In-stent Neointima Formation Research Articles

Three-dimensional reconstruction imaging by C-arm computed tomography accurately visualizes in-stent neointimal formation in patients with stent-assisted coil embolization.

Stent apposition to the vessel wall and in-stent neointimal formation after stent-assisted coil embolization for intracranial aneurysm are important factors associated with postoperative thromboembolic complications. No assessment methods have been established to depict 3-dimensional (3D) all-round in-stent neointimal formation. To demonstrate the superiority of Dyna-3D imaging assessment as a modality for all-round ISNF in comparison with conventional two-dimensional digital subtraction angiography (2D-DSA). Consecutive patients who underwent braided stent-assisted coil embolization for unruptured aneurysm between November 2016 and September 2021 were enrolled. Radiological assessments for stent apposition to the parent vessel after stent deployment and in-stent neointimal formation after 3 months were obtained. Dyna-3D was reconstructed by overlapping a plain image showing stent struts with a rotational DSA image showing the vessel lumen. Reconstructed Dyna-3D images can be rotated to any angle on the screen to evaluate to stent apposition around the vessel and in-stent neointimal formation in 3D, for comparison with 2D-DSA evaluations. Among the 73 patients enrolled, 70 patients (96%) showed complete stent wall apposition on Dyna-3D. Higher intra-rater agreement was confirmed on assessment of in-stent neointimal formation with Dyna-3D (Cohen's κ = 0.811) than with conventional 2D-DSA (Cohen's κ = 0.517). in-stent neointimal formation could not be confirmed on conventional imaging in 9 cases (16%) and on Dyna-3D in 2 cases (3%). The number of in-stent neointimal formations rated as stent wire completely outside the endothelial line was significantly higher with Dyna-3D than with 2D-DSA (p = 0.0001). All-round 3D evaluation by Dyna-3D imaging appears useful for confirming in-stent neointimal formation after braided stent deployment in patients after stent-assisted coil embolization.

Improvement of Outcome for Treatment of ‘Restenosis-prone’ Vascular Lesions? Potential Impact of the Paclitaxel dose on Late Lumen Loss in Porcine Peripheral Arteries

PurposeClinical data indicate that the drug density on drug-coated balloons (DCBs) might have a role on treatment effect and durability. The aim of the current study was to investigate inhibition of neointimal formation and potential adverse effects after treatment with a novel double-dose DCB in swine.Material and methodsA four-week study was performed in peripheral arteries of 12 domestic pigs after vessel injury and stent implantation. The novel double-dose DCB with 6-µg paclitaxel (Ptx)/mm2 balloon surface (1 × 6) was compared to a standard DCB with 3.5 µg Ptx/mm2 (3.5) and uncoated balloons (POBA). Potential adverse effects were stimulated by using three fully overlapping DCBs with 6 µg Ptx/mm2 each (3 × 6). Quantitative angiography, histomorphometry and histopathological analyses were performed.ResultsHigher paclitaxel doses per square millimeter of treated arteries were associated with reduced late lumen loss (LLL) in quantitative angiography 4 weeks after treatment (POBA: 0.91 ± 0.75 mm; 3.5: 0.45 ± 0.53 mm; 1 × 6: 0.21 ± 0.41 mm; 3 × 6: − 0.38 ± 0.65 mm). In histomorphometry, maximal neointimal thickness and neointimal area were the lowest for the 1 × 6 group (0.15 ± 0.06 mm/1.5 ± 0.4 mm2), followed by 3 × 6 (0.20 ± 0.07 mm/1.8 ± 0.4 mm2), 3.5 (0.22 ± 0.12 mm/2.2 ± 1.1 mm2) and POBA (0.30 ± 0.07 mm/3.2 ± 0.7 mm2). Downstream tissue showed histopathological changes in all groups including POBA, in larger number and different quality (e.g., edema, inflammation, vessel wall necrosis, vasculitis and perivasculitis) in the 3 × 6 group, which did not cause clinical or functional abnormalities throughout the study.ConclusionTreatment with the double-dose DCB (6 µg Ptx/mm2) tended to increase inhibition of in-stent neointimal formation and to diminish LLL after peripheral intervention in the porcine model compared to a market-approved DCB with 3.5 µg Ptx/mm2.

Mussel adhesive protein fused with VE-cadherin extracellular domain promotes endothelial-cell tight junctions and in vivo endothelization recovery of vascular stent.

Improving the surface properties of vascular stents to accelerate endothelialization in vivo could play an important role in minimizing the risk of late thrombosis. We previously showed that mussel adhesive protein fused with VE-cadherin extracellular domain (VE-M) specifically triggered endothelial cell adhesion in vitro. In this study, using stent implants coated with VE-M, we evaluated the clinical applicability of VE-M in endothelialization recovery in vivo. First, we explored the effect of VE-M on hemocompatibility and tight junctions between endothelial cells (ECs) in vitro. VE-M significantly inhibited platelet adhesion and promoted EC proliferation. Furthermore, VE-M drastically increased the centralization of F-actin in human umbilical vein endothelial cells (HUVECs) along the cell contacts, reduced fluorescein isothiocyanate (FITC)-dextran transport across the HUVECs, and elevated expression levels of tight junction proteins (TJPs) in ECs. We then evaluated the effect of VE-M on endothelialization recovery in vivo through implantation of vascular stents. At 1 day after implantation, stents coated with VE-M recruited more endothelial progenitor cells (EPCs) than bare stents. At 7 days after implantation, VE-M stents had a greater coverage of ECs than bare stents. At 1 month after implantation, ECs on VE-M stents were appropriately elliptical in morphology and closely resembled physiological morphology. Hematoxylin-eosin (HE) staining revealed little in-stent neointima formation on VE-M stents, and SEM images revealed that smooth endothelium had formed on VE-M stents without adherent platelets. Taken together, these findings indicate that VE-M accelerates in vivo endothelialization of vascular stents via recruitment of EPCs and promotes endothelium formation and could be explored as a potential bioactive coating for vascular implant. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:94-103, 2020.

A novel PDGF receptor inhibitor-eluting stent attenuates in-stent neointima formation in a rabbit carotid model.

A novel drug-eluting stent (DES) is required to target vascular smooth muscle cells (SMCs) without harming endothelial cells (ECs). Platelet-derived growth factor (PDGF) is critical for the proliferation and migration of SMCs. Sunitinib [a PDGF receptor (PDGFR) tyrosine kinase inhibitor]-eluting stents may therefore inhibit neointimal formation. The aim of the present study was to examine the stent-based delivery of sunitinib in a rabbit carotid model; in addition, the effects of sunitinib were evaluated in vitro. Local administration of sunitinib markedly reduced neointimal formation without delaying re-endothelialization in the carotid artery model. In vitro, sunitinib inhibited SMC proliferation; however, no effects were observed on ECs. Sunitinib caused necrosis of SMCs. In addition, sunitinib attenuated PDGF-stimulated SMC migration in a scratch wound assay and inhibited α-SMA cytoskeleton polymerization. Furthermore, sunitinib inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase in vitro and in vivo. Therefore, this novel DES may be a potential strategy for the treatment of vascular disorders.

Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice.

Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE-/- carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.

Pattern of instent neointimal formation compared to native atherosclerosis in the coronary bifurcation lesions: volumetric intravascular ultrasound analysis

Background No clinical study has systematically analyzed and compared circumferential neointimal and plaque distribution of stent neointimal proliferation and in native atherosclerotic plaques. This study aimed to investigate and compare the pattern of instent neointimal formation and native atherosclerosis in the coronary bifurcation lesions by volumetric analysis using systematic intravascular ultrasound (IVUS). Methods We examined bifurcation lesions in native coronary artery (plaque group, n=102) and stented bifurcations at 9-month follow-up (neointima group, n=51) using volumetric IVUS analysis of both the main vessel (MV) and side branch (SB). Three 5-mm segments were analyzed; the proximal MV (MVp), distal MV (MVd) and SB ostium (SBo). For each segment, volumetric analysis was performed in each of four quadrants (divided according to the branch takeoff and the geometric center of the lumen); carinal, epicardial, abcarinal, and myocardial. The eccentricity index was defined as the ratio of the abcarinal plaque (or neointimal) volume to the carinal plaque (or neointimal) volume. Results The plaque distribution differed significantly between the four quadrants, with the largest in the abcarinal quadrant, followed by the myocardial, epicardial, and carinal quadrants. The distribution of neointima was similar in the MV, but the four quadrants in the SB did not differ significantly. The eccentricity indices of both the MVd (P <0.001) and SBo (P=0.001) were significantly higher for the plaque group than the neointima group. Conclusions The distribution of neointimal proliferation seems to have a similar pattern to that of atherosclerotic plaque in native coronary arteries, particularly in the main vessel, but the trend is less prominent.

ASSA13-15-3 The Pattern of Instent Neointimal Formation Compared to Native Atherosclerosis in the Coronary Bifurcation Lesions: Volumetric Intravascular Ultrasound Analysis

Objective To investigate and compare the pattern of instent neointimal formation and native atherosclerosis in the coronary bifurcation lesions by volumetric analysis using systematic intravascular ultrasound (IVUS). Methods This study examined 102 native coronary artery bifurcation lesions and 51 post-stenting bifurcation lesions treated with drug-eluting stents using the T-stenting technique at 9-month follow-up IVUS images for both main vessel and side branch. Three interested segments were analysed: proximal main vessel (MVp) ostium, distal main vessel (MVd) and side branch ostium (SBo). At each segment, four quadrant analysis was performed per 1 mm by measuring the vessel area (stent area in the post-stenting lesions), lumen area and calculating the plaque area for volumetric analysis. Results In the plaque group, the plaque volume differed significantly between the four quadrants (P When the left main (LM) bifurcation (n = 38) was analysed separately, the abcarinal quadrant still had the largest plaque volume and the carinal quadrant the least in all three segments, while the epicardial and myocardial quadrant did not differ in the MVp (P = 0.99). In the MVd and SBo, the plaque volume of myocardial quadrant was still significantly greater than the epicardial quadrant (P In the neointima group, the neointimal volume differed significantly in the MVp and MVd (P = 0.002, P = 0.002, separately), while the four quadrants did not differ in the SB (P = 0.281). In the MVp and MVd, the neointimal volume was larger in the abcarinal than the carinal quadrant (in MVp, 4.8 mm3 [IQR 2.7.6.3 mm3] vs.2.1 mm3 [IQR 0.5.3.9 mm3], P When comparing the eccentricity indices between plaque and neointima groups, there was no difference in the MVp, while the neointima group was significantly smaller than plaque group in the MVd (1.6 [IQR 0.8, 2.8] vs. 4.7 [IQR 2.1, 8.7], P Conclusions The distribution of neointimal proliferation and seems to have a similar pattern to that of atherosclerotic plaque in native coronary arteries, particularly in the main vessel, but the trend is less prominent.

Inverse Association of Coronary Soluble Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (sTRAIL) Levels to In-Stent Neointimal Hyperplasia

Objectives: Soluble tumor necrosis factor-related apoptosis inducing ligand (sTRAIL) has been shown to exert protective action against atherosclerosis. The aim of this study was to investigate potential associations of coronary sTRAIL levels with indices of in-stent neointimal hyperplasia. Methods: 67 patients who underwent percutaneous coronary intervention with drug-eluting stent were followed up at approximately 12 months with determination of coronary sTRAIL concentration, angiography and intravascular ultrasound evaluation of the stent sites. Results: Mean sTRAIL concentration was 72.2 ± 2.8 pg/ml. sTRAIL was negatively correlated to indices of neointimal hyperplasia and positively correlated to in-stent minimum lumen area (p < 0.001). Neointimal obstruction and maximal in-stent cross-sectional neointima burden in patients in the upper sTRAIL quartile were 3.8 ± 1.2 and 12.6 ± 3.3%, respectively, versus 14.0 ± 0.7 and 49.8 ± 2.7% in the lower quartile (p < 0.001 for both). sTRAIL levels were significantly lower in patients with binary restenosis (48.7 ± 3.0 vs. 75.2 ± 2.9 pg/ml; p < 0.001). In the multivariate analysis, sTRAIL was an independent predictor of neointimal hyperplasia. Conclusion: This study demonstrates a negative association of sTRAIL to in-stent neointima formation. The potential pathophysiologic substrate of this effect implicates modulation of apoptosis in various cell types. These observations should prompt further evaluation of the link between sTRAIL and in-stent restenosis.

Endothelial cell repopulation after stenting determines in-stent neointima formation: effects of bare-metal vs. drug-eluting stents and genetic endothelial cell modification

AimsUnderstanding endothelial cell repopulation post-stenting and how this modulates in-stent restenosis is critical to improving arterial healing post-stenting. We used a novel murine stent model to investigate endothelial cell repopulation post-stenting, comparing the response of drug-eluting stents with a primary genetic modification to improve endothelial cell function.Methods and resultsEndothelial cell repopulation was assessed en face in stented arteries in ApoE−/− mice with endothelial-specific LacZ expression. Stent deployment resulted in near-complete denudation of endothelium, but was followed by endothelial cell repopulation, by cells originating from both bone marrow-derived endothelial progenitor cells and from the adjacent vasculature. Paclitaxel-eluting stents reduced neointima formation (0.423 ± 0.065 vs. 0.240 ± 0.040 mm2, P = 0.038), but decreased endothelial cell repopulation (238 ± 17 vs. 154 ± 22 nuclei/mm2, P = 0.018), despite complete strut coverage. To test the effects of selectively improving endothelial cell function, we used transgenic mice with endothelial-specific overexpression of GTP-cyclohydrolase 1 (GCH-Tg) as a model of enhanced endothelial cell function and increased NO production. GCH-Tg ApoE−/− mice had less neointima formation compared with ApoE−/− littermates (0.52 ± 0.08 vs. 0.26 ± 0.09 mm2, P = 0.039). In contrast to paclitaxel-eluting stents, reduced neointima formation in GCH-Tg mice was accompanied by increased endothelial cell coverage (156 ± 17 vs. 209 ± 23 nuclei/mm2, P = 0.043).ConclusionDrug-eluting stents reduce not only neointima formation but also endothelial cell repopulation, independent of strut coverage. In contrast, selective targeting of endothelial cell function is sufficient to improve endothelial cell repopulation and reduce neointima formation. Targeting endothelial cell function is a rational therapeutic strategy to improve vascular healing and decrease neointima formation after stenting.

Anti-Inflammatory Gene Therapy for Cardiovascular Disease

Inflammation in the vascular wall is an essential hallmark during the development of atherosclerosis, for which major leukocytes infiltrated in the lesions are monocytes/macrophages. Therefore, monocyte chemoattractant protein-1 (MCP-1) and its primary receptor CC chemokine receptor 2 (CCR2) are feasible molecular targets for gene therapy to inhibit monocyte/macrophage-mediated inflammation in atherogenesis. A mutant MCP-1 that lacks N-terminal 7 amino acids (7ND) has been shown to heterodimerize with native MCP-1, bind to CCR2 and block MCP-1-mediated monocyte chemotaxis by a dominant-negative manner. Gene therapy using intramuscular transfection with plasmid DNA encoding 7ND showed inhibitory effects on atherosclerosis in hypercholesterolemic mice, and neointima formation after vascular injury in animal models. Bare metal stents for coronary intervention were coated with multiple thin layers of biocompatible polymer with 7ND plasmid. The 7ND gene-eluting stent inhibited macrophage infiltration surrounding stent struts and in-stent neointima formation in rabbit femoral arteries and cynomolgus monkey iliac arteries. Finally, the authors describe new application of 7ND plasmid encapsulated in polymer nanoparticle (NP) that functions as gene delivery system with unique in vivo kinetics. NP-mediated 7ND gene delivery inhibited MCP-1-induced chemotaxis of mouse peritoneal macrophage ex vivo, which may be applicable for the treatment of atherosclerotic cardiovascular disease. In conclusion, anti-inflammatory gene therapy targeting MCP-1/CCR2 signal, with a novel NP-mediated gene delivery system, is a potent therapeutic strategy for the treatment of cardiovascular diseases.

Evaluation of a novel paclitaxel-eluting stent with a bioabsorbable polymeric surface coating in the porcine artery injury model

Purpose Drug-eluting stents (DES) are unique in allowing sustained release after a single short intervention. The challenge with DES still remaining is the optimal combination of a biocompatible drug-eluting matrix including an antiproliferative drug. We studied the role of a novel paclitaxel-eluting stent with a bioabsorbable polymer coating in preventing vascular restenosis in the porcine artery injury model.Material and methods Bare metal stents (BMS); polymer-coated-only stents (POLY); and polymer-based paclitaxel-eluting stents (PACL) were randomly implanted in pig femoral arteries. The dose density of paclitaxel was 1 μ g/mm2 with in vitro studies demonstrating a gradual elution overa course of 6 month.Results After 1-, 3- and 6-month follow-up, respectively, the animals underwent angiographic restudy and were terminated for histomorphometrical and histopathological analyses. At 1 month, the PACL group had the lowest histological percent stenosis when compared to the BMS and POLY groups (20 ± 4% vs 39 ± 6% and 41 ± 6%, respectively, P < 0.05). At 3 months, the PACL group still presents the lowest level of histological percent stenosis among the three groups (27 ± 6% vs 50 ± 10% and 46 ± 5%, respectively, P < 0.01). Six months later, the PACL group showed a similar histological percent stenosis as the BMS and POLY groups (44 ± 9% vs 56 ± 11% and 53 ± 9%, respectively, P= 0.145).Conclusions This study shows favourable vascular compatibility and effi cacy for a novel DES to inhibit in-stent neointima formation and preserve lumen area in the porcine artery model.

Effects of circumferential stretch vs. deep injury on the in-stent neointimal formation in the atherosclerotic iliac rabbit arteries

Effects of circumferential stretch vs. deep injury on the in-stent neointimal formation in the atherosclerotic iliac rabbit arteries Jianing Yue , Takamitsu Nakamura, Yuqi Wang , Weiguo Fu, Dongming Guo , Nicolas Chronos c Vascular Surgery Department of Zhongshan Hospital Fudan University, Shanghai, China Department of Internal Medicine II, University of Yamanashi, Chuo, Japan Saint Joseph's Translational Research Institute, Atlanta, GA, USA

Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation. Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells. In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-β), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NP-eluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib-NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization. These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.

New Drug-Eluting Stents

Drug-eluting stents (DES)were primarily conceived to reduce in-stent neointimal formation and therefore minimize the occurrence of restenosis, the major drawback of percutaneous coronary interventions with bare-metal stents (BMS). The development of DES has been pioneered through a combination of the increased understanding of the biology of restenosis, the selection of drugs that target 1 or more pathways in the restenotic process, controlled-release drug delivery strategies, and the use of the stent as a delivery platform. Although first-generation DES Cypher (sirolimus-eluting stent; Cordis Corporation, Johnson & Johnson, Warren, NJ) and Taxus (paclitaxel-eluting stent; Boston Scientific Corporation, Natick, Mass) have effectively achieved their main goal, reducing restenosis across virtually all lesion and patient subsets, their safety has been limited by suboptimal polymer biocompatibility, delayed stent endothelialization leading to late and very late thrombosis, and local drug toxicity.1,–,9 Both Cypher and Taxus use durable thick polymers to carry and control the release of their antiproliferative agents. The permanent presence of these polymers has been correlated to inflammatory responses and local toxicity in preclinical analysis.10,–,13 Furthermore, durable polymers used in first-generation DES have been associated with mechanical complications (eg, polymer delamination and “webbed” polymer surface leading to stent expansion issues)14 and nonuniform coating resulting in erratic drug distribution. As a consequence, in recent years, the focus of clinical research has been on the development of novel drug carrier systems including absorbable (or biodegradable) polymers and nonpolymeric stent surfaces. Additional improvements include the development of more modern platforms (eg, better deliverability, radiopacity, flexibility, and radial strength) as well as the use of novel antiproliferative agents or reduced doses of current approved antiproliferative drugs. This review focuses on describing next-generation drug-eluting stent systems based on the use of novel coatings and carrier systems developed to …

Comparison of Neointimal Hyperplasia With Drug-Eluting Stents Versus Bare Metal Stents in Patients Undergoing Intracoronary Bone-Marrow Mononuclear Cell Transplantation Following Acute Myocardial Infarction

The aims of this study were to assess the safety of drug-eluting stent (DES) use and to compare the incidence of in-stent restenosis (ISR) and neointimal hyperplasia formation according to the type of stent implanted (DES vs bare-metal stents [BMS]) in patients who underwent intracoronary bone marrow mononuclear cell transplantation after acute ST elevation myocardial infarction. Fifty-nine patients with successfully revascularized ST elevation myocardial infarction (37 using BMS and 22 using DES) underwent paired angiographic examinations at baseline and 6 to 9 months after the intracoronary injection of 91 million +/- 56 million autologous bone marrow mononuclear cells. A subgroup of 30 patients also underwent serial intravascular ultrasound examinations. Off-line angiographic assessment showed 4 cases of binary ISR, primarily in BMS (3 cases), and no major adverse cardiac events were associated with stent type (mean follow-up period 41 +/- 10 months). At follow-up, angiographic late luminal loss was significantly lower in patients with DES than in those patients with BMS (0.35 +/- 0.66 vs 0.71 +/- 0.38 mm, p = 0.011). Multivariate analysis identified the use of DES (beta = -0.32, 95% confidence interval [CI] -0.57 to -0.26, p = 0.03) and a smaller baseline reference vessel diameter (beta = 0.29, 95% CI 0.04 to 0.54, p = 0.02) as independent predictors of lower late loss. Moreover, intravascular ultrasound showed a significant reduction of in-stent neointimal hyperplasia formation related to DES use compared with BMS use (Delta neointimal hyperplasia volume 5.4 mm(3) [95% CI 2.7 to 28.1] vs 35.9 mm(3) [95% CI 22.0 to 43.6], p = 0.035). In conclusion, these findings suggest that the use of DES is safe and may prevent ISR and neointimal hyperplasia formation in patients who undergo intracoronary bone marrow mononuclear cell transplantation after a successfully revascularized ST elevation myocardial infarction.

Long-Term Effects of Novel Biodegradable, Polymer-Coated, Sirolimus-Eluting Stents on Neointimal Formation in a Porcine Coronary Model

The postulated relationship between nonbiodegradable polymers and late stent thrombosis has led to a concerted effort to seek alternative biodegradable polymers for drug delivery. The purpose of this study was to evaluate the long-term effects of novel sirolimus-eluting stents (SES) with biodegradable polylactic-co-glycolic acid (PLGA) polymer on neointimal thickening in a porcine coronary model. Three types of stents were implanted in different coronary arteries of the same mini-swine: bare cobalt-chromium stents (BMS); PLGA-coated-only stents (PCOS); and PLGA-coated, sirolimus-eluting stents (PCSES). A total of 26 animals underwent successful placement of 78 oversized stents (each stent-group, n = 26) in the coronary arteries with histopathologic analysis and Western blot at 28 days, 3 months, or 1 year. At 28 days and 3 months, the mean neointimal area was about two-fold lower in PCSES versus BMS or PCOS. At 1 year, the mean intimal area was similar for PCSES (1.76 +/- 0.28 mm(2)) and BMS (2.06 +/- 0.23 mm(2), P = 0.051). Western blot analysis demonstrated decreased expression of p27(kip1) in the vessel wall 3 months after PCSES implantation as compared with 28 days. PCSES effectively reduced in-stent neointimal formation for the first 3 months in this porcine coronary model. Beyond 3 months, neointimal proliferation was not substantially inhibited by PCSES. The observed delayed neointimal hyperplasia with PCSES may be partly related to the potential side effects of sirolimus and/or late insufficient arterial drug levels.

Meta-analysis of the Effects of Paclitaxel-Eluting Stents Versus Bare Metal Stents on Volumetric Intravascular Ultrasound in Patients With Versus Without Diabetes Mellitus

Diabetes mellitus is a strong predictor of in-stent restenosis after bare-metal stent placement because of exaggerated intimal hyperplasia (IH). In this study, serial intravascular ultrasound was used to evaluate the effects of polymer-based, paclitaxel-eluting stents (PES) on in-stent neointima formation in patients with and without diabetes. A volumetric IVUS meta-analysis of 956 patients randomized to PES or bare-metal stents in the TAXUS IV (n=268), TAXUS V (n=509), and TAXUS VI (n=179) trials was performed. Diabetes was present in 273 of the 956 patients (28.6%). Stent, luminal, and IH areas were measured every millimeter within the stent, and volumes, percentage IH (%IH), and neointima-free stent length were calculated. Patients with diabetes treated with bare-metal stents had greater IH volumes (78.9 vs 61.2 mm3, p=0.0095) and %IH (34.9% vs 30.1%, p=0.0186) compared with those without diabetes. However, patients with diabetes treated with PES had similar median IH volume (22.8 vs 16.3 mm3, p=0.35) and median %IH (9.1% vs 9.2%, p=0.27) compared with those without diabetes and significantly less IH volume and %IH than after bare-metal stent implantation (p<0.0001 for the 2 comparisons). In conclusion, serial volumetric IVUS analysis showed that treatment with PES neutralizes the propensity of patients with diabetes to develop greater IH, such that patients with and without diabetes treated with PES have similar vascular responses and restenosis rates.

Rosuvastatin attenuates angiotensin II-induced neointimal formation after stent implantation in the rat

We investigated the efficacy of oral rosuvastatin treatment to reduce in-stent neointima formation, both in the absence and presence of high levels of the proproliferative substance angiotensin II (Ang II). Drawbacks of current drug-eluting stents include inhibition of reendothelialization, induction of abnormal coronary endothelial function, and, most importantly, late in-stent thrombosis. Statin treatment might be a more subtle approach, with known beneficial vascular effects. Wistar rats were allocated to four treatment groups by two consecutive randomization steps: one to allocate rosuvastatin 0.047% (wt/wt) supplemented rat chow, and one to implant an osmotic minipump releasing Ang II (200 ng/kg). Stents were implanted in the abdominal aorta in all groups. After 4 weeks, in-stent neointima formation and vascular function in the thoracic aorta were determined. In the absence of Ang II, rosuvastatin reduced neointima formation by 23% as compared with control (0.66+/-0.06 versus 0.51+/-0.02 mm2; P<0.05). The presence of Ang II enhanced neointimal area by 30%. This was inhibited to the same extent by rosuvastatin (0.88+/-0.06 versus 0.67+/-0.03 mm2; P<0.05). In parallel, rosuvastatin improved endothelial-dependent vasodilatation, both in the presence and absence of high levels of Ang II. Ang II infusion increases in-stent neointima formation and decreases endothelial function. We now provide evidence that rosuvastatin effectively inhibits in-stent neointima formation and in parallel improves endothelial dilator function, both in the presence and absence of high Ang II levels.

Exeqüibilidade, eficácia e segurança do sistema de stent CardioMindTM no tratamento de lesões em vasos de fino calibre: um estudo seriado com angiografia e ultra-som intracoronário

INTRODUCAO: A intervencao coronaria percutânea em vasos de fino calibre esta associada a piores resultados imediatos e tardios, com elevadas taxas de reestenose, motivando o desenvolvimento de novos instrumentais para tal finalidade. OBJETIVO: Avaliar a exequibilidade, a eficacia e a seguranca do novo sistema de stent CardioMindTM para o tratamento de lesoes em vasos de fino calibre. METODO: Dez pacientes portadores de lesoes unicas, de novo, < 14 mm, em arterias coronarias nativas < 2,5 mm de diâmetro foram submetidos a implante do stent CardioMindTM. Todos os pacientes foram submetidos a angiografia e ultra-sonografia intracoronaria (USIC) posprocedimento e aos seis meses, com o desfecho primario de eficacia avaliado pela perda luminal tardia (PT) a angiografia e porcentagem (%) de obstrucao do stent a USIC. RESULTADOS: A media das idades foi de 63 ± 10,6 anos, 60% dos pacientes eram do sexo feminino e 60%, diabeticos. O diâmetro de referencia do vaso e a extensao da lesao foram de 2,06 ± 0,27 mm e 9,35 ± 1,39 mm, respectivamente. Sucesso do dispositivo e do procedimento foi obtido em todos os pacientes. Aos seis meses, a PT foi de 0,53 ± 0,60 mm e o volume de obstrucao do stent a USIC, de 24,1 ± 8,7%. Um paciente apresentou reestenose binaria, necessitando nova revascularizacao. Nao houve obitos e/ou infarto do miocardio no acompanhamento clinico de seis meses. CONCLUSOES: Este estudo piloto, com a utilizacao pela primeira vez em humanos do sistema de stent CardioMindTM em arterias coronarias de fino calibre, demonstrou ser esse stent factivel e seguro, com resultados animadores na reducao da hiperplasia intimal. O impacto clinico desses achados deve ser avaliado numa coorte maior de pacientes.

Local Delivery of Anti-Monocyte Chemoattractant Protein-1 by Gene-Eluting Stents Attenuates In-Stent Stenosis in Rabbits and Monkeys

We have previously shown that the intramuscular transfer of the anti-monocyte chemoattractant protein-1 (MCP-1) gene (called 7ND) is able to prevent experimental restenosis. The aim of this study was to determine the in vivo efficacy and safety of local delivery of 7ND gene via the gene-eluting stent in reducing in-stent neointima formation in rabbits and in cynomolgus monkeys. We here found that in vitro, 7ND effectively inhibited the chemotaxis of mononuclear leukocytes and also inhibited the proliferation/migration of vascular smooth muscle cells. We then coated stents with a biocompatible polymer containing a plasmid bearing the 7ND gene, and deployed these stents in the iliac arteries of rabbits and monkeys. 7ND gene-eluting stents attenuated stent-associated monocyte infiltration and neointima formation after one month in rabbits, and showed long-term inhibitory effects on neointima formation when assessments were carried out at 1, 3, and 6 months in monkeys. Strategy of inhibiting the action of MCP-1 with a 7ND gene-eluting stent reduced in-stent neointima formation with no evidence of adverse effects in rabbits and monkeys. The 7ND gene-eluting stent could be a promising therapy for treatment of restenosis in humans.