Inhibition of Neointima Formation by a Novel Drug-Eluting Stent System That Allows for Dose-Adjustable, Multiple, and On-Site Stent Coating
Rainer WesselyJörg HausleiterCornelia MichaelisBirgit JaschkeMichael VogeserStefan MilzBoris BehnischThomas SchratzenstallerMagdalena Renke-GluszkoMichael D. StoverErich WintermantelAdnan KastratiAlbert Schömig
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Abstract:
The risk of in-stent restenosis can be considerably reduced by stents eluting cytostatic compounds. We created a novel drug-eluting stent system that includes several new features in the rapidly evolving field of stent-based drug delivery.The aim of the present study was the preclinical evaluation of a stent-coating system permitting individual, on-site coating of stents with a unique microporous surface allowing for individualizable, dose-adjustable, and multiple coatings with identical or various compounds, designated ISAR (individualizable drug-eluting stent system to abrogate restenosis). Stents were coated with 0.75% rapamycin solution, and high-performance liquid chromatography (HPLC)-based determination of drug release profile indicated drug release for >21 days. Rapamycin-eluting microporous (REMP) stents implanted in porcine coronary arteries were safe. To determine the efficacy of REMP stents, this novel drug-eluting stent platform was compared with the standard sirolimus-eluting stent. At 30 days, in-stent neointima formation in porcine coronary arteries was similar in both groups, yielding a significant decrease of neointimal area and injury-dependent neointimal thickness compared with bare-metal stents.The ISAR drug-eluting stent platform as a novel concept for stent coating allows for a safe, effective, on-site stent coating process, thus justifying further clinical evaluation to decrease in-stent restenosis in humans.Keywords:
Neointima
Sirolimus
Coronary arteries
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Intravascular Ultrasound
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Neointima
Atherectomy
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Neointima
Neointimal hyperplasia
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Objective: To establish an animal model of the restenosis after carotid endarterectomy. Methods: Thirty Japanese white rabbits were operated after 2 weeks fat enriched feeding. The right common carotid arteries of rabbits were merely exposed as the control group. Carotid endarterectomy was performed on the left common carotid arteries in rabbits as the experimental group. Results: Twenty-seven rabbits remained alive no restenosis were observed in the control segments of arteries. Restenosis were observed in all the segments of arteries performed the carotid endarterectomy. Restenosis were mainly caused by the formation of neointima. The neointima area grew consistently in time and reached the peak at 8 weeks after the operation. Conclusion: It is a highly effective and steady animal model of restenosis after carotid endarterectomy and fat enriched feeding.
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Endarterectomy
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Objective:To evaluate efficacy,feasibility and safety of 32 P liquid filled balloon irradiation in preventing restenosis in swine.Methods:After overstretch balloon angioplasty injury,the left anterior descending branch(LAD) of coronary artery was treated with 32 P or control 35 days later ,the morphometry and histopathologic analyses were carried out in the injured segments.Results:The lumen area was significantly larger ( P 0 01) while the neointima area( P 0 01),percent area stenosis ( P 0 01) and PCNA positive cells ( P 0 01) reduced sighificantly in the radiotherapeutic animals than in the control animals. Conclusion:The approach was safe,effective and feasible in preventing restenosis.
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Lumen (anatomy)
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Objective:To observe the pathological changes and expression of connexin(Cx)in rabbit iliac artery restenosis models.Method:Twenty New Zealand White rabbits were randomly divedied into 2groups:control group(n=10)and restenosis group(n=10).Restenosis group followed high-fat diet combined with double-balloon injury to establish restenosis model.Four weeks later,all rabbits were killed and iliac arteries were then cut down for HE staining,immunohistochemiscal analysis,and detecting the expression of Cx mRNA by RT-PCR as well.Result:Computer-assisted histomorphometric analysis showed the intima thickness of restenosis group increased compared with that of control group[(266.12±70.27)μm vs(2.85±0.19)μm,P0.01].We also observed the stenosis rates of restenosis group were higher than those of controls[(89.32±6.93)% vs(23.00±3.53)%,P0.01].By using immunohistochemistry to detectα-smooth muscle actin(α-SMA),we confirmed that the proliferated cells in neointima were VSMCs in restenosis group.Immuohistochemical analysis indicated Cx43 expressed in all iliac arteries of two groups.Compared with controls,more Cx43 expression was detected in neointima in restenosis group.Additionally,the Cx40 expression of controls was a little lower than that of restenosis group.Compared with control group,the expression of Cx43 mRNA increased in restenosis group(P0.01).As for the expression of Cx40 mRNA,there was no difference between two groups.Conclusion:It is not Cx40 but Cx43in gap junction that contributes to the process of the migration and proliferation of VSMCs in neointima formation,which plays an important role in the pathogenesis of restenosis.
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In-stent restenosis remains a clinical therapeutic challenge. Rotational atherectomy (RA) is an attractive treatment option as it may cause less vascular injury than balloon angioplasty (BA) and, therefore, limit further neointimal response. In an animal model of coronary in-stent restenosis, thermal injury and stenting created neointima (old NI). The treatment of in-stent restenosis with either BA (n = 9) or RA (n = 11) also generated neointima (new NI). The average areas (mm2) of old NI in the BA and RA groups were similar (3.77 ± 0.40 vs. 3.67 ± 0.53; P = 0.32). However, new NI formed after treatment of in-stent restenosis was significantly less in the RA as compared to the BA group (0.33 ± 0.12 vs. 0.73 ± 36, P < 0.01). In this porcine coronary artery model of in-stent restenosis, treatment with rotational atherectomy resulted in significantly less recurrent neointimal hyperplasia than balloon angioplasty. This animal study, thus, provides a rationale for the clinical use of rotablation in the treatment of in-stent restenosis. Cathet. Cardiovasc. Diagn. 45:332–336, 1998. © 1998 Wiley-Liss, Inc.
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Neointimal hyperplasia
Atherectomy
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Restenosis is a complicated disease. Neointima formation and unfavorable remodeling seem to contribute to the development of restenosis after angioplasty. Remodeling, a relatively new hypothesis, might be more crucial than neointima formation, although the two could well be inter-related. Stenting prevents unfavorable remodeling to some extent and lowers restenosis rates as compared to conventional balloon angioplasty. However, restenosis still occurs at too high a rate with stent angioplasty. A great many drugs have been tested in humans for the prevention of restenosis and failed, as most addressed the neointima formation problem only. Future drug design for restenosis should address both remodeling and neointima formation and some antioxidants, such as probucol, have shown promising results in this respect.
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