title: Interaction of MIF Family Proteins in Myocardial Ischemia/Reperfusion Damage and Their Influence on Clinical Outcome of Cardiac Surgery Patients.
abstract: OBJECTIVE
  Cardiac 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.
  
  
  RESULTS
  MIF 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).
  
  
  METHODS
  The current study comprehensively highlights the kinetics and clinical relevance of MIF family proteins and the MIF genotype in cardiac surgery patients.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .|2 Department of Anesthesiology, University Hospital, RWTH Aachen University , Aachen, Germany .
authors.forename: Christian
authors.initials: C
authors.lastname: Stoppe
authors.affiliation: 3 Department of Anesthesiology, University Hospitals Leuven , Leuven, Belgium .|4 Department of Cardiovascular Sciences, University of Leuven , Leuven, Belgium .
authors.forename: Steffen
authors.initials: S
authors.lastname: Rex
authors.affiliation: 5 Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen University , Aachen, Germany .
authors.forename: Andreas
authors.initials: A
authors.lastname: Goetzenich
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .|5 Department of Thoracic, Cardiac and Vascular Surgery, University Hospital, RWTH Aachen University , Aachen, Germany .
authors.forename: Sandra
authors.initials: S
authors.lastname: Kraemer
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .
authors.forename: Christoph
authors.initials: C
authors.lastname: Emontzpohl
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .
authors.forename: Josefin
authors.initials: J
authors.lastname: Soppert
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .
authors.forename: Luisa
authors.initials: L
authors.lastname: Averdunk
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .|6 Department of Burn Surgery, Shanghai Hospital, Second Military Medical University , Changhai, People's Republic of China .
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 2 Department of Anesthesiology, University Hospital, RWTH Aachen University , Aachen, Germany .
authors.forename: Rolf
authors.initials: R
authors.lastname: Rossaint
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .
authors.forename: Hongqi
authors.initials: H
authors.lastname: Lue
authors.affiliation: 7 Department of Medicine, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Caleb
authors.initials: C
authors.lastname: Huang
authors.affiliation: 7 Department of Medicine, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: 8 Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pantouris
authors.affiliation: 8 Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.affiliation: 7 Department of Medicine, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: 7 Department of Medicine, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Wibke
authors.initials: W
authors.lastname: Schulte
authors.affiliation: 7 Department of Medicine, Yale University School of Medicine , New Haven, Connecticut.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: 9 Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich , Munich, Germany .|10 German Center for Cardiovascular Research (DZHK), Munich Heart Alliance , Munich, Germany .
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: 1 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany .|11 August-Lenz-Stiftung, Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich , Munich, Germany .
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
mesh_terms: D000368:Aged; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002465:Cell Movement; D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000097:blood; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000097:blood* / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000097:blood*; D009504:Neutrophils / Q000502:physiology; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D011184:Postoperative Period; D065840:Protective Factors; D051381:Rats; D016896:Treatment Outcome
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D015415:Biomarkers; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C042501:dopachrome isomerase