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Background: Struts have been considered as covered when tissue overlying the struts is >0 μm by optical coherence tomography (OCT). However, there is no confirmatory study to validate this definition by histology which is the gold standard. The aim of the present study was to assess the appropriate cutoff value of neointimal thickness of stent strut coverage by OCT with histology confirmation., Methods: We performed ex vivo OCT imaging of human coronary arteries with stents at autopsy. A total of 46 stents in 39 vessels from 25 patients were examined in this study, and a total of 165 cross-sectional images were co-registered with histology to determine the optimal cutoff value for strut coverage by OCT which was defined as luminal endothelial cells with 2 abluminal layers of smooth muscles cells and matrix. Considering the resolution of OCT is 10 to 20 μm, the cutoff values were assessed at ≥20, ≥40, and ≥60 μm., Results: A total of 2235 struts were reviewed by histology, 1216 were considered as well-matched struts which were analyzed in this study. By histology, 160 struts were identified as uncovered, while 1056 struts were covered. The OCT assessment without consideration of neointimal thickness yielded a poor specificity of 37.5% and sensitivity 100%. Of 3 cutoff values, the cutoff value of ≥40 μm yielded the best sensitivity (99.3%), specificity (91.0%), positive predictive value (98.6%), and negative predictive value (95.6%) as compared with ≥20 and ≥60 μm., Conclusions: Neointimal thickness ≥40 μm by OCT yielded the most accurate cutoff value to identify stent strut coverage validated by histology.

Introduction : Coronary bifurcation lesions are involved in up to 20% of all percutaneous coronary interventions (PCI). However, bifurcation lesion intervention is associated with a high complication rate, and optimal treatment of coronary bifurcation is an ongoing debate. Areas covered : Both different stenting techniques and a variety of devices have been suggested for bifurcation treatment, including the use of conventional coronary stents, bioresorbable vascular scaffolds (BVS), drug-eluting balloons (DEB), and stents dedicated to bifurcations. This review will summarize different therapeutic approaches with their advantages and shortcomings, with special emphasis on histopathologic and physiologic effects of each treatment strategy. Expert opinion : Histopathology and clinical data have shown that a more simple treatment strategy is beneficial in bifurcation lesions, achieving superior results. Bifurcation interventions through balloon angioplasty or placement of stents can importantly alter the bifurcation's geometry and accordingly modify local flow conditions. Computational fluid dynamics (CFD) studies have shown that the outcome of bifurcation interventions is governed by local hemodynamic shear conditions. Minimizing detrimental flow conditions as much as possible should be the ultimate strategy to achieve long-term success of bifurcation interventions.

Objectives: The objective of this study was to comprehensively evaluate the pathology of acute and chronic femoral stenting in symptomatic atherosclerotic patients and to understand the causes of stent failure (SF) using multimodality imaging including micro-computed tomography., Background: Although the pathology of coronary stenting has been well studied, the pathology of lower extremity femoral stenting remains poorly understood., Methods: Twelve stented femoral lesions removed at surgery (n = 10) and at autopsy (n = 2) were obtained from 10 patients (median age 74 years; interquartile range [IQR]: 66 to 82 years) with histories of peripheral artery disease (critical limb ischemia in 7) (7 men and 3 women). All specimens underwent radiography, micro-computed tomography, and histological assessment., Results: The median duration of implantation was 150 days (IQR: 30 to 365 days), the median stent diameter was 5.90 mm (IQR: 5.44 to 7.16 mm), and the median stent length was 39.5 mm (IQR: 27 to 107.5 mm). Of the 12 stented lesions, 2 had drug-eluting stents, and 10 had bare-metal stents. SF was observed in 8 of 12 lesions. The major cause of SF was acute thrombosis (6 of 8), but causes varied (delayed healing, stent underexpansion, false lumen stenting, and fracture), and 2 had restenosis. Stent fractures were observed in 3 cases by micro-computed tomography. Both drug-eluting stents, implanted for >1 year, showed delayed healing with circumferential peristrut fibrin deposition and SF., Conclusions: This histological study is the first to examine the pathological cause of SF. Stent thrombosis was the major cause of SF. Delayed healing was a common feature of bare-metal stents implanted for <90 days, while all drug-eluting stents, despite implantation duration >1 year, showed delayed healing., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Durable fluoropolymer-coated everolimus-eluting stents (FP-EES) have shown lower rates of stent thrombosis (ST) versus bare metal stents (BMS) and first-generation bioabsorbable polymer (BP) DES. The aim of the study was to evaluate the specific role of the FP in thromboresistance., Methods and Results: A total of 57 stents were assessed in three separate ex vivo swine arteriovenous shunt model experiments (first shunt experiment, custom-made fluoropolymer-coated BMS [FP-only] vs. BMS [n=8 each]; second shunt experiment, FP-EES vs. abluminally coated biodegradable polymer sirolimus-eluting stents [BP-SES] vs. BMS [n=8 each]; and third shunt experiment, FP-EES vs. polymer-free Biolimus A9-coated stents [PF-BCS] vs. BMS [n=6 each]). After one hour of circulation, stents were bisected, and each half was dual-immunostained using a platelet cocktail and a marker for inflammation. Antibody staining was visualised by confocal microscopy. In addition, stents were evaluated by scanning electron microscopy. FP-only stents showed significantly lower platelet adherence compared with BMS (% fluorescence-positive area: FP-only=1.8%, BMS=5.6%, p=0.047) with similar inflammatory cell density. FP-EES also demonstrated the lowest platelet adherence compared with BP-SES (p=0.056), PF-BCS (p=0.013) and BMS (p=0.003) with the significantly lowest inflammatory cell density., Conclusions: Fluoropolymer coating imparts greater thromboresistance relative to BMS and to polymer-free DES designs, which reflects an unique phenomenon known as fluoropassivation, representing one proposed mechanism for clinically observed low ST rates in FP-EES.

The internal mammary artery (IMA) is the most durable conduit for bypassing the left anterior descending (LAD) coronary artery in patients undergoing coronary artery bypass graft surgery (CABG). However, little is known about how the IMA reacts histologically to stent implantation. From CVPath stent registry (1048 lesions, 614 cases), we obtained 4 stent lesions (2 bare metal stents, 2 drug-eluting stents) involving IMA grafts. The mean age of our patients was 63 years and the duration of stent implantation in the IMA ranged from 5 days to 5 years. Stented arteries were dissected from hearts and embedded in plastic, segmented at 3 mm intervals, sectioned at 4-6 microns and stained with H&E and Movat pentachrome stains. Histological observations were performed. Majority of stents (3 of 4) were implanted in anastomosis between IMA and LAD while 1 stent was implanted in IMA body. One stent with duration of 5 days showed stent thrombosis while others were all patent with fully coverage by varying degrees of neointima. Foamy macrophage, lipid pool and calcification in neointima were observed in 1 stent with duration of 5 years but it was limited only to the distal LAD part within the stented segment. Overall, in this small pathologic series, the majorities of stents were implanted in IMA-to-LAD anastomosis site and demonstrated acceptable pathologic responses.

Introduction: Bare metal stents (BMS) and drug eluting stents (DES) have been deployed in single and overlap configurations, the latter mostly to cover long-lesions. Both type of stents in overlap configuration increases the risk of adverse events., Areas Covered: We present the rationale for either BMS or DES usage utilizing both preclinical and clinical studies for the use of single vs. overlapped stents. Further, employing experimental and pathological studies, we discuss the disadvantages of stent overlapping vs. single stenting and propose that vessel injury, local blood flow disturbance, higher drug/polymer dose are mechanisms leading to poor clinical outcomes including in-stent restenosis (ISR), delayed arterial healing, thrombosis, and hypersensitivity reactions. We also explore whether newer generation (2 nd generation) DES with reduced strut thickness, optimized drug release profiles, better polymer biocompatibility minimize the disadvantages of stent overlap seen in 1 st generation DES. Finally, we examine the reasons why fully bioabsorbable scaffolds resulted in increased adverse events., Expert Commentary: DES innovations have minimized the risk of ISR and repeat revascularization. In contradistinction to 1 st generation DES, major adverse cardiac events (MACE) is similar between single and overlapped stents in 2 nd generation DES, suggestion stent design play an important role in clinical outcomes.

Background: Arterial Remodeling Technologies bioresorbable scaffold (ART-BRS), composed of l- and d-lactyl units without drug, has shown its safety in a porcine coronary model at 6 months. However, long-term performance remains unknown. The aim of this study was to evaluate the ART-BRS compared to a bare metal stent (BMS) in a healthy porcine coronary model for up to 3 years., Methods and Results: Eighty-two ART-BRS and 66 BMS were implanted in 64 Yucatan swine, and animals were euthanatized at intervals of 1, 3, 6, 9, 12, 18, 24, and 36 months to determine the vascular response using quantitative coronary angiography, optical coherence tomography, light and scanning electron microscopy, and molecular weight analysis. Lumen enlargement was observed in ART-BRS as early as 3 months, which progressively increased up to 18 months, whereas BMS showed no significant difference over time. Percentage area stenosis by optical coherence tomography was greater in ART-BRS than in BMS at 1 and 3 months, but this relationship reversed beyond 3 months. Inflammation peaked at 6 months and thereafter continued to decrease up to 36 months. Complete re-endothelialization was observed at 1 month following implantation in both ART-BRS and BMS. Scaffold dismantling started at 3 months, which allowed early vessel enlargement, and bioresorption was complete by 24 months., Conclusions: ART-BRS has the unique quality of early programmed dismantling accompanied by vessel lumen enlargement with mild to moderate inflammation. The main distinguishing feature of the ART-BRS from other scaffolds made from poly-l-lactic acid may result in early and long-term vascular restoration., (© 2017 The Authors and Arterial Remodeling Technologies. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objectives: The aim of this study was to explore the pathology of in-stent chronic total occlusion (IS-CTO) in bare-metal (BMS) versus drug-eluting stents (DES)., Background: Despite a relatively high prevalence of IS-CTO, little is known about the underlying etiology and histopathologic characteristics of the occlusion., Methods: From CVPath Institute's stent registry of human native coronary arteries, the authors identified 56 lesions (32 BMS and 24 DES) from 54 patients with IS-CTO. Sections of stented coronary arteries were examined for histological features of IS-CTO. The underlying mechanisms of IS-CTO were determined along with the histopathological characteristics., Results: The pathological prevalence of IS-CTO was significantly higher in BMS versus DES cases at autopsy (11.7% vs. 5.9%; p = 0.01). The most frequent etiology of IS-CTO was acute thrombotic occlusion (51% in BMS vs. 67% in DES), followed by restenosis (31% vs. 8%) and neoatherosclerotic rupture (9% vs. 4%). The proximal lumen pattern was abrupt in 67% of BMS and in 57% of DES, whereas the distal lumen was tapered in 68% of BMS and in 74% of DES. BMS showed longer fibrous cap of IS-CTO than DES in both proximal (4.6 mm vs. 1.6 mm; p = 0.06) and distal (5.3 mm vs. 2.0 mm; p = 0.06)., Conclusions: At autopsy, IS-CTO was observed more frequently in BMS versus DES, with acute thrombotic occlusion being the most frequent cause, followed by restenosis (especially in BMS) and neoatherosclerotic rupture. Our findings shed new light upon the frequency, mechanisms, and pathology of IS-CTO., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to identify histological features that correlate with terms commonly used to describe optical coherence tomographic (OCT) and optical frequency-domain imaging (OFDI) images of stented vessels, by means of a histopathological validation study using stented human coronary arteries., Background: OCT imaging and OFDI are used to evaluate vascular responses to stent implantation. Descriptive terms such as "peristrut low attenuation" and "heterogeneous" have been used to describe neointimal characteristics that may have clinical relevance. However, only limited histopathological correlations are available., Methods: Using the CVPath stent registry, 19 cases were identified in whom implantation duration was >30 days and OCT imaging or OFDI and histological findings were available. Consecutive OCT or OFDI frames (n = 1,063) of stented coronary arteries were categorized according to their predominant imaging features in 1-mm intervals. Coregistration of OCT or OFDI frames and histopathological cross sections was performed in 111 frames., Results: Seven distinct OCT or OFDI patterns were found: homogenous (45%), layered (15%), high intensity with high attenuation (14%), intraluminal protruding masses (8%), peristrut low attenuation (7%), heterogeneous (2%), and honeycomb (1%). Histopathologically, the homogenous pattern correlated most often with smooth muscle cells within collagenous/proteoglycan matrix and less often with organized thrombus. The layered pattern correlated with healed neointimal rupture or erosion, peristrut neovascularization, or smooth muscle cells within collagen/proteoglycan matrix. High intensity with high attenuation correlated with superficial macrophage accumulation in the majority of cases, but with other histological findings in 30% of cases. The diagnostic accuracy was greater in restenotic lesions. The only OCT or OFDI finding that had a single histological feature was the honeycomb pattern., Conclusions: This study suggests a lack of correlation between OCT image patterns and distinct histological tissue characteristics., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Adjunctive devices are commonly employed in the treatment of wide necked cerebral aneurysms. Balloon remodeling and permanent stent implantation may lead to thromboembolic complications or the need for antiplatelet use. A temporary stent that does not lead to complete flow arrest may be beneficial., Methods: We studied 20 New Zealand white rabbits in whom aneurysms were created using elastase and ligation of the right common carotid artery. The aneurysms were then embolized with bare platinum coils along with adjunctive treatment using the Comaneci device or the Hyperglide balloon. Assessments were made for endothelial injury using scanning electron microscopy (SEM) and light microscopy., Results: 20 rabbits of mean±SD weight 3.1±0.2 kg were studied. Twelve rabbits were treated with the Comaneci device and eight with the Hyperglide balloon. There were no substantial differences on SEM or light microscopy in the subacute and chronic phase to suggest the Comaneci device caused endothelial injury., Conclusions: The Comaneci device is a new adjuvant treatment for bridging of wide necked aneurysms with the advantage of averting flow arrest during deployment. There does not appear to be any evidence of significant endothelial damage during deployment in preclinical studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: This study provides preliminary data on the safety and feasibility of the use of a novel focal implant for managing post-percutaneous transluminal balloon angioplasty (post-PTA) dissection., Background: Post-PTA dissection of the lower extremity arteries is managed with stent placement. This provides an acceptable post-intervention result but has long-term disadvantages, such as in-stent restenosis. Focal treatment of post-PTA dissection and avoidance of stents are the objectives of the Tack-It (Intact Vascular, Inc., Wayne, Pennsylvania) device., Methods: A preclinical study and first-in-human data are presented. Seven swine underwent superficial femoral artery device placement, with a self-expanding nitinol stent on 1 side and a series of 4 Tack-It devices on the other side. Specimens were harvested at 28 days. The clinical study included 15 limbs that underwent revascularization for critical limb ischemia (n = 9) or claudication (n = 6). Twenty-five lesions were treated in the superficial femoral (n = 8), popliteal (n = 7), and tibial (n = 10) arteries., Results: The preclinical study demonstrated a reduction in stenosis with the Tack-It (16.8 ± 2.6%) compared with stents (46.4 ± 9.8%). Neointimal thickness and injury score decreased with the Tack-It. Clinically, Tack-It placement resulted in acute technical success with resolution of the post-PTA dissection in 100% of lesions. There were no device-related complications or major amputations. Eighteen of the 25 lesions were available for angiographic follow-up at 1-year, and patency was 83.3%., Conclusions: Preclinical data suggest that the Tack-It device causes minimal vessel injury. Clinical use of the Tack-It to manage post-PTA dissection was safe and feasible in this early study and resulted in apposition of dissection flaps without stent placement., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Advances in the understanding of healing mechanisms after stent implantation have led to the recognition of stent strut thickness as an essential factor affecting re-endothelialization and overall long term vessel healing response after Percutaneous Coronary Interventions (PCI). Emergence of Drug-eluting stents (DESs) with anti-proliferative coating has contributed to reducing the incidence of restenosis and Target Lesion Revascularization (TVR), while progress and innovations in stent materials have in the meantime facilitated the design of newer platforms with more conformability and thinner struts, producing lesser injury and improving integration into the vessel wall. Recent advances in biodegradable metal and polymer materials now also allow for the design of fully biodegradable platforms, which are aimed at scaffolding the vessel only temporarily to prevent recoil and constrictive remodeling of the vessel during the initial period required, and are then progressively resorbed thereby avoiding the drawback of leaving an unnecessary implant permanently in the vessel. The aim of this article is to review recent evolution in stent material and stent strut design while understanding their impact on PCI outcomes. The article describes the different metallic alloys and biodegradable material properties and how these have impacted the evolution of stent strut thickness and ultimately outcomes in patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months., Methods and Results: A total of 335 devices (263 Absorb and 72 XV) were implanted in 2 or 3 main coronary arteries of 136 nonatherosclerotic swine and examined by light microscopy, scanning electron microscopy, pharmacokinetics, and gel permeation chromatography analyses at various time points. Vascular responses to Absorb and XV were largely comparable at all time points, with struts being sequestered within the neointima. Inflammation was mild to moderate (with absence of inflammation at 1 month) for both devices, although the scores were greater in Absorb at 6 to 36 months. Percent area stenosis was significantly greater in Absorb than XV at all time points except at 3 months. The extent of fibrin deposition was similar between Absorb and XV, which peaked at 1 month and decreased rapidly thereafter. Histomorphometry showed expansile remodeling of Absorb-implanted arteries starting after 12 months, and lumen area was significantly greater in Absorb than XV at 36 and 42 months. These changes correlated with dismantling of Absorb seen after 12 months. Gel permeation chromatography analysis confirmed that degradation of Absorb was complete by 36 months., Conclusions: Absorb demonstrates comparable long-term safety to XV in porcine coronary arteries with mild to moderate inflammation. Although Absorb was associated with greater percent stenosis relative to XV, expansile remodeling was observed after 12 months in Absorb with significantly greater lumen area at ≥ 36 months. Resorption is considered complete at 36 months., (© 2014 American Heart Association, Inc.)

Aims: Restenosis in drug-eluting stents (DESs) occurs infrequently, however, it remains a pervasive clinical problem. We interrogated our autopsy registry to determine the underlying mechanisms of DES restenosis, and further we investigated the neointimal characteristics of DESs and compared with bare metal stents (BMSs)., Methods and Results: Coronary lesions from patients with DES implants (n = 82) were categorized into four groups based on cross-sectional area narrowing: patent (<50%), intermediate (50-74%), restenotic (≥ 75% with residual lumen), and total occlusion (organized thrombus within the stent). Restenosis and occlusion were significantly dependent on the total stented length: restenosis (26.7 mm) and occlusion (25.7 mm) compared with patent DESs (17.3 mm). Further, restenotic and occluded lesions were located more distally in the coronary arteries and had greater vessel injury and uneven strut distribution suggesting local drug gradient. Multivariate analysis revealed that normalized maximum inter-strut distance was associated with DES restenosis (OR: 17.4, P = 0.04) while medial tear length was a predictor of DES occlusion (OR: 5.1, P = 0.03). No differences were observed between different DESs (sirolimus-, paclitaxel-, and everolimus-eluting stents) for restenosis and occlusion. Further, neointimal compositions of restenotic DESs demonstrated greater proteoglycan deposition and less smooth muscle cellularity over time, when compared with BMS with greater cell density and collagen deposition., Conclusions: Our study indicates the impacts of inadequate drug concentration due to wider inter-strut distance and vessel injury as primary mechanisms of DES restenosis and occlusion, respectively. Moreover, the differences in neointimal compositions between DESs and BMSs might serve as a potential target for the suppression of late neointima growth via inhibition of proteoglycans in DESs.

Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation, and migration followed by remodelling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, and transition from a contractile to a synthetic phenotype; the molecular mechanisms responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles' heel of interventional cardiologists.

Oxidative stress greatly influences the pathogenesis of various cardiovascular disorders. Coronary interventions, including balloon angioplasty and coronary stent implantation, are associated with increased vascular levels of reactive oxygen species in conjunction with altered endothelial cell and smooth muscle cell function. These alterations potentially lead to restenosis, thrombosis, or endothelial dysfunction in the treated artery. Therefore, the understanding of the pathophysiological role of reactive oxygen species (ROS) generated during or after coronary interventions, or both, is essential to improve the success rate of these procedures. Superoxide O2(·-) anions, whether derived from uncoupled endothelial nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, or mitochondria, are among the most harmful ROS. O2(·-) can scavenge nitric oxide, modify proteins and nucleotides, and induce proinflammatory signaling, which may lead to greater ROS production. Current innovations in stent technologies, including biodegradable stents, nitric oxide donor-coated stents, and a new generation of drug-eluting stents, therefore address persistent oxidative stress and reduced nitric oxide bioavailability after percutaneous coronary interventions. This review discusses the molecular mechanisms of ROS generation after coronary interventions, the related pathological events-including restenosis, endothelial dysfunction, and stent thrombosis-and possible therapeutic ways forward., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries., Methods: Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry., Results: The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both)., Conclusion: This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia., (Copyright © 2011 Wiley Periodicals, Inc.)

Objectives: The purpose of this study was to assess the pathological responses of atherosclerotic saphenous vein bypass grafts (SVBGs) to drug-eluting stents (DES) versus bare-metal stents (BMS)., Background: Repeat bypass surgery is typically associated with a high rate of morbidity and mortality. Percutaneous coronary interventions have emerged as the preferred treatment; however, only limited data are available on SVBGs pathological responses to DES and BMS., Methods: Formalin-fixed SVBG of >2 years duration (n = 31) were collected to histologically characterize advanced atherosclerotic lesions in native SVBG. In a separate group, SVBGs treated with DES (n = 9) and BMS (n = 9) for >30 days duration were assessed for morphological and morphometric changes., Results: Necrotic core lesions were identified in 25% of SVBG sections, and plaque rupture with luminal thrombosis was observed in 6.3% of histological sections (32% [10 of 31] vein grafts examined). Morphometry of DES demonstrated reduction in neointimal thickening versus BMS (0.13 mm [interquartile range: 0.06 to 0.16 mm] vs. 0.30 mm [interquartile range: 0.20 to 0.48 mm], p = 0.004). DES lesions also showed greater delayed healing characterized by increased peristrut fibrin deposition, higher percentage of uncovered struts, and less endothelialization compared with BMS. Stent fractures (DES 56% vs. BMS 11%, p = 0.045) and late stent thrombosis (DES 44% vs. BMS 0%, p = 0.023) were more common in DES versus BMS., Conclusions: Advanced SVBG atherosclerotic lesions are characterized by large hemorrhagic necrotic cores. Stenting of such lesions is associated with delayed vascular healing and late thrombosis particularly following DES implantation, which may help explain the higher rates of cardiovascular events observed in SVBG stenting as compared with native coronary arteries., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This study examined the utility of a stabilized cyclic RGD peptide chemically modified to selectively bind to titanium-oxide for enhanced biocompatibility of self-expanding nitinol stents. Endothelial cells express integrin receptors that promote attachment to subendothelial matrix proteins. Integrin binding to arginine-glycine-aspartic acid (RGD) peptide derivatives mimic naturally occurring adherent interactions. Irreversible covalent surface coating of conventional nitinol stents with a cyclic RGD (cRGD) peptide highly specific for integrin alpha v beta 3 might foster endothelialization after stent implantation. A selective cRGD peptide was irreversibly immobilized onto titanium oxide-rich nitinol coupons or self-expanding stents. Functionality of the engrafted RGD peptide was demonstrated using in vitro endothelial bioassays. A subsequent 7-day in vivo endothelialization study was performed using cRGD-coated self-expanding nitinol stents in rabbits. cRGD peptide coating effectively promoted endothelial cell anchorage, migration, and proliferation confirmed by increased focal adhesions. Proof-of-concept studies of rabbit cRGD stent implants showed a significant increase in endothelial coverage above stent struts relative to stents coated with BSA (cRGD = 70.1 ± 21.9 vs. BSA = 49.9 ± 21.8%, p < 0.03). Immobilization of cRGD peptides on strut surfaces represents an innovative strategy to improve endothelialization, which may facilitate vascular healing after stent implantation., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: This study sought to examine the capability of optical frequency domain imaging (OFDI) to characterize various morphological and histological responses to stents implanted in human coronary arteries., Background: A precise assessment of vascular responses to stents may help stratify the risk of future adverse events in patients who have been treated with coronary stents., Methods: Fourteen human stented coronary segments with implant duration ≥ 1 month from 10 hearts acquired at autopsy were interrogated ex vivo by OFDI and intravascular ultrasound (IVUS). Comparison with histology was assessed in 134 pairs of images where the endpoints were to investigate: 1) accuracy of morphological measurements; 2) detection of uncovered struts; and 3) characterization of neointima., Results: Although both OFDI and IVUS provided a good correlation of neointimal area with histology, the correlation of minimum neointimal thickness was inferior in IVUS (R(2) = 0.39) as compared with OFDI (R(2) = 0.67). Similarly, IVUS showed a weak correlation of the ratio of uncovered to total stent struts per section (RUTSS) (R(2) = 0.24), whereas OFDI maintained superiority (R(2) = 0.66). In a more detailed analysis by OFDI, identification of individual uncovered struts demonstrated a sensitivity of 77.9% and specificity of 96.4%. Other important morphological features such as fibrin accumulation, excessive inflammation (hypersensitivity), and in-stent atherosclerosis were characterized by OFDI; however, the similarly dark appearance of these tissues did not allow for direct visual discrimination. The quantitative analysis of OFDI signal reflections from various in-stent tissues demonstrated distinct features of organized thrombus and accumulation of foamy macrophages., Conclusions: The results of the present study reinforce the potential of OFDI to detect vascular responses that may be important for the understanding of long-term stent performance, and indicate the capability of this technology to serve as a diagnostic indicator of clinical success., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The Genous™ Bio-engineered R™ stent (GS) aims to promote vascular healing by capture of circulatory endothelial progenitor cells (EPCs) to the surface of the stent struts, resulting in accelerated re-endothelialization. Here, we assessed the function of the GS in comparison to bare-metal stent (BMS), when exposed to the human and animal circulation., Methods and Results: First, 15 patients undergoing coronary angiography received an extracorporeal femoral arteriovenous (AV) shunt containing BMS and GS. Macroscopical mural thrombi were observed in BMS, whereas GS remained visibly clean. Confocal and scanning electron microscopic (SEM) analysis of GS showed an increase in strut coverage. Quantitative polymerase chain reaction (qPCR) analysis of captured cells on the GS demonstrated increased expression of endothelial markers KDR/VEGFR2 and E-selectin, and a decrease in pro-thrombogenic markers tissue factor pathway inhibitor and plasminogen activator inhibitor-1 compared with BMS. Secondly, a similar primate AV shunt model was used to validate these findings and occlusion of BMS was observed, while GS remained patent, as demonstrated by live imaging of indium-labelled platelets. Thirdly, in an in vitro cell-capture assay, GS struts showed increased coverage by EPCs, whereas monocyte coverage remained similar to BMS. Finally, the assessment of re-endothelialization was studied in a rabbit denudation model. Twenty animals received BMS and GS in the aorta and iliac arteries for 7 days. Scanning electron microscopic analysis showed a trend towards increased strut coverage, confirmed by qPCR analysis revealing increased levels of endothelial markers (Tie2, CD34, PCD31, and P-selectin) in GS., Conclusion: In this proof-of-concept study, we have demonstrated that the bio-engineered EPC-capture stent, Genous™ R™ stent, is effective in EPC capture, resulting in accelerated re-endothelialization and reduced thrombogenicity.

Purpose: The objective of this study was to investigate potential differences in vascular response to stenting of coronary arteries with bare metal (BMS) and drug-eluting (DES) stents in juvenile vs. mature swine., Methods and Materials: Twenty-one mature (> 3 years) and 22 juvenile (6-9 months) Yucatan swine were implanted with 3 × 12-mm XIENCE V DES and ML VISION BMS in coronary arteries. After 7 and 28 days, vessels were analyzed using light microscopy (n = 5-7) and confocal and scanning electron microscopy (n = 5-10). Messenger RNA expression levels of inflammatory and endothelial gene markers were tested from stented tissue at 7 and 28 days (n = 3). A 2 × 2 analysis of variance followed by t tests compared treatment and/or age effects., Results: No age differences in neointimal area and percentage stenosis were measured. Juvenile swine exhibited increased fibrin scores compared to mature swine (2.6 ± 0.5 vs. 2.2 ± 0.5, P < .05) at 7 days, with no age-related difference at 28 days. At 7 days, significant increases in para-strut inflammation (P < .01) and in VCAM-1, ICAM-1, CD40 and MCP-1 gene expression (P < .05) were observed in mature swine, but differences were largely resolved by 28 days. DES exhibited less endothelial coverage than BMS at 7 days, but this difference was abrogated by 28 days, with no difference between age groups., Conclusions: Our results indicate that mature swine exhibited an increased foreign body response compared to mature swine at 7 and 28 days following stenting that may indicate marginal delays in resolution of foreign body response in aged populations. These differences are unlikely to affect methodologies for preclinical stent safety evaluations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Microcomputed tomography is an important tool for preclinical vascular imaging, with micron-level resolution. This nondestructive means of imaging allows for rapid collection of 2D and 3D reconstructions to visualize pathologic specimens. Postmortem analysis of stented arteries has yielded significant insights into the 'natural' history of stented arteries. This article outlines a protocol for ex vivo, postmortem cardiac examination of stented arterial segments with microcomputed tomography followed by histopathologic analysis and highlights the complementary nature of these modalities.

Aims: Despite recent abundance of data on drug-coated balloon technology, the biological effects of paclitaxel coated balloon (PCB) treatment followed by bare metal stent (BMS) implantation in peripheral arteries (simulating bail-out stenting, a common clinical scenario), have not been published., Methods and Results: PCB technology containing a paclitaxel-iopromide coating and identical iopromide-coated controls (without paclitaxel) were used in 16 porcine ilio-femoral arteries. The biological effects of inflating one (PCBx1) or two sequential (PCBx2) paclitaxel coated balloons before BMS implantation were compared to the single application of a control balloon (CCBx1; contrast coated balloons). At 30 days PCBx2 displayed significantly reduced late lumen loss by angiography (58% reduction vs. CCBx1; p=0.04) and neointimal area by histomorphometry (35% reduction vs. CCBx1 and 30% vs. PCBx1; p=0.02). Similarly, percent area stenosis in the PCBx2 group was reduced by 45% as compared to CCBx1 and PCBx1 (p=0.04). At this time, all parameters of vessel wall healing (including injury score, inflammation, and endothelialisation) following drug coated balloon treatment were comparable to the control group., Conclusions: Paclitaxel delivery to porcine ilio-femorals using PCB followed by BMS implantation effectively decreased neointimal proliferation. More extensive and prolonged proliferative response of the vessel after stenting (necessitating higher drug dose) could potentially explain the undetectable effect of PEBx1 relative to CCBx1 in this pilot study. Histological analysis confirmed the safety and biocompatibility of PCB technology.

Objectives: This study sought to validate the sensitivity and specificity of the Academic Research Consortium's (ARC) classification of stent thrombosis., Background: Classification of stent thrombosis according to ARC criteria has become widely accepted. The criteria have not been validated against an autopsy standard., Methods: An autopsy registry of 139 subjects with prior coronary stenting underwent detailed histopathological analysis to assess for stent thrombosis. Based on clinical data only, cases were adjudicated according to ARC stent thrombosis criteria, including a proposed modification of the possible classification to include death beyond 30 days due only to sudden death or acute ischemia., Results: Autopsy results confirmed 51 cases as positive and 88 as negative for stent thrombosis. Clinical adjudication classified 105 cases as definite (10), probable (31), or possible (64) ARC stent thrombosis. Specificity was high for definite (99%) and definite plus probable (83%) criteria, but sensitivity was poor at 18% and 51%, respectively. Including the possible cases improved sensitivity to 92% but reduced specificity to 34% (58 false positives). The modified possible criteria eliminated 13 false positive cases (specificity = 49%) and was the best approximation of a hypothetical gold standard in a sensitivity analysis if late death represented at least 20% of all stent thrombosis cases., Conclusions: In a selected autopsy sample, restricting ARC stent thrombosis to definite or definite plus probable criteria results in substantial under-reporting of confirmed cases. Inclusion of a modified possible classification may provide the best estimate of late and very late stent thrombosis rates., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to determine the histopathology of patent ductus arteriosus (PDA) in-stent stenosis after hybrid stage I palliation. The hybrid approach to palliation of hypoplastic left heart syndrome can be complicated by the development of in-stent stenosis of the PDA. This may obstruct retrograde aortic arch flow, decrease systemic circulation, and lead to interstage interventional procedures. Stented PDA samples removed from eight patients undergoing comprehensive stage II repair were examined by way of radiography and histochemistry (hematoxylin and eosin, Movat pentachrome, α-smooth muscle actin, and proliferating cell nuclear antigen). A retrospective chart review of the patients was also performed. PDA stents were in place in the PDA for a mean period of 169 ± 28 days in patients who had a mean age of 176 ± 30 days at the time of stent removal. Stent deployment caused chronic inflammation, caused fibrin deposition, and induced vascular smooth muscle-cell (VSMC) proliferation in the area immediately surrounding the stent struts. The neointimal region was composed largely of smooth muscle cells that appeared to be fully differentiated by the lack of PCNA staining. Neointimal thickening occurs in the PDA after stent placement for hybrid palliation of HLHS and is the result of inflammation, extracellular matrix deposition, and smooth muscle-cell proliferation in the peristrut region. This finding suggests that proliferating VSMCs in the peristrut region may provide the impetus for inward neointimal formation and therefore the manifestation of in-stent stenosis.

Objectives: Human coronary bare-metal stents (BMS) and drug-eluting stents (DES) from autopsy cases with implant duration >30 days were examined for the presence of neointimal atherosclerotic disease., Background: Neointimal atherosclerotic change (neoatherosclerosis) after BMS implantation is rarely reported and usually occurs beyond 5 years. The incidence of neoatherosclerosis after DES implantation has not been reported., Methods: All available cases from the CVPath stent registry (n = 299 autopsies), which includes a total of 406 lesions-197 BMS, 209 DES (103 sirolimus-eluting stents [SES] and 106 paclitaxel-eluting stents [PES])-with implant duration >30 days were examined. Neoatherosclerosis was recognized as clusters of lipid-laden foamy macrophages within the neointima with or without necrotic core formation., Results: The incidence of neoatherosclerosis was significantly greater in DES lesions (31%) than BMS lesions (16%; p < 0.001). The median stent duration with neoatherosclerosis was shorter in DES than BMS (DES, 420 days [interquartile range [IQR]: 361 to 683 days]; BMS, 2,160 days [IQR: 1,800 to 2,880 days], p < 0.001). Unstable lesions characterized as thin-cap fibroatheromas or plaque rupture were more frequent in BMS (n = 7, 4%) than in DES (n = 3, 1%; p = 0.17), with relatively shorter implant durations for DES (1.5 ± 0.4 years) compared to BMS (6.1 ± 1.5 years). Independent determinants of neoatherosclerosis identified by multiple logistic regression included younger age (p < 0.001), longer implant durations (p < 0.001), SES usage (p < 0.001), PES usage (p = 0.001), and underlying unstable plaques (p = 0.004)., Conclusions: Neoatherosclerosis is a frequent finding in DES and occurs earlier than in BMS. Unstable features of neoatherosclerosis are identified for both BMS and DES with shorter implant durations for the latter. The development of neoatherosclerosis may be yet another rare contributing factor to late thrombotic events., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

First generation drug-eluting stents (DES) have significantly improved the treatment options for patients with symptomatic coronary artery disease by decreasing rates of restenosis after percutaneous coronary revascularisation procedures. However, early enthusiasm was tempered by reports of late stent thrombosis, primarily in "off-label" use. In particular, the treatment of atherosclerotic plaques at coronary bifurcations has been challenging for interventional cardiologists regardless of the stent choice due to the underlying nature of the atherosclerotic disease and the use of multiple stents. In this article we illustrate the location and severity of plaque and investigate the healing following both bare metal stents (BMS) and drug-eluting stents (DES) at bifurcations using post-mortem specimens. The presented data will demonstrate that neointimal growth following stent implantation correlate to flow conditions, as there is less underlying atherosclerotic disease at high shear regions and subsequently less neointimal growth is observed in these regions versus low shear regions. The occurrence of late stent thrombosis in DES is also shown to be associated with greater presence of uncovered stent struts at the high shear region, which is likely due to local flow mechanics.

Objective: The objective of this study was to identify the predictors of distal embolization (DE) during protected renal artery angioplasty and stenting., Background: DE may contribute to worsening renal function after renal artery stenting. The factors associated with DE, rates of platelet-rich emboli, and treatments that may prevent DE during renal stenting have not been evaluated., Methods: The current study evaluated patients randomized to receive an embolic protection device (EPD) in the RESIST trial. Forty-two patients were identified for inclusion in this study. These patients were further randomized to abciximab (N = 22) or placebo (N = 20). Modification in Diet in Renal Disease glomerular filtration rate (GFR) was used as the primary measure of renal function. Creatinine was measured by a modified Jaffe reaction using the IDMS-traceable assay. The primary endpoint was capture of platelet rich emboli in the angioguard basket., Results: DE occurred in 15/42 (35%) of the patients and platelet rich DE in 10 (24%) of the patients who received an EPD. Of the angiographic characteristics only lesion length was significantly higher in patients with DE (16 +/- 7 mm vs. 10 +/- 5 mm, P = 0.04). Preprocedural abciximab reduced DE from 42 to 8% (P = 0.02). The rate of platelet rich emboli was 50% with neither abciximab nor a thienopyridine, 36% with thienopyridine only, 15% abciximab only, and 0% in patients who received both a thienopyridine and abciximab. Only Abciximab use was associated with improved renal function at 1-month, thienopyridine was not. Angiographic characteristics including percent stenosis, minimal luminal diameter (MLD), reference diameter, change in MLD, contrast volume, and procedure time were not predictors of DE during renal stenting., Conclusion: Capture of DE and specifically platelet DE are common during protected renal stenting using a filter-type EPD. Abciximab use, and potentially combined thienopyridine and abciximab use, decreased the rate of platelet rich DE; however, only abciximab improved renal function at 1-month., ((c) 2010 Wiley-Liss, Inc.)

First generation drug-eluting stents (DES) have significantly improved the treatment options for patients with symptomatic coronary artery disease by decreasing rates of acute vessel closure and restenosis after percutaneous coronary revascularization procedures. However, early enthusiasm was temperd by reports of late stent thrombosis (LST), which raised concerns about safety. Since millions of DES have been implanted in patients worldwide, it is imperative to understand the pathology of DES in man. Autopsy studies from the CVPath DES registry documented that delayed arterial healing is accompanied by poor endothelialization of stent struts which is the single best predictor of late stent thrombosis. Arterial healing of DES is highly heterogeneous and is dependent on underlying plaque morphology as well as on the stent location. We identified several anatomical and pathological changes in man, which were associated with LST; these include hypersensitivity reaction to polymer, plaque rupture, bifurcation sites, malapposition and stent fracture. DES was also associated with premature atherosclerotic changes versus BMS.

Objectives: In this study, we hypothesized that an antihuman-CD34 antibody immobilized on the surface of commercially available sirolimus-eluting stents (SES) could enhance re-endothelialization compared with SES alone., Background: Previous experience with antihuman-CD34 antibody surface modified Genous stents (GS) (OrbusNeich Medical, Fort Lauderdale, Florida) has shown enhanced stent endothelialization in vivo., Methods: In the phase 1 study, stents were deployed in 21 pig coronary arteries for single stenting (9 vessels: 3 GS, 3 SES, and 3 bare-metal stents) and overlapping stenting with various combinations (12 vessels: 4 GS+GS, 4 SES+SES, and 4 GS+SES) and harvested at 14 days for scanning electron and confocal microscopy. In phase 2, immobilized anti-CD34 antibody coating was applied on commercially available SES (SES-anti-CD34, n = 7) and compared with GS (n = 8) and SES (n = 7) and examined at 3 and 14 days by scanning electron/confocal microscopy analysis., Results: In phase 1, single stent implantation showed greatest endothelialization in GS (99%) and in bare-metal stent (99%) compared with SES (55%, p = 0.048). In overlapping stents, endothelialization at the overlapping zone was significantly greater in GS+GS (95 +/- 6%) and GS+SES (79 +/- 5%) compared with the SES+SES (36 +/- 14%) group (p = 0.007). In phase 2, SES-anti-CD34 resulted in increased endothelialization compared with SES alone at 3 days (SES-anti-CD34 36 +/- 26%; SES 7 +/- 3%; and GS 76 +/- 8%; p = 0.01), and 14 days (SES-anti-CD34 82 +/- 8%; SES 53 +/- 20%; and GS 98 +/- 2%; p = 0.009)., Conclusions: Immobilization of anti-CD34 antibody on SES enhances endothelialization and may potentially be an effective therapeutic alternative to improve currently available drug-eluting stents., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The histologic response to self-expanding stent implantation into advanced atherosclerotic lesions has not been systematically investigated. We tested the hypothesis of whether gradual expansion of advanced atherosclerotic plaques by self-expanding stents would be an appropriate method to seal atherosclerotic lesions without causing plaque disruption as is usually observed with balloon-expandable stents., Methods and Results: Twelve New Zealand white rabbits were fed an atherogenic diet (1% cholesterol) followed by arterial denudation and injection of washed autologous erythrocytes. Nitinol self-expanding stents of two different stent designs and strengths (n=12 for SX and n=12 for Micro-SX) were implanted into the previously formed lesions within the abdominal aorta six weeks following injection of erythrocytes. Four weeks following stent implantation, animals were sacrificed, specimens harvested and processed for histology. Histomorphometry was performed on stented and adjacent non-stented regions. Atherosclerotic lesions were composed of foam cells, cholesterol clefts and necrotic plaque. While SX stents showed an unfavourable outcome with respect to vessel remodelling and the percentage of uncovered stent struts, Micro-SX stents had fewer uncovered stent struts, less positive remodelling and less plaque injury., Conclusions: Nitinol Micro-SX self-expanding stents might be a valuable approach to seal high risk atherosclerotic lesions.

For peripheral endovascular intervention, self-expanding (SE) stents are commonly oversized in relation to target arteries to assure optimal wall apposition and prevent migration. However, the consequences of oversizing have not been well studied. The purpose of this study was to examine the effects of SE stent oversizing (OS) with respect to the kinetics of late stent expansion and the long-term histological effects of OS. Pairs of overlapped 8 x 28-mm Nitinol SE stents were implanted into the iliofemoral arteries of 14 Yucatan swine. Due to variations in target artery size, the stent-to-artery ratio ranged from 1.2:1 to 1.9:1. Lumen and stent diameters were assessed by quantitative angiography at the time of implantation. Following angiographic assessment at 6 months, stented arteries were perfusion-fixed, sectioned, and stained for histological analysis. Immediately following implantation, the stents were found to be expanded to a range of 4.7-7.1 mm, largely conforming to the diameter of the recipient target artery. The stents continued to expand over time, however, and all stents had enlarged to nearly their 8-mm nominal diameter by 6 months. The histological effects of OS were profound, with marked increases in injury and luminal area stenosis, including a statistically significant linear correlation between stent-to-artery ratio and area stenosis. In this experimental model of peripheral endovascular intervention, oversized Nitinol SE stents are constrained by their target artery diameter upon implantation but expand to their nominal diameter within 6 months. Severe OS (stent-to-artery ratio >1.4:1) results in a profound long-term histological response including exuberant neointimal proliferation and luminal stenosis.

Objective: The aim of this study was to evaluate whether complete embolic protection is superior to partial embolic protection for preservation of kidney function during renal artery angioplasty and stenting., Background: Renal artery angioplasty and stenting (RAAS) is a common treatment for atherosclerotic renal artery stenosis. However, RAAS may be complicated by peri-procedural loss of kidney function., Methods: In total, 44 patients were randomized to embolic protection devices (EPD) use; 25 complete and 19 partial embolic protection. These patients were further randomized to receive abciximab (n = 23) or placebo (n = 21). [corrected] MDRD glomerular filtration rate (GFR), was used as the primary measure of renal function. Creatinine was measured by a modified Jaffe reaction using the IDMS-traceable assay. The primary endpoint was the percent change in estimated glomerular filtration rate (eGFR) 1 month following stent placement., Results: There was no difference in percent change eGFR at 1 month between complete or partial protection (-4 +/- 25 vs. +3 +/- 30, P = 0.45). Abciximab was associated with a net improvement in eGFR when compared with placebo (+0.5 +/- 27 vs. -11 +/- 20, P = 0.04). On subgroup analysis, the use of abciximab was associated with significantly improved eGFR in the partial distal embolic protection group (+14 +/- 33 vs. -17 +/- 13 %, P = 0.018) but not in the complete distal embolic protection group (+2.5 +/- 26 vs. -11 +/- 24, P = 0.42), however, there was no interaction between completeness of protection and abciximab on eGFR (P = ns). Capture of embolic material was more likely with complete protection when compared with those receiving partial protection (51% vs. 21%, P < 0.05)., Conclusion: Complete protection was superior to partial protection for the capture of athermanous debris during renal artery stenting. However, this was not associated with improved renal function. Importantly, Abciximab conferred a benefit for renal function that was independent of the degree of embolic protection.

Objective: TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids., Methods and Results: Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5+/-4.4 versus 31.0+/-8.4 and 29.5+/-8.1%, P<0.03)., Conclusions: TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.

Objectives: We compared the healing and inflammatory responses of polymer-free bare-metal stents (BMS), polymer-free sirolimus-eluting stents (SES) and polymer-free sirolimus-eluting stents plus estradiol (SES+ED) to Cypher drug-eluting stents (CDES) in a rabbit model of overlapping stent placement., Background: Inflammatory responses to polymers and delayed healing remain important safety issues associated with CDES. Whether nonpolymeric stents that elute sirolimus or sirolimus and estradiol provoke less inflammation and heal better is unknown., Methods: Twenty-eight rabbits received 2 overlapping stents in each iliac artery: SES, SES+ED, BMS, or CDES, and vessels were harvested at 28 days for histology and scanning electron microscopy., Results: Although similar at nonoverlapping segments, neointimal thickness within the overlap site of CDES was significantly less than in SES, SES+ED, and BMS (0.07 +/- 0.04 mm vs. 0.16 +/- 0.03 mm, 0.14 +/- 0.03 mm, and 0.15 +/- 0.03 mm, p < 0.0001). Endothelialization was greater in SES, SES+ED, and BMS compared with CDES in nonoverlapping sections (80.0 +/- 5.0% vs. 95.3 +/- 5.0%, 97.5 +/- 2.5%, and 96.7 +/- 3.8%; p = 0.0028) and overlapping sections (85.8 +/- 2.9% vs. 90.8 +/- 6.3%, 89.2 +/- 6.3%, and 48.3 +/- 2.9%; p < 0.0001). The number of luminal eosinophils was also less in overlapping sections of SES, SES+ED, and BMS versus CDES but was similar in nonoverlapping sections., Conclusions: Polymer-free stents coated with SES or SES+ED result in less robust neointimal suppression but markedly improved arterial healing compared with CDES in the rabbit model.

Background: Preservation of renal function is an important objective of renal artery stent procedures. Although atheroembolization can cause renal dysfunction during renal stent procedures, whether adjunctive use of embolic protection devices or glycoprotein IIb/IIIa inhibitors improves renal function is unknown., Methods and Results: One hundred patients undergoing renal artery stenting at 7 centers were randomly assigned to an open-label embolic protection device, Angioguard, or double-blind use of a platelet glycoprotein IIb/IIIa inhibitor, abciximab, in a 2x2 factorial design. The main effects of treatments and their interaction were assessed on percentage change in Modification in Diet in Renal Disease-derived glomerular filtration rate from baseline to 1 month using centrally analyzed creatinine. Filter devices were analyzed for the presence of platelet-rich thrombus. With stenting alone, stenting and embolic protection, and stenting with abciximab alone, glomerular filtration rate declined (P<0.05), but with combination therapy, it did not decline and was superior to the other allocations in the 2x2 design (P<0.01). The main effects of treatment demonstrated no overall improvement in glomerular filtration rate; although abciximab was superior to placebo (0+/-27% versus -10+/-20%; P<0.05), embolic protection was not (-1+/-28% versus -10+/-20%; P=0.08). An interaction was observed between abciximab and embolic protection (P<0.05), favoring combination treatment. Abciximab reduced the occurrence of platelet-rich emboli in the filters from 42% to 7% (P<0.01)., Conclusions: Renal artery stenting alone, stenting with embolic protection, and stenting with abciximab were associated with a decline in glomerular filtration rate. An unanticipated interaction between Angioguard and abciximab was seen, with combination therapy better than no treatment or either treatment alone.

The aim of the present study was to analyse the long-term histology and immunohistochemistry of the plaque composition and cellular infiltration of SVGs (saphenous vein grafts) containing metallic stents. Percutaneous interventions in SVGs have a worse long-term clinical outcome compared with stenting of coronary arteries. Whether the pathological features of old degenerated SVGs condition the efficacy of drug-eluting stents is also unknown. Histology and immunohistochemistry of seven SVGs in the coronary circulation containing 12 metallic stents implanted 5 to 61 months before retrieval were analysed in patients undergoing a second aorto-coronary bypass surgery at a mean time of 11+/-6 years. The pathology of the old SVGs showed an important thrombotic and necrotic composition of the plaque, with plaque protrusion through the stent wires and a fragile media layer that could easily be damaged by stent placement with subsequent neointimal proliferation; indeed, stents with medial fracture had significantly greater mean neointimal thickness than those without (1.37+/-0.68 compared with 0.81+/-0.47 mm(2); P<0.02). Neointimal inflammatory cell density correlated with increased neointimal thickness in patent vessels (r(2)=0.43, P<0.001). Immunostaining showed the total absence of ERs (oestrogen receptors), a poor cellular proliferative state as indicated by the presence of the Ki-67 marker, and persistent inflammation close to the stent wires as revealed by KP-1 and ACE (angiotensin-converting enzyme) immunostaining in most inflammatory cells in contact with the metal. These pathological findings may contribute to the more severe progression of disease and worse clinical outcome observed after conventional stented angioplasty of SVGs and might also interfere with the efficacy of drug-eluting stents in this specific atherosclerotic milieu.

Purpose: To determine the diagnostic accuracy of virtual histology intravascular ultrasound imaging (VH IVUS) of carotid plaque and to assess the feasibility of VH IVUS to identify plaque with embolic potential in patients undergoing carotid artery stenting (CAS)., Methods: Thirty patients (17 men; mean age 74+/-7 years) were entered nonrandomly into a single-center, prospective, 2-arm study following FDA and Institutional Review Board approval. In one arm, 15 patients underwent VH IVUS examination of carotid plaque with a cerebral protection device immediately followed by carotid endarterectomy (CEA). A comparison of "virtual" with true histology was then performed, classifying plaque type by VH IVUS and histopathology in a blinded study. In the second arm, 15 patients undergoing CAS had a preliminary VH IVUS scan performed with cerebral protection. Debris collected from the filter following stenting was examined histologically and compared with the VH IVUS data., Results: The diagnostic accuracy of VH IVUS to agree with true histology in different carotid plaque types was 99.4% in thin-cap fibroatheroma, 96.1% for calcified thin-cap fibroatheroma, 85.9% in fibroatheroma, 85.5% for fibrocalcific, 83.4% in pathological intimal thickening, and 72.4% for calcified fibroatheroma. Filter debris was captured in 2 patients prior to CEA and in 4 patients undergoing CAS for restenosis; VH IVUS classification of plaque composition was consistent with the histological evaluation of filter fragments. Calcified nodules projecting into the carotid artery lumen were associated with a higher incidence of previous neurological symptoms (66.7% versus 33.3%, p<0.05), while patients on aspirin has significantly less necrotic lipid core plaque detected by VH IVUS than patients not taking aspirin (6.4%+/-4.7% versus 9.7%+/-2.8%, p<0.05)., Conclusion: This study showed a strong correlation between VH IVUS plaque characterization and the true histological examination of the plaque following endarterectomy, particularly in "vulnerable" plaque types. The feasibility study to examine VH IVUS data and the filter debris histology in CAS patients supports a larger prospective study.

Atherosclerotic plaque at the carotid bifurcation is the primary cause of ischemic strokes and the degree of carotid stenosis is strongly associated with stroke risk in symptomatic patients. Stroke is the third-leading cause of death in the United States, constituting approximately 700,000 cases each year. In this article, the authors discuss the natural history of carotid and intracranial atherosclerosis, based on their broader knowledge of coronary atherosclerosis. Early to more advanced progressive lesions of the carotid are categorized, based on descriptive morphologic events originally cited for the coronary circulation. The histologic features associated with symptomatic and asymptomatic carotid disease are also addressed, along with the issues surrounding current stent-based therapies for the prevention of major recurrent vascular events.

Objectives: The aim of this study was to compare the effects of systemic prednisone in combination with a bare-metal stent (BMS) or a paclitaxel-eluting stent (Taxus, Boston Scientific Corp., Natick, Massachusetts) on neointimal inhibition and vessel healing in an atherosclerotic rabbit model., Background: Inflammation plays a critical role in neointimal formation after coronary artery stenting. The efficacy of immunosuppressive doses of oral prednisone to inhibit in-stent neointimal proliferation was compared with BMS and with a commercially available paclitaxel-eluting stent (Taxus) in a rabbit model of established atherosclerosis., Methods: Bilateral iliac artery injury in atherosclerotic New Zealand White rabbits fed an atherogenic diet was followed by stent implantation. Animals randomly received Taxus stents, BMS (Express, Boston Scientific Corp.) and placebo, or BMS and oral prednisone (2.1 mg/kg/day for the first 7 days, followed by 1.4 mg/kg/day for 14 days and 0.7 mg/kg/day for 21 days). Stented arterial segments were harvested at 42 days and processed for light microscopy, immunohistochemistry, and organoid culture., Results: Compared with control subjects, prednisone-treated animals showed a 30% reduction in percent stenosis (p = 0.009), a 35% decrease in neointimal area (p < 0.003), and a 66% decrement in neointimal thickness (p < 0.001). Taxus stents also reduced all 3 parameters significantly (-34%, -39%, and -83%, respectively), but showed significantly more inflammatory cells and fibrin deposition and less endothelialization compared with the other 2 groups. Plaque burden was equal among groups, as shown by the identical stent and vessel area, and no remodeling was observed., Conclusions: Systemic prednisone treatment and Taxus stents reduce neointimal formation compared with BMS. The extent of neointimal reduction is similar between prednisone- and Taxus stent-treated animals; however, Taxus stents resulted in a significantly greater delay in healing. Targeting of inflammatory pathways after percutaneous coronary intervention may be an efficacious way to prevent restenosis without the long-term risk of late thrombosis.

Polymer-based sirolimus- (Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI). Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis. Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined.

Polymer-based sirolimus- (Cypher) and paclitaxel-eluting stents (Taxus), so-called drug-eluting stents (DES), have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary revascularization (PCI). While these stents have reduced rates of restenosis and late lumen loss compared to bare-metal stents (BMS), late thrombosis, a life-threatening complication of this technology, has emerged as a major concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that the DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared to BMS. This so-called delayed healing is "identified as" the primary substrate of an underlying cause of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis include penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions. These represent additional barriers to healing and should be avoided if DES are to be used in order to minimize the late thrombotic risks of these devices. Since the time course of complete healing with DES is unknown, the optimal duration of antiplatelet treatment remains to be determined.