Adventitial nab-rapamycin injection reduces porcine femoral artery luminal stenosis induced by balloon angioplasty via inhibition of medial proliferation and adventitial inflammation.
Adventitial nab-rapamycin injection reduces porcine femoral artery luminal stenosis induced by balloon angioplasty via inhibition of medial proliferation and adventitial inflammation.
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DOI：
10.1161/circinterventions.113.000195
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Owens CD
中科院分区：
文献类型：
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作者：
Gasper WJ;Jimenez CA;Walker J;Conte MS;Seward K;Owens CD
对外周动脉的血管内介入治疗受到高再狭窄率的限制。我们的假设是，在猪股动脉球囊血管成形术模型中，外膜注射雷帕霉素纳米颗粒是安全的，并可减少管腔狭窄。包括18只幼年雄性杂交猪。比较了单损伤（40%-60%股动脉球囊过度拉伸损伤; n=2）和双损伤模型（20%-30%过度拉伸损伤前2周内皮剥脱损伤; n=2）。双损伤模型在28天时产生了显著更多的管腔狭窄，P=0.002，并且在中膜纤维化或炎症方面没有差异。将四只猪随机分配至双重损伤模型，并用血管内微输注导管外膜注射盐水（n=2）或500 μg纳米颗粒白蛋白结合的雷帕霉素（nab-雷帕霉素; n=2）。手术成功率为100%，内皮再生无差异。在第28天，nab-雷帕霉素导致管腔狭窄显著减少，17%（四分位数范围，12%-35%）对10%（四分位数范围，8.3%-14%），P=0.001，中膜细胞增殖，P<0.001，和纤维化，P<0.001。外膜白细胞在第3天明显减少，P<0.001，但在第28天无差异。药代动力学分析（单损伤模型）发现，1小时时，血管周围组织中的雷帕霉素浓度比血液中高1500倍。血管周围雷帕霉素持续≥8天，在28天时未检测到。在猪股动脉球囊血管成形术模型中，外膜注射nab-雷帕霉素是安全的，并显著降低了管腔狭窄。观察到的早期外膜白细胞浸润和晚期中膜细胞增殖和纤维化的减少表明免疫抑制和抗增殖机制。用于外膜注射的腔内微输注导管代表了基于支架或球囊的局部药物输送的替代方案。
Endovascular interventions on peripheral arteries are limited by high rates of restenosis. Our hypothesis was that adventitial injection of rapamycin nanoparticles would be safe and reduce luminal stenosis in a porcine femoral artery balloon angioplasty model. Eighteen juvenile male crossbred swine were included. Single-injury (40%–60% femoral artery balloon overstretch injury; n=2) and double-injury models (endothelial denudation injury 2 weeks before a 20%–30% overstretch injury; n=2) were compared. The double-injury model produced significantly more luminal stenosis at 28 days, P=0.002, and no difference in medial fibrosis or inflammation. Four pigs were randomized to the double-injury model and adventitial injection of saline (n=2) or 500 μg of nanoparticle albumin-bound rapamycin (nab-rapamycin; n=2) with an endovascular microinfusion catheter. There was 100% procedural success and no difference in endothelial regeneration. At 28 days, nab-rapamycin led to significant reductions in luminal stenosis, 17% (interquartile range, 12%–35%) versus 10% (interquartile range, 8.3%–14%), P=0.001, medial cell proliferation, P<0.001, and fibrosis, P<0.001. There were significantly fewer adventitial leukocytes at 3 days, P<0.001, but no difference at 28 days. Pharmacokinetic analysis (single-injury model) found rapamycin concentrations 1500× higher in perivascular tissues than in blood at 1 hour. Perivascular rapamycin persisted ≥8 days and was not detectable at 28 days. Adventitial nab-rapamycin injection was safe and significantly reduced luminal stenosis in a porcine femoral artery balloon angioplasty model. Observed reductions in early adventitial leukocyte infiltration and late medial cell proliferation and fibrosis suggest an immunosuppressive and antiproliferative mechanism. An intraluminal microinfusion catheter for adventitial injection represents an alternative to stent- or balloon-based local drug delivery.