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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?

AbstractPURPOSE:
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.
AuthorsThomas Jahnke, Fritz K W Schäfer, Hendrik Bolte, Gerrit Heuer, Ulf Karbe, Joachim Brossmann, Michael Brandt, Martin Heller, Stefan Müller-Hülsbeck
JournalJournal of endovascular therapy : an official journal of the International Society of Endovascular Specialists (J Endovasc Ther) Vol. 12 Issue 3 Pg. 332-42 (Jun 2005) ISSN: 1526-6028 [Print] United States
PMID15943508 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Actins
  • Immunosuppressive Agents
  • Sirolimus
Topics
  • Actins (metabolism)
  • Angioplasty, Balloon (adverse effects)
  • Animals
  • Aorta, Abdominal (injuries, metabolism, pathology)
  • Arterial Occlusive Diseases (etiology, pathology, prevention & control)
  • Cell Count
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Follow-Up Studies
  • Hyperplasia (pathology, prevention & control)
  • Immunosuppressive Agents (administration & dosage, therapeutic use)
  • Male
  • Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
  • Rats
  • Rats, Inbred Lew
  • Secondary Prevention
  • Sirolimus (administration & dosage, therapeutic use)
  • Time Factors
  • Treatment Outcome
  • Tunica Intima (drug effects, metabolism, pathology)

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