvatchko Y, Tedgui A. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res. 2001; 89: e41–e45. 8) Stefan Blankenberg, Laurence Tiret, Christoph Bickel, Dirk Peetz, François Cambien, Jürgen Meyer, and Hans J. Rupprecht; Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina; Circulation published June 3, 2002 References

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