title: Molecular markers of programmed cell death in donor hearts before transplantation.
abstract: BACKGROUND
  In this study we investigate whether pro-apoptotic, pro-inflammatory and other early signaling markers indicative of increased propensity for cell death processes were evident in human donor heart allografts immediately before transplantation, and whether there is an association with primary graft failure.
  
  
  METHODS
  A prospective study was performed utilizing donor left atrial myocardium collected at the time of implantation of hearts from brain-dead donors (BDD, n = 29). In addition, to explore the potential of donor hearts from donation after circulatory death (DCD), myocardial samples were obtained during transplantation of lungs from DCD donors (n = 6). A comparator reference group (n = 7) consisted of left atrial specimens from patients undergoing mitral valve surgery.
  
  
  RESULTS
  Significantly raised levels of caspase-3 specific activity, activated hypoxia inducible factor-1 (HIF-1α) and 8-hydroxy-2'-deoxyguanosine were evident in the transplanted hearts (from BDD) that developed primary graft failure (n = 11). DCD hearts did not differ from BDD with regard to mRNA expression levels of FAS, Bax, IL-6 and caspase-3. Although DCD hearts exhibited lower caspase-3 specific activity and activated hypoxia-inducible factor-1 protein, they had higher levels of mRNA for NF-κB, Bnip3 and caspase-1 mRNA. Increased 8-hydroxy-2'-deoxyguanosine levels reflected greater oxidative stress and reactive oxygen species-related DNA fragmentation.
  
  
  CONCLUSIONS
  Our data indicate a significant role of pro-apoptotic and pro-inflammatory activity in allografts that subsequently exhibit primary graft failure. The relatively lower levels of apoptotic and inflammatory activity in DCD hearts suggest they may represent a potentially usable donor cardiac allograft pool. This possibility requires further detailed molecular and clinical research.
authors.affiliation: Cardiothoracic Surgery Unit, The Alfred Hospital, Melbourne; Department of Surgery, Monash University, Melbourne. Electronic address: s.marasco@alfred.org.au.
authors.forename: Silvana F
authors.initials: SF
authors.lastname: Marasco
authors.affiliation: Heart Research, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne.
authors.forename: Freya L
authors.initials: FL
authors.lastname: Sheeran
authors.affiliation: Cardiothoracic Surgery Unit, The Alfred Hospital, Melbourne; Department of Surgery, Monash University, Melbourne.
authors.forename: Krishanu
authors.initials: K
authors.lastname: Chaudhuri
authors.affiliation: Cardiothoracic Surgery Unit, The Alfred Hospital, Melbourne.
authors.forename: Matthew
authors.initials: M
authors.lastname: Vale
authors.affiliation: Department of Epidemiology & Preventative Medicine, Monash University, Melbourne, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Department of Surgery, Monash University, Melbourne; Heart Research, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pepe
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D064591:Allografts; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D001926:Brain Death; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D016027:Heart Transplantation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D011446:Prospective Studies; D012307:Risk Factors; D012769:Shock; D014019:Tissue Donors
chemical_list: D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000080242:8-Hydroxy-2'-Deoxyguanosine; D053148:Caspase 3; D003849:Deoxyguanosine
keywords: apoptosis; donation after circulatory death; donor heart; heart transplantation; primary graft failure