Neointima

Objective: Excessive neointima formation often occurs after arterial injury. Interleukin-1b (IL-1b) is a potent pleiotropic cytokine that has been shown to regulate neointimal proliferation. We investigated the effects of the IL-1b modulator gevokizumab in a rat carotid denudation model. Methods: SpragueeDawley rats were subjected to balloon denudation of the right carotid artery and were then randomized to receive a single subcutaneous infusion immediately after balloon injury of saline (control group, n ¼ 13) or gevokizumab (gevokizumab groups, n ¼ 15 in each group: 1, 10 and 50 mg/kg). We evaluated the treatment effects on carotid intima-media thickness (IMT) using ultrasonography, on endothelial regrowth using Evans Blue staining and on inflammatory response using histology. We also assessed the effects of IL-1b and gevokizumab on human umbilical vein endothelial cells (HUVEC) and rat smooth muscle cells. Results: We found that carotid IMT, in the proximal part of the denuded artery at day 28, was decreased by gevokizumab 1 mg/kg compared with controls. Neointima area and the intima/media area ratio were both reduced in the gevokizumab 1 mg/kg-treated group. Gevokizumab at the 1 mg/kg dose also improved endothelial regrowth. No effect was observed with gevokizumab 10 or 50 mg/kg. Gevokizumab also decreased the inflammatory effect of IL-1b in in vitro cell experiments and protected HUVECs from IL-1b's deleterious effects on cell migration, apoptosis and proliferation. Conclusion: A single administration of gevokizumab 1 mg/kg improves endothelial regrowth and reduces neointima formation in rats following carotid denudation, at least in part through its beneficial effects on endothelial cells.

Aims: The success of percutaneous coronary intervention (PCI) has been limited by restenosis and stent thrombosis. Delayed or incomplete endothelial regeneration is believed to be a key factor responsible for these events. Developing a stent with an accelerated healing profile may be of benefit. We aimed to evaluate the feasibility and safety of seeding a bare metal stent (BMS) with human trophoblastic endovascular progenitor cells (hTEC) derived from human embryonic stem cells. EuroIntervention 2014;10:709-716 Abbreviations -SMA alpha smooth muscle actin BMS bare metal stents CD cluster of differentiation Cpm counts per minute DAPI 4',6 diamidino-2-phenylindole DES drug-eluting stents DMEM Dulbecco's modified eagle medium EDTA ethylenediaminetetraacetic acid EPC endothelial progenitor cells FACS fluorescence activated cell sorting FCS foetal calf serum FISH fluorescent in situ hybridisation FITC fluorescein isothiocyanate HLA-G human leucocyte antigen-G hTEC human trophoblastic endovascular progenitor cell IVUS intravascular ultrasound LAD left anterior descending artery LLL late lumen loss MLA minimal lumen area MLD minimal lumen diameter MSA minimal stent area PBMC peripheral blood mononuclear cells PAoEC porcine aortic endothelial cell PCI percutaneous coronary intervention QCA quantitative coronary angiography RCA right coronary artery SM-MHC smooth muscle myosin heavy chain VEGF vascular endothelial growth factor vWF von Willebrand factor

Incomplete stent endothelialization is associated with late and very late stent thrombosis. In a post hoc analysis of the BASE-ACS trial, we sought to assess neointimal coverage and coronary flow reserve (CFR) 9 months after implantation of titanium-nitride-oxidecoated bioactive stents (BAS) versus everolimus-eluting stents (EES) in patients with acute coronary syndrome (ACS). In the BASE-ACS trial, 827 patients with ACS were randomized to receive either BAS or EES. In the current study, we examined neointimal growth and strut coverage by optical coherence tomography and CFR by trans-thoracic echocardiography in 28 consecutive nondiabetic patients with the culprit lesion in the left anterior descending coronary artery. The primary endpoints were binary stent strut coverage and CFR at 9-month follow-up. A total of 13 patients were included in the BAS group (2,033 struts); 15 in the EES group (2,898 struts). Binary stent strut coverage was higher and malapposed struts lower with BAS versus EES (99.4 vs 89.2, and 0.2 vs 4.6 %, respectively, p \ 0.001 for both). Neointimal hyperplasia thickness was greater with BAS versus EES (274.2 vs 100.1 lm, respectively, p \ 0.001). CFR was lower with EES versus BAS (2.2 ± 0.8 vs 3.0 ± 0.5, respectively, p = 0.001). Abnormal CFR (\2.5) were detected in 10 patients in the EES group versus one in the BAS group (p = 0.002). The current study demonstrated that in patients with ACS, BAS resulted in improved neointimal stent strut coverage and better coronary vasodilator function as compared with EES at 9-month follow-up.

Estradiol is converted to the biologically active metabolite 2-methoxyestradiol via the activity of the enzyme catechol-O-methyltransferase (COMT). Exogenous administration of both estradiol and 2-methoxyestradiol reduces experimental atherosclerosis and neointima formation, and COMT-dependent formation of 2-methoxyestradiol likely mediates the antimitogenic effect of estradiol on smooth muscle cells in vitro. This study evaluated whether 2-methoxyestradiol mediates the vasculoprotective actions of estradiol in vivo. Wild-type (WT) and COMT knockout (COMTKO) mice on an apolipoprotein E-deficient background were gonadectomized and treated with estradiol or placebo. Exogenous estradiol reduced atherosclerotic lesion formation in both females (WT, Ϫ78%; COMTKO, Ϫ82%) and males (WT, Ϫ48%; COMTKO, Ϫ53%) and was equally effective in both genotypes. We further evaluated how exogenous estradiol affected neointima formation after ligation of the carotid artery in ovariectomized female mice; estradiol reduced intimal hyperplasia to a similar extent in both WT (Ϫ80%) and COMTKO (Ϫ77%) mice. In ovarianintact female COMTKO mice, atherosclerosis was decreased (Ϫ25%) compared with WT controls. In conclusion, the COMT enzyme is dispensable for vascular protection by exogenous estradiol in experimental atherosclerosis and neointima formation in vivo. Instead, COMT deficiency in virgin female mice with intact endogenous production of estradiol results in relative protection against atherosclerosis.

Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neointimal formation after stent implantation. However, the role of ESS on the composition of neointima and underlying plaque remains unclear. Patients recruited in the Comfortable AMI-IBIS 4 study implanted with bare metal stents (BMS) or biolimus eluting stents (BES) that had biplane coronary angiography at 13month follow-up were included in the analysis. The intravascular ultrasound virtual-histology (IVUS-VH) and the angiographic data were used to reconstruct the luminal surface, and the stent in the stented segments. Blood flow simulation was performed in the stent surface, which was assumed to represent the luminal surface at baseline, to assess the association between ESS and neointima thickness. The predominant ESS was estimated in 3-mm segments and was correlated with the amount of neointima, neointimal tissue composition, and with the changes in the underlying plaque burden and com...

Methods and results Otsuka Long–Evans Tokushima fatty rats were divided into the following three groups: control (normal saline); SAM15; and SAM30 (15 and 30 mg/kg per day, respectively; n = 10 per group). SAM was administered orally from 1week before carotid ...

Background: Patients at high bleeding risk would benefit from a shorter dual antiplatelet therapy after PCI. Compared to first-generation devices, the design of newer generation drug-eluting stents may facilitate more rapid anatomical and functional healing of stented vessel based on thinner stent platforms, biodegradable/biocompatible polymers and rapid drug elution.

Rosiglitazone has been the focus of extensive discussion. To evaluate the effects of rosiglitazone on iliac arteries, both at the injury site and the contralateral artery, of hypercholesterolemic rabbits undergoing balloon catheter injury. White male rabbits were fed a hypercholesterolemic diet by oral gavage for 6 weeks and divided into two groups as follows: rosiglitazone group (14 rabbits treated with rosiglitazone during 6 weeks) and the control group (18 rabbits without rosiglitazone). Animals underwent balloon catheter injury of the right iliac artery on the 14th day. In the contralateral iliac artery, there was no significant difference in the intima/media layer area ratio (IMR) between the control and rosiglitazone groups. Rosiglitazone did not reduce the probability of type I, II, or III lesions (72.73% vs 92.31%; p=0.30) and type IV or V lesions (27.27% vs 7.69%; p=0.30). As for the homolateral iliac artery, the intimal area was significantly lower in the rosiglitazone gro...

The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1. Here, we hypothesised that selective blockade of the CD40L-Mac-1 interaction may also retard restenosis. We induced neointima formation in C57/BL6 mice by ligation of the left carotid artery. Mice were randomised to daily intraperitoneal injections of either cM7, a small peptide selectively inhibiting the CD40L-Mac-1 interaction, scM7, a scrambled control peptide, or saline for 28 days. Interestingly, cM7-treated mice developed neointima of similar size compared with mice receiving the control peptide or saline as assessed by computer-assisted analysis of histological cross sections. These data demonstrate that the CD40L-Mac-1 interaction is not required for the development of restenosis. In contrast, CD40-deficient mice subjected to carotid ligation in parallel, developed significantly reduced neointimal lesions compared with respective wild-type controls (2872 ± 843 µm² vs 35469 ± 11870 µm²). Flow cytometry in CD40-deficient mice revealed reduced formation of platelet-granulocyte and platelet-inflammatory monocyte-aggregates. In vitro, supernatants of CD40-deficient platelet-leukocyte aggregates attenuated proliferation and increased apoptosis of smooth muscle cells. Unlike in the setting of atherosclerosis, CD40L mediates neointima formation via its classic receptor CD40 rather than via its recently described novel interaction with Mac-1. Therefore, selective targeting of CD40L-Mac-1 binding does not appear to be a favorable strategy to fight restenosis.

In the present study, we aimed to deterimine the dose-related effects of ticagrelor, the first reversible inhibitor of the P2Y12 receptor, found in smooth muscle cells as well as platelets, during neointimal hyperplasia in a rabbit carotid anastomosis model. This study was an experimental, prospective, randomized controlled study including 20 New Zealand white female rabbits (6-months old; weighing 2300 ± 300 g). Under general anaesthesia, the rabbits underwent transection of the right carotid artery and subsequent anastomosis of both ends. The study animals were divided into the following 4 groups: T1 (ticagrelor 5 mg/kg, orally, daily), T2 (ticagrelor 10 mg/kg, orally, daily), T3 (ticagrelor 20 mg/kg, orally, daily) and control (no ticagrelor treatment). The single oral doses were administered in phosphate-buffered saline. The control group received sterile phosphate-buffered saline (2 ml/kg/day, orally) for 3 weeks postoperatively. At the end of the study, the animals were killed...

A B S T R A C T Superoxide (O2 •− ) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ( • NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether • NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether • NO exerts cell-specific, differential modulation of O2 •− levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates • NO-dependent inhibition of neointimal hyperplasia. In vivo, • NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, • NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2 •− levels. Lastly, to determine the role of SOD-1 in • NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without • NO. Interestingly, • NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2 •− by • NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of • NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia.

Neointimal proliferation after sirolimus-eluting stent (SES) implantation is generally inhibited by the pharmacological effects of sirolimus in comparison to bare metal stent (BMS). Neointimal hyperplasia after BMS implantation is mainly composed of vascular smooth muscle cells, and is usually observed as a white mass by angioscopy and as a layer of uniform signal intensity without attenuation on optical coherence tomography (OCT). In this case, angioscopic color of the neointima covering the SES was obviously yellow and OCT signal patterns of the neointima showed rapid attenuation similar to lipid tissues in atherosclerotic lesions. These findings suggest that neointima within the SES is quite different from that of the BMS and may contain atherosclerotic components.