Abstract 201: Adventitial Nab-Rapamycin Injection Reduces Porcine Femoral Artery Luminal Stenosis Induced by Balloon Angioplasty via Inhibition of Medial Proliferation and Adventitial Inflammation
Introduction: Balloon angioplasty of peripheral arteries induces a substantial inflammatory response and has a high rate of restenosis. Our hypothesis was that peri-adventitial injection of the antiproliferative, immunosuppressant drug rapamycin would reduce luminal stenosis in a porcine femoral artery model of balloon angioplasty injury.
Methods: 16 male crossbred swine had a balloon angioplasty overstretch injury of the femoral artery followed by peri-adventitial injection of saline or 500μg of nanoparticle albumin-bound (nab) rapamycin with an intraluminal microinfusion catheter. Qualitative and quantitative assessments of the femoral arteries, including histomorphometric measurements, were performed on H&E, Masson’s trichrome or immunohistochemistry stained sections. Blood and tissue rapamycin concentration were assessed by liquid chromatography and mass spectrometry at 1h, 3d, 8d and 28d.
Results: There was 100% procedural success with periadventitial injection. At 28 days, femoral arteries treated with nab-rapamycin had a 42% reduction in luminal stenosis, 19.5 ± 3.3% vs 11.4 ± 0.84%, p=0.01 t-test (figure). Nab-rapamycin also significantly reduced medial fibrosis by qualitative analysis, p<0.0001 t-test, and media cell proliferation by Ki-67 staining, p=0.02 t-test. There were significantly fewer adventitial leukocytes at 3 days, p=0.03 t-test, but no difference at 28 days. One hour after injection, the perivascular concentration of nab-rapamycin was 1500-times higher than serum and rapamycin persisted in the tissue for at least 8 days. Rapamycin was not detectable in serum or tissue at 28 days. There was no difference in endothelial coverage or regeneration by Factor VII and H&E staining at 3, 8 or 28 days.
Conclusions: A single periadventitial dose of nab-rapamycin significantly reduced luminal stenosis in a porcine model of femoral artery balloon angioplasty injury. The observed reduction in early adventitial infiltration by leukocytes and decrease in medial cell proliferation and fibrosis at 28 days suggests a mechanism by which nab-rapamycin may have an effect. Adventitial injection with an intraluminal microinfusion catheter is safe and efficient and represents an alternative to stent- or balloon-based local drug delivery.
- © 2012 by American Heart Association, Inc.