Segmental vessel wall shear stress and neointimal formation after sirolimus-eluting stent implantation: physiological insights in a porcine coronary model

BACKGROUND: Low vessel-wall shear stress promotes atherosclerosis and restenosis. We conducted serial analysis of vessel-wall shear stress following placement of metal and sirolimus (SRL) stents to determine the relationship between shear stress and neointima. METHODS: Serial quantitative coronary angiography, intracoronary ultrasound (IVUS), and Doppler flow analysis were performed at baseline, immediately poststent, and at 30 and 90 days on 16 stents (metal, n = 8; SRL, n = 8) implanted in the coronary arteries of eight miniswine. Segmental vessel-wall shear stress (dyn/cm2) was calculated at 10 sections within the stent and normalized to the average proximal and distal reference vessel shear stress using IVUS and hyperemic average peak flow velocity. At 90 days, histological analysis was completed to determine vessel-wall morphometry on corresponding sections from each stent. RESULTS: Stent placement resulted in a similar degree of in-stent stenosis (-5% to 25%) and immediate post-in-stent shear stress. At 30 days, the IVUS neointimal cross-sectional area and percentage of area stenosis were significantly less in SRL (1.2+/-0.8 mm2; 12.7+/-8.5%) versus metal stents (2.3+/-0.4 mm2; 28.2+/-3.4%, P < .003). In-stent normalized shear stress was less for SRL (0.93+/-0.07) versus metal (1.07+/-0.08, P = .002) stents. At 90 days, the mean neointimal area was similar for the SRL (2.50+/-0.47 mm2) and metal stents (2.72+/-1.15 mm2). Linear regression documented a negative correlation between poststent shear stress and neointima for metal stents (r = .61, P < .0001). In the SRL stents, however, the post-in-stent shear stress had a positive correlation with neointima (r = .40, P = .0002). CONCLUSIONS: The placement of oversized stents causes alteration of segmental vessel-wall shear stress, which appears to be an important physiological stimulus for neointimal formation, and may influence the pharmacodynamics of SRL-eluting stent in the porcine coronary model.     

无载体西罗莫司洗脱支架在小型猪冠状动脉模型中预防冠状动脉支架再狭窄的实验研究

目的评价新型无载体西罗莫司药物洗脱支架（polymer-free sirolimus-eluting stent,PFSES）在小型猪冠状动脉模型中抑制新生内膜增殖的有效性和安全性。方法金属裸支架（baremental stent,BMS,n=13）、无载体纳米微孔裸支架（polymer-free bare mental stent,PFBMS,n=13）、聚合物载体西罗莫司洗脱支架（polymeribased sirolimus-eluting stent,PSES,n=13）以及PFSES（n=13）被分别随机置入26头小型猪的前降支（n=26）和回旋支（n=26）。支架置入28天和90天后,复查冠状动脉造影评价管腔丢失。90天后处死部分动物（n=12）行塑料包埋硬组织切片染色组织形态学分析。结果置入28天（n=24）及90天（n=12）,PFSES与BMS相比,显著降低管腔丢失（0.69±0.49 mm比1.27±0.36 mm,P=0.041;0.77±0.44 mm比1.33±0.29 mm,P〈0.01）。在90天组织形态学分析中,损伤积分相似的情况下,PFSES较BMS明显减少新生内膜面积（2.412±1.149 mm2比4.475±1.345 mm2,P〈0.05）。PFSES炎症反应与BMS相似,且明显低于PSES。结论PFSES在置入小型猪冠状动脉28及90天后,可以安全有效地抑制内膜增殖和预防支架内再狭窄。     

Stent-based delivery of ABT-578 via a phosphorylcholine surface coating reduces neointimal formation in the porcine coronary model.

Stent-based delivery of the antiproliferative and immunosuppressive macrocyclic lactone sirolimus reduces neointimal formation and restenosis by cytostatic inhibition of vascular smooth muscle cell proliferation. The objective of this study was to determine the feasibility and efficacy of stent-based delivery of ABT-578, a structurally unique macrocyclic lactone. Stainless steel balloon-expandable stents were coated with thin layer of phosphorylcholine (PC) or PC with ABT-578 (10 microg/mm). Fifteen juvenile domestic pigs underwent placement of oversized bare metal (n = 15), PC (n = 8), and PC with ABT-578 (n = 9) stents in the coronary arteries. At 28 days, histology demonstrated similar mean injury scores for the control, PC-, and ABT-578-coated stents. The mean neointimal area (mm2) was significantly reduced for ABT-578 (1.70 +/- 0.47) as compared with PC (2.82 +/- 1.24) and control (2.89 +/- 1.91) stents (P < or = 0.05). The 40% reduction in neointimal area resulted in significantly less mean percent diameter stenosis for ABT-578 (19.4% +/- 4.0%) as compared with PC (30.3 +/- 12.1 %) and control (29.4% +/- 15.5%) stents (P < or = 0.03). Twelve of the 45 bare metal stent cross-sections (26.7%) exhibited a giant cell reaction, while none of the sections from the ABT-578-eluting stents had a giant cell reaction (P = 0.004). Stent-based delivery of ABT-578 via a PC surface coating inhibits neointimal formation at 28 days in the porcine coronary model. Further study is necessary to determine the dose-response and long-term effects ABT-578-eluting stents in the porcine coronary model.     

Metallic surface modification.

The potential beneficial effect of metal surface treatment using electrochemical polishing on stent thrombogenicity and neointimal hyperplasia was evaluated in a rat A-V model and a porcine coronary model. Thrombogenicity of polished stents (n=6) was compared to non-polished stents (n=5) in a rat A-V shunt model using 125I-fibrinogen and 51Cr-labelled platelets. Total clot weight after 30 min was significantly lower in the polished stents (32.1+/-2.8 vs 18.1+/-4.4: p<0.001). Also, 125I-fibrinogen deposition was significantly lower in the polished stents (1.30+/-0.07 vs 0.66+/-0.04: p<0.001). Platelet deposition was, however, not significantly reduced (12.7+/-3.4 vs 9.87+/-1.9, NS). Subsequently, the effect of electrochemical polishing on neointimal hyperplasia was evaluated in a porcine coronary model. Polished (n=10) and non-polished stents (n=10) were randomly implanted in the right coronary artery of healthy pigs. Neointimal hyperplasia was significantly decreased in the polished stents (0.56+/-0.28 vs 0.94+/-0.34 mm2: p<0.01).     

Safety and efficacy of bioabsorbable magnesium alloy stents in porcine coronary arteries.

OBJECTIVE: We aimed to determine the safety and efficacy of biobasorbable magnesium alloy stents in porcine coronary arteries. Bioabsorbable magnesium stents carry the potential to overcome the limitations posed by permanent metallic stents such as chronic inflammation, late stent thrombosis, prolonged antiplatelet therapy, and artifacts when imaged by multislice-computed tomography or magnetic resonance imaging. METHODS: Magnesium alloy stents or stainless steel stents were randomly deployed in coronary arteries of domestic or minipigs. Domestic pigs were sacrificed at 3 days (n = 2) or 28 days, and minipigs at 3 months. RESULTS: At 3 days, magnesium alloy stents were intact, but started to show signs of degradation by 28 days. There was no evidence of stent particle embolization, thrombosis, excess inflammation, or fibrin deposition. At 28 days and 3 months, neointimal area was significantly less in magnesium alloy stent segments (2.44 +/- 0.88 mm(2) and 1.16 +/- 0.19 mm(2)) as compared with the stainless steel stent segments (5.03 +/- 1.5 mm(2) and 1.72 +/- 0.68 mm(2), P < 0.001 and 0.02). Quantitative coronary analysis indicates that percentage area stenosis and percentage diameter stenosis in magnesium alloy stent segments improved significantly at 3 months as compared to 28 days. Despite decreased neointimal hyperplasia, lumen area of the magnesium alloy stented vessels did not improve significantly. CONCLUSION: Magnesium alloy stents are safe and are associated with less neointima formation; however, reduced neointima did not result in larger lumen.     

Experimental Evaluation of a New Single Wire Stainless Steel Fishscale Coronary Stent (Freedomª)

Recent randomized clinical trials revealed a significant reduction in angiographic restenosis rates when adjunctive stenting was performed after conventional coronary balloon angioplasty. Current approved coronary stents are however hampered by their rigidity, limiting their trackability in tortuous vessels and furthermore, needing high pressure deployment for optimal vessel apposition. New coronary stents are currently under development, using more biocompatible metal alloys and/or designs which better align to the vessel wall at moderate deployment pressures. We evaluated the safety, efficacy, angiographic and histological effect of a new stainless steel fishscale designed stent (Freedoma, Global Therapeutics, Co., USA) in a porcine coronary and peripheral artery model. Implantation in the right coronary artery was successful in all 20 pigs. Control angiograms at 6 weeks follow-up demonstrated patent vessels and morphologic evaluation showed only a mild fibromuscular neointimal response resulting in an area stenosis of 28.7 +/- 0.18% and a mean neointimal hyperplasia of 0.18 +/- 0.25 mm. Comparison with the Palmaz-Schatza coronary stent in a porcine peripheral artery model demonstrated similar quantitative angiographic and morphologic vessel analysis results. Also the morphometric data were comparable. Area stenosis: Palmaz-Schatz: 37 +/- 0.24%, Freedom: 21 +/- 0.14%, p = 0.07. Mean neointimal hyperplasia: Palmaz-Schatz: 0.33 +/- 0.24 mm, Freedom: 0.18 +/- 0.08 mm, p = 0.08. CONCLUSION: Freedom coronary stent implantation in a porcine model resulted in a high procedural success without subacute thrombotic occlusions, despite no further anticoagulation nor antiplatelet therapy. Six weeks histopathological and morphometric evaluation demonstrated only a mild fibromuscular neointimal hyperplasia.     

Mytrolimus药物洗脱支架预防支架内再狭窄的实验研究

目的评价新型聚烯烃类高分子化合物涂层携载雷帕霉素衍生物-Mytrolimus(CCI-779)洗脱支架在小型猪冠状动脉模型预防再狭窄的疗效。方法小型猪冠状动脉分别置入裸支架、单纯聚烯烃类高分子化合物涂层支架和Mytrolimus洗脱支架(160μg/18mm)。术后4周重复冠状动脉造影后处死动物,测定3组支架血管段的损伤指数、冠状动脉横截面积、管腔面积、支架上平均内膜厚度、支架间平均内膜厚度、新生内膜面积、面积再狭窄百分比,并作比较。结果裸支架组(置入支架数n=10)、单纯聚烯烃类高分子化合物涂层支架组(n=10)和Mytrolimus洗脱支架组(n=8)3组冠状动脉大小和血管损伤程度基本相同,术后4周,单纯聚烯烃类高分子化合物涂层组与裸支架比较多项参数差异均无统计学意义。Mytrolimus药物洗脱支架组和裸支架组的支架上内膜厚度分别为(0.18±0.08)mm和(0.33±0.25)mm(P<0.05);支架间内膜厚度分别为(0.14±0.05)mm和(0.28±0.23)mm(P<0.05);新生内膜面积分别为(1.09±0.24)mm2和(2.44±1.59)mm2(P<0.05)。上述多项参数在Mytroliums洗脱支架组均显著少于裸支架组。Mytrolimus组新生内膜面积比裸支架组少了55.33%,且Mytrolimus组无一例再狭窄。结论Mytrolimus洗脱支架在置入小型猪冠状动脉4周时可有效抑制内膜增生、预防冠状动脉实验性支架内再狭窄。     

Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks.

AIMS: The addition of drug elution to coronary stents plays an integral role in coronary restenosis prevention. The present study was undertaken to determine the mechanism of action and the in vitro and in vivo efficacy of zotarolimus, a new chemical entity designed specifically for elution from phosphorylcholine (PC)-coated stents, for the reduction of neointimal hyperplasia in porcine coronary arteries. METHODS AND RESULTS: In vitro studies of Zotarolimus bound to FKBP-12 potently inhibited smooth muscle cells (SMCs) and endothelial cell (EC) proliferation. Twenty PC-only and 20 stents eluting zotarolimus 10 microg/mm were implanted in the coronary arteries of 20 domestic juvenile swine. After 28 days, zotarolimus stents exhibited less area stenosis (22.4+/-8.6 vs. 35.7+/-13%, P = 0.01), less neointimal area (1.69+/-0.55 vs. 2.78+/-1.07 mm(2), P = 0.01), less neointimal thickness (0.25+/-0.07 vs. 0.38+/-0.13 mm, P = 0.01), and greater lumen area (6.07+/-1.39 vs. 5.02+/-1.3 mm2, P = 0.01). All arteries in both the polymer-only and polymer/drug stent showed near-complete healing and minimal toxicity. Zotarolimus did not affect the extrastent segments nor alter the overall artery size (external elastic lamina cross-sectional area 9.18+/-1.19 vs. 9.06+/-1.28 mm2, P = 0.7). CONCLUSION: Zotarolimus binds to FKBP-12 and in vitro inhibits SMC and EC proliferation. Zotarolimus applied to PC-coated stents reduces neointima in the swine coronary model after 28 days. These results suggest potentially promising human clinical application for coronary stenting with this polymer/drug combination.     

Effect of abciximab-coated stent on in-stent intimal hyperplasia in human coronary arteries

The investigators tested whether abciximab-coated stents prevent neointimal hyperplasia (NIH) formation in coronary de novo lesions. Abciximab-coated stents were compared with control stents. All patients underwent follow-up coronary angiography and intravascular ultrasound (IVUS). All stents were successfully deployed, and patients were discharged home without clinical events. At follow-up coronary angiography, the restenosis rate and late loss were 14% and 0.33 +/- 0.28 mm in the abciximab-coated stent group and 28.6% and 0.64 +/- 0.32 mm in the control stent group (p = 0.099 and p = 0.014, respectively). At follow-up IVUS, the intrastent luminal area and intrastent NIH area were 5.7 +/- 1.6 and 2.0 +/- 1.6 mm(2), respectively, in the abciximab-coated stent group and 4.2 +/- 0.8 and 3.4 +/- 1.7 mm(2), respectively, in the control stent group (p = 0.001 and p = 0.001, respectively). Abciximab-coated stents are feasible and significantly inhibit NIH, with potential therapeutic benefit in preventing stent restenosis.     

可降解聚乳酸涂层西罗莫司洗脱支架在小型猪冠状动脉模型中的实验研究

目的评价新型L605钴铬合金平台可降解聚乳酸共聚物载体西罗莫司药物洗脱支架（bioabsorbable polymeric sirolimus-eluting stent,BPSES）在小型猪冠状动脉抑制新生内膜增殖的有效性和安全性。方法金属裸支架（bare mental stent,BMS）18枚、单纯可降解聚乳酸共聚物涂层支架（bioabsorbable polymer-only stent,BPOS）18枚以及BPSES 18枚被分别随机置入18头小型猪的前降支（18枚）、回旋支（18枚）以及右冠状动脉（18枚）。置入28天和90天,复查冠状动脉造影评价管腔丢失。置入7天、28天以及90天处死部分动物行塑料包埋硬组织切片染色组织形态学分析。结果置入28天及90天,BPSES与BMS相比,显著降低管腔丢失（28天0.54±0.45 mm比1.11±0.45mm,P=0.048;90天0.42±0.34 mm比0.96±0.41 mm,P=0.024）。在损伤积分相似的情况下,置入28天时BPSES较BMS新生内膜面积明显减少（0.90±0.40 mm2比1.88±0.71 mm2,P=0.015）,而在90天时亦叮见此趋势,7天、28天和90天BPSES和BPOS炎症反应及内皮化程度与BMS相似。结论BPSES在置入小型猪冠状动脉28天后,可以安全有效地抑制新生内膜增殖,90天时亦可见此趋势。     

Experimental Evaluation of a New Tubular Coronary Stent (V-Flexª)

The safety, efficacy, angiographic and histological effects of a new 316 L, SS seamless stainless steel tubular stent (V-Flexa, Global Therapeutics, Broomfield, Colorado) was evaluated in a porcine coronary and peripheral artery model. Implantation in the right coronary artery was successful in all 16 pigs. Eight pigs were angiographically controlled after 6 weeks and then sacrificed for morphometric analysis. All stented coronary vessels were widely patent at this moment and morphometric analysis showed only a mild fibromuscular neointimal hyperplasia resulting in a neointimal hyperplasia of 1.15 +/- 0.38 mm2. The remaining 8 pigs were controlled and sacrificed at 12 weeks. At that time, all stented vessels were patent and neointimal hyperplasia was 1.22 +/- 0.34 mm2. Comparison with the Palmaz-Schatza coronary stent (Cordis, Miami, Florida) in a porcine peripheral artery model demonstrated significantly less neointimal hyperplasia at 6 weeks (1.11 +/- 0.73 vs. 2.40 +/- 0.36, p = 0.001) and at 12 weeks (1.53 +/- 0.42 vs. 2.47 +/- 0.63, p = 0.003) for the V-Flex stent. In conclusion, V-Flex coronary stent implantation in a porcine coronary and peripheral arteries results in a high procedural success rate without subacute thrombotic occlusions, despite no further anticoagulation nor antiplatelet therapy. Six and 12 week histopathological and morphometric evaluation demonstrated only a mild fibromuscular neointimal hyperplasia. Comparison with the Palmaz-Schatz coronary stent in a peripheral artery model showed significantly less neointimal hyperplasia in the V-Flex stent.     

"Head-to-head comparison between sirolimus-eluting and paclitaxel-eluting stents in patients with complex coronary artery disease: an intravascular ultrasound study".

BACKGROUND: The aim of this study was to assess neointimal hyperplasia following sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) implantation in a patients with complex coronary disease. METHOD: Between January to December 2004, 70 patients were enrolled in this study (SES = 37; PES = 33. The primary objective was to assess the efficacy of SES and PES on neointimal proliferation inhibition in patients with complex coronary lesions by volumetric 3D intravascular ultrasound (IVUS) assessment at six-month follow-up. RESULTS: Baseline clinical, demographic or angiographic characteristics were well balanced in both groups. All procedures as well as hospitalisation were uneventful. The percentage of B2/C lesions in our study was > 90% in both groups. The IVUS-assessed in-stent mean neointimal hyperplasia volume was significantly lower in lesions treated with SES compared to PES (4.1 +/- 11 mm3 vs. 17.4 +/- 23 mm3, p < 0.002) at 6 month follow-up. No difference in both MACE (3.0 versus 6.0%, p = NS) and restenosis (5.4 versus 9.1%, p = NS) were found. The in-segment late loss at six month was 0.26 mm in the SES and 0.48 mm in the PES group (p = NS). CONCLUSIONS: The present study showed reduced neointimal proliferation after sirolimuseluting as compared to paclitaxel-eluting stents in patients with complex coronary artery disease. Both SES and PES were associated with low rate of angiographic restenosis or major adverse cardiovascular events.     

Effect of anti-oxidant (carvedilol and probucol) loaded stents in a porcine coronary restenosis model.

BACKGROUND: The long-term clinical efficacy of intracoronary stenting is limited by restenosis and delivery by the stent of agents inhibiting cell cycle progression should prevent in-stent neointimal hyperplasia. Carvedilol is an antioxidant that inhibits smooth muscle cell proliferation and migration, whereas probucol is a vascular protectant and reduces stent restenosis by improving the lumen dimension at the stent placement site. METHODS AND RESULTS: BiodivYsio phosphorylcholine-coated stents were dip-coated with carvedilol (5 mg/ml) or probucol (50 mg/ml) by immersion in respective methanol solutions. Twenty-four stents (carvedilol=8, probucol=8, control=8) were placed in 12 pigs and histopathologic analysis was done 4 weeks later. Histomorphometry of the carvedilol-coated stent group compared with the control groups showed that the neointimal area decreased by 42% (1.12+/-0.55 mm2 in the carvedilol group vs 1.92+/-0.52 mm2 in the control, p=0.004) and the lumen area increased by 20% (5.15+/-0.90 mm2 vs 4.17+/-0.87 mm2, p=0.008), resulting in a 43% reduction of the percent area stenosis (18.22+/-9.6% vs 31.9+/-9.2%, p=0.002). In the probucol-coated stent group, the lumen area, neointimal area, and %area stenosis did not different significantly from the control group. There were 7.7+/-2.97% proliferating nuclear cell antigen-positive cells in the carvedilol-coated stent group compared with 17.8+/-1.45% in the control group (p=0.0001) and 15.9+/-1.91% in the probucol group (vs control, p=NS). CONCLUSIONS: The carvedilol-coated stent, but not the probucol-coated one, inhibited neointimal hyperplasia in a porcine stent restenosis model.     

Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries

OBJECTIVE: Tyrphostin AGL-2043 is a potent tricyclic quinoxaline inhibitor of PDGF beta-receptor tyrosine kinase (PTK), Kit, and Flt3. We have shown previously that selective inhibition of PDGF beta-receptor PTK by tyrphostins markedly reduces SMC proliferation and migration in vitro, reduces neointima formation in balloon-injured porcine femoral arteries, and reduces neointimal stenosis in stented porcine coronary arteries when administered intramurally within biodegradable nanoparticles. The present study was designed to determine the effect of AGL-2043 delivered from a stent-based, biodegradable polymeric coating on neointima formation in the porcine coronary artery model. METHODS AND RESULTS: Stents coated with biodegradable, polylactic/glycolic acid (PLGA) polymer, with (n=13) or without (n=11) 180 mcg AGL-2043 were implanted into the proximal LAD of 24 Sinclair mini-pigs (34+/-4 kg) to achieve a 1.1:1 stent/artery diameter ratio. The delivery of drug from stent to tissue was confirmed by high-performance liquid chromatography. After 28 days, histomorphometric analysis showed that in-stent stenosis in animals treated with AGL-2043 was reduced by 50% (51+/-21% versus 26+/-10%, p=0.001), the absolute neointimal area was reduced by 44% (2.38+/-1.04 versus 1.31+/-0.43 mm(2), p=0.004), and the absolute luminal area was increased by 57% (2.19+/-1.09 versus 3.39+/-0.59 mm(2), p=0.003). There were no significant differences between control and AGL-2043 in injury score (1.24+/-0.11 vs. 1.15+/-0.12, p=0.07) or inflammation score (1.19+/-0.35 vs. 1.07+/-0.33, p=0.41). Moreover, the difference in % in-stent stenosis between control and treated animals remained highly significant even after normalizing the % stenosis to the degree of injury (p=0.0008) or to the inflammation score (p=0.001). Mortality for this study was zero. Tissue concentration in segments 1 cm proximal and distal to the stents, were negligible or zero at 1 h, 24 h, and 4 weeks after stent implantation. CONCLUSION: Stent-based delivery of tyrphostin AGL-2043 from a biodegradable polymeric coating reduces in-stent neointimal hyperplasia in porcine coronary arteries by 50% after 28 days and preserves lumen area. Long-term studies should be the next step in testing applicability to the human interventional setting.     

Experimental efficacy of an everolimus eluting cobalt chromium stent.

INTRODUCTION: Rapamycin and its analogs are now being coated on different stent platforms, using different polymer matrices to prevent restenosis by impairing vascular smooth muscle cell proliferation and neointimal formation. METHODS: We evaluated the feasibility and compared the efficacy of biostable polymeric everolimus and sirolimus (CYPHER, Cordis) eluting stents in a porcine coronary model. Cobalt chromium balloon expandable stents (ML VISION, Guidant) were coated with a polymer containing everolimus (190 mug/cm(2)). Twelve pigs underwent placement of 36 oversized sirolimus (n = 12), everolimus (n = 12), and bare metal (cobalt chromium, n = 12) stents in the coronary arteries. RESULTS: At day 28, vessel injury scores were low (<0.25) and similar between each of the three test groups. The mean neointimal thickness was significantly lower in the everolimus- (0.13 +/- 0.07 mm, P = 0.02) and sirolimus-eluting stents (0.13 +/- 0.08 mm, P = 0.04) versus the bare metal stents (0.20 +/- 0.07 mm). The mean percent area stenosis was similar for the everolimus-eluting stents [(20.8 +/- 6.9)%] and the sirolimus-eluting stents [(20.8 +/- 7.6)%], and each was significantly less than that of bare metal stents [(26.1 +/- 7.8)%, P = 0.05]. CONCLUSION: Stent-based delivery of sirolimus and everolimus delivered via durable polymeric matrices are equally effective in the suppression of neointimal formation at day 28 in the porcine coronary model. Further study is necessary to document dose response and long-term comparative effects of these drug-eluting stents.     

Experimental Evaluation of a New Single Wire Tantalum Coil Coronary Stent (Wiktor-iª)

To improve scaffolding properties, a new more densely woven Wiktor stent, the Wiktor-ia stent, was developed. Although the metal coverage remains still low compared to other stents, increased metal/vessel area raises the concern of increased thrombogenicity and neointimal hyperplasia. In this study we evaluated the Wiktor-i stent in a porcine peripheral and coronary model and compared the thrombogenicity and neointimal hyperplasia with the Wiktor-GX coronary stent. In a first study, a Wiktor-i and a Wiktor-GX coronary stent were implanted symmetrically in a preselected side branch of the right and left iliac artery of 10 healthy pigs. Quantitative vessel analysis showed comparable data before, immediately after and at follow-up. Hyperplasia measured by morphometry was also comparable in both groups (Wiktor-GX: 1.43 mm2 vs. Wiktor-i: 1.17 mm2, NS). Also, area stenosis was very similar (Wiktor-GX: 32% vs. Wiktor-i: 29%, NS). In a second study, 20 Wiktor (Wiktor-i: n=10, Wiktor-GX: n=10) coronary stents were implanted in the right coronary artery of 20 healthy pigs. Quantitative coronary analysis before, immediately after and at follow-up was comparable in both stents. The hyperplasia measured morphometrically was also comparable in both stents. (Wiktor-GX: 1.51 +/- 0.47 mm2 vs. Wiktor-i: 1.46 +/- 0.66 mm2, NS). Also the area stenosis was not significantly different (Wiktor-GX: 31% vs. Wiktor-i: 35%). In conclusion, this study shows that the increased metal/vessel area of the Wiktor-i stent does not result in an increased neointimal hyperplasia. Both stents show to be very biocompatible when implanted in porcine coronary and peripheral vessels.     

Preventive effects of the heparin-coated stent on restenosis in the porcine model.

The coronary stent reduces acute coronary arterial occlusion and late restenosis during and after coronary intervention. However, stent thrombosis and restenosis are still major limitations in the widespread use of the coronary stent. Local drug delivery using the heparin-coated stent may be a new approach, which reduces the incidence of stent thrombosis and restenosis. In order to evaluate the effects of the heparin-coated stent on stent restenosis, heparin-coated stents were compared with control stents in a porcine coronary stent restenosis model. Stent overdilation injury (stent:artery = 1.3:1.0) was performed with bare Wiktor stents (group I, n = 10) and heparin-coated Wiktor stents (group II, n = 20; HEPAMED, Medtronics) in porcine coronary arteries. Follow-up quantitative coronary angiography (QCA) was performed at 4 weeks after stenting, and histo-pathologic assessments of stented porcine coronary arteries were compared in both groups. On QCA, percent diameter stenosis was significantly higher in group I than in group II (16.3% +/- 6.62% vs. 9.6% +/- 5.06%, P < 0.05). The injury score of stented porcine coronary arteries was the same in both groups (1. 26 +/- 0.23 vs. 1.20 +/- 0.22). The area of pathologic stenosis of the stented arteries was higher in group I than in group II (41.6% +/- 12.5% vs. 27.1% +/- 9.9%, P < 0.005). The neointimal area was higher in group I than in group II (4.58 +/- 1.41 mm(2) vs. 2.57 +/- 1.07 mm(2), P < 0.05). By immunohistochemistry, the proliferating cell nuclear antigen (PCNA) index was higher in group I compared with group II (11.2% +/- 6.75% vs. 6.3% +/- 4.14%, P < 0.05). The heparin-coated stent is effective in the prevention of late coronary stent restenosis in a porcine coronary stent restenosis model. This may be related to the inhibition of neointimal cell proliferation.     

Low-energy gamma-emitting stents inhibit intimal hyperplasia with minimal "edge effects" in a pig coronary artery model.

PURPOSE: The objective of this study was to determine the effects of different doses of gamma-emitting radioactive stents on intimal hyperplasia in a porcine coronary stent model at 28 days. METHODS: Sixty-four bare stents and those coated with palladium-103 [activities of 0 (control), 0.5, 1.0, 2.0, and 4.0 mCi] were implanted in the coronary arteries of 32 pigs. Stented segments were evaluated by histomorphometry at 28 days. RESULTS: There was significantly more intima in the 0.5- and 1-mCi stents than in controls (4.27+/-0.52 and 4.71+/-1.13 vs. 1.71+/-0.61 mm(2); P<.0001). Neointimal formation in 2-mCi stents was similar to that in controls, while that in 4-mCi stents was reduced compared to that in controls (2.34+/-1.61 and 0.82+/-0.25 vs. 1.71+/-0.61 mm(2); P=NS and P<.05, respectively). Stent margin neointimal response was representative of that within the stent body, with nonsignficant modest increases in intimal area at adjacent nonstented segments in radioactive stent groups. There was a dose-dependent increase in inflammation scores. Radioactive stents had lower intimal smooth muscle and higher fibrin scores. There was an increase in adventitial fibrosis in 1- and 2-mCi stents versus controls (1.26+/-0.99, and 2.25+/-1.27 vs. 0.21+/-0.31; P<.001). CONCLUSION: Dose-response inhibition of in-stent hyperplasia with minimal "edge effects" occurs with low-energy gamma-emitting stents. An increased inflammatory response at higher doses in palladium-103 stents indicates that later follow-up studies are necessary.     

p27-p16 fusion gene inhibits angioplasty-induced neointimal hyperplasia and coronary artery occlusion

Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury-induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10(12) viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus-treated vessels. The average intimal area of the AV-W9-treated group 10 days after balloon injury and treatment was 0.42+/-0.36 mm(2), whereas the AV-null group demonstrated an intimal area of 0.70+/-0.52 mm(2). At day 10 the average intimal thickness of the AV-W9-treated vessels was 9.1 microm (n=5, x 20 magnification) compared with 21.2 microm (n=5, x 20 magnification) in control virus-treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9-treated vessels demonstrated an average intimal thickness of 4.7 microm (n=8, x 20 magnification) compared with 13.3 microm (n=3, x 20 magnification) in control virus-treated vessels and 7.3 microm (n=5, x 20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty-induced intimal hyperplasia in the coronary artery.     

Stent-mediated methylprednisolone delivery reduces macrophage contents and in-stent neointimal formation

OBJECTIVE: Corticosteroids have a wide range of biological effects. Stent-based methylprednisolone delivery could effectively suppress peri-strut inflammation and neointima induced by a polymer matrix. We tested the safety and efficacy of local stent-mediated methylprednisolone delivery using a biological coating on in-stent neointimal formation in a porcine coronary stent model. METHODS: Stainless steel coronary stents were dip-coated in a biological polymer/ methylprednisolone solution, resulting in total load of 530 mug methylprednisolone per stent. In-vitro drug release was performed. Stainless steel bare stents, polymer-only and methylprednisolone-coated stents (MP) were implanted in coronary arteries of pigs with a stent/artery ratio of 1.2 : 1. Histopathologic evaluation, morphometry and immunohistochemistic staining were analyzed at 4-week follow-up. RESULTS: In-vitro drug release studies showed sustained release up to 10 weeks. In vivo the vascular response of polymer-only-coated stents was comparable with the bare stents. No increased peri-strut inflammation and neointimal hyperplasia were observed. The in-stent neointimal formation of methylprednisolone-coated stents was significantly reduced compared with the bare and polymer-only-coated stents (bare, 1.92+/-0.73; polymer-only, 2.14+/-1.50; MP, 1.01+/-0.47 mm, P=0.019). The macrophage content of methylprednisolone-coated stents (bare, 30.74+/-48.67; polymer-only, 19.55+/-24.60; MP, 1.16+/-3.33/mm, P=0.072) was dramatically decreased. However, there were no significant difference among the three group in terms of the proliferating cells expressed by proliferation cell nuclear antigens. CONCLUSION: Stent-based local methylprednisolone delivery could effectively decrease both vascular macrophage infiltration and in-stent neointimal hyperplasia.