Cardiac allograft atherosclerosis in the rat. The effect of histocompatibility factors, cyclosporine, and an angiotensin-converting enzyme inhibitor.

Cardiac transplant atherosclerosis is thought to result from immune-mediated vessel wall injury. The present experiments were designed to test whether CsA alone or in combination with the ACE-inhibitor cilazapril has any effect on graft atherosclerosis in a rat cardiac transplant model. Cardiac grafts were transplanted heterotopically into either syngeneic or allogeneic recipients and followed by daily palpation; long-surviving grafts were removed after 100 days and the extent and degree of atherosclerosis was assessed using computerized morphometry. Atherosclerosis was more extensive in grafts removed from untreated allogeneic recipients compared with syngeneic recipients; CsA treatment increased the extent of atherosclerosis in syngeneic transplants. The extent and degree of vascular occlusion in allogeneic grafts from recipients treated with 15 mg/kg of CsA every other day was not different from that in grafts removed from recipients that received initially higher CsA doses. Cilazapril had no effect on the extent of graft atherosclerosis but decreased the degree of luminal narrowing in grafts from CsA-treated recipients significantly. Some grafts showed neovascularization in the subendocardial region adjacent to organized intraventricular clots, suggesting the release of angiogenic factors from such clots; such growth factors may contribute to the atherosclerotic vessel wall reaction in this model. We conclude that CsA promotes the development of graft atherosclerosis in heterotopically transplanted syngeneic cardiac grafts in the rat. We furthermore found that cilazapril has a beneficial effect on the degree of atherosclerosis in CsA-treated recipients.