• Christian Stoppe, Steffen Rex, Andreas Goetzenich, Sandra Kraemer, Christoph Emontzpohl, Josefin Soppert, Luisa Averdunk, Yu Sun, Rolf Rossaint, Hongqi Lue, Caleb Huang, Yan Song, Georgios Pantouris, Elias Lolis, Lin Leng, Wibke Schulte, Richard Bucala, Christian Weber, and Jürgen Bernhagen.
• 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .
• Antioxid. Redox Signal. 2015 Oct 10; 23 (11): 865-79.

AimsCardiac surgery involves myocardial ischemia/reperfusion (I/R) with potentially deleterious consequences. Macrophage migration inhibitory factor (MIF) is a stress-regulating chemokine-like cytokine that protects against I/R damage, but functional links with its homolog, d-dopachrome tautomerase (MIF-2), and the circulating soluble receptor CD74 (sCD74) are unknown. In this study, we investigate the role of MIF, MIF-2, sCD74, and MIF genotypes in patients scheduled for elective single or complex surgical procedures such as coronary artery bypass grafting or valve replacement.ResultsMIF and MIF-2 levels significantly increased intraoperatively, whereas measured sCD74 decreased correspondingly. Circulating sCD74/MIF complexes were detectable in 50% of patients and enhanced MIF antioxidant activity. Intraoperative MIF levels were independently associated with a reduced risk for the development of atrial fibrillation (AF) (odds ratio 0.99 [0.98-1.00]; p=0.007). Circulating levels of MIF-2, but not MIF, were associated with an increased frequency of organ dysfunction and predicted the occurrence of AF (area under the curve [AUC]=0.663; p=0.041) and pneumonia (AUC=0.708; p=0.040). Patients with a high-expression MIF genotype exhibited a reduced incidence of organ dysfunction compared with patients with low-expression MIF genotypes (3 vs. 25; p=0.042).InnovationThe current study comprehensively highlights the kinetics and clinical relevance of MIF family proteins and the MIF genotype in cardiac surgery patients.ConclusionOur findings suggest that increased MIF levels during cardiac surgery feature organ-protective properties during myocardial I/R, while the soluble MIF receptor, sCD74, may enhance MIF antioxidant activity. In contrast, high MIF-2 levels are predictive of the development of organ dysfunction. Importantly, we provide first evidence for a gene-phenotype relationship between variant MIF alleles and clinical outcome in cardiac surgery patients.

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