Interaction of the allogeneic state and hypercholesterolemia in arterial lesion formation in experimental cardiac allografts.

To learn more about the interaction of allogeneic transplantation and hypercholesterolemia in the formation of arterial lesions, we performed heterotopic cardiac transplantation in rabbits. We analyzed lesions in both the coronary arteries and the proximal ascending aorta 6 weeks after surgery in both transplanted and native hearts of normocholesterolemic rabbits and those with diet-induced hypercholesterolemia (serum cholesterol, 1638 +/- 366 mg/dL, n = 6, 6 weeks after transplantation). All animals received cyclosporin A (5 mg.kg-1.d-1) for immunosuppression. The transplanted aortas of hypercholesterolemic animals had thicker intimal lesions than did the native aortas (intima/media ratio, 0.67 +/- 0.4 versus 0.08 +/- 0.1, P < .05) and contained more T cells (37.4 +/- 12.8 versus 5.7 +/- 6.2 per high-power field, P < .001). In normocholesterolemic animals (n = 5) the coronary arteries had negligible lesions in the native heart and only slight and inconsistent intimal lesions in the transplanted heart. In the hypercholesterolemic animals, more coronary arteries had intimal lesions in the transplanted hearts than in the native hearts (74% versus 43%). Coronary artery lesions in the native hearts consisted mostly of foam cells, while those in transplanted hearts had more abundant smooth muscle cells as determined by alpha-actin staining. Intimal endothelial cells in transplanted aortas expressed increased levels of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 compared with the native vessels subjected to identical levels of cholesterolemia. Medial smooth muscle cells in transplanted aortas contained much higher levels of immunoreactive tumor necrosis factor-alpha than did medial cells of the native aorta in the same hypercholesterolemic animals. The intima of transplanted aortas contained prominent microvessels compared with the native aorta of the hypercholesterolemic rabbits. We conclude that even during treatment with doses of cyclosporine that control acute myocardial rejection, hypercholesterolemia and the allogeneic state act together to augment allograft atherosclerosis, T-cell accumulation, intimal neovascularization, local cytokine expression, and indices of cell activation in arteries.