Short-term rapamycin for inhibition of neointima formation after balloon-mediated aortic injury in rats: is there a window of opportunity for systemic prophylaxis of restenosis?
OBJECTIVE
To evaluate the efficacy of limited short-term systemic administration of rapamycin to prevent neointimal intimal hyperplasia (NIH) in a double-injury rat model of restenosis.


METHODS
Aortic lesions were induced by perivascular placement of silicone cuffs around the aorta of 36 Lewis rats. After 3 weeks, the cuffs were removed, and the vessels were subjected to secondary balloon injury. Rapamycin (sirolimus) was intravenously administered for 5 days in dosages of 0.5 or 2 mg/kg/d beginning at various time points relative to the balloon injury: (1) days -2 to +2, (2) days 1 to 5, or (3) days 7 to 11. For each treatment period, 6 rats received the 5-day course of the lower or higher dose of rapamycin. Eight rats served as controls undergoing 2-stage injury without rapamycin treatment. Morphometry and immunohistochemistry were performed at 21 days after angioplasty.


RESULTS
NIH and intimal alpha-actin expression were inhibited by both dosages when treatment started 2 days before or 1 day after angioplasty. Results were statistically significant for the lower dose when started 1 day after angioplasty (p < 0.01) and for the higher dose when initiated 2 days before the intervention (p < 0.05). Treatment commencing at 7 days did not reduce NIH in either dosage group.


CONCLUSIONS
In a double-injury rat model, NIH can be inhibited by short-term systemic rapamycin, but suppression of early cell migration and proliferation is pivotal. A limited peri-interventional antiproliferative therapy may be of value as an adjunct to control restenosis after balloon angioplasty and/or stenting.
Jahnke
Thomas
T
Department of Diagnostic Radiology, University Clinics Schleswig-Holstein (UKSH), Campus Kiel, Germany. jahnke@medscape.com
Schäfer
Fritz K W
FK
Bolte
Hendrik
H
Heuer
Gerrit
G
Karbe
Ulf
U
Brossmann
Joachim
J
Brandt
Michael
M
Heller
Martin
M
Müller-Hülsbeck
Stefan
S
D000199:Actins / Q000378:metabolism; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D055502:Secondary Prevention; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D000199:Actins; D007166:Immunosuppressive Agents; D020123:Sirolimus