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Interleukin 18 in acute myocardial infarction
  1. Second Department of Internal Medicine
  2. *Department of General Medicine
  3. Department of Laboratory Medicine
  4. Gunma University School of Medicine
  5. 3-39-15, Showa-machi, Maebashi 371, Japan
  6. Hayashibara Biochemical Laboratories Inc
  7. 675-1, Fujisaki, Okayama, 702-8006 Japan
  8. kanda{at}

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Interleukin 18 (IL-18), which is a recently cloned cytokine synthesised by Kupffer cells, has been shown to activate macrophages.1 Macrophages and T cells have been reported to be activated in patients with acute myocardial infarction (MI).2 IL-18 is postulated to play a role in the development of myocardial dysfunction through activation of immune cells. However, the circulating concentration of IL-18 has not been reported in patients with acute MI.

To elucidate the changes in the release of IL-18 in patients with coronary artery disease, we examined the correlation between IL-18 concentrations and the serum activities of myocardial enzymes, estimating myocardial necrosis or atrial natriuretic peptide (ANP). Our goal was to determine whether measurement of IL-18 could be used as a new indicator of myocardial damage in patients with acute MI.

We evaluated 24 patients with acute MI (19 men and five women aged 39–79 years). Patients diagnosed with acute MI had to have been admitted within six hours of the onset of symptoms. The diagnosis of acute MI was based on the presence of typical chest pain which persisted for at least 30 minutes, ST segment elevations > 0.2 mV in at least two contiguous leads, and an increase in serum creatine kinase activity to twice the upper limit of normal (> 250 IU/l). The diagnosis of congestive heart failure was based on a history of dyspnoea and symptomatic exercise intolerance with signs of pulmonary congestion or peripheral oedema at clinical examination, and following usual investigations. As a control group, we included 12 age and sex matched patients who had no evidence of coronary stenosis or coronary spasm on coronary angiography. No patient had evidence of septicaemia, collagen vascular disease, advanced liver disease, renal failure, malignancy or infectious disease.

Blood was sampled immediately after admission and at 1, 2, 3, 6, and 9 hours after admission and then every 12 hours until five days after admission. Blood was drawn from the antecubital vein into silicone tubes (4.5 ml of blood and 0.5 ml of 0.13 M/l sodium citrate), and centrifuged for 15 minutes at 1600 g at 40°C. The plasma was stored at −80°C until assayed. Human IL-18 was measured by an enzyme linked immunosorbent assay (ELISA) developed by Hayashibara Inc, Okayama, Japan.3 Serum creatine kinase-MB (CK-MB), myoglobin, lactate dehydrogenase (LDH) activities, and leucocyte counts were measured by an autoanalyser. Data are expressed as mean (SD). Values for patients with acute MI and the control group were compared using an unpaired t test. The minimum concentration of IL-18 is 10 pg/ml. Correlations between IL-18 concentrations and other parameters were analysed by linear regression. A probability value of p < 0.05 was considered significant.

Plasma IL-18 concentrations were significantly higher in patients with acute MI than in controls (46 (16) pg/ml and 26 (10) pg/ml, respectively, p < 0.05). IL-18 and other indicators of acute MI at the time of maximal rise and the peak titre are shown in table 1. The maximal rise of IL-18 was later than that of myoglobin and CK-MB, but significantly earlier than that of LDH. The peak IL-18 concentration in patients with acute MI correlated with the serum activities of CK-MB, aspartate transaminase (AST), and LDH (r = 0.54, p < 0.05;r = 0.48, p < 0.01; andr = 0.55, p < 0.05, respectively). The circulating IL-18 was positively correlated with plasma concentrations of ANP.

Table 1

IL-18 and indicators of acute myocardial infarction

This study shows that circulating concentrations of IL-18 increase in patients with acute MI. We hypothesise that higher concentrations of IL-18 may be a new marker of cardiac damage in the development of acute MI.

Based on our findings, the clinical role of IL-18 can be hypothesised. IL-18 induces IFN-γ gene expression in activated T cells and macrophages, and also induces apoptosis in Fas-expressing activated T cells.4 Thus, increases in IL-18 in patients with acute MI induces apoptosis in activated T cells, leading to persistent T cell mediated reaction to self antigens in myocytes.5 On the other hand, apoptosis is the major form of myocardial damage after infarction, since the expression of Fas is enhanced in the ischaemic myocytes.6 Therefore, increases in serum IL-18 concentrations may induce apoptosis in myocytes, leading to persistent myocardial damage in acute MI.

In conclusion, increased secretion of IL-18 occurs in patients with acute MI and correlates with the severity of myocardial damage. In the clinical setting, our results suggest that measurement of IL-18 may be a new marker of cardiac damage in patients with acute MI.