Interleukin-1 receptor antagonist myocardial synthesis in ischemic cardiomyopathy

Plasma levels of systemic markers of inflammation have been used to monitor the risk of coronary artery disease (CAD). Interleukin-1 receptor antagonist (IL-1Ra) modulates the production and the activity of IL-1, a cytokine associated with inflammatory response. In order to ascertain whether detection of increased levels of IL-1Ra may be useful in the characterization of ischemic syndromes, we investigated IL-1ra levels in a first series of 117 consecutive patients undergoing coronary angiography with a clinical diagnosis of Braunwald's unstable or chronic stable angina, or atypical chest pain (lesion-free coronary arteries at coronary angiography). Characteristics of the patients were similar in the three groups. Clinical and laboratory assessment excluded active immune diseases. A statistically significant (p<0.001) increase of IL-1ra was found in unstable angina, compared to stable chronic angina and normal control group patients. In contrast, there were not significant differences between normal controls and chronic stable angina patients. On the other hand, C-reactive protein (CRP) levels were significantly higher in pts with stable and unstable angina as compared to subjects without corornary disease (P=0.034), but they did not discriminate between stable and unstable pts (P=0.7). IL-1Ra plasma levels were then measured upon Emergency Department (ED) admission in 44 consecutive pts with ST-segment elevation acute myocardial infarction (aMI). A comparison between IL-1Ra and common indicators of myocardial necrosis [creatin-kinase (CK), CK-MB, Troponin I and Myoglobin] or systemic inflammation [CRP] was also performed. On admission to ED, 82% of pts had elevated IL-1Ra levels vs 41% of pts 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. Sensitivity of IL-1Ra determination to identify in the Emergency Department pts with aMI raised to 86% if pre-coronary time was <3 hours and to 91% if heralded infarction occurred. We then investigated the actual source of IL-1Ra in subjects with myocardial ischemic disease. Myocardial samples were taken in the peri-infarct and remote regions at time of explant for heart transplant in 4 subjects with ischemic cardiomyopathy and previous AMI. IL-1Ra production was evaluated using in situ hybridization for IL-1Ra mRNA and immunostaining with anti-IL-1Ra-protein specific antibodies. Myocardial IL-1Ra expression was found in all cases, particularly in the peri-infarct regions, with cardiomyocytes being the prevalent source for IL-1Ra. Conclusions. IL-1Ra, a cytokine with potential anti-inflammatory properties, is produced by the ischemic myocardium. Elevation of serum IL-1ra may identify pts with unstable angina with greater sensitivity than CRP and precedes the release of markers of necrosis in pts with aMI.