Author + information
- Received April 30, 2003
- Revision received July 4, 2003
- Accepted July 14, 2003
- Published online January 7, 2004.
- Giuseppe Patti, MD*,
- Andrea D'Ambrosio, MD*,
- Simona Mega, MD*,
- Gabriele Giorgi, MD†,
- Enrico Maria Zardi, MD†,
- Domenico Maria Zardi, MD†,
- Giordano Dicuonzo, MD*,
- Aldo Dobrina, MD* and
- Germano Di Sciascio, MD, FACC, FESC*,* ()
- ↵*Reprint requests and correspondence:
Dr. Germano Di Sciascio, Department of Cardiovascular Sciences, Campus Bio-Medico University, Via E. Longoni, 83, 00155 Rome, Italy.
Objectives We sought to evaluate interleukin-1 receptor antagonist (IL-1Ra) levels in patients with ST-segment elevation acute myocardial infarction (AMI) upon emergency department (ED) admission in order to assess the sensitivity of such a determination by comparison with common markers of myocardial necrosis.
Background Inflammatory markers are elevated in patients with unstable coronary syndromes, but IL-1Ra levels during the early phases of AMI have not been previously investigated.
Methods Levels of IL-1Ra were measured in 44 consecutive patients with AMI and compared with creatine kinase (CK), CK-MB, troponin I, myoglobin, and C-reactive protein (CRP).
Results Upon admission, 82% of patients had elevated (>230 pg/ml) IL-1Ra levels, compared with 41% of patients with raised CK (p = 0.001), CK-MB (45%, p = 0.002), troponin I (57%, p = 0.027), myoglobin (48%, p = 0.004), and CRP (57%, p = 0.019) levels. The IL-1Ra values were significantly higher in patients with heralded AMI than in those without pre-infarction angina (671 vs. 320 pg/ml, p = 0.013). The sensitivity of IL-1Ra determination increased to 86% when chest pain duration was ≤3 h and to 91% if heralded infarction occurred.
Conclusions Our study indicates that, unlike markers of necrosis, an increase of IL-1Ra levels occurs early in patients with AMI, is more significant in those with heralded infarction and symptom onset ≤3 h, and precedes the release of markers of necrosis. Thus, IL-1Ra determination may be an important early adjuvant toward the diagnosis of AMI in the ED.
Identification of markers of necrosis is essential for the diagnosis of acute myocardial infarction (AMI), and indicators characterized by early detection and high sensitivity and specificity may facilitate an accurate diagnosis. Creatine kinase (CK), CK-MB isoenzyme, and troponin levels become raised 3 to 6 h after symptom onset, but CK-MB may be normal in 25% to 50% of patients with AMI at the time of emergency department (ED) presentation (1,2). Troponins have great specificity; however, normal values may be detected in about 40% of patients with acute cardiac events up to 6 h from AMI onset (2). An increase in myoglobin is precocious, appearing 1 to 2 h after symptoms, but its clinical value is limited by the brief duration of the increase (<24 h) and the low specificity (3). Inflammation is involved in the pathogenesis of unstable coronary syndromes (4). Elevated levels of interleukin-1 receptor antagonist (IL-1Ra) were observed in patients with stable coronary artery disease (5), and recently, we identified IL-1Ra as a sensitive diagnostic marker in patients with unstable angina (6). The IL-1Ra was also associated with a worse prognosis after AMI (7)and with adverse events after coronary stenting (8,9). The IL-1Ra blocks the binding of the pro-inflammatory cytokine IL-1-beta to IL-1 membrane receptors (10), and it is a more reliable marker of IL-1 system activation and easier to detect than IL-1 (11,12). The goal of this study was to determine IL-1Ra levels in patients with ST-segment elevation AMI upon ED admission and to assess their sensitivity in the diagnosis of AMI compared with the sensitivity of common markers of myocardial necrosis (i.e., CK, CK-MB, troponin I, myoglobin).
The study population consists of 44 consecutive patients with AMI admitted to the ED. Myocardial infarction was defined as: 1) chest pain lasting >30 min; 2) ST-segment elevation ≥0.2 mV in two or more contiguous leads, persisting after nitrate administration; and 3) a rise of serum CK and CK-MB above diagnostic levels (reference range 5 to 195 and 5 to 25 IU/l, respectively) during hospitalization. Upon admission, venous blood samples were drawn to measure levels of IL-1Ra, troponin I, CK, CK-MB, myoglobin, and C-reactive protein (CRP); serial CK and CK-MB levels during the stay in the coronary care unit were also obtained. No patient had clinical or laboratory evidence of malignancy, infections, inflammatory disease, or recent (<2 months) surgery or trauma. Thirty-nine patients (89%) received intravenous thrombolysis with front-loaded recombinant tissue-type plasminogen activator. All patients developed Q-wave AMI. Infarction was defined as “heralded” when prodromal angina occurred in the previous seven days and as “unheralded” when it occurred without preceding anginal symptoms. Levels of IL-1Ra were also compared with those of a historical, non-concurrent control group, including 126 patients with ischemic syndromes other than AMI (58 with stable and 68 with unstable angina [Braunwald class IIB-IIIB]) and 15 patients with atypical chest pain and normal coronary arteries (without pericarditis, pulmonary embolism, or gastroesophageal reflux disease).
Each patient gave informed consent to the study.
Venous blood samples for IL-1Ra and CRP determination were centrifuged at 2,000 gat 4°C for 30 min. The plasma was frozen at −80°C until it was assayed. The IL-1Ra kits were purchased from R&D System (Minneapolis, Minnesota), and the assays employed the quantitative sandwich enzyme-linked immunoassay technique. The microplate reader was LP400 from Sanofi-Diagnostics Pasteur (Milan, Italy); the lower level of detection was 49 pg/ml. Levels of CRP were determined by high-sensitivity-rate nephelometry (DADE-Behring, Scoppito, L'Aquila, Italy), and in samples with <2.5 mg/l, by a monoclonal antibody, solid-phase, enzyme immunoassay (Immunodiagnostik, Bensheim, Germany); 90% of normal values for CRP is <3 mg/l. Blood samples for immediate CK, CK-MB, troponin I, and myoglobin dosage were centrifuged at 4,000 gfor 10 min. Measurements for CK and CK-MB were obtained by chemical kinetics (Alpha-Wasserman, Milan, Italy); the assays for troponin I and myoglobin level detection employed the fluorescence immunoassay (Biosite Diagnostics, San Diego, California), with normal values ranging from 0 to 0.03 and 0 to 107 ng/ml, respectively.
Data are expressed as mean ± SD for variables normally distributed (as detected by skewness and Kurtosis indexes) and median and interquartile range for IL-1Ra. The McNemar test was used to compare the results of different assays in the same patients, and the Cochran Q test was used to compare several dependent variables. Correlations were done by the Spearman rank test. The Mann-Whitney Utest was used to compare continuous, non-normally distributed variables. A p value <0.05 was considered statistically significant.
The demographic and clinical characteristics of the 44 patients are described in Table 1. The mean duration of chest pain before ED presentation was 228 ± 170 min. Acute myocardial infarction was heralded in 22 patients and unheralded in the remaining. In-hospital mortality was 7% (3 of 44 patients). Thirty-three patients (75%) underwent elective coronary angiography: 20 had single-vessel coronary artery disease, 12 had multivessel disease, and 1 had non-significant coronary stenosis.
Upon ED admission, only 18 patients (41%) had elevated CK levels, 20 (45%) had increased CK-MB, and troponin I and myoglobin values were raised in 25 (57%) and 21 (48%) patients, respectively. Conversely, IL-1Ra levels were elevated in 36 patients (82%); the prevalence of patients with elevated IL-1Ra levels was significantly higher than that of patients with raised indexes of myocardial necrosis (p ≤ 0.027) or CRP (57%, p = 0.019) (Table 2). A rise in markers of myocardial necrosis (i.e., CK, CK-MB, troponin I, myoglobin) and CRP was correlated to the duration of chest pain (p < 0.01), whereas IL-1Ra elevation was independent of the time of chest pain onset (p = 0.26) and of all indexes of myocardial necrosis (p > 0.4) or CRP (p = 0.50) (Fig. 1). As illustrated in Figure 1, in the ED, IL-1Ra levels were already elevated in patients with a shorter duration of chest pain and remained relatively constant over time, unlike markers of necrosis. Despite a similar ischemic burden upon admission (measured by ST-segment shift), necrosis extension, left ventricular function, and coronary artery disease extension, patients with heralded AMI had IL-1Ra values significantly higher than those without prodromal chest pain (p = 0.013) (Fig. 2), whereas CRP levels were not statistically different in patients with heralded (4.5 mg/l) and unheralded (2.9 mg/l, p = 0.12) AMI. The sensitivity of IL-1Ra in identifying patients with AMI was greater than markers of myocardial necrosis (82% vs. 57% for troponin I, p = 0.027); it rose to 86% if the duration of chest pain was ≤3 h (vs. 62% for troponin I, p = 0.040) (Fig. 1) and to 91% with heralded infarction (Fig. 2). Levels of IL-1Ra were related to the extension of myocardial necrosis (measured by in-hospital CK and CK-MB peak levels, p = 0.001) but not to the number of vessels with significant stenoses on coronary angiography (p = 0.09).
In the control group, patients with non-cardiac chest pain had normal levels of IL-1Ra (105 pg/ml); this value increased to 112 pg/ml in patients with stable angina and to 160 pg/ml in those with unstable angina (p = 0.003 vs. both). In the current study group of AMI patients, IL-1Ra levels were 456 pg/ml (p < 0.001).
Our findings indicate that the inflammatory marker IL-1Ra, measured by a single-point determination in the ED, is elevated early in patients with ST-segment elevation AMI, especially in the presence of heralded infarction. Interleukin-1 is a pro-inflammatory cytokine involved in tissue inflammation, ischemia reperfusion injury, and coronary atherosclerosis (10,13,14). The receptor antagonist of IL-1 is a competitive inhibitor of the IL-1 membrane receptors modulating the inflammatory response, and its levels correlate well with the severity of inflammation, even when plasma IL-1 levels are low, as in septic shock (10,12–14). The IL-1Ra is an acute-phase protein released from hepatocytes stimulated by circulating inflammatory mediators, and it is also synthesized by locally activated monocytes (10,11,15,16). Monocyte activation within coronary plaques is considered a key event in plaque destabilization because monocytic metalloproteinases cause rupture of the plaque fibrous cap (4), with subsequent superimposed thrombosis; IL-1Ra elevation may therefore be an early marker of plaque instability, which is the common pathogenetic mechanism of acute coronary syndromes. This may explain the elevation of IL1-Ra in patients with unstable angina (6)and the early rise observed in this study in patients with AMI, with higher sensitivity when the infarction is heralded by prodromal anginal symptoms. Because IL-1Ra release reflects the “inflammatory status” of infarct-related plaques, it may be copiously produced in the infarct-related vulnerable plaques or may be locally secreted in the ischemic myocardium in the acute phase of infarction (11).
To our knowledge, these are the first observations on the patterns of IL-1Ra detection in patients with AMI. Our study indicates that IL-1Ra elevation may precede release of necrosis indexes and CRP; moreover, its sensitivity may be greater than that of standard markers and may be enhanced if AMI is heralded or the symptom duration is ≤3 h. This is a time frame when cardiac enzymes may not yet be detected (Fig. 1). In fact, while the enzymes increase with time, IL-1Ra remains relatively constant. Thus, the discriminant value of this inflammatory marker augments early diagnostic power in AMI. We believe that in patients with a clinical suspicion of AMI and high IL-1Ra levels upon ED admission, a higher degree of alertness and closer monitoring are warranted, even when necrosis markers are not elevated. The significant correlation between IL-1Ra levels and peak CK-MB levels confirms previous observations (7)and suggests a relation to the extension of necrosis and consequently to the prognosis. It still needs to be determined whether the action of IL-1Ra in decreasing cellular proliferation and neutrophil infiltration, limiting cytokine activation and apoptosis, would decrease infarct size or stabilize the plaque in a manner similar to that which has prompted its use in rheumatoid arthritis (17)or inflammatory bowel disease (10). Because IL-1Ra may increase in other inflammatory diseases, those need to be ruled out. Because of the relatively high cost (about $800 for 50 assays) of IL-1Ra determinations, less expensive assays need to be developed. Further studies on a greater number of unselected patients are required to definitely validate the independent adjunctive value of IL-1Ra in the diagnosis of AMI.
- acute myocardial infarction
- creatine kinase
- C-reactive protein
- emergency department
- interleukin-1 receptor antagonist
- Received April 30, 2003.
- Revision received July 4, 2003.
- Accepted July 14, 2003.
- American College of Cardiology Foundation
- Zimmerman J.,
- Fromm R.,
- Meyer D.,
- et al.
- de Winter R.J.,
- Koster R.W.,
- Sturk A.,
- Sanders G.T.
- Dinarello C.
- Fischer E.,
- Van Zee K.J.,
- Marano M.A.,
- et al.
- Nicklin M.J.H.,
- Hughes D.E.,
- Barton J.L.,
- Ure J.M.,
- Duff G.W.