Experimental graft coronary disease in rat heterotopic heart transplantation

Graft coronary disease (GCD) is responsible for the majority of late deaths among long-term heart transplant survivors. Noninvasive and invasive methods are too insensitive to detect early stages of GCD and usually the diagnosis can be made after the occurrence of considerable intimal proliferation. To assess the time course, distribution, and extent of endothelial- and endocardial-directed cellular rejection we studied heterotopic transplants of Lewis Brown Norway (LBN RT1 n )F1 hearts into Lewis (LEW RT1 1 ) rats. Five groups were investigated: group 1 (n=13, killed 1–21 days post-Tx) no immunosuppression; group 2 (n=11, 1–7 days) standard cyclosporine A (CsA) therapy; group 3 (n=11, 14–69 days) CsA standard temporary (7 days); group 4 (n=6, 1–14 days) low-dose CsA; group 5 (n=7, 1–100 days) isograft recipients, no immunosuppression. Semiquantitative (score 0–3), immunohistochemical (W3/ 25, Ox-1, Ox-8, Ox-33, APAAP) and qualitative histological analysis of small (SVV) and large vessel vasculopathy (LVV) showed in all nonisogeneic groups that SVVâ©Ÿ1 occurred 7 days post-Tx. Endocardial lymphocytic infiltrates appeared also in group 1, pointing to be CsA-independent and representing endocardial rejection (ER). In most groups (groups 1, 2, 3), SVV preceded LVV. Immunohistologically Ox-8+(CD8+) cells dominated in ER and SVV. In 92% of the histological slides analyzed, the extent of SVV was homologous to ER. Isografts did not develop SVV, LVV, or ER. We conclude that SVV and ER cannot be influenced by standard CsA therapy. They can serve as early morphological indicators of GCD large vessel therapy.