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      Comparison of Vascular Responses Following New‐Generation Biodegradable and Durable Polymer‐Based Drug‐Eluting Stent Implantation in an Atherosclerotic Rabbit Iliac Artery Model

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          Abstract

          Background

          Incomplete endothelialization is the primary substrate of late stent thrombosis; however, recent reports have revealed that abnormal vascular responses are also responsible for the occurrence of late stent failure. The aim of the current study was to assess vascular response following deployment of biodegradable polymer‐based Synergy (Boston Scientific) and Nobori (Terumo) drug‐eluting stents and the durable polymer‐based Resolute Integrity stent (Medtronic) in an atherosclerotic rabbit iliac artery model.

          Methods and Results

          A total of 24 rabbits were fed an atherogenic diet, and then a balloon injury was used to induce atheroma formation. Synergy, Nobori, and Resolute Integrity stents were randomly implanted in iliac arteries. Animals were euthanized at 28 days for scanning electron microscopic evaluation and at 90 days for histological analysis. The percentage of uncovered strut area at 28 days was lowest with Synergy, followed by Resolute Integrity, and was significantly higher with Nobori stents (Synergy 1.1±2.2%, Resolute Integrity 2.0±3.9%, Nobori 4.6±3.0%; P<0.001). At 90 days, inflammation score was lowest for Synergy (0.27±0.45), followed by Nobori (0.62±0.59), and was highest for Resolute Integrity (0.89±0.46, P<0.001). Foamy macrophage infiltration within neointima (ie, neoatherosclerosis) was significantly less with Synergy (0.62±0.82) compared with Nobori (0.85±0.74) and Resolute Integrity (1.39±1.32; P=0.034).

          Conclusions

          The biodegradable polymer‐coated thin‐strut Synergy drug‐eluting stent showed the fastest stent strut neointimal coverage and the lowest incidence of neoatherosclerosis in the current animal model.

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          Most cited references21

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          A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.

          The need for repeated treatment of restenosis of a treated vessel remains the main limitation of percutaneous coronary revascularization. Because sirolimus (rapamycin) inhibits the proliferation of lymphocytes and smooth-muscle cells, we compared a sirolimus-eluting stent with a standard uncoated stent in patients with angina pectoris. We performed a randomized, double-blind trial to compare the two types of stents for revascularization of single, primary lesions in native coronary arteries. The trial included 238 patients at 19 medical centers. The primary end point was in-stent late luminal loss (the difference between the minimal luminal diameter immediately after the procedure and the diameter at six months). Secondary end points included the percentage of in-stent stenosis of the luminal diameter and the rate of restenosis (luminal narrowing of 50 percent or more). We also analyzed a composite clinical end point consisting of death, myocardial infarction, and percutaneous or surgical revascularization at 1, 6, and 12 months. At six months, the degree of neointimal proliferation, manifested as the mean (+/-SD) late luminal loss, was significantly lower in the sirolimus-stent group (-0.01+/-0.33 mm) than in the standard-stent group (0.80+/-0.53 mm, P<0.001). None of the patients in the sirolimus-stent group, as compared with 26.6 percent of those in the standard-stent group, had restenosis of 50 percent or more of the luminal diameter (P<0.001). There were no episodes of stent thrombosis. During a follow-up period of up to one year, the overall rate of major cardiac events was 5.8 percent in the sirolimus-stent group and 28.8 percent in the standard-stent group (P<0.001). The difference was due entirely to a higher rate of revascularization of the target vessel in the standard-stent group. As compared with a standard coronary stent, a sirolimus-eluting stent shows considerable promise for the prevention of neointimal proliferation, restenosis, and associated clinical events.
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            A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.

            Restenosis after coronary stenting necessitates repeated percutaneous or surgical revascularization procedures. The delivery of paclitaxel to the site of vascular injury may reduce the incidence of neointimal hyperplasia and restenosis. At 73 U.S. centers, we enrolled 1314 patients who were receiving a stent in a single, previously untreated coronary-artery stenosis (vessel diameter, 2.5 to 3.75 mm; lesion length, 10 to 28 mm) in a prospective, randomized, double-blind study. A total of 652 patients were randomly assigned to receive a bare-metal stent, and 662 to receive an identical-appearing, slow-release, polymer-based, paclitaxel-eluting stent. Angiographic follow-up was prespecified at nine months in 732 patients. In terms of base-line characteristics, the two groups were well matched. Diabetes mellitus was present in 24.2 percent of patients; the mean reference-vessel diameter was 2.75 mm, and the mean lesion length was 13.4 mm. A mean of 1.08 stents (length, 21.8 mm) were implanted per patient. The rate of ischemia-driven target-vessel revascularization at nine months was reduced from 12.0 percent with the implantation of a bare-metal stent to 4.7 percent with the implantation of a paclitaxel-eluting stent (relative risk, 0.39; 95 percent confidence interval, 0.26 to 0.59; P<0.001). Target-lesion revascularization was required in 3.0 percent of the group that received a paclitaxel-eluting stent, as compared with 11.3 percent of the group that received a bare-metal stent (relative risk, 0.27; 95 percent confidence interval, 0.16 to 0.43; P<0.001). The rate of angiographic restenosis was reduced from 26.6 percent to 7.9 percent with the paclitaxel-eluting stent (relative risk, 0.30; 95 percent confidence interval, 0.19 to 0.46; P<0.001). The nine-month composite rates of death from cardiac causes or myocardial infarction (4.7 percent and 4.3 percent, respectively) and stent thrombosis (0.6 percent and 0.8 percent, respectively) were similar in the group that received a paclitaxel-eluting stent and the group that received a bare-metal stent. As compared with bare-metal stents, the slow-release, polymer-based, paclitaxel-eluting stent is safe and markedly reduces the rates of clinical and angiographic restenosis at nine months. Copyright 2004 Massachusetts Medical Society
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              Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization.

              Late stent thrombosis (LST) after Cypher and Taxus drug-eluting stent placement has emerged as a major concern. Although the clinical predictors of LST have been reported, specific morphological and histological correlates of LST remain unknown. From a registry totaling 81 human autopsies of drug-eluting stents, 46 (62 lesions) had a drug-eluting stent implanted >30 days. We identified 28 lesions with thrombus and compared those with 34 of similar duration without thrombosis using computer-guided morphometric and histological analyses. LST was defined as an acute thrombus within a coronary artery stent in place >30 days. Multiple logistic generalized estimating equations modeling demonstrated that endothelialization was the best predictor of thrombosis. The morphometric parameter that best correlated with endothelialization was the ratio of uncovered to total stent struts per section. A univariable logistic generalized estimating equations model of occurrence of thrombus in a stent section versus ratio of uncovered to total stent struts per section demonstrated a marked increase in risk for LST as the number of uncovered struts increased. The odds ratio for thrombus in a stent with a ratio of uncovered to total stent struts per section >30% is 9.0 (95% CI, 3.5 to 22). The most powerful histological predictor of stent thrombosis was endothelial coverage. The best morphometric predictor of LST was the ratio of uncovered to total stent struts. Heterogeneity of healing is a common finding in drug-eluting stents with evidence of LST and demonstrates the importance of incomplete healing of the stented segment in the pathophysiology of LST.
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                Author and article information

                Contributors
                gnakazawa@tokai-u.jp
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                19 October 2016
                October 2016
                : 5
                : 10 ( doiID: 10.1002/jah3.2016.5.issue-10 )
                : e003803
                Affiliations
                [ 1 ] Department of CardiologyTokai University School of Medicine Isehara KanagawaJapan
                Author notes
                [*] [* ] Correspondence to: Gaku Nakazawa, MD, PhD, FACC, Department of Cardiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259‐1193, Japan. E‐mail: gnakazawa@ 123456tokai-u.jp
                Article
                JAH31838
                10.1161/JAHA.116.003803
                5121480
                27792651
                08df0e6a-9d82-448e-86b3-488ec146b476
                © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 28 April 2016
                : 23 September 2016
                Page count
                Figures: 5, Tables: 2, Pages: 8, Words: 4380
                Categories
                Original Research
                Original Research
                Interventional Cardiology
                Custom metadata
                2.0
                jah31838
                October 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.7 mode:remove_FC converted:08.11.2016

                Cardiovascular Medicine
                atherosclerosis,endothelialization,polymer,stent,animal models of human disease

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