Neointimal Thickness Research Articles

Serial Comparison of Neointimal Coverage between Two Different Concept Stents: Optical Coherence Tomographic Evaluation

Recently, two different concept drug-eluting stents including biolimus A9-eluting stents (BES) with biodegradablepolymer and everolimus-eluting stents (EES) with durable biocompatible-polymer are available. However, serial comparison of BES and EES on neointimal coverage is not fully investigated. We performed serial evaluation of neointimal coverage at 8 months (BES polymer remained) and 20 months follow-up (BES polymer absorbed) by optical coherence tomography (OCT) for 14 BESs and 10 EESs, and compared uncovered strut proportion (%Uncovered), malapposed strut proportion (%Malapposed) and average neointimal hyperplasia thickness (Ave- NHT), numbers of extra stent lumen (ESL) and multiple interstrut hollow (MIH) calculated by OCT between two DESs, at 8 months and 20 months follow-up, respectively. As a result. at 8 months, Ave-NHT of EES was significantly higher than BES (124 ± 65 E¥m vs 83 ± 47 E¥m, p<0.001) but %Uncovered and %Malapposed were similar between the two groups. At 20 months, %Uncovered and ESL of EES were significantly lower than BES (0.8 ± 5.7% vs 4.8 ± 12.7%, p<0.001 and 0.86 ± 1.28 vs 0.09 ± 0.16, p=0.043) and Ave-NHT of EES was significantly higher than BES (185 ± 88 E¥m vs 90 ± 46 E¥m, P<0.001). In conclusion, EES showed favorable neointimal healing compared to BES

Early adventitial activation characterized by NADPH oxidase expression and neovascularization in an aortic transplantation model

Increasing evidence has suggested that arterial adventitia may contribute to pathological vessel remodeling by producing reactive oxygen species and promoting neovascularization. However, these processes have not been studied yet in transplantation-induced vascular pathologies. We characterized the dynamic changes in NADPH oxidase expression and adventitial angiogenic response in a model of allograft aortic transplantation. The thoracic aorta from Fischer 344 rats were transplanted into the abdominal aorta of Lewis rats. Graft specimens were collected on days 0.5, 3, 7, and 14 for morphometry, immunohistochemistry, immunofluorescence staining, and quantitative PCR tests. Following transplantation, adventitial thickening was found as early as day 3, while neointima was observed from day 7. As compared to normal adventitial tissue, the expression levels of NADPH oxidase subunits gp91phox and p47phox in graft adventitia were elevated from day 3 and further increased up to day 14. Immunohistochemistry staining showed that infiltrating macrophages appeared to be a major source of NADPH oxidase expression. Increases in NADPH oxidase expression were also detected in fibroblasts isolated from the graft adventitia. Gene silencing of p47phox significantly suppressed proliferation and migration of the graft fibroblast cells. We also showed that adventitial thickening was accompanied by increased adventitial neovascularization; at day 14, there was a positive correlation between the density of adventitial microvessels and the neointimal thickness. Transplantation injury induces NADPH oxidase expression and neovascularization in the adventitia, raising the possibility that the activated adventitia may represent a target site for prevention of transplantation-induced transplant vasculopathy.

Impact of Age on Stent Strut Coverage and Neointimal Remodeling as Assessed by Optical Coherence Tomography.

While older age associates with adverse percutaneous coronary intervention (PCI) outcomes, detailed information relating age to stent strut coverage and neointimal characteristics is lacking.One hundred nineteen patients with 123 sirolimus-eluting stents (SESs) were divided into 3 groups: group A (≤55 years), group B (56–65 years), and group C (>65 years). At 6 and 12 months of follow-up, optical coherence tomography was performed to assess strut coverage and neointimal remodeling.At 6 months, the proportion of uncovered struts increased with age: 6.1% in group A versus 7.3% in group B versus 11.7% in group C (P < 0.001) while the proportion of embedded struts decreased: 72.1% versus 57.0% vs. 55.0%, respectively (P < 0.001). Mean neointimal thicknesses were 90 μm versus 60 μm versus 60 μm, respectively (P < 0.001), and neointimal areas were 0.82 mm2 versus 0.52 mm2 versus 0.57 mm2 (P < 0.001). At 12 months, the proportion of uncovered struts increased with age (3.9% vs. 3.3% vs. 4.9 %; P < 0.001), while mean neointimal thicknesses were 100 versus 70 versus 80 μm (P < 0.001) and neointimal areas were 0.87 versus 0.60 versus 0.67 mm2 (P < 0.001).Patients ≤55 years receiving SES showed highest strut coverage and neointimal repair rate compared with the other 2 groups. A “catch-up phenomenon” appeared to occur in the oldest patients, as in the first 6 months the neointima showed lowest endothelial cell coverage and lowest neointimal proliferation rate, whereas from 6 to 12 months, the highest neointimal proliferation rate was seen in the oldest patients.

Abstract 18189: Neointimal Response to Everolimus-eluting Bioresorbable Scaffolds Implanted at Bifurcating Coronary Segments: An Optical Coherence Tomography Study

Background: Previous studies have described different patterns of neointimal coverage between the outer wall and inner wall at coronary bifurcations lesions (BL) treated with metallic drug-eluting stents (DES) due to endothelial shear stress. Everolimus-eluting bioresorbable scaffolds (BRS) have thicker struts and could therefore have a stronger influence on endothelial shear stress compared to DES. However, the neointimal coverage of BL treated with BRS has not been adequately studied. We sought to evaluate the vascular response to BRS struts deployed at BL using optical coherence tomography (OCT). Methods: 50 patients (64 lesions) underwent follow-up OCT 11.0 ± 2.1 months after BRS implantation. Cross-sectional area of BL with a side branch more than 1mm using OCT was analyzed every 200μm. All images were divided into 3 regions according to shear stress: the 1/2 circumference of the vessel opposite to the ostium (OO), side branch ostium (SO), and the vessel wall adjacent to the ostium (AO). %uncovered strut of all struts and the averaged neointimal thickness (NIT) in 3 regions were evaluated. Additionally, to assess the impact of the side branch size on neointimal proliferation in BL, we calculated the ratio of the diameter of side branch ostium (Ds) to the diameter of main branch (Dm) (Ds/Dm) and divided patients into two groups based on median value of Ds/Dm of 0.318 as follow: large ratio side branch group (LRSB, n=32) and small ratio side branch group (SRSB, n=32). Results: Mean BRS diameter and length were 3.01±0.37 and 20.7±5.5mm. Mean diameter of all side branches was 1.69±0.51mm. In all patients, there was a significant difference in NIT among 3 regions (OO, 121±66 vs. AO, 96±32 vs. SO, 82±43μm, p=0.03). A significant difference was shown in %uncovered strut among 3 regions (OO, 0.45 vs. AO, 1.5 vs. SO, 4.7%, p=0.03). Further, in LRSB group, there was a significant difference in NIT among 3 regions (OO, 130±63 vs. AO, 92±38 vs. SO, 75±39 μm, p=0.01), and a significant difference was shown in %uncovered strut among 3 regions (OO, 0.37 vs. AO, 2.0 vs. SO, 8.8%, p=0.01). Conclusion: Different patterns of neointimal coverage are observed between the outer wall and inner wall of BL treated with BRS. Neointimal coverage is least at and adjacent to large side branches.

Abstract 18127: The Relationship Between Nonuniform Strut Distribution and Neointimal Coverage After Everolimus-eluting Bioresorbable Scaffolds Implantation

Objects: The number and distribution of stent struts have been reported to affect neointimal coverage of metalic drug-eluting stent (DES). According to previous reports, the thick struts of everolimus-eluting bioresorbable scaffolds (BRS) created areas of low endothelial shear stress, which may contribute to neointimal formation. The aim of the present study is to investigate the relationship between the distribution of BRS struts and neointimal coverage. Methods: 43 patients (50 lesions) underwent follow-up optical coherence tomography (OCT) 11.8 ± 2.6 months after BRS implantation. Cross sectional area (CSA) of OCT images were analyzed at 1-mm intervals. Scaffold area and neointimal thickness were evaluated. Additionally, scaffold eccentricity (SE) was defined as follows: SE = [maximum (Max) diameter - minimum(Min) diameter]/ Max diameter. Furthermore, to assess the impact of the strut distribution, CSAs of BRS were divided into four regions. The average neointimal thickness (ANT) and the number of strut in each region were measured. The number of strut in each region was classified into 1, 2, 3 and ≥4. Further, the ANT acquired in each area was divided by ANT of all struts in the same CSA to describe an unevenness score, and its Max and Min values were defined as Max-unevenness score and Min-unevenness score. Results: Mean scaffold diameter and length were 3.17±0.37 and 19.9±5.2 mm. In almost all cases, pre- (90%) and post- (80%) dilatation were performed at initial percutaneous coronary intervention. There was a significant difference in the unevenness score among regions with differenrt strut numbers (unevenness score=1,04±0.34 in regions with 1 strut (N=400); 0.97±0.25 in regions with 2 struts (N=616); 1.00±0.25 in regions with 3 struts (N=894);1.04±0.20 in regions with ≥4 struts (N=938); p=0.01). Furthermore, a significant correlation was observed between SE and the dispersion of neointimal coverage in each CSA, which was expressed as Max-unevenness score - Min- unevenness score (N=792, R=0.10, p=0.02). Conclusion: Unlike metallic DES, crowding of struts as well as spare distribution of struts is associated with increased neointimal proliferation after BRS implantation. In addition, SE might be associated with uneven neointimal coverage.

Abstract 14910: Vascular Cells Originating From Perivascular Adipose Tissue Contribute to Vasa Vasorum Neovascularization in Atherosclerosis

Introduction: Proliferation of vasa vasorum (VV) is observed in the adventitia of arteries with atherosclerotic plaques. It was reported that fat tissue transplantation to carotid artery exaggerated neointimal formation and VV proliferation after wire injury in a hypercholesterolemic mouse model. However, there is no in vivo histological evidence that vascular cells originating from perivascular adipose tissue (PAT) contribute to VV neovascularization. Methods: We established a new mouse model of atherosclerosis, in which the carotid artery is partially ligated (CPL) and exogenous adipose tissue is transplanted in the perivascular area (PVAT). The three branches (external and internal carotid, occipital) of the left carotid artery (LCA) of 20- to 25- week-old male apolipoprotein E-deficient (ApoE-/-) mice were ligated. Then epididymal adipose tissue from a donor ApoE-/- mouse was transplanted around the LCA (CPL+PVAT, n=5). Carotid partial ligation alone was performed as a control (CPL, n=3). After 8 weeks, on western type diet, LCA was harvested with PAT after biotinylated-Lycopersicon Esculentum (Tomato) lectin perfusion staining. Next, epididymal fat tissue from a male enhanced green fluorescent protein (EGFP) mouse was transplanted around the LCA of another set of male ApoE -/- mice after CPL (n=4). After 8 weeks, LCA was harvested with PAT after perfusion staining of microvessels, embedded in plastic resin, and observed under a confocal microscope. Results: The transplanted adipose tissue engrafted and atherosclerotic lesion developed in LCAs. Intima/media ratio of CPL+PVAT group was similar with that of CPL alone group (p=0.39). Whereas, VV density in adventitial area (outside the elastic lamina within a distance of the thickness of neointima plus media, excluding PAT) near three -fold increased than CPL alone group (p&lt;0.05). In the EGFP fat transplanted mice, a significant portion of VV was GFP positive (GFP positive /total microvessels in adventitia: 12.5 ± 6.2 % ). Conclusions: The vascular cells derived from PAT contribute to VV neovascularization, at least in part, in atherosclerosis.

Abstract 15140: VEGFR2 Blockade in Murine Vein Grafts Reduces Intraplaque Hemorrhage due to Enhanced Plaque Neovessel Maturation

Introduction: Vein graft patency rates are poor due to the development of extensive neointimal thickening, atherosclerosis and lesion instability. We have previously shown that murine vein graft lesions exhibit leaky neovessels and that intraplaque hemorrhage induces lesion growth. Immature plaque neovessels contribute to atherosclerotic plaque instability by leakage of erythrocytes and leukocytes (intraplaque haemorrhage) in the plaque. Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), together with the angiopoietin (Ang)-Tie2 system, regulates the maturation of neovessels. Hypothesis: VEGFR2 blockade induces plaque neovessel maturation resulting in reduced intraplaque hemorrhage and plaque instability. Methods: Donor caval veins were engrafted in carotid arteries of recipient hypercholesterolemic ApoE3*Leiden mice (n=14/group). Mice were treated at day 14, 17, 21 and 25 with VEGFR2 blocking antibodies (DC101) or control IgG antibodies. At day 28 vein grafts were harvested for histological and RNA analysis. Results: Morphometric analysis revealed a striking 50% decrease in vein graft segments that expressed intraplaque hemorrhage in the DC101 treated group. This was accompanied by a significant 25-fold decrease in extravasated erythrocytes. DC101 treatment resulted in a decrease in VEGF expression whereas VEGFR1 and VEGFR2 expression was comparable between the two groups. Connexin 37 and 43 expression was also comparable between the groups, indicating that gap junctions were not affected upon DC101 treatment. However, lesions that exhibit intraplaque hemorrhage showed a strong increase in destabilizing Ang-2. The vein graft lesion area was significantly reduced in the DC101 group, which was accompanied by an increased plaque stability phenotype as a result of a significant reduction in macrophage content and increases in smooth muscle cells and collagen content. Conclusions: Blockade of VEGFR2 leads to reduced intraplaque hemorrhage, decreased vein graft lesion area and increased plaque stability as a result of increased neovessel maturation. This identifies plaque neovascularization as an attractive target for the treatment of unstable atherosclerotic diseases.

Prevention of occlusive arterial thrombus formation by a single loading dose of prasugrel suppresses neointimal hyperplasia in mice

The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3–3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose–response study, a single administration of prasugrel at 0.3–3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-β mRNA levels on Day 2 (24h after the injury) and Day 8 (1week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-β, in the injured arteries.

Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D.

The goal of this study was to determine whether and how adenosine affects the proliferation of human coronary artery smooth muscle cells (HCASMCs). In HCASMCs, 2-chloroadenosine (stable adenosine analogue), but not N(6)-cyclopentyladenosine, CGS21680, or N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide, inhibited HCASMC proliferation (A2B receptor profile). 2-Chloroadenosine increased cAMP, reduced phosphorylation (activation) of ERK and Akt (protein kinases known to increase cyclin D expression and activity, respectively), and reduced levels of cyclin D1 (cyclin that promotes cell-cycle progression in G1). Moreover, 2-chloroadenosine inhibited expression of S-phase kinase-associated protein-2 (Skp2; promotes proteolysis of p27(Kip1)) and upregulated levels of p27(Kip1) (cell-cycle regulator that impairs cyclin D function). 2-Chloroadenosine also inhibited signaling downstream of cyclin D, including hyperphosphorylation of retinoblastoma protein and expression of cyclin A (S phase cyclin). Knockdown of A2B receptors prevented the effects of 2-chloroadenosine on ERK1/2, Akt, Skp2, p27(Kip1), cyclin D1, cyclin A, and proliferation. Likewise, inhibition of adenylyl cyclase and protein kinase A abrogated 2-chloroadenosine's inhibitory effects on Skp2 and stimulatory effects on p27(Kip1) and rescued HCASMCs from 2-chloroadenosine-mediated inhibition. Knockdown of p27(Kip1) also reversed the inhibitory effects of 2-chloroadenosine on HCASMC proliferation. In vivo, peri-arterial (rat carotid artery) 2-chloroadenosine (20 μmol/L for 7 days) downregulated vascular expression of Skp2, upregulated vascular expression of p27(Kip1), and reduced neointima hyperplasia by 71% (P<0.05; neointimal thickness: control, 37 424±18 371 pixels; treated, 10 352±2824 pixels). In conclusion, the adenosine/A2B receptor/cAMP/protein kinase A axis inhibits HCASMC proliferation by blocking multiple signaling pathways (ERK1/2, Akt, and Skp2) that converge at cyclin D, a key G1 cyclin that controls cell-cycle progression.

Optical coherence tomography study of chronic-phase vessel healing after implantation of bare metal and paclitaxel-eluting self-expanding nitinol stents in the superficial femoral artery

BackgroundThis study aimed to assess chronic-phase suppression of neointimal proliferation and arterial healing following paclitaxel-coated (PTX) and bare metal stent (BMS) implantation in the superficial femoral artery using optical coherence tomography (OCT). MethodsTwenty-five patients with 68 stents underwent an 8-month OCT follow-up. Besides standard OCT variables, neointimal characterization and frequencies of peri-strut low-intensity area (PLIA), macrophage accumulation, and in-stent thrombi were evaluated. ResultsThe mean neointimal thickness was significantly less with PTX stents (544.9±202.2μm vs. 865.0±230.6μm, p<0.0001). The covered and uncovered strut frequencies were significantly smaller and larger, respectively, in the PTX stent group vs. the BMS group (93.7% vs. 99.4%; p<0.0001, 4.0% vs. 0.4%; p<0.0001, respectively). Heterogeneous neointima was only observed in the PTX stent group (12.5% vs. 0%, p=0.017). The frequencies of PLIA and macrophage accumulation were significantly greater in the PTX stent group (87.2% vs. 67.6%, p=0.001 and 46% vs. 9.1%, p=0.003, respectively). ConclusionAfter 8 months, reduced neointimal proliferation was observed with PTX stent implantation. On the other hand, delayed arterial healing was observed compared with BMS.

Impact of coronary calcifications 12 months after everolimus-eluting stent implantation: an optical coherence tomography study

To assess the endothelial coverage and neointimal proliferation at 12 months after everolimus-eluting stent (EES) implantation in patients with coronary calcifications by optical coherence tomography (OCT). Seventeen patients who received an EES in culprit coronary lesions of acute coronary syndrome (ACS) underwent follow-up OCT examination at 12 months. Eleven patients in whom spotty calcifications were detected in stent segment vessels by OCT were included in the final analysis. The percentage of uncovered struts (6.0 vs. 2.0%, P < 0.001) and the stent symmetry index (0.883 ± 0.040 vs. 0.913 ± 0.026, P = 0.018) differed significantly between cross sections of EESs over calcified lesions (calcium cross sections) and those over lesions without calcification (non-calcium cross sections). In addition, in calcium cross sections, the neointimal thickness differed significantly between struts over lesions with (calcium struts) and without calcification (non-calcium struts; 138 ± 65 vs. 99 ± 60 μm, P = 0.006). Cross-sectional OCT images of EESs implanted at sites of calcification in ACS patients showed more uncovered struts, and a worse stent symmetry index, compared with those of EESs implanted at sites without calcification. In calcium cross sections, calcium struts had greater neointimal thickness than non-calcium struts. Future prospective in vivo studies are required to validate the relationship between the findings in this study and clinical events.

Abstract P041: Inhibition of MicroRNA-221 by Estradiol Contributes to its Differential Effects on Smooth Muscle Cell Growth and Endothelial Cell Capillary Formation

MicroRNAs play a key role in vascular remodeling associated with cardiovascular disease. MiR-221 actively contributes to injury-induced neointima formation by inhibiting endothelial cell (EC) growth and promoting smooth muscle cell (SMC) growth. Since estradiol (E2) prevents neointimal thickening, we hypothesize that E2 mediates its vasoprotective actions by downregulating miR-221 expression and abrogating its effects on SMC and EC growth. RT-qPCR confirmed that both Human Umbilical Vein ECs (HUVECs) and Human Coronary Artery SMCs (HCASMCs) produce miR-221. Treatment of HCASMCs with PDGF-BB (20ng/ml) induced miR-221 levels from 100±8% to 189±9% (p&lt;.05) and treatment with E2 (100nM) inhibited this to 126±4% (p&lt;.05 vs PDGF). PDGF-BB stimulated DNA synthesis (BrdU incorporation), CyclinD1 expression (Western Blot) and migration (Scratch assay) in HCASMCs and these effects were mimicked by miR-221 (25nM) overexpression; and abrogated in HCASMCs transfected with miR-221 antimiR (25nM). E2 inhibited PDGF-induced HCASMC numbers by 30±4% and these effects were reversed by miR-221 (p&lt;0.05). Inhibitory effects of E2 on PDGF-induced miR-221 production in HCASMCs were mimicked by estrogen receptor (ER) α agonist PPT, but not by ERβ and GPER agonists; and blocked by ERα antagonist MPP, suggesting these effects are ERα mediated. In contrast to SMCs, transfection of HUVECs with miR-221 mimic inhibited capillary formation and wound healing by 39±8% and 27±6%, respectively (p&lt;.05). Neutralization of miR-221 with antimiR induced capillary formation and wound closure by 26±3 % and 51±15%, respectively (p&lt;.05). E2 (10nM) inhibited miR-221 levels in HUVECs from 100 to 73±6% (p&lt;.05). Moreover, transfection of HUVECs with miR-221 mimic inhibited E2-induced capillary formation (from137±9% to 85±13%; p&lt;.05 vs E2) and wound closure (from 125±5% to 82±12%; p&lt;.05 vs E2). Our findings provide the first evidence that E2 inhibits miR-221 production in HCASMCs and HUVECs and these effects contribute to its antimitogenic effects on HCASMCs and capillary promoting effects in HUVECs. Modulation of miR-221 by E2 represents a novel mechanism by which E2 may mediate its differential effects on SMC and EC growth, and confer vascular protection.

Tadalafil attenuates graft arteriosclerosis of aortic transplant in a rat model.

Tadalafil can restore endothelial function and treat atherosclerosis. However, the effect of tadalafil on transplant arteriosclerosis remains unclear. In this study, we explore the effects of tadalafil on allograft vasculopathy. Male Brow-Norway rats supplied aorta grafts for Male Lewis rats. All recipients were divided into 3 groups: saline as placebo (control) treated group, low dose tadalafil (0.5 mg/kg/day) treated group, and high dose tadalafil (1.0 mg/kg/day) treated group. Eight weeks after transplantation, the grafts were harvested at and analyzed by histological and Western blot analysis. An enzyme-linked immunosorbent assay (ELISA) was used for measure of plasma cyclic guanylate monophosphate (cGMP). the treatment with tadalafil significantly alleviated the neointimal thickness of aortas compared with the control group (P<0.05). Tadalafil also remarkably enhanced the production of cGMP in plasma and expression of cGMP-dependent kinase I (PKG-I) and RhoA compared with control group (P<0.05). These results showed that tadalafil can attenuate graft arteriosclerosis by cGMP -PKG-I pathway.

Expression of V3 Versican by Rat Arterial Smooth Muscle Cells Promotes Differentiated and Anti-inflammatory Phenotypes

Arterial smooth muscle cells (ASMCs) undergo phenotypic changes during development and pathological processes in vivo and during cell culture in vitro. Our previous studies demonstrated that retrovirally mediated expression of the versican V3 splice variant (V3) by ASMCs retards cell proliferation and migration in vitro and reduces neointimal thickening and macrophage and lipid accumulation in animal models of vascular injury and atherosclerosis. However, the molecular pathways induced by V3 expression that are responsible for these changes are not yet clear. In this study, we employed a microarray approach to examine how expression of V3 induced changes in gene expression and the molecular pathways in rat ASMCs. We found that forced expression of V3 by ASMCs affected expression of 521 genes by more than 1.5-fold. Gene ontology analysis showed that components of the extracellular matrix were the most significantly affected by V3 expression. In addition, genes regulating the formation of the cytoskeleton, which also serve as markers of contractile smooth muscle cells (SMCs), were significantly up-regulated. In contrast, components of the complement system, chemokines, chemokine receptors, and transcription factors crucial for regulating inflammatory processes were among the genes most down-regulated. Consistently, we found that the level of myocardin, a key transcription factor promoting contractile SMC phenotype, was greatly increased, and the proinflammatory transcription factors NFκB1 and CCAAT/enhancer-binding protein β were significantly attenuated in V3-expressing SMCs. Overall, these findings demonstrate that V3 expression reprograms ASMCs promoting differentiated and anti-inflammatory phenotypes.

Excellent very early neointimal coverage of bioactive stents by optical coherence tomography

Objectives. In a prospective study, we explored the extent of neointimal coverage of stent struts by optical coherence tomography 14 days following the implantation of bioactive stents in an unselected cohort. Design. We enrolled 15 consecutive patients who underwent bioactive stent implantation. Optical coherence tomography images were obtained at 14-day follow-up. Morphometric analysis, strut coverage, strut apposition, neointimal hyperplasia, and possible thrombosis were evaluated at 1-mm intervals. Binary stent strut coverage was defined as the percentage of covered struts of all analyzed struts. Results. Patients underwent optical coherence tomography examination at an average of 14.5 ± 2.3 days following stent implantation. Mean age was 62 ± 11 years; 86.7% were males; 26.7% diabetic. Three-hundred eighteen cross-sections were analyzed, including 2935 struts, an average of 9.2 ± 3 struts per cross-section. Binary stent strut coverage was 96.3%; the prevalence of malapposed struts 1.8%. No thrombi were detected. Mean neointimal hyperplasia thickness was 71.5 ± 53.7 μm. Conclusions. In the current evaluation by optical coherence tomography at 14-day follow-up after bioactive stent implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts was low.

Metallic zinc exhibits optimal biocompatibility for bioabsorbable endovascular stents.

Although corrosion resistant bare metal stents are considered generally effective, their permanent presence in a diseased artery is an increasingly recognized limitation due to the potential for long-term complications. We previously reported that metallic zinc exhibited an ideal biocorrosion rate within murine aortas, thus raising the possibility of zinc as a candidate base material for endovascular stenting applications. This study was undertaken to further assess the arterial biocompatibility of metallic zinc. Metallic zinc wires were punctured and advanced into the rat abdominal aorta lumen for up to 6.5months. This study demonstrated that metallic zinc did not provoke responses that often contribute to restenosis. Low cell densities and neointimal tissue thickness, along with tissue regeneration within the corroding implant, point to optimal biocompatibility of corroding zinc. Furthermore, the lack of progression in neointimal tissue thickness over 6.5months or the presence of smooth muscle cells near the zinc implant suggest that the products of zinc corrosion may suppress the activities of inflammatory and smooth muscle cells.

Oxidative stress induces early-onset apoptosis of vascular smooth muscle cells and neointima formation in response to injury.

The present study dissects the mechanisms underlying the rapid onset of apoptosis that precedes post injury vascular remodelling. Using the rat balloon injury model, we demonstrated that a significant number of arterial vascular smooth muscle cells (VSMC) undergo apoptosis at 90min after the procedure. This apoptotic wave caused significant loss in media cellularity (>90%) over the next 3h and was accompanied by a marked accumulation of oxidative stress by-products in the vascular wall. Early apoptotic VSMC were rich in p38 mitogen-activated protein kinase (MAPK) and the transcription factor c-Jun and secreted IL-6 and GRO/KC into the milieu as determined using multiplex bead assays. Neointima thickness increased steadily starting on day 3 as a result of pronounced repopulation of the media. A second apoptotic wave that was detected at 14days after injury affected mostly the neointima and was insufficient to control hyperplasia. Suppression of reactive oxygen species (ROS) production using either the NAD(P)H oxidase inhibitor VAS2870 or pegylated superoxide dismutase (PEG-SOD) significantly decreased the number of apoptotic cells during the first apoptotic wave and showed a trend towards reduction in the neointima-to-media thickness ratio at 30days post injury. These results indicate that oxidative stress in response to injury induces early-onset apoptosis of VSMC through the activation of redox-sensible MAPK pro-apoptotic pathways. This remodelling process leads to the local accumulation of inflammatory cytokines and repopulation of the media, which ultimately contribute to neointima formation.

Differences in Vessel Healing Between Sirolimus- and Everolimus-Eluting Stent Implantation for Bifurcation Lesions: The J-REVERSE Optical Coherence Tomography Substudy

BackgroundWe aimed to clarify the differences in vessel healing after stenting of bifurcation lesions using sirolimus-eluting stents (SESs) or everolimus-eluting stents (EESs). MethodsJapanese Registry Study in Comparison Between Everolimus-Eluting Stent and Sirolimus-Eluting Stent for the Bifurcation Lesion (J-REVERSE) is a prospective multicentre registry of 303 bifurcation lesions that were treated with provisional SES or EES with or without final kissing inflation. The first 115 lesions at selected study sites were predefined for inclusion in the optical coherence tomography (OCT) substudy, and 9-month follow-up OCT was conducted in 64 lesions (SES, n = 18; EES, n = 46). In addition to standard OCT parameters, stent eccentricity index (SEI; minimum divided by the maximum stent diameter), neointimal unevenness score (NUS; maximum neointimal thickness in the cross-section [CS] divided by the average neointimal thickness [NIT] of the same CS; uniformity of the neointima suppression) were averaged for each segment (proximal, bifurcation, and distal segments). ResultsOverall, the average stent and luminal area, NIT, and frequency of uncovered struts were similar. The frequency of malapposed struts and SEI were significantly lower in the EES group than in the SES group. The EES group had a significantly smaller NUS in the proximal and distal segments. ConclusionsEESs offer homogeneous vessel healing with less malapposition in the treatment of bifurcation lesions.

Preclinical evaluation of a novel abluminal surface coated sirolimus eluting stent with biodegradable polymer matrix.

Second generation of drug eluting stents (DES) has attempted to improve safety using abluminal sirolimus drug delivery with biodegradable polymers matrix. The present preclinical study was designed to investigate the safety and efficacy profile of Abluminus™ stents (SES). This is a new coronary stent with sirolimus and biodegradable polymer matrix coated on abluminal stent and balloon surface. SES were compared with two controls: bare metal stent (BMS) and BMS + polymer coated stents (PC). All devices (40 stents) were implanted in porcine coronary arteries with primary endpoint of endothelialization at 7 days and subsequent histological and morphometric evaluations at 7, 30 and 90 days. Early endothelialization at seven days was complete in all stents. Histology at 30 days revealed minimum inflammation in all groups and increased at 90 days in PC group while it was absent at 180 days. Thirty day morphometry showed significantly reduction of neointimal area in Abluminus™ (SES 0.96±0.48 mm(2); BMS 1.83±0.34 mm(2); PC 1.76±0.55 mm(2); P<0.05); after 90 days neointimal area was 1.10±0.54 mm(2) for SES; 1.92±0.36 mm(2) for BMS; and 1.94±0.48 mm(2) for PC; P<0.05). Neointimal thickness at 30 and 90 days respectively was 0.15±0.07 and 0.18±0.10 mm for SES, 0.57±0.08 and 0.61±0.09 mm for BMS and 0.52±0.09 and 0.59±0.08 mm, P<0.001 for PC group. The most significant experimental evidence appears to be earlier endothelialization at 7 days for SES which led to safety of the device. Efficacy of the device was also observed by a reduced neointimal thickness and minimized inflammatory score at all follow-ups. Termination of antiplatelet at 30 days has not shown any further complications. Polymer thickness was almost in negligible amount at 180 days with no inflammation.

Effect of homoarginine administration on neointimal thickening in balloon-injured rat carotid arteries

Effect of homoarginine administration on neointimal thickening in balloon-injured rat carotid arteries