Clopidogrel reduces the development of transplant arteriosclerosis

Background: Transplant arteriosclerosis, the hallmark feature of chronic rejection, is still the major limiting factor for the long-term success of heart transplantation. Platelets have been implicated to play a role in the pathogenesis of this disease. Therefore the aim of this study was to investigate whether platelet inhibition alone has a positive effect on the development of transplant arteriosclerosis. Methods: Fully major histocompatibility complex-mismatched C57BL/6 (H2(b)) donor aortas were transplanted into CBA (H2(k)) recipients, and mice received different doses (1, 10, and 20 mg/kg) of clopidogrel or control saline as a daily intraperitoneal injection for 30 days. Blood was analyzed on days 2, 7, 14, and 30 by using a platelet aggregation test (adenosine diphosphate) for effectiveness of the treatment. Grafts were analyzed by means of histology and morphometry on day 30 after transplantation. Results: When mice were treated daily with 1 mg/kg clopidogrel in the absence of any other immunosuppression, transplant arteriosclerosis was significantly reduced compared with that seen in saline-treated control animals (intimal proliferation of 66%+/- 9% [1 mg/kg clopidogrel] vs 77%+/- 5% [control], n=7, P <=.03). Daily application of 10 mg/kg and 20 mg/kg clopidogrel also significantly reduced the development of transplant arteriosclerosis compared with that seen in control animals (intimal proliferation of 61%+/- 11% [10 mg/kg clopidogrel] vs 54%+/- 10% [20 mg/kg clopidogrel] vs 77%+/- 5% [control], n=8, P <=.003). There was, however, no additional beneficial effect when compared with mice treated with 1 mg/kg clopidogrel (P=.06). Isografts did not show any signs of vascular lesions on day 30 after transplantation. Conclusion: These results demonstrate that monotherapy with clopidogrel can effectively reduce the formation of transplant arteriosclerosis in a murine aortic allograft model.