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Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries.

ABSTRACT: BACKGROUND: Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, concerns about the safety of DES still exist. OBJECTIVE: To investigate the vascular pathology and transcriptional responses to sirolimus and paclitaxel in a murine model for restenosis on underlying diseased atherosclerotic arteries. METHODS: Atherosclerotic lesions were induced by placement of a perivascular cuff around the femoral artery of hypercholesterolaemic ApoE*3-Leiden transgenic mice. Two weeks later these cuffs were replaced either by sirolimus- or paclitaxel-eluting cuffs. The vascular pathological effects were evaluated after two additional weeks. RESULTS: Both anti-restenotic compounds significantly inhibited restenotic lesion progression on the atherosclerotic plaques. Vascular histopathological analyses showed that local delivery of sirolimus has no significant adverse effects on vascular disease. Conversely, high dosages of paclitaxel significantly increased apoptosis, internal elastic lamina disruption, and decreased medial and intimal smooth muscle cells and collagen content. Moreover, transcriptional analysis by real-time RT-PCR showed an increased level of pro-apoptotic mRNA transcripts (FAS, BAX, caspase 3) in paclitaxel-treated arteries. CONCLUSIONS: Sirolimus and paclitaxel are effective in preventing restenosis. Sirolimus has no significant effect on arterial disease. In contrast, paclitaxel at high concentration demonstrated adverse vascular pathology and transcriptional responses, suggesting a narrower therapeutic range of this potent drug. Since the use of overlapping stents is becoming more common in DES technology, this factor is important, given that higher dosages of paclitaxel may lead to increased apoptosis in the vessel wall and, consequently, to a more unstable phenotype of the pre-existing atherosclerotic lesion.

SUBMITTER: Pires NM

PROVIDER: S-EPMC1994420 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries.

Pires Nuno M M NM Eefting Daniel D de Vries Margreet R MR Quax Paul H A PH Jukema J Wouter JW

Heart (British Cardiac Society) 20070420 8

<h4>Background</h4>Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, concerns about the safety of DES still exist.<h4>Objective</h4>To investigate the vascular pathology and transcriptional responses to sirolimus and paclitaxel in a murine model for restenosis on underlying diseased atherosclerotic arteries.<h4>Methods</h4>Atherosclerotic lesions were induced by placement of a perivascular cuff around the femora ...[more]

PMID: 17449502

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Project description:BACKGROUND::Polymer-free drug-eluting stents (DES) without permanent-polymer coating may be associated with rapid vessel healing, providing a rationale to reduce dual-antiplatelet therapy (DAPT). The aim of the current study was to compare vessel healing of a polymer-free sirolimus-eluting stent (PF-SES), its bare metal stent (BMS) analogue to a permanent polymer-based sirolimus-eluting stent (SES) with proven effectiveness in porcine coronary arteries. MATERIAL AND METHODS::An ultrathin-strut cobalt-chromium PF-SES, its BMS analogue and an SES with a permanent polymer were used to study vessel healing and their antistenotic potential. Stents were implanted in porcine coronary arteries for histopathologic analysis at 7, 28 and 180?days. In an additional in vitro study, the thrombogenicity of PF-SES was compared with a fluoropolymer-coated everolimus-eluting stent (EES) which demonstrated low stent thrombosis rates in numerous studies. RESULTS::In the animal study, neointimal growth and injury scores were minimal and inflammation scores were low in the neointima and adventitia in all study groups. After 28?days, neointimal area was lowest in PF-SES when compared with SES and BMS (1.48 ± 0.55?mm² versus 2.43 ± 0.69?mm² versus 1.90 ± 0.85?mm², respectively, p < 0.05) and endothelialization of luminal surfaces was nearly complete in all groups, though SES show the least coverage with occasional adherent luminal inflammatory cells ( p > 0.05). At 180?days, neointimal area and thickness were most pronounced in SES ( p < 0.05) and comparable with BMS implantations, which were characterized by nearly completed vessel healing. PF-SES and BMS had complete endothelialization, absence of fibrin and sustained low inflammatory reaction when compared with the permanent polymer-based SES (inflammation score: PF-SES 0.41 ± 0.74 versus SES 2.52 ± 1.72 versus BMS 0.30 ± 0.65, respectively, p < 0.05 BMS versus SES). Granuloma formation and fibrin accumulation were most pronounced in SES but did not reach statistical significance, p > 0.05). In the in vitro thrombogenicity study, the PF-SES confirmed comparable antithrombogenic properties with regard to the parameters fibrin and platelet binding, and platelet aggregation when compared with the EES. CONCLUSIONS::As compared with BMS, the ultrathin-strut cobalt-chromium PF-SES showed similar endothelialization at 28?days and comparable healing characteristics at 180?days efficacious inhibition of neointimal proliferation in porcine coronary arteries with low inflammation responses and a BMS-like endothelialization at 180?days. In addition, in an in vitro model, the PF-SES also confirmed low thrombogenicity as compared with the EES.

Dataset Information

Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries.

Publications

Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries.

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