Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts

Objective: Immunosuppressive agents have been proposed to reduce neointimal hyperplasia in synthetic vascular grafts. Thus, the purpose of the present study was to evaluate the safety and efficacy of rapamycins (systemic vs, local vs. oral administration) and mycophenolate mofetil (MMF) to reduce in timal hyperplasia in infrarenal synthetic vascular grafts of the rat. Metho ds: Fifty-four Wistar rats (250 g) completed the study after a synthetic va scular graft (ePTFE, Gore-tex, 2 mm diameter, 10 mm length) was implanted e nd-to-end in the infrarenal aorta. The animals were divided into three grou ps: group 1 consisted of 12 control animals, group 2 consisted of 37 rats r eceiving rapamycins, either per os (RAD, 1.5 or 3 mg/kg), intraperitoneally (RPM, 1.5 or 3 mg/kg) or locally (RPM soaking of the graft); and in group 3 (n = 5), MMF (40 mg/kg) was administered orally. The animals were followe d weekly with weight controls and signs of toxicity for 30 (n = 37) and 60 (n = 17) days, respectively. Ali animals were sacrificed and underwent hist ological examination at completion of the study. Results: All animals survi ved in groups 1 and 3, but five died in group 2. The weight gain was normal in all groups, except for the subgroup 2a receiving high dose rapamycins o rally. All rats in group 3 suffered from diarrhea, whereas animals receivin g high dose rapamycins showed toxic signs (hair loss, wound healing problem s). Histological examination showed a significant increase in intimal hyper plasia in group 1 (0.83 +/- 0.01 and 0.14 +/- 0.05 mum after 30 and 60 days , respectively; P < 0.01). Rapamycins in either application or dosage had n o significant effect on intimal hyperplasia Conclusions: Local or systemic administration of rapamycins has no effect on intimal hyperplasia in synthe tic vascular grafts. In contrast, toxic signs with weight loss were observe d in animals treated with high dose rapamycins, but not in those treated wi th MMF. Thus, in the rat model, immunosuppression with rapamycins or MMF ca nnot be recommended for the prevention of intimal hyperplasia in the synthe tic vascular graft model. (C) 2001 Elsevier Science B.V. All rights reserve d.