辛伐他丁对支架新生内膜的作用

目的观察他丁类调脂药物对支架再狭窄和支架内新生内膜的影响.方法对单支冠脉病变行支架植入术的患者随机接受或不接受调脂药物的治疗,10月后复查冠脉造影和血管内超声检查.结果 65位患者随机接受辛伐他丁10mg治疗.辛伐他丁组患者在接受降脂治疗后血清总胆固醇降低15%,低密度脂蛋白胆固醇下降了26%,高密度脂蛋白胆固醇增加12%.辛伐他丁组和对照组支架再狭窄率无差异(分别为30.3%和37.5%,P>0.05).定量冠脉造影结果两组比较,两组参考段血管直径、支架最小管腔直径以及直径狭窄率均无明显差异.血管内超声发现辛伐他丁组参考段血管内膜腔截面积、最小血管内膜腔截面积以及最小支架截面积均无显著性差异.新生内膜截面积两组比较对照组大于辛伐他丁组,但无统计学意义.结论辛伐他丁长期治疗能够有效降低血中致动脉粥样硬化的脂蛋白.但10 mg/日的辛伐他丁对支架的再狭窄率以及支架内膜增生无明显影响.     

Impact of preinterventional arterial remodeling on in-stent neointimal hyperplasia and in-stent restenosis after coronary stent implantation.

BACKGROUND: Patterns of arterial remodeling during the course of plaque development have been shown to play an important role in both the progression of de novo atherosclerosis and in the restenotic process following coronary intervention. The aim of the present prospective study was to evaluate the effect of pre-interventional arterial remodeling on in-stent neointimal hyperplasia (NIH) and in-stent restenosis (ISR) after stenting. METHODS AND RESULTS: Pre-interventional arterial remodeling was assessed in 85 native coronary lesions by using intravascular ultrasound (IVUS). The remodeling index (RI) was 1.09+/-0.20 in the positive remodeling (PR)/intermediate remodeling (IR) group and 0.84+/-0.12 in the negative remodeling (NR) group. The plaque plus media cross sectional area (P&M CSA) at pre-intervention and NIH CSA at follow-up in the minimal lumen CSA were significantly larger in the PR/IR group (9.2+/-2.9 mm2 vs 6.2+/-1.8 mm2, 3.3+/-1.2 mm2 vs 1.5+/-0.9 mm2; p = 0.001, p = 0.001, respectively). On 3-dimensional analysis of IVUS images at follow-up, the lumen volume was significantly smaller in the PR/IR group than that in the NR group (62+/-15 mm3 vs 75 +/-20 mm3; p = 0.001), and neointima hyperplasia volume was significantly larger in the PR/IR group than that in the NR group (46+/-15 mm3 vs 26+/-10 mm3; p = 0.001). A significant positive correlation was found between pre-interventional RI and follow-up NIH CSA (r = 0.25, p = 0.022). The incidence of ISR and repeat intervention was significantly higher in the PR/IR group (30.8% vs 18.2%, 28.8% vs 15.2%; p = 0.032, 0.035, respectively). CONCLUSION: Measuring pre-interventional arterial remodeling patterns by IVUS may be helpful to stratify lesions at high-risk of ISR.     

Efficacy and feasibility of helixcision for debulking neointimal hyperplasia for in-stent restenosis.

The Helixcision system is a novel 6 Fr-compatible catheter designed to debulk tissue for in-stent restenosis lesions. The purpose of this study was to determine the efficacy and feasibility of this new system for removing neointimal hyperplasia. A total of 32 in-stent restenosis lesions in 32 patients were treated with helixcision followed by balloon angioplasty. Debulking efficacy was assessed with serial baseline intravascular ultrasound (IVUS) in a subset of 18 lesions. To investigate longitudinal efficacy, 3D analysis was also performed in 12 lesions with automated pullback to calculate average cross-sectional areas across the stent. Prior to procedure, the angiographic reference diameter was 2.60 +/- 0.46 mm. Immediately after procedure, minimum lumen diameter improved from 0.84 +/- 0.33 to 2.19 +/- 0.41 mm (P < 0.0001). IVUS showed a significant reduction of intimal area (IA) after helixcision (from 4.95 +/- 2.04 to 2.88 +/- 1.48 mm(2); P < 0.001). Adjunctive balloon angioplasty further improved lumen area (LA) mainly by stent expansion rather than IA reduction at the site of minimum lumen area. The degrees of IA reduction and LA improvement were closely similar in volumetric analysis. Thirty-day and 6-month clinical follow-up were available in 97% (n = 31) and 72% (n = 23) of the enrolled patients, respectively. At 30-day follow-up, no major adverse cardiac event was reported except for periprocedural CK elevation in two patients (6%). Target legion revascularization within 6 months was performed in six patients (26%). Preliminary results of helixcision indicate that this system is safe and feasible for the treatment of in-stent restenosis. The concordant results between 2D and 3D IVUS analyses suggest that this unique technology can achieve uniform longitudinal debulking throughout the stent. The long-term outcomes appeared to be favorable, considering the relatively diffuse lesion morphology.     

Adenosine A1 receptors in neointimal hyperplasia and in-stent stenosis in Ossabaw miniature swine

BACKGROUND: Stent-induced neointimal hyperplasia is a major cause of morbidity following stent deployment in patients with coronary artery disease. Importantly, however, mechanisms underlying stent-induced neointimal hyperplasia are unclear. This pathological response to stent placement is more aggressive when stents are over-expanded, suggesting that vascular injury may play a role. In this study we tested the hypothesis that adenosine A1 receptor upregulation is associated with neointimal hyperplasia within coronary artery stents. METHODS: Adult male Ossabaw swine were used as our experimental model. Neointima formation and gene expression were studied 4 weeks after coronary stents were placed at 1.0x or 1.3x luminal diameter. RESULTS: Neointima formation was observed in 1.0x stents and more than doubled in 1.3x stents, thus verifying the response to overexpansion injury. A1 receptor mRNA was increased four-fold and seven-fold in stents at 1.0x and 1.3x luminal diameter, suggesting that increased A1 receptor activity might contribute to stent-induced neointimal hyperplasia. Coronary artery organ culture model of arterial injury demonstrated A1 receptor activation increased DNA synthesis three-fold, an effect abolished by A1 receptor antagonism. CONCLUSION: Our data indicate that A1 receptor expression is increased within stents and that activation of A1 receptors increases smooth muscle cell proliferation. We suggest that inhibition of A1 receptor signaling may be a promising therapeutic target for management of in-stent stenosis.     

Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit.

Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.     

Increased blood flow inhibits neointimal hyperplasia in endothelialized vascular grafts

Intimal hyperplasia is a primary cause of failure after vascular reconstruction and may be affected by blood flow. We have studied the effects of increased blood flow on intimal hyperplasia in porous polytetrafluoroethylene grafts implanted in baboons. These grafts develop an endothelial lining by 2 weeks and neointimal thickening due to proliferation of underlying smooth muscle cells by 1 month. Creation of a distal arteriovenous fistula increased flow (from 230 +/- 35 to 785 +/- 101 ml/min, p less than 0.001) and mean shear (from 26 +/- 4 to 78 +/- 10 dynes/cm2, p less than 0.001) without causing a drop in pressure across the grafts. Fistula flow did not alter the pattern of endothelial coverage but did cause a marked reduction in the cross-sectional area of the neointima (from 2.60 +/- 0.52 to 0.42 +/- 0.07 mm2 at 3 months, p less than 0.01). Detailed morphometric analysis revealed an equivalent percentage decrease in smooth muscle cells and matrix content, suggesting that the primary effect of increased flow was to reduce smooth muscle cell number without affecting the amount of matrix produced by individual cells. The neointima remained sensitive to changes in flow at late times; ligation of the fistula after 2 months resulted in a rapid increase in neointimal thickness (from 0.60 +/- 0.03 mm2 after 2 months of fistula flow to 3.88 +/- 0.55 mm2 1 month after ligation of fistula, p less than 0.01). These results support the hypothesis that changes in blood flow affect the structure of diseased as well as normal vessels.     

Relation between vascular morphologic changes during stent implantation and the magnitude of in-stent neointimal hyperplasia

Intimal hyperplasia usually occurs after balloon overstretch injury or wire coil stimuli to coronary arteries. We examined whether the degree of vessel wall stretch during coronary stent placement could predict the amount of in-stent neointimal hyperplasia after a 6-month follow-up. Serial (preintervention, postballooning, poststent implantation, and a follow-up after 6 months) intravascular ultrasound (IVUS) was used to study 457 consecutive cross-sectional areas in 28 patients. IVUS imaging, using a motorized pullback system at 0.5 mm/s, allowed 1-mm axial increment measurements of the total vascular, stent, and lumen cross-sectional areas. The mean total vascular area changed from 10.89 +/- 2.50 mm2 before to 11.27 +/- 2.49 mm2 after ballooning, to 12.80 +/- 2.59 mm2 after stenting, and to 12.58 +/- 2.41 mm2 at follow-up (p < 0.0001). The mean lumen area changed from 3.36 +/- 1.95 mm2 before to 4.21 +/- 1.65 mm2 after ballooning, to 5.16 +/- 1.09 mm2 after stenting, and to 3.57 +/- 1.23 mm2 at follow-up (p < 0.0001). The mean stent area decreased from 5.25 +/- 1.17 mm2 after stenting to 5.09 +/- 0.90 mm2 at follow-up (p < 0.0001). Stepwise logistic regression analysis showed that delta total vascular area (after stent implantation - before intervention) was a strong predictor of the amount of intimal hyperplasia (r = 0.57, p < 0.0001). Vascular overstretch caused by the stenting procedure promotes intimal hyperplasia in proportion to the degree of sectional vascular stretch.     

High-dose granulocyte-colony stimulating factor promotes neointimal hyperplasia in the early phase and inhibits neointimal hyperplasia in the late phase after vascular injury

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) affects injured arteries through early endothelialization. Some reports, however, have cautioned that the restenosis rate may increase after G-CSF injection. In the present study, high-dose G-CSF was administered to mice with vascular injury to clarify its effect. METHODS AND RESULTS: Mice were received daily subcutaneous injections of saline or a high dose (300 microg/kg) of G-CSF for 5 days after vascular injury. In the FACS analysis, CD34-/Sca-1-positive progenitor cells were more abundant in the G-CSF group (p<0.05). Neointimal hyperplasia was more evident in the G-CSF group at 1 week (p<0.05), whereas at 4 weeks it was more evident in the control group (p<0.01). TUNEL-positive cells in the arterial wall were more numerous in the G-CSF group at day 1 (p<0.01). CD34-positive cells were observed in the G-CSF group at 1 week. Re-endothelialization appeared earlier in the G-CSF group (at 4 weeks; p<0.01). An increased number of 1A4-positive smooth muscle cells were found in bone marrow cell culture treated with G-CSF. CONCLUSION: High-dose G-CSF induced neointimal proliferation through excessive inflammation and bone marrow cell mobilization in the early phase. In the late phase, however, it induced early re-endothelialization and thereby inhibited neointimal hyperplasia.     

p27-p16 fusion gene inhibits angioplasty-induced neointimal hyperplasia and coronary artery occlusion

Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury-induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10(12) viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus-treated vessels. The average intimal area of the AV-W9-treated group 10 days after balloon injury and treatment was 0.42+/-0.36 mm(2), whereas the AV-null group demonstrated an intimal area of 0.70+/-0.52 mm(2). At day 10 the average intimal thickness of the AV-W9-treated vessels was 9.1 microm (n=5, x 20 magnification) compared with 21.2 microm (n=5, x 20 magnification) in control virus-treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9-treated vessels demonstrated an average intimal thickness of 4.7 microm (n=8, x 20 magnification) compared with 13.3 microm (n=3, x 20 magnification) in control virus-treated vessels and 7.3 microm (n=5, x 20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty-induced intimal hyperplasia in the coronary artery.     

Sirolimus- and taxol-eluting stents differ towards intimal hyperplasia and re-endothelialization

Restenosis is a direct result of vessel injury, local inflammation, and remodeling following balloon angioplasty and coronary stenting resulting in luminal narrowing. The process involves a complex interplay of released growth factors that stimulate smooth muscle cells (SMCs) to migrate and proliferate, as well as activating endothelial cells (ECs) at injury sites. The latter re-establishes the luminal endothelial monolayer that keeps a barrier to circulating cells from underlying extracellular matrix and SMCs. Understanding the cellular mechanisms of intimal hyperplasia and re-endothelialization is important in that uncontrolled cellular processes account for coronary luminal narrowing, leading to the recurrence of clinical symptoms, hospitalizations, and repeat interventions. The evolution of drug-eluting stents that inhibit intimal hyperplasia has revolutionized percutaneous coronary interventions in that potential late luminal narrowing is attenuated. Sirolimus and paclitaxel are two medications utilized for their efficacy at inhibiting intimal hyperplasia and subsequent clinical events. The effects of these drugs on EC biology have not been well investigated. This article discusses basic cellular processes of vessel repair after balloon angioplasty and stenting, and focuses on the differential molecular mechanisms of sirolimus and paclitaxel towards proliferation and migration. These drugs inhibit both SMC and EC proliferation, but by different mechanisms, and paclitaxel inhibits EC migration, whereas sirolimus does not. Their discriminating effects towards re-endothelialization may clinically differentiate these two drugs. Inhibiting re-endothelialization may translate into more adverse clinical events.     

Stent-mediated methylprednisolone delivery reduces macrophage contents and in-stent neointimal formation

OBJECTIVE: Corticosteroids have a wide range of biological effects. Stent-based methylprednisolone delivery could effectively suppress peri-strut inflammation and neointima induced by a polymer matrix. We tested the safety and efficacy of local stent-mediated methylprednisolone delivery using a biological coating on in-stent neointimal formation in a porcine coronary stent model. METHODS: Stainless steel coronary stents were dip-coated in a biological polymer/ methylprednisolone solution, resulting in total load of 530 mug methylprednisolone per stent. In-vitro drug release was performed. Stainless steel bare stents, polymer-only and methylprednisolone-coated stents (MP) were implanted in coronary arteries of pigs with a stent/artery ratio of 1.2 : 1. Histopathologic evaluation, morphometry and immunohistochemistic staining were analyzed at 4-week follow-up. RESULTS: In-vitro drug release studies showed sustained release up to 10 weeks. In vivo the vascular response of polymer-only-coated stents was comparable with the bare stents. No increased peri-strut inflammation and neointimal hyperplasia were observed. The in-stent neointimal formation of methylprednisolone-coated stents was significantly reduced compared with the bare and polymer-only-coated stents (bare, 1.92+/-0.73; polymer-only, 2.14+/-1.50; MP, 1.01+/-0.47 mm, P=0.019). The macrophage content of methylprednisolone-coated stents (bare, 30.74+/-48.67; polymer-only, 19.55+/-24.60; MP, 1.16+/-3.33/mm, P=0.072) was dramatically decreased. However, there were no significant difference among the three group in terms of the proliferating cells expressed by proliferation cell nuclear antigens. CONCLUSION: Stent-based local methylprednisolone delivery could effectively decrease both vascular macrophage infiltration and in-stent neointimal hyperplasia.     

Alpha-lipoic acid inhibits fractalkine expression and prevents neointimal hyperplasia after balloon injury in rat carotid artery

Vascular inflammation induced by the proinflammatory cytokine/NF-kappaB pathway is one of the key mechanisms in the development of neointimal hyperplasia. Accumulating evidence suggests that a recently identified chemokine, fractalkine, is involved in arterial inflammation and atherogenesis. However, no study has examined the expression of neointimal fractalkine and the effects of pharmacological agents on this process. The purposes of this study were to measure neointimal fractalkine expression in the rat carotid artery following balloon injury and to determine if alpha-lipoic acid (ALA) inhibits fractalkine expression and neointimal hyperplasia. Balloon injury of the rat carotid artery induced fractalkine expression in the medial as well as neointimal regions. ALA inhibited this expression and consequently prevented neoinitmal hyperplasia in a balloon-injured rat carotid artery. Additionally, ALA inhibited TNF-alpha-stimulated fractalkine expression in cultured vascular smooth muscle cells (VSMCs), a process which is mediated through the NF-kappaB pathway. In addition to fractalkine, ALA successfully inhibited TNF-alpha-stimulated expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 in cultured VSMCs. These data suggest that the cytokine-fractalkine system is involved in the pathogenesis of restenosis. The present study supports the possibility that ALA, which inhibits the NF-kappaB/fractalkine pathway, may be used to prevent neointimal hyperplasia after angioplasty or stenting.