Neointima

Interferon (IFN)-γ has been implicated in restenosis, however its precise role in the pathophysiology of neointimal formation following angioplasty is unclear, as it has been shown to both promote and inhibit neointimal formation. Dietary-induced hypercholesterolemia enhances injury-mediated neointimal formation, associated with increased systemic inflammation and serum IFN-γ. This study examined the effect of IFN-γ gene deficiency ((-/-)) on neointimal formation in a mouse model of endothelial injury combined with an atherogenic diet. Neointimal formation was induced via endoluminal endothelial injury of the common iliac arteries of IFN-γ(-/-) and wild-type (WT) C57Bl/6 mice. Histopathological analysis of the arteries was performed at 3 and 6 weeks post-surgery. IFN-γ(-/-) mice demonstrated a significant reduction in neointimal formation at the 3-week time point, compared to their WT counterpart. No significant differences in plasma lipid profile and the extent of re-endothelializa...

This study sought to evaluate the relationship between coronary endothelial function and neointimal coverage after drug-eluting stent (DES) implantation. The mechanisms of endothelial dysfunction after DES implantation remain to be fully elucidated. We hypothesized that poor neointimal coverage after DES implantation may be associated with endothelial dysfunction distal to the stent site. Sixty-six stable angina patients treated with a first-generation DES were enrolled. At 9-month follow-up, coronary endothelial function was evaluated with intracoronary infusion of incremental doses of acetylcholine (10(-8), 10(-7), and 10(-6) mol/l) and nitroglycerin (200 μg). Vascular responses at the segments proximal and distal to the stent site were angiographically and quantitatively measured. At the same time, the degree of neointimal coverage was evaluated using coronary angioscopy and classified into 4 grades: 0 (no coverage) to 3 (full coverage). We divided the subjects into poor-coverage (grades 0 to 1, n = 33) and good-coverage (grades 2 to 3, n = 33) groups. Acetylcholine induced dose-dependent coronary vasoconstrictions in both groups. At the segment distal to the stent, the magnitude of vasoconstriction to acetylcholine in the poor-coverage group was significantly greater than in the good-coverage group (p < 0.001), whereas vasomotor responses proximal to the stent and vasodilation by nitroglycerine were similar between the 2 groups. Coronary endothelial dysfunction distal to the stent was associated with poor neointimal coverage after DES implantation.

The purpose of this study was to investigate the roles of the kallikrein-kinin system and matrix metalloproteinases (MMPs) in the development of arterial restenosis attributable to intimal hyperplasia in the femoropopliteal arteries. This report describes a single-center prospective study of 27 patients with peripheral artery disease who required percutaneous transluminal angioplasty and stenting of the femoropopliteal segment using covered stent grafts. The blood concentrations of total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein was evaluated by the colorimetric method. Tissue kallikrein was evaluated by the spectrophotometric method. The activity of kininase II was measured by fluorometric analysis. Quantification of MMPs was performed by zymography, and tissue inhibitors of metalloproteinases were measured by enzyme-linked immunosorbent assay. Four (15%) of the treated patients developed restenosis at the 6-month follow-up evaluation. ...

Bifurcations represent challenging lesions which may benefit from improved understanding of stent-related vessel complications. Since optical coherence tomography (OCT) allows us to detect post-stenting vessel injuries, we sought to assess the geographic pattern of stent-related complications occurring during provisional stenting of bifurcated lesions. Fifty-one patients with bifurcated lesions treated by provisional stenting and undergoing intra-procedural OCT assessment were enrolled. OCT images were acquired with the aim of guiding the percutaneous coronary intervention but were re-analysed off-line for the present study. The stented bifurcation was divided into four segments [three in the main vessel (MV) and one in the side branch (SB)]. The following acute post-stenting vessel injuries/complications at the different bifurcation segments were evaluated: (i) stent under-expansion, (ii) stent malapposition, (iii) stent edge dissection, (iv) side-branch ostium dissection, (v) tiss...

We report optical coherence tomography (OCT) findings in 33 patients who presented with very late stent thrombosis (VLST) after either drug-eluting stent (DES) or bare-metal stent (BMS) implantation. VLST is a potentially life-threatening complication, but the underlying mechanisms remain unclear. In 33 patients (27 DES- and 6 BMS-treated lesions) with definite VLST, OCT images were acquired before either thrombus aspiration or intravascular ultrasonography (IVUS) imaging. The median duration from implantation was 61.5 months in the DES group and 109.1 months in the BMS group. In the overall cohort, combining DES and BMS, 94% showed intraluminal thrombi. VLST was associated with in-stent neointimal rupture in 23 patients (70%); 22 had thrombi near the site of neointimal rupture. Stent malapposition was observed in 14 (42%) lesions, but only 9 of them showed thrombi at the site of stent malapposition; moreover, 6 (18%) stented segments with malapposition also had neointimal rupture. ...

Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice. Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-...

Interleukin-1 receptor antagonist (IL-1Ra) negatively regulates IL-1 signaling by blocking the functional receptor. We previously demonstrated that IL-1Ra-deficient (IL-1Ra-/-) mice exhibit marked neointimal formation after injury. IL-1Ra is expressed on bone marrow (BM)-derived cells as well as non-BM intrinsic arterial cells. However, the importance of various cell types as sources of IL-1Ra remains unknown. The aim of this study was to test the hypothesis that IL-1Ra originating from BM-derived cells and non-BM intrinsic cells helps to suppress both inflammation and neointimal formation after vascular injury using a model of BM cell transplantation (BMT). In order to determine the contribution of IL-1Ra-deficient (Ra-/-) and wild-type (WT) BM cells to neointimal formation, we developed four types of BM chimeric mice (BMT(WT→WT) (n=12), BMT(Ra-/-→WT) (n=12), BMT(WT→Ra-/-) (n=12) and BMT(Ra-/-→Ra-/-) (n=12)). At four weeks after BMT, we induced vascular injury by placing a non-occl...

Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters ... Neointima Formed by Arterial Smooth Muscle Cells ... Expressing Versican ...

This study aimed to investigate the structural integrity and dynamic changes in chronically occluded residual arteries found in post-myocardial infarction (MI) scar. A transmural MI was induced in middle-aged, male Sprague-Dawley rats by left coronary artery ligation. The rats were euthanized 3 days and 1, 2, 4, 8, and 12 weeks after MI, and their hearts were processed into paraffin for histology, immunohistochemistry, and quantitative morphometry. It has been found that large- and medium-sized arteries were able to survive inside the transmural scars for 12 post-MI weeks. Furthermore, most residual arteries preserved their structural integrity for up to 2 weeks post-MI, but gradually all disused vessels had undergone neointimal hyperplasia and inward remodeling at later time periods. In addition, the replacement of vascular smooth muscle cells in the wall of residual arteries by extracellular matrix components led to a disruption of the vessel integrity and progressive obliteration of their lumen between 4 and 12 post-MI weeks. Taken together, this study demonstrate that residual arteries in post-infarcted region were capable of maintaining their structural integrity, including the patent lumen, during two post-MI weeks, suggesting that during this period they can be used as potential conduits for conceivable reflow of arterial blood within the scarred region of the heart.

This study sought to assess device-specific outcomes after implantation of bare-metal stents (BMS), zotarolimus-eluting Endeavor Sprint stents (ZES-S), paclitaxel-eluting stents (PES), or everolimus-eluting stents (EES) (Medtronic Cardiovascular, Santa Rosa, California) in all-comer patients undergoing percutaneous coronary intervention. Few studies have directly compared second-generation drug-eluting stents with each other or with BMS. We randomized 2,013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group received up to 6 or 24 months of clopidogrel therapy. The key efficacy endpoint was the 2-year major adverse cardiac event (MACE) including any death, myocardial infarction, or target vessel revascularization, whereas the cumulative rate of definite or probable stent thrombosis (ST) was the key safety endpoint. Clinical follow-up at 2 years was complete for 99.7% of patients. The MACE rate was lowest in EES (19.2%; 95% confidence interval [CI]: 16.0 to...

Most drug-eluting stents currently in use are coated with a polymer carrying the drug that is released for several weeks. However, a durable polymer may provoke hypersensitive reaction, delayed artery healing, and eventually stent thrombosis. The aim of this study was to investigate the safety and efficacy of a polymer-free paclitaxel-eluting stent (PF-PES) versus a polymer-based PES (PB-PES). Eligible patients undergoing percutaneous coronary intervention were randomized 1:1 to receive either PF-PES or PB-PES. The primary end point was late loss at 9 months. Intravascular ultrasound analysis at 9 months and final 2-year clinical follow-up were also performed. From October 2007 to April 2009, 164 patients were enrolled and randomized into 2 groups (PF-PES: n = 84; PB-PES: n = 80). Mean in-stent lumen loss was 0.90 ± 0.59 mm for PF-PES and 0.49 ± 0.52 mm for PB-PES (P < 0.001). Mean neointimal area by intravascular ultrasound was higher in PF-PES than in PB-PES (1.42 ± 1.09 versus...

To follow up the restenosis in arteries stented during an angioplasty is an important current clinical problem. A new approach to monitor the growth of neointimal tissue inside the stent is proposed on the basis of electrical impedance spectroscopy (EIS) sensors and the oscillation-based test (OBT) circuit technique. A mathematical model was developed to analytically describe the histological composition of the neointima, employing its conductivity and permittivity data. The bioimpedance model was validated against a finite element analysis (FEA) using COMSOL Multiphysics software. A satisfactory correlation between the analytical model and FEA simulation was achieved in most cases, detecting some deviations introduced by the thin "double layer" that separates the neointima and the blood. It is hereby shown how to apply conformal transformations to obtain bioimpedance electrical models for stack-layered tissues over coplanar electrodes. Particularly, this can be applied to...

Reduced frequency of atherosclerotic plaques is observed in interleukin-1 receptor-associated kinase-1 (IRAK1)-deficient mice; however, the underlying mechanism is not clear. Therefore, this study investigate the role of IRAK1 in vascular smooth muscle cell proliferation and neointimal hyperplasia. Stimulation of rat primary vascular smooth muscle cells with fetal bovine serum (10%) or platelet-derived growth factor-BB (20 ng/mL) for 15 minutes to 24 hours induced a time-dependent increase in IRAK1 and extracellular signal-regulated kinase (ERK) activation, proliferating cell nuclear antigen upregulation and p27Kip1 downregulation as assessed by Western blotting. Inhibitors of ERK pathway (U0126, 10 μmol/L), IRAK (IRAK1/4, 3 μmol/L), protein kinase C (PKC; Ro-31-8220, 1 μmol/L), siRNA of toll-like receptor-4 (200 nmol/L), and PKC-ε (200 nmol/L) significantly attenuated these changes. Platelet-derived growth factor induced endogenous IRAK-ERK-PKC-ε association in a toll-like receptor...

Synopsis Coronary artery disease is treated by vein grafting and stent implantation. Late vein graft failure and restenosis of stented arteries reduce the success rates of these approaches and are caused by neointima formation. We have previously shown that Wnt proteins are up-regulated during intimal thickening, and have speculated that these lead to activation of downstream genes with β-catenin/T-cell factor (TCF)-responsive promoters. In the present study, we aimed to provide evidence that β-catenin/TCF signalling promotes neointima formation and assess whether targeting this pathway has potential for reducing neointima formation. We utilized a gene therapy approach selectively targeting cells in which the β-catenin/TCF pathway is activated by using a recombinant adenovirus Ad-TOPTK, which carries a herpes simplex virus thymidine kinase (HSV-TK) gene under the control of a β-catenin/TCF-response promoter. Cells with activated β-catenin will therefore be selectively killed. Ad-TOP...

Objective— Several matrix metalloproteinases (MMPs) have been implicated in extracellular matrix destruction and other actions that lead to plaque rupture and myocardial infarction. Conversely, other MMPs have been shown to promote vascular smooth muscle cell (VSMC)–driven neointima formation, which contributes to restenosis, fibrous cap formation, and plaque stability. MMP-3 knockout reduced VSMC accumulation in mouse atherosclerotic plaques, implicating MMP-3 in neointima formation. We therefore investigated the effect of MMP-3 knockout on neointima formation after carotid ligation in vivo and VSMC migration in vitro. Methods and Results— Twenty-eight days after left carotid ligation, MMP-3 knockout significantly reduced neointima formation (75%, P <0.01) compared with wild-type (WT) littermates, and also reduced remodeling of ligated and contralateral carotid arteries. Gelatin zymography illustrated that MMP-3 knockout abolished MMP-9 activation in ligated carotids and scratch...