title: Prolonged cold ischemic times and less donor-recipient histocompatibility accelerate graft vascular disease.
abstract: BACKGROUND
  The long-term success of cardiac transplantation is limited by graft atherosclerosis, also known as graft vascular disease (GVD). GVD is currently the leading cause of late allograft failure in cardiac transplant recipients. The aim of this study was to assess the effects of cold ischemic preservation time (CIPT) and degree of donor-recipient histocompatibility on GVD using a rat heterotopic cardiac transplantation model.
  
  
  METHODS
  ACI-Lewis (n=9), Lewis-F344 (n=9), and Lewis-Lewis (n=9) donor-recipient rat strain combinations were subjected to variable durations of CIPT (0, 4, and 24 hours in University of Wisconsin solution at 4°C) prior to transplantation (n=81 total). The ACI-Lewis allografts differed in both major histocompatibility complex (MHC) class I and II antigens, the Lewis-F344 allograft combination differed in multiple non-MHC antigens, and the Lewis-Lewis isograft combination was syngeneic. Grafts were harvested at 90 days. Intimal area ratio (IAR), intimal thickness score (ITS), and rejection score (RS) were determined for each specimen.
  
  
  RESULTS
  The Lewis-Lewis transplant group had a significantly higher mean RS (P=.036) with 24 hours than with 0 hours of CIPT in this rat heterotopic transplantation model at 90 days. The Lewis-F344 group had a significantly higher IAR (P=.035), ITS (P=.030), and RS (P=.017) with 24 hours than with 0 hours of CIPT. The ACI-Lewis group had high levels of GVD with all durations of CIPT (0, 4, and 24 hours); as a consequence, there were no significant differences in the ITS, IAR, or RS. With 0 hours of CIPT, the ACI-Lewis transplantation group yielded a significantly higher mean IAR (P=.029), ITS (P=.003), and RS (P=5.02×10(-5)) than the Lewis-Lewis group. The Lewis-F344 group had a significantly higher mean RS (P=.003) than the Lewis-Lewis (syngeneic) group. The ACI-Lewis transplantation group had a significantly higher mean IAR (P=.035), and trended toward a higher ITS (P=.058) than the Lewis-F344 group.
  
  
  CONCLUSIONS
  Longer cold ischemic preservation time and less donor-recipient histocompatibility were associated with more advanced GVD in a rat heterotopic transplantation model, especially when there were multiple MHC mismatches as in ACI-Lewis allografts, but also occurred when there were differences in multiple non-MHC antigens as in the Lewis-F344 allografts. There was a lesser effect of longer cold ischemic time on GVD in the Lewis-Lewis syngeneic (isograft) group, suggesting that greater histocompatibility can mitigate the adverse effects of longer ischemic times.
authors.affiliation: Division of Cardiology, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. Lawrence.czer@cshs.org
authors.forename: L S C
authors.initials: LS
authors.lastname: Czer
authors.forename: A V
authors.initials: AV
authors.lastname: Wong
authors.forename: H
authors.initials: H
authors.lastname: Soukiasian
authors.forename: S
authors.initials: S
authors.lastname: Gallagher
authors.forename: M
authors.initials: M
authors.lastname: De Robertis
authors.forename: A
authors.initials: A
authors.lastname: Trento
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D050377:Cold Ischemia / Q000009:adverse effects*; D003324:Coronary Artery Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005978:Glutathione / Q000494:pharmacology; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D006648:Histocompatibility; D006649:Histocompatibility Antigens / Q000276:immunology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D019188:Organ Preservation Solutions / Q000494:pharmacology; D011887:Raffinose / Q000494:pharmacology; D051381:Rats; D011912:Rats, Inbred ACI; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D006649:Histocompatibility Antigens; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose