Cyclosporine mitigates graft coronary artery disease in murine cardiac allografts: description and validation of a novel fully allogeneic model.
BACKGROUND
The effect of cyclosporine (CsA) on the development of graft coronary artery disease (GCAD) is controversial. We developed a novel allogeneic mouse model of heart transplantation and investigated the effect of CsA on acute rejection and GCAD.


METHODS
Hearts of FVB mice (H-2(q)) were heterotopically transplanted into 60 C57BL/6 mice (H-2(b)). CsA was administered to recipients at 10, 20 or 30 mg/kg/day for 10 or 30 days after transplantation. Untreated recipients as well as isograft recipients served as controls. Viability of the grafts was assessed daily by palpation. Parenchymal rejection was scored in grafts surviving 30 days in the 30-day treatment groups. GCAD was evaluated by the percentage of luminal narrowing, intima/media ratio and percentage of diseased vessels. Blood CsA and creatinine levels were also evaluated. Results were evaluated statistically.


RESULTS
All groups except the untreated control group and the allograft groups treated with 10 or 20 mg for 10 days showed significant graft survival (>/=33% survival for 30 days). An inverse correlation was observed between CsA treatment dose, parenchymal rejection score and degree of GCAD in the 30-day treatment groups. However, graft survival in the 20-mg/kg/day group was significantly better than that in the 30-mg/kg/day group. Serum creatine levels showed no nephrotoxicity.


CONCLUSIONS
Relatively high-dose CsA mitigated parenchymal rejection and GCAD of the mouse cardiac allografts. In addition, a valuable mouse model mimicking the clinical course of GCAD was achieved with CsA treatment of 20 mg/kg/day for 30 days.
Tanaka
Masashi
M
Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, California 94305, USA. masashi@omiya.jichi.ac.jp
Mokhtari
Golnaz K
GK
Balsam
Leora B
LB
Cooke
David T
DT
Kofidis
Theo
T
Zwierzchonievska
Monika
M
Robbins
Robert C
RC
D000818:Animals; D002853:Chromatography, Liquid; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D008401:Gas Chromatography-Mass Spectrometry; D006084:Graft Rejection / Q000097:blood / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine