Interleukin-18 as a Predictor of Future Events in Patients With Acute Coronary Syndromes
Objective—The aim of this study was to assess the short- and long-term prognostic significance of interleukin-18 (IL-18) levels in patients with acute coronary syndromes (ACS).
Methods and Results—In patients hospitalized with ACS (median age, 66 years; 30% females), we evaluated associations of serum IL-18 levels from day 1 (n=1261) with the short- (<3 months) and long-term (median, 7.6 years) risk of death, development of congestive heart failure (CHF), and myocardial infarction (MI). IL-18 was not significantly associated with short-term mortality. In the long term, IL-18 levels were significantly related to all-cause mortality, even after adjustment for clinical confounders (hazard ratio [HR], 1.19; 95% confidence interval, 1.07 to 1.33; P=0.002). Long-term, cardiovascular mortality was univariately related to IL-18, and the adjusted relation between noncardiovascular mortality and IL-18 was highly significant (HR, 1.36; 95% confidence interval, 1.11 to 1.67; P=0.003). IL-18 independently predicted CHF, MI, and cardiovascular death/CHF/MI in both the short and long term. Measurements from day 1 of ACS and 3 months after ACS had a similar power to predict late outcome.
Conclusion—The addition of the measurement of IL-18 to clinical variables improved the prediction of risk of all-cause and noncardiovascular mortality. The association between IL-18 and noncardiovascular mortality is intriguing and warrants further study.
Inflammation is essential for atherogenesis,1 and many inflammatory markers have been analyzed for their association with short- and long-term outcome in patients with manifestations of coronary artery disease2 and in apparently healthy subjects.3 The proinflammatory cytokine interleukin-18 (IL-18), an interferon-γ-inducing factor that stimulates interferon-γ production in T-lymphocytes and natural killer cells, is of particular interest as a predictor of cardiovascular events, because both clinical and experimental studies have supported its role in atherosclerotic plaque progression and destabilization.4–7 According to these findings, IL-18 may play a major role in the process that terminates in plaque rupture, thrombus formation, and an acute coronary syndrome (ACS).
Several partly conflicting reports on the power of single baseline measurements of IL-18 to predict cardiovascular mortality and composite end points in population studies8,9 and patients with coronary artery disease are available.10–12 Few studies have studied fatal and nonfatal myocardial infarction (MI) and the development of congestive heart failure (CHF).13 Given the mechanisms by which IL-18 is supposed to act, these end points, in addition to death, are of interest. The present study included a large number of ACS patients who were followed for a median of 7.6 years. Our aim was to study the associations of levels of IL-18 with the risk of mortality and cardiovascular morbidity during short- and long-term follow-up. Another aim was to compare serum levels of IL-18 from the acute phase with those from a later stable phase, without the influence of myocardial necrosis and reperfusion injury, and to evaluate the association of these 2 measurements with the risk of outcome events.
Between September 1995 and March 2001, all patients admitted to the coronary care unit at Sahlgrenska University Hospital with signs or symptoms of an ACS were recruited for a study of prognosis and risk factors in ACS. This study has been described in detail.14 All patients who had a MI, with or without ST segment elevation, or unstable angina were included, unless they lived outside the hospital’s catchment area, were ≥80 years old, had an anticipated survival of less than 1 year because of factors unrelated to coronary heart disease, had already been included in the study, or were unwilling to participate. The study was approved by the Regional Ethics Committee of Gothenburg University, and informed consent was obtained from all subjects.
Detailed information on medical history related to angina, MI, CHF, risk factors, and medication was obtained from the medical records and by personal interviews performed by a research nurse. The patients were prospectively classified by ECG changes at admission, Killip class at admission and during hospitalization, and treatment before and after admission.
Blood samples were obtained at 3 specified time points—the first morning after admission, the morning of approximately day 4, and the 3-month follow-up visit. Sample sizes for each analysis are given in the results section. Serum creatine kinase MB fractions (CK-MB) were analyzed routinely (Roche Diagnostics, Mannheim, Germany) throughout the study period. Measurements of troponin T were gradually incorporated into clinical practice during the late 1990s. Echocardiography was performed by an experienced investigator within 5 days after hospital admission.
Outcomes were as follows: all-cause mortality based on survival confirmation and date of death from the Swedish National Population Registry; cardiovascular mortality with International Statistical Classification of Disease, Ninth Revision (ICD-9) codes 390 to 459 or Tenth Revision (ICD-10) codes I00 to I99; noncardiovascular mortality with ICD-9 and ICD-10 codes excluding cardiovascular disease; development of CHF or recurrence of MI during the index hospitalization, or rehospitalization for CHF (ICD-9 code 428 or ICD-10 code I50) or for acute MI (ICD-9 code 410 or ICD-10 code I21 or I22); and the composite end point cardiovascular death/CHF/MI. Information on cardiovascular/noncardiovascular mortality was obtained from the Swedish National Cause of Death Register, and morbidity data were obtained from the Swedish Hospital Discharge Register. Outcomes were studied during 3 separate time periods: within 3 months from the index episode of ACS (short-term prognosis); from the index event until the end of follow-up, January 1, 2007 (long-term prognosis); and from month 3 until the end of follow-up (late long-term prognosis). The median follow-up was 7.6 years (interquartile range, 5.8 to 9.2 years).
Blood Sampling and Laboratory Analyses
Peripheral venous blood was obtained by venipuncture of an antecubital vein after a rest of >30 minutes. Serum samples were centrifuged after 1 hour at room temperature; plasma samples were drawn into precooled EDTA tubes and cold centrifuged within 30 minutes. All plasma and serum samples were stored at −70°C before analysis. Plasma for C-reactive protein (CRP) and serum for IL-18 analyses was thawed once at the Wallenberg Laboratory, Sahlgrenska University Hospital. Because EDTA plasma was not obtained during the early phase of the study, CRP data are not available for all patients with IL-18 values. Circulating IL-18 levels were determined with an enzyme-linked immunosorbent assay (Medical and Biological Laboratories, Nagoya, Japan). CRP was measured with an ultrasensitive immunoturbidimetric method (Orion Diagnostica, Espoo, Finland) on a Konelab 20 autoanalyzer (Thermo Fisher Scientific, Vantaa, Finland). The glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault formula.
Categorical variables were presented as proportions and continuous variables as mean or median values, with standard deviation and interquartiles, respectively. The associations between baseline characteristics and IL-18 levels were tested using the Mann-Whitney U test for dichotomous variables and the Spearman rank-order statistic for continuous variables. The former was also used to test for difference between the no-event group and each of the 4 other outcome groups in Table 2, with regard to continuous baseline variables, whereas the Fisher exact test was used for corresponding dichotomous variables. Actuarial methods were used to analyze mortality and morbidity. Event-free individuals were censored at time of death (for morbidity and specific cause of death end points) or time of emigration (for the 10 patients who were lost from follow-up for this reason) or January 1, 2007 (end of follow-up), whichever occurred first. To visualize the relationship between IL-18 and mortality, a Kaplan-Meier plot was generated. Cox proportional hazards regression analysis was used to calculate crude and adjusted risk estimates associated with a 1 SD increase in logarithmically transformed IL-18 levels for the different outcomes. In the multivariate analyses, we adjusted for 13 potential confounders deemed to be of clinical relevance. These were age, gender, previous MI, previous angina, previous CHF, previous diabetes, previous hypertension, current smoker, ST segment elevation at admission, heart rate at admission, peak CK-MB, estimated GFR, and Killip class >1 at admission. In addition, in the subgroup where CRP measurements were available, we also adjusted for this variable.
Changes in IL-18 levels between different time points were tested using the Wilcoxon signed rank test, and Mann-Whitney U test was used to analyze differences between diagnosis groups. Spearman rank order correlation was used to test and estimate association between IL-18 levels and markers of myocardial injury, as well as left ventricular ejection fraction.
Probability values below 0.05 (2-sided test) were considered statistically significant.
The median age of the 1261 ACS patients included in this report was 66 years (range, 32 to 79 years), and 30% of the patients were women. The index diagnosis was ST segment elevation MI in 525 (42%) patients, non–ST segment elevation MI in 441 (35%), and unstable angina in 295 (23%). There were 387 deaths, 271 cardiovascular and 116 noncardiovascular, during a median follow-up of 7.6 years. Among the latter, cancer was the cause of death in 66 cases, and an additional 3 were diagnosed with cancer. Baseline characteristics in relation to IL-18 levels are given in Table 1. Female gender was associated with lower levels of IL-18. Diabetes, ST segment elevation and Q-waves on the admission ECG, low systolic blood pressure, and increased heart rate were associated with higher levels. Higher IL-18 levels were also associated with indices of CHF (eg, Killip class and ejection fraction), body mass index, and CRP levels. IL-18 was inversely associated with subacute revascularization procedures during the index event. There were no significant associations between IL-18 levels and medications for ACS.
In Table 2, IL-18 levels and clinical characteristics are given according to outcome in terms of CHF, MI, cardiovascular or noncardiovascular death, or no event. Patients with no event were younger. In this group, and also in patients with noncardiovascular death, the frequency of diabetes was lower than among patients with cardiovascular events. The groups with cardiovascular outcomes were similar for most variables, except for signs of more extensive myocardial damage in patients with CHF. Levels of IL-18 were lower in patients with no event than in the other 4 groups.
IL-18 in Relation to Short-Term Mortality and Morbidity
IL-18 levels were not significantly associated with the risk of short-term mortality; the hazard ratio (HR) associated with a 1 SD increase in logarithmically transformed IL-18 levels at day 1 was 1.22 (95% confidence interval [CI], 0.94 to 1.59; P=0.14; Table 3). All 56 deaths during the first 3 months were cardiovascular. IL-18 levels were significantly related to CHF, reinfarction, and the composite end point of cardiovascular death/CHF/MI, both in univariate analyses and after adjustment for clinical confounders, as described in Methods (uni- and multivariate HRs for the composite cardiovascular end point, 1.35; 95% CI, 1.20 to 1.51; P<0.0001; and HR, 1.21; 95% CI 1.07 to 1.38; P=0.002, respectively). After further adjustment for CRP in patients in whom it had been measured (n=705), the relationships between IL-18 and events were no longer significant.
IL-18 in Relation to Long-Term Mortality and Morbidity
The Figure (n=1261) shows all-cause mortality in IL-18 quartiles from the index event through 10 years. When comparing the 4th quartile with the 1st quartile of IL-18 levels, the risk of death in the 4th quartile was more than doubled, with an HR of 2.24 and 95% CI of 1.66 to 3.02 (P<0.0001). The risk of death in the 2nd and 3rd quartiles was very similar, ≈50% higher than in the 1st. Table 4 shows the HRs per 1 SD increase in logarithmically transformed IL-18 values for all-cause mortality, cardiovascular mortality, development of CHF and MI, the composite cardiovascular end point (death/CHF/MI), and noncardiovascular mortality. IL-18 levels were significantly associated with long-term all-cause mortality, not only in univariate analyses but also after adjustment for clinical confounders, as described in Methods (HR, 1.19. 95% CI, 1.07 to 1.33; P=0.002). The association with cardiovascular mortality was not statistically significant after adjustment for clinical risk factors (HR, 1.13; 95% CI, 0.99 to 1.29; P=0.07). IL-18 was an independent predictor of CHF (HR, 1.18; 95% CI, 1.04 to 1.33; P=0.008), MI (HR, 1.20; 95% CI, 1.04 to 1.38; P=0.01) and the combined cardiovascular end point (HR, 1.15; 95% CI, 1.05 to 1.26; P=0.003). Interestingly, IL-18 was strongly associated with noncardiovascular long-term mortality in univariate analyses, as well as after adjustment for clinical confounders (HR, 1.36; 95% CI, 1.11 to 1.67; P=0.003). After adjustment for CRP, the associations between IL-18 and all-cause mortality, CHF, and noncardiovascular mortality remained statistically significant.
For 630 subjects, IL-18 measurements were available from day 1 and month 3. The associations between these 2 measurements and the late long-term follow-up (from month 3) are shown in Table 5. Measurements from day 1 and month 3 were both independently associated with all-cause mortality and noncardiovascular mortality, but they were associated with cardiovascular death only in univariate analyses. The associations with outcome variables were of approximately the same magnitude for the 3-month and the day 1 IL-18 measurements.
IL-18 in the Acute and Subacute Phases and After 3 Months
In 3 subgroups of patients, IL-18 measurements from different time points were available, allowing intraindividual comparisons (days 1 and 4 during index hospitalization and at a follow-up visit after 3 months [n=116], days 1 and 4 [n=263], and day 1 and month 3 [n=630]). IL-18 levels were significantly higher at day 4 than at day 1 (P<0.0001), but they were similar at day 1 and month 3. During the index event, there were no significant differences in IL-18 levels between patients with various types of ACS, and the increase from day 1 to day 4 was not significantly larger in MI patients than in those with unstable angina
Correlations Between IL-18, CRP, and Markers of Myocardial Injury and Left Ventricular Function
There was a statistically significant, yet fairly weak, correlation between IL-18 and CRP at day 1 (r=0.161, n=730; P<0.0001). In the subgroup in which CRP values were available, IL-18 did not correlate significantly with CK-MB (r=0.060, n=730; P=0.10) or left ventricular ejection fraction (r=−0.074, n=582; P=0.07), whereas CRP was significantly correlated with these 2 variables (r=0.344, n=730; P<0.0001; and r=−0.291, n=582; P<0.0001, respectively). There was a strong correlation between IL-18 levels from day 1 and month 3 (r=0.84, n=630; P<0.0001).
In this study, in patients hospitalized for a broad spectrum of ACS, the serum IL-18 levels predicted a risk of all-cause mortality and noncardiovascular mortality and added prognostic information to clinical variables. The association between IL-18 levels and risk of cardiovascular mortality, although of similar strength in univariate analysis, did not reach statistical significance after adjustment for clinical confounders. The serum concentration of IL-18 was independently associated with the risk of developing CHF and recurrent MI and the combined cardiovascular end point of death/CHF/MI. In previous reports on IL-18 as a significant predictor of outcomes in population studies and patients with cardiovascular diseases, the end point in the majority of cases has been a composite of cardiovascular death and coronary events.8,11,12,15 The AtheroGene Investigators presented data on IL-18 in relation to death from cardiovascular causes in patients with coronary artery disease and found that, although it is a strong independent predictor during the first years,10 the serum IL-18 level is no longer predictive of cardiovascular death occurring after 4 years of follow-up.16 In our study, no statistically significant risk association between IL-18 and death, either cardiovascular or all-cause, appeared during the first months, but it was present later on, although cardiovascular risk indication was abolished by adjustment for confounders. The lack of any statistically significant association with early death in our study may have several explanations. All deaths up to 3 months were cardiovascular, and the total number of deaths was low. It is possible that an early univariate association with cardiovascular mortality would have been found if the number had been larger. It is also possible that adverse effects associated with elevated IL-18 levels develop into clinical expression only after a longer time period. It is worth noting that the composite cardiovascular end point was predicted in our study in both the short and long term, as were the single outcomes, CHF and MI. In agreement with the AtheroGene study,10 this lends support to the hypothesis that IL-18 plays a role in atherosclerosis and its complications.
Our finding of a close independent association between IL-18 and noncardiovascular mortality is new and intriguing. Univariately, the association between IL-18 and cardiovascular and noncardiovascular long-term mortality was similar. It seems unlikely that the finding could be explained by an association between the IL-18-dependent risk increment and medication, because there were no significant associations between IL-18 levels and any of the standard drugs used for treatment of ACS. IL-18 is a proinflammatory cytokine involved in both innate and acquired immune responses and, in addition to atherosclerosis and its complications, it has been suggested that it plays a role in tumors, infections and autoimmune and inflammatory diseases.17–20 One important disease area associated with IL-18 is the metabolic syndrome, in which elevated levels have been reported even before the diagnosis of diabetes has been established.21 In line with this, diabetes mellitus was an important characteristic of our patients with higher IL-18 levels. However, an association with diabetes could hardly explain the relationship between IL-18 and noncardiovascular mortality, because among the patients that died from other causes, the frequency of diabetes was less than half of that in patients with a cardiovascular death. The only characteristic of the patients with noncardiovascular deaths that appears to fit with any of the suggested IL-18-related diseases would be cancer, because more than half of them had a tumor diagnosis. Additional studies to explore the relationship between IL-18 and cancer in population studies are warranted.
Among our ACS patients, increased IL-18 levels were associated with a less favorable prognosis both before and after adjustment for CRP levels. In one study of patients with stable and unstable angina, IL-18 was a strong predictor of death from cardiovascular causes, and the association remained unaffected not only by CRP but also by IL-6 and fibrinogen.10 The latter 3 variables, all acute-phase reactants, were strongly correlated and, in agreement with our findings, CRP showed only a modest correlation with IL-18. This suggests that the pathophysiological mechanisms that link IL-18 to cardiovascular events are different from those of CRP and other acute-phase reactants. In another study in patients with a previous MI, IL-18 was significantly associated with coronary plaque area, and the risk of restenosis was increased in patients with elevated IL-18 levels after percutaneous coronary intervention for acute MI.5,22 These findings support the theory that IL-18 is a cytokine with particular involvement in atherosclerotic plaque progression and instability. Further support for this theory is the finding of a much higher expression of IL-18 in human atherosclerotic plaques than in normal arteries6 and the finding that the overexpression of IL-18 in apolipoprotein E–deficient mice increases vulnerability to plaque rupture, as judged from plaque morphology.4
In the present study, IL-18 levels were independent predictors of CHF in both the short and long term and, in the latter case, also after adjustment for CRP. In addition to its proatherogenic effects, IL-18 has been implicated in myocardial dysfunction and the development of CHF.23,24 For example, IL-18 levels have been found to be significantly elevated in patients with CHF and were higher in those who died than in those who survived.25 Elevated levels of IL-18 were also observed in cardiac tissue and in the circulation after myocardial ischemia and reperfusion; in animal experiments, the administration of IL-18-neutralizing antibodies significantly reduced infarct size.26
The increase in IL-18 concentrations during the acute event was not significantly larger in our patients with MI than in those with unstable angina, and the correlation between IL-18 and traditional marker of myocardial injury was weak. However, in contrast, CRP correlated strongly with CK MB, indicating, in line with suggestions by James et al,27 that the CRP response in ACS most probably reflects the myocardial necrosis and not the ruptured atherosclerotic plaque or the total arteriosclerotic burden. Although we saw a slight increase in IL-18 in connection with the index hospitalization, it seems unlikely that this elevation reflects the same type of pathophysiological course of events as the increase in CRP.
Our close association between IL-18 measurements from the acute coronary episode and from a stable phase 3 months later and the lack of difference between them appear to indicate that IL-18 levels are fairly stable and are raised for reasons other than the acute coronary event.
Strength and Limitations
One strength of the present single-center study is the large sample size and the long follow-up, with few dropouts and with a large number of end points. One limitation is the fact that data on IL-18 and CRP were not available for all patients at all the time points, necessitating subgroup analyses. The subgroups with repeated measurements of IL-18, ie, patients who survived their acute event and accepted repeated blood sampling, cannot be regarded as totally representative of the whole study population. We cannot exclude the possibility that our finding related to the day 4 levels of IL-18 might have been somewhat different had the number of patients been larger and also included the most ill patients with the largest infarctions.
In patients with ACS, IL-18 levels were strongly and independently associated with late all-cause mortality, and we also found an independent association with the development of CHF and MI. IL-18 therefore adds prognostic information to clinical variables and to other inflammation markers. The effect of IL-18 appears to be mediated by mechanisms other than other acute-phase reactants. One unexpected finding was that IL-18 predicts noncardiovascular mortality and, in this group of patients, adds information to clinical variables. Because most of the noncardiovascular deaths were cancer related, this may suggest a link between cancer and IL-18.
Sources of Funding
This study was supported by the Swedish Research Council (Grant 14231), the Swedish Heart and Lung Foundation, the Västra Götaland Region, AstraZeneca R&D, the Vardal Foundation, Gothenburg University, and the Göteborg Medical Society.
Received on: December 31, 2009; final version accepted on: July 23, 2010.
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