Prevention of allograft heart valve failure in a rat model

Objective: Allograft heart valves are commonly used in cardiac surgery. Des pite mounting evidence that these valves are immunogenic, leading to premat ure failure, current clinical practice does not attempt to minimize or cont rol such a response. The objective of this study was to evaluate immune mod ulatory approaches to ameliorate allograft valve failure in a rat model. Method: Aortic valve grafts were implanted infrarenally into Lewis rat reci pients (n = 32). There were 4 transplant groups: syngeneic grafts (Le vis t o Lewis), untreated allografts (Brown Norway to Lewis), allograft recipient s treated with cyclosporine (INN: ciclosporin) (10 mg/kg per day for 7 or 2 8 days), and allograft recipients treated with anti-alpha4 integrin and ant i-beta2 integrin monoclonal antibodies for 7 days. At 7 and 28 days the val ves were examined for structural integrity and cellular infiltration. Results: Both cyclosporine and anti-alpha4/beta2 integrin treatment resulte d in significant reduction in leaflet infiltration by macrophages (ED1(+)), T cells (CD3(+)), and CD8(+) T cells at 7 days with preservation of struct ural integrity when compared with control allografts. Twenty-eight days aft er implantation, daily treatment with cyclosporine preserved leaflet struct ural integrity and inhibited cellular infiltration. However, a short course of cyclosporine (7 days) failed to prevent destruction of the valves at 28 days. Conclusions: Immune modulatory approaches aimed at T-cell activation or tra fficking decrease leaflet cellular infiltration and prevent allograft valve structural failure. However, short-course therapy does not appear to be su fficient and must be maintained to allow long-term preservation of leaflet structural integrity (28 days).