Dose-dependent suppression of transplant arteriosclerosis in aorta-allografted, cholesterol-clamped rabbits. Suppression not eliminated by the cholesterol-raising effect of cyclosporine.
Cyclosporine may suppress transplant arteriosclerosis; however, it also raises plasma cholesterol, which could promote the disease. Our aim was to test these hypotheses experimentally. In experiment 1 (n = 34), cholesterol was clamped at a human level of 5 to 7 mmol/L, and rabbits were given either saline or cyclosporine in a low, medium or high dose. In experiment 2 (n = 15), in which dietary cholesterol was fixed at 0.05 g.kg-1.d-1, and experiment 3 (n = 16), in which no dietary cholesterol was added to the chow, rabbits were given either medium-dose cyclosporine, saline, or vehicle. The duration of each experiment was 5 weeks. In experiment 1, cyclosporine attenuated the development of transplant arteriosclerosis dose dependently (trend test: P < .0001). Cyclosporine also suppressed, in a dose-dependent manner, the activation of the immune system (trend test: P < .05) and the presence of T lymphocytes (trend test: P < .0001) and macrophages in the intima (trend test: P < .01). Despite a higher plasma cholesterol level in cyclosporine-treated rabbits compared with saline-treated rabbits in both experiment 2 (4.9 versus 2.9 mmol/L) and experiment 3 (1.6 versus 0.8 mmol/L), transplant arteriosclerosis was significantly reduced by cyclosporine (Mann-Whitney U test; P < .05 and P < .05). These results suggest that cyclosporine suppresses experimental transplant arteriosclerosis dose dependently. Accordingly, in the assessment of the optimal cyclosporine dose to heart-transplanted patients, it should be taken into account that a dose reduction may promote transplant arteriosclerosis.
Andersen
H O
HO
Department of Thoracic Surgery, Rigshospitalet, Hellerup, Denmark.
Holm
P
P
Stender
S
S
Hansen
B F
BF
Nordestgaard
B G
BG
D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery*; D001013:Aorta, Thoracic / Q000293:injuries / Q000637:transplantation*; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D019917:Blood Vessel Prosthesis Implantation / Q000009:adverse effects*; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D011817:Rabbits; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014284:Triiodothyronine / Q000097:blood
D002791:Cholesterol, Dietary; D007166:Immunosuppressive Agents; D014284:Triiodothyronine; D016572:Cyclosporine; D002784:Cholesterol