What is the significance of perioperative release of macrophage migration inhibitory factor in cardiac surgery?

Abstract

Cardiac surgery is associated with release of the pleiotropic cytokine macrophage migration inhibitory factor (MIF). The trigger for MIF release has not yet been elucidated. Owing to its intrinsic antioxidative activity, MIF might reduce oxidative stress and protect from myocardial ischemia and reperfusion (I/R) injury. In the present study, patients scheduled for elective cardiac surgery (n=46) were randomized to undergo coronary artery bypass grafting either conventionally with cardiopulmonary bypass and cardioplegic arrest-induced I/R (cCABG) or in an off-pump procedure (OPCAB) with minimized I/R. We report that only patients who underwent cCABG exhibited a postoperative increase of MIF (p=0.024), while both groups showed an increase in interleukin-6. MIF release appears to be primarily mediated by I/R and to a lesser extent by inflammation. Endogenous peroxidase activity (p=0.021) and serum levels of thioredoxin (p=0.003) were significantly higher in patients who underwent cCABG after surgery. Interestingly, perioperative MIF release was associated with an enhanced antioxidant capacity and a significantly reduced postoperative incidence of atrial fibrillation (p=0.018) and acute kidney injury (p=0.048). The present study highlights the role of MIF increase during cardiac surgery in response to oxidative stress. Based on current observations, we hypothesize that intraoperative MIF secretion is due to I/R and enhances the antioxidant capacity in patients during cardiac surgery.

FIG. 1.

Flowchart according to the consort statement for randomized clinical trials. In total, 50 patients were enrolled in the present study. Four patients were excluded from further analysis. cCABG, conventional coronary artery bypass grafting; OPCAB, off-pump coronary artery bypass grafting.

FIG. 2.

MIF release and corresponding measurement of oxidative stress. Comparison of perioperative time course of MIF (A), Lipid-Ox^® (B), and EPA (C) in patients who underwent conventional on-pump cardiac surgery with the use of cardiopulmonary bypass (cCABG) and those who underwent beating-heart cardiac surgery without the use of CPB (OPCAB). The gray shaded area indicates the duration of cardiac surgery. **p<0.01 versus baseline. ^§p<0.05 versus OPCAB. MIF, macrophage migration inhibitory factor; CPB, cardiopulmonary bypass; EPA, endogenous peroxidase activity; INT, interaction.

FIG. 3.

Comparison of perioperative inflammation in the serum of patients who underwent conventional cardiac surgery with the use of cardiopulmonary bypass (cCABG) and those who underwent beating-heart cardiac surgery without the use of cardiopulmonary bypass (OPCAB). Perioperative inflammation was assessed through measuring the serum concentrations of interleukin (IL)-6 (A), procalcitonin (PCT) (B), and anti-inflammatory IL-10 (C). The extent of myocardial damage was determined by the serum concentrations of creatine kinase isoenzyme (CKMB) (D). The gray shaded area indicates the duration of cardiac surgery. *p<0.05 and **p<0.01 versus baseline. ^§p<0.05 versus OPCAB.

FIG. 4.

Correlation analysis of MIF levels and EPA at admission to the ICU. Data are depicted as linear regression (black line) with 95% confidence intervals (long dashed line). ICU, intensive care unit.

FIG. 5.

Role of human thioredoxin-1 during ischemia and reperfusion. (A) Comparison of human thioredoxin-1 (TRX-1) release in the serum of patients who underwent conventional cardiac surgery through cardiopulmonary bypass (cCABG) and those who underwent beating-heart cardiac surgery without cardiopulmonary bypass (OPCAB). (B) Correlation analysis of serum MIF concentrations and human TRX-1 values for the whole observation period. Data are depicted as linear regression (black line) with 95% confidence intervals (long dashed line). *p<0.05 and **p<0.01 versus baseline. ^§p<0.05 and ^§§p<0.01 versus OPCAB.

FIG. 6.

Receiver-operating characteristic analysis for the accuracy of MIF levels and EPA at admission to the ICU to predict freedom from atrial fibrillation in the postoperative period. AUC, area under the receiver-operating curve.