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 intimal hyperplasia in infrarenal synthetic vascular grafts of the rat.


METHODS
Fifty-four Wistar rats (250 g) completed the study after a synthetic vascular graft (ePTFE, Gore-tex, 2 mm diameter, 10 mm length) was implanted end-to-end in the infrarenal aorta. The animals were divided into three groups: group 1 consisted of 12 control animals, group 2 consisted of 37 rats receiving 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 followed weekly with weight controls and signs of toxicity for 30 (n=37) and 60 (n=17) days, respectively. All animals were sacrificed and underwent histological examination at completion of the study.


RESULTS
All animals survived 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 orally. All rats in group 3 suffered from diarrhea, whereas animals receiving high dose rapamycins showed toxic signs (hair loss, wound healing problems). Histological examination showed a significant increase in intimal hyperplasia in group 1 (0.03+/-0.01 and 0.14+/-0.05 microm after 30 and 60 days, respectively; P<0.01). Rapamycins in either application or dosage had no significant effect on intimal hyperplasia.


CONCLUSIONS
Local or systemic administration of rapamycins has no effect on intimal hyperplasia in synthetic vascular grafts. In contrast, toxic signs with weight loss were observed in animals treated with high dose rapamycins, but not in those treated with MMF. Thus, in the rat model, immunosuppression with rapamycins or MMF cannot be recommended for the prevention of intimal hyperplasia in the synthetic vascular graft model.
Walpoth
B H
BH
Department of Cardiovascular Surgery, University Hospital, Insel, Bern, Switzerland. beat.walpoth@insel.ch
Pavlicek
M
M
Celik
B
B
Nicolaus
B
B
Schaffner
T
T
Althaus
U
U
Hess
O M
OM
Carrel
T
T
Morris
R E
RE
D000714:Anastomosis, Surgical; D000818:Animals; D001807:Blood Vessel Prosthesis; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D011138:Polytetrafluoroethylene; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D017539:Tunica Intima / Q000473:pathology*; D014654:Vascular Patency
D007166:Immunosuppressive Agents; D011138:Polytetrafluoroethylene; D009173:Mycophenolic Acid; D020123:Sirolimus