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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

Stefan Blankenberg, MD; Laurence Tiret, PhD; Christoph Bickel, MD; Dirk Peetz, MD; François Cambien, MD; Jürgen Meyer, MD; Hans J. Rupprecht, MD, for the AtheroGene Investigators^*

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

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
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

	Introduction

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Inflammatory mediators are intimately associated with the cascade of events leading to atherosclerotic plaque initiation, development, and rupture.^1,2 This recognition has stimulated the evaluation of several markers of inflammation as potential tools for cardiovascular risk prediction.^3,4

Interleukin (IL)-18, originally identified as an interferon (IFN)-–inducing factor in Kupffer cells and macrophages, ⁵ plays a central role in the inflammatory cascade and in the processes of innate and acquired immunities because of its ability to induce IFN- production in T lymphocytes and natural killer cells, which is believed to play a crucial role in atherosclerotic plaque rupture.^6,7 Furthermore, IL-18 acts in synergy with IL-12 to promote the development of T helper 1 (T_H1) responses.^8–10

Recently, increased IL-18 expression has been reported in human atherosclerotic plaque,¹¹ mediating INF- release locally.¹² Furthermore, animal models support the proatherogenic role of IL-18¹³ as well as the beneficial effect of inhibiting IL-18 on plaque progression and composition.¹⁴ Although one study demonstrated elevated levels of IL-18 in patients with acute myocardial infarction,¹⁵ no data exist on the prognostic impact of IL-18 on future cardiovascular events.

On the basis of the above-mentioned experimental data, we evaluated whether baseline serum levels of IL-18 might be predictive of future fatal cardiovascular events in patients with coronary artery disease (CAD). We especially aimed to investigate the predictive power of IL-18 in comparison with other markers of chronic inflammation.

	Methods

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Study Population
Between November 1996 and June 2000, 1299 patients who underwent coronary angiography at the II Medical Department of the Johannes Gutenberg-University Mainz or the Bundeswehrzentralkrankenhaus Koblenz, with at least 1 stenosis >30% diagnosed in a major coronary artery were enrolled in a cardiovascular registry (AtheroGene Study). For the present study, we excluded 70 patients with acute myocardial infarction within the preceding 48 hours; therefore the final study cohort consisted of 1229 patients, who provided plasma and serum samples that were stored at -80°C until analysis. A detailed study description has been outlined elsewhere.¹⁶ Briefly, exclusion criteria of the AtheroGene study were evidence of hemodynamically significant valvular heart disease, surgery or trauma within the prior month, known cardiomyopathy, known malignant diseases, febrile conditions, or oral anticoagulant therapy within the prior 4 weeks. Unstable angina (n=374) was classified by Braunwald classification (class B or C).

Patients were followed up during a median of 3.9 (maximum: 5.2) years. Follow-up information was obtained about death from cardiovascular causes (n=95), death from causes not related to heart disease (n=18), and nonfatal myocardial infarction (n=43). Information about the cause of death or clinical events was obtained from hospital or general practitioner charts.

Study participants had German nationality. The ethics committee of the University of Mainz approved the study. Participation was voluntary, and each study subject gave written informed consent.

Laboratory Methods
Serum IL-18 was measured with a commercially available ELISA method (MBL Co, Ltd). Coefficients of variation ranged from 3% to 14%, and repeat determinations on the same serum sample were highly correlated (r=0.98). C-reactive protein was determined by a highly sensitive, latex particle–enhanced immunoassay (detection range of 0 to 20 mg/L, Roche Diagnostics), IL-6 by ELISA (EASIA, Biosource Europe), fibrinogen by a derived method, and troponin I by an immunoassay (DADE Behring). Lipid serum levels were measured immediately.

Statistical Considerations
Mean levels of variables were compared across quartiles of IL-18 by ANOVA for normal variables, Kruskall-Wallis test for skewed variables, and ² test for categorical variables. In all survival analyses, the end point was death from cardiovascular causes, and data on patients who died of other causes were censored at the time of death. The association of IL-18 with outcome was evaluated by Cox regression analysis adjusted for potential confounders. In these analyses, IL-18 and other inflammatory markers were considered either as continuous variables (log-transformed) or in quartiles. Hazard risk ratios (HRRs) and 95% CIs are reported with 2-tailed probability values. A value of P<0.05 was considered to be significant. All computations were carried out with SPSS, version 10.07.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Characteristics of the Study Population
Table 1 gives patient characteristics according to quartiles of IL-18. The median IL-18 level was 59.6 pg/mL (25th/75th interquartile, 45.0/77.7). When stratifying data for patients with stable or unstable angina, similar results were observed in the two groups except for the association with high-sensitive C-reactive protein (hs-CRP) and IL-6, which was mainly driven by patients with unstable angina.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Patients With CAD According to Quartiles of IL-18

IL-18, Markers of Inflammation and Necrosis, and Cardiovascular Risk Factors
Unlike the other inflammatory markers (IL-6, hs-CRP, and fibrinogen), IL-18 levels did not correlate with age (Table 2). By contrast, the negative correlation of HDL cholesterol and IL-18 was of a magnitude similar to that observed with other inflammatory markers. IL-18 concentrations showed a modest correlation with hs-CRP and IL-6, mainly in patients with unstable angina, but did not correlate with fibrinogen levels. This result strikingly contrasted with the strong associations observed within the cluster of the 3 acute phase reactants. In unstable angina, levels of the myocardial necrosis marker troponin I correlated with hs-CRP, IL-6, or fibrinogen but not with IL-18 (Table 2).

View this table: [in this window] [in a new window]   Table 2. Association Between Inflammatory Markers, Lipid Values, and Prognostic Factors in Patients With Stable and Unstable Angina

IL-18 Concentrations and Future Death From Cardiovascular Causes
As shown in Figure 1, median serum concentrations of IL-18 at baseline were significantly higher among patients who had a fatal cardiovascular event during follow-up than among those who did not (68.4 versus 58.7 pg/mL, P<0.0001). The upper two quartiles of IL-18 had the highest probability of death from cardiovascular causes during the entire follow-up period (Figure 2). As further demonstrated in Table 3, each quartile increase in baseline IL-18 concentration was associated with a 1.46 (95% CI, 1.21 to 1.76; P<0.0001) increase in risk for future cardiovascular death. The association of IL-18 and future fatal events was present in all patients regardless of target vessel revascularization. However, the strongest relation between IL-18 levels and future events was seen in those individuals who were not treated by invasive strategy. Furthermore, the relation between IL-18 concentration and future cardiovascular events was mainly present in patients without statin intake at baseline, although the interaction term did not reach significance (P=0.4). However, these results must be interpreted with caution because there were only a small number of cardiovascular deaths in patients receiving statin therapy at baseline (n=24).

View larger version (23K): [in this window] [in a new window]   Figure 1. Distribution (box plot representation) of IL-18 according to follow-up cardiovascular (CV) fatal event.

View larger version (17K): [in this window] [in a new window]   Figure 2. Kaplan-Meier curves for survival according to quartiles of IL-18. Log-rank test was computed for increasing quartiles.

View this table: [in this window] [in a new window]   Table 3. Independent Predictors of Death From Cardiovascular Causes After a Median Follow-Up of 3.9 Years in 3 Cox Regression Models in 1229 Patients With CAD

To assess whether the effect of baseline IL-18 on risk was independent of hs-CRP, IL-6, and fibrinogen, a Cox regression model was applied including all four markers simultaneously (Table 3, Model 2). Adjustment for these inflammatory markers had no impact on the association between IL-18 and future cardiovascular events. If hs-CRP was introduced in the multivariate model comparing the inflammatory variables as a categorical variable by use of the threshold of upper versus lower quartiles (1.3 mg/dL), patients within the highest hs-CRP quartile revealed a 1.5 (95% CI, 0.9 to 2.5; P=0.1) increase in risk. The association of IL-18 with future fatal events remained highly significant regardless of the way hs-CRP was introduced into the model.

Figure 3 shows the HRRs for cardiovascular death according to quartiles of IL-18 from different Cox regression models. The clear increase of HRRs with increasing levels of IL-18 was observed whatever the model considered. From the final model, which included most potential confounders such as the strong predictor ejection fraction as well as the inflammatory variables, it was estimated that patients within the highest quartile of IL-18 had a 3.3-fold (95% CI, 1.3 to 8.4; P=0.01) increase in hazard risk compared with patients within the lowest quartile.

View larger version (18K): [in this window] [in a new window]   Figure 3. Hazard risk ratios for death from cardiovascular causes according to quartiles of IL-18. Lowest quartile serves as reference group. Gray squares (Model 1) indicate HRRs adjusted for age and sex; black circles (Model 2) indicate HRRs further adjusted for body mass index, prevalence of diabetes, hypertension, smoking status, HDL cholesterol, and triglycerides (log-transformed) as continuous variables, unstable angina, extent of vessel disease, history of myocardial infarction, statin and ß-blocker intake, invasive therapy, and ejection fraction as continuous variables. Gray diamonds (Model 3) indicate HRRs further adjusted for high-sensitive C-reactive protein, fibrinogen, and IL-6 included as log-transformed variables.

Outcome in Patients With Stable or Unstable Angina
We further explored the predictive value of IL-18 on cardiovascular death separately in patients with stable angina and patients with unstable angina at admission (Table 4). In both groups, there was a clear increase of risk according to IL-18. It appeared that the threshold above which there was a net excess of risk was shifted toward higher values in the group of patients with unstable angina. However, caution is needed with regard to this observation because the quartile analyses in unstable angina are based on a small sample size compared with the overall study population.

View this table: [in this window] [in a new window]   Table 4. HRRs of Future Cardiovascular Mortality According to Baseline IL-18 Levels

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
In this prospective and contemporary cohort of patients with documented CAD, we demonstrated for the first time that baseline measurement of IL-18 provides powerful information for future fatal cardiovascular events across the entire spectrum of patients with stable CAD and patients with unstable CAD. The relation between IL-18 and future cardiovascular events was independent of other risk factors and clinical features such as ejection fraction and remained unaffected by various markers of inflammation such as hs-CRP, fibrinogen, or IL-6.

Along with increasing experimental evidence implicating inflammatory and immune reactions in atherothrombosis,^1,4 a wide range of circulating markers of inflammation predict cardiovascular risk in a variety of clinical settings.^3,4 Consistent findings support a predictive role of CRP in initially healthy individuals^17,18 as well as in patients with stable angina and patients with unstable angina.^19–21 Furthermore, other inflammatory markers predict future cardiovascular events. Determination of IL-6—the most potent inducer of CRP—provides independent information on future fatal and nonfatal events in different populations,^22–24 as does measurement of soluble adhesion molecules.^25–27

IL-18 acts as an important regulator of both innate and acquired immune responses.^8–10 There are now strong experimental data supporting the hypothesis that a novel pathway for signaling in atherogenesis and plaque vulnerability involves the IL-18 receptor/ligand dyad. IL-18 has been first identified in human atherosclerotic lesions with significantly higher levels of IL-18 mRNA in unstable plaques.¹¹ Furthermore, in vitro stimulation of the IL-18 receptors on endothelial cells or smooth muscle cells triggers atheroma-associated processes such as stimulation of the cytokines IL-6 and IL-8 and expression of adhesion molecules and matrix metalloproteinases.¹² Administration of IL-18 was reported to lead to an increase in lesion size and to promote an elevation in the number of lesion-associated T-lymphocytes in animal models. Both effects were abolished in IFN-–deficient mice, strongly suggesting the importance of the IFN-–dependent pathway.¹³ Moreover, inhibition of IL-18 signaling by IL-18 binding protein has been shown to reduce lesion progression and to change plaque composition toward a stable feature, with a decrease of inflammatory cells and lipid content and an increase of smooth muscle cells and collagen.¹⁴

Taking into account the experimental background together with the present results showing the prognostic value of serum IL-18, this cytokine appears to be an excellent candidate linking local vessel wall pathology with systemic inflammation. The association between serum IL-18 and future cardiovascular events seemed somewhat different from that observed with other acute phase reactants such as hs-CRP, IL-6, or fibrinogen. First, whereas there were moderate to strong interdependencies between hs-CRP, IL-6, and fibrinogen in both stable and unstable angina, IL-18 exhibited a weak correlation with the above-mentioned inflammatory markers. Consequently, when including the inflammatory predictors simultaneously into one model, the predictive value of all acute phase reactants was weakened, whereas the relation between IL-18 and prognosis remained almost unchanged. Second, the predictive power of the inflammatory markers hs-CRP, fibrinogen, and to a lesser extent, IL-6, decreased when adjusted for ejection fraction, whereas the role of IL-18 remained nearly unaffected. It cannot be excluded that the levels of inflammatory markers might serve—at least in part—as surrogates of impaired ejection fraction. However, the ability of IL-18 to induce proatherogenic features¹² might have implications on both plaque instability and myocardial dysfunction. In the subgroup of patients with unstable angina, levels of hs-CRP, IL-6, and fibrinogen correlated with troponin I values. This indicates that in the presence of an acute coronary syndrome, elevation of hs-CRP levels might also derive from myocardial (micro)-necrosis. By contrast, levels of serum IL-18 did not correlate with troponin I values, suggesting that elevation of this marker is not a consequence of perfusion or reperfusion injury.

Interleukin-18 gene expression is stimulated by proinflammatory cytokines as well as by lipopolysaccharides. Therefore, infections might be discussed as distant triggers of IL-18, which could provide a potential link between the controversial association of previous infections and future cardiovascular events in patients with CAD.^16,28,29

Several limitations of our study deserve consideration. First, measurement of IL-18 was performed at one time only. However, previous studies have shown a continuous release of inflammatory markers during an acute coronary syndrome. Therefore, examining the time course of IL-18 during the cardiovascular event might improve its predictive value. Second, measurement of IL-18 was performed on samples that were stored at -80°C. We cannot exclude the possibility of protein degradation. Assessment of IL-18 is presently an expensive and time-consuming procedure, and before entering in clinical settings, standardized and reproducible assays as well as a consistent series of prospective studies—especially in initially healthy populations—should be available.

In conclusion, in this prospective evaluation of several inflammatory variables, we could demonstrate for the first time the strong and independent association between serum levels of IL-18 and future cardiovascular events in patients with a broad spectrum of CAD. This finding strongly supports the possibility, already suggested by experimental work, that inhibiting IL-18 might constitute a new therapeutic strategy for plaque stabilization.

	Acknowledgments

 
This study was supported by "Stiftung Rheinland-Pfalz für Innovation," Ministry for Science and Education (AZ 15202-386261/545), Mainz, Germany; Stefan Blankenberg was supported by a grant from the Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. We are indebted to Susanne Prigge, Ruediger Walscheid, and Axel Thuy (Labor Koblenz) for determining the IL-18 ELISA and to Margot Neuser for graphic work.

	Footnotes

 
*The AtheroGene investigators and recruitment centers are listed in the Appendix.

This article originally appeared Online on June 3, 2002 (Circulation. 2002;105:r143–r149).

	Appendix

Top Abstract Introduction Methods Results Discussion Appendix References

 
The AtheroGene Group: Hans-Jürgen Rupprecht, Stefan Blankenberg, Christoph Bickel, Christine Espinola-Klein, Jürgen Meyer; Department of Medicine II, Johannes-Gutenberg University Mainz; Laurence Tiret, Odette Poirier, Viviane Nicaud, Jean-Louis Georges, François Cambien; INSERM U525, Paris.

AtheroGene Recruitment Centers: Department of Medicine II, Johannes-Gutenberg University Mainz; Innere Abteilung, Bundeswehrzentralkrankenhaus, Koblenz.

Received April 10, 2002; revision received April 23, 2002; accepted April 23, 2002.

	References

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				T. K. Tso, W.-N. Huang, H.-Y. Huang, and C.-K. Chang Relationship of plasma interleukin-18 concentrations to traditional and non-traditional cardiovascular risk factors in patients with systemic lupus erythematosus Rheumatology, September 1, 2006; 45(9): 1148 - 1153. [Abstract] [Full Text] [PDF]

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				P. Maffia, G. Grassia, P. Di Meglio, R. Carnuccio, L. Berrino, P. Garside, A. Ianaro, and A. Ialenti Neutralization of Interleukin-18 Inhibits Neointimal Formation in a Rat Model of Vascular Injury Circulation, August 1, 2006; 114(5): 430 - 437. [Abstract] [Full Text] [PDF]

				S. Blankenberg, M. J. McQueen, M. Smieja, J. Pogue, C. Balion, E. Lonn, H. J. Rupprecht, C. Bickel, L. Tiret, F. Cambien, et al. Comparative Impact of Multiple Biomarkers and N-Terminal Pro-Brain Natriuretic Peptide in the Context of Conventional Risk Factors for the Prediction of Recurrent Cardiovascular Events in the Heart Outcomes Prevention Evaluation (HOPE) Study Circulation, July 18, 2006; 114(3): 201 - 208. [Abstract] [Full Text] [PDF]

				S. Blankenberg, T. Godefroy, O. Poirier, H. J. Rupprecht, S. Barbaux, C. Bickel, V. Nicaud, R. Schnabel, F. Kee, C. Morrison, et al. Haplotypes of the Caspase-1 Gene, Plasma Caspase-1 Levels, and Cardiovascular Risk Circ. Res., July 7, 2006; 99(1): 102 - 108. [Abstract] [Full Text] [PDF]

				K. Esposito and D. Giugliano Whole-grain intake cools down inflammation Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1440 - 1441. [Full Text] [PDF]

				R. S. Vasan Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations Circulation, May 16, 2006; 113(19): 2335 - 2362. [Full Text] [PDF]

				K. Esposito, M. Ciotola, D. Carleo, B. Schisano, F. Saccomanno, F. C. Sasso, D. Cozzolino, R. Assaloni, D. Merante, A. Ceriello, et al. Effect of Rosiglitazone on Endothelial Function and Inflammatory Markers in Patients With the Metabolic Syndrome Diabetes Care, May 1, 2006; 29(5): 1071 - 1076. [Abstract] [Full Text] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				E. J. Armstrong, D. A. Morrow, and M. S. Sabatine Inflammatory Biomarkers in Acute Coronary Syndromes: Part I: Introduction and Cytokines Circulation, February 14, 2006; 113(6): e72 - e75. [Full Text] [PDF]

				V. A. Korshunov, T. A. Nikonenko, V. A. Tkachuk, A. Brooks, and B. C. Berk Interleukin-18 and Macrophage Migration Inhibitory Factor Are Associated With Increased Carotid Intima-Media Thickening Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 295 - 300. [Abstract] [Full Text] [PDF]