Rho激酶与支架内再狭窄

目的 支架内再狭窄与血管平滑肌分化、迁移,细胞外基质的过度增值所致新生内膜增生密切相关.Rho激酶参与支架置入引起的新生内膜增生的调节.长期抑制Rho激酶的表达可阻止新生内膜的增生,可能成为防止支架内再狭窄的一种方法.     

药物涂层支架--介入心脏病学的突破性进展

经皮冠状动脉腔内成形术 (PTCA)和支架置入术后的最突出问题是术后 3～ 8个月再狭窄 ,单纯球囊扩张术后再狭窄发生率高达 30 %～ 5 0 %。其机制主要由于血管局部对球囊损伤的过度愈合反应 ,包括早期血管弹性回缩 ,晚期血管负性重塑(remodeling)及新生内膜过度增生。支架置入术由于有效地制止了血管弹性回缩和负性重塑 ,使再狭窄率明显降低 ,但由于动脉壁损伤、血栓形成及炎性反应 ,刺激各种生长因子和细胞因子产生 ,通过血管平滑肌细胞 (VSMC)受体 ,使平滑肌细胞分裂 ,导致平滑肌细胞增生、基质分泌并向内膜迁移 ,使新生内膜过度增生 ,…     

通心络对实验家兔血管球囊损伤后血管重构的抑制作用

以往认为新生内膜过度增生是导致经皮冠状动脉腔内成形术(PTCA)后血管再狭窄形成的根本原因,但近来研究发现血管重构在再狭窄形成中起重要作用。本研究探讨通心络对实验家兔球囊成形术后血管重构及再狭窄的影响及其可能机制。     

血管内照射对经皮冠脉球囊成形术后再狭窄的影响

经皮冠脉球囊成形术后再狭窄机制复杂,血管平滑肌细胞增殖是导致再狭窄的主要机制之一。β、γ放射源血管内照射治疗均能抑制新生内膜增生,促进血管平滑肌细胞凋亡,能有效降低再狭窄,为预防临床经皮冠脉球囊成形术后再狭窄提供了有效手段。     

低分子量肝素对血管球囊损伤后新生内膜生成影响的实验研究(摘要)

低分子量肝素对血管球囊损伤后新生内膜生成影响的实验研究（摘要）李明阳笪冀平胡益云何志原⒇血管中层平滑肌细胞向内膜迁移、增生，形成增厚的新生内膜，在各种血管腔内成形术后的再狭窄中起重要作用。我们观察了低分子量肝素对家兔血管球囊损伤后新生内膜生成的影响。...     

微管抑制剂与球囊成形术后新生内膜增生和收缩性血管重塑

球囊成形术后再狭窄的主要病理基础是新生内膜增生和收缩性血管重塑.而作为细胞骨架重要组成部分的微管,具有维持细胞形态、参与细胞分裂增生并与细胞跨膜信号转导和基因表达有关,在细胞活动中起重要作用.具有微管动力学稳定作用的紫杉醇,经局部转运即能显著抑制球囊成形术后新生内膜增生又能改善收缩性血管重塑,有望开辟再狭窄防治新领域.     

血管内膜损伤后内皮修复与再生的研究进展

血管内膜损伤主要表现为内皮细胞功能异常或结构破坏,可能导致动脉粥样硬化、血栓形成,腔内介入治疗损伤后可能出现新生内膜增生,引起管腔再狭窄等病理生理改变。血管内膜损伤后机体即启动内皮修复程序,包括自噬与细胞再生,后者在损伤范围较大时应重视。通过对一系列信号转导途径适当干预,促进骨髓多能干细胞的动员和定向分化,增加内皮祖细胞数量及其在受损内膜定植效率,同时抑制新生内膜增生,完成再内皮化,从而增强修复能力。现综述近年来关于血管内膜损伤后内皮修复与再生方面研究。     

γ干扰素对兔血管内膜损伤后平滑肌细胞表达血小板源性生长因子B-mRNA和增殖的影响

目的探讨γ干扰素抑制血管内膜增生和防治血管再狭窄的体内机制。方法建立兔血管狭窄模型,动态观察肌内给予重组γ干扰素对损伤后不同时期血管内膜平滑肌细胞(vSMCs)原位表达血小板源性生长因子B链mRNA(PDGF-BmRNA)和增殖细胞核抗原的影响。结果γ干扰素显著抑制1周和4周时内膜vSMCs表达增殖细胞核抗原,抑制率分别为88.5％和58.9％;显著抑制各观察时期新生内膜表达PDGF-BmRNA。结论γ干扰素通过下调vSMCs原位表达PDGF-BmRNA抑制血管vSMCs的增殖和内膜增生,可能用于临床再狭窄的防治。     

血管重构,血管外膜与冠状动脉介入后再狭窄的关系

血管成形术所致再狭窄有两个成分：细胞增生所致内膜增生和血管几何形态改变所致重构。内膜增生不能完全解释再狭窄现象,血管重构可能是从再狭窄形成的重要因素之一。血管外膜成纤维细胞增生变性和外膜细胞胶原合成机化所成的疤痕组织是收缩性重构形成的重要原因之一。本文综述了再狭窄的基本过程,血管重构定义,机制及其与狭窄的关系,外膜改变在血管重构中的作用以及再狭窄血管重构实验和临床对策。     

E-选择素介导的炎症反应与冠状动脉内支架术后再狭窄

再狭窄是限制冠状动脉内支架术远期成功的重要因素。它是一个由内皮损伤触发的多种因子参与的损伤修复过程,主要包括：机械损伤内皮处非阻塞性血栓形成、新生内膜增生及血管重构等反应。E-选择素仅表达于活化的内皮细胞表面,主要作用是在炎症发生时介导白细胞与血管内皮细胞的起始黏附,以及介导白细胞之间、白细胞与血小板之间的黏附形成血栓,从而对支架置入后损伤的内膜增生过程产生影响。E-选择素的研究对揭示再狭窄发生机制及寻找新的治疗途径均具有重要意义。     

Pathophysiology of coronary artery in-stent restenosis

In-stent restenosis reflects the interaction of a cascade of molecular and cellular events occurring within the vessel wall. Coronary stenting induces localized injury to the vessel wall, which leads to the release of thrombogenic, vasoactive, and lymphocytes mitogenic factors that result in processes causing re-narrowing at the injured site. Three major processes have been identified that lead to the in-stent restenosis: neointimal hyperplasia, elastic recoil, and negative arterial remodeling. The most important one is intimal hyperplasia. As the time course of neointimal hyperplasia is unknown, a causal relationship between the development of new blood vessels and clinical restenosis cannot be firmly established.     

Directional atherectomy for treatment of restenosis within coronary stents: clinical, angiographic and histologic results.

OBJECTIVES. The safety and long-term results of directional coronary atherectomy in stented coronary arteries were determined. In addition, tissue studies were performed to characterize the development of restenosis. METHODS. Directional coronary atherectomy was performed in restenosed stents in nine patients (10 procedures) 82 to 1,179 days after stenting. The tissue was assessed for histologic features of restenosis, smooth muscle cell phenotype, markers of cell proliferation and cell density. A control (no stenting) group consisted of 13 patients treated with directional coronary atherectomy for restenosis 14 to 597 days after coronary angioplasty, directional coronary atherectomy or laser intervention. RESULTS. Directional coronary atherectomy procedures within the stent were technically successful with results similar to those of the initial stenting procedure (2.31 +/- 0.38 vs. 2.44 +/- 0.35 mm). Of five patients with angiographic follow-up, three had restenosis requiring reintervention (surgery in two and repeat atherectomy followed by laser angioplasty in one). Intimal hyperplasia was identified in 80% of specimens after stenting and in 77% after coronary angioplasty or atherectomy. In three patients with stenting, 70% to 76% of the intimal cells showed morphologic features of a contractile phenotype by electron microscopy 47 to 185 days after coronary intervention. Evidence of ongoing proliferation (proliferating cell nuclear antigen antibody studies) was absent in all specimens studied. Although wide individual variability was present in the maximal cell density of the intimal hyperplasia, there was a trend toward a reduction in cell density over time. CONCLUSIONS. Although atherectomy is feasible for the treatment of restenosis in stented coronary arteries and initial results are excellent, recurrence of restenosis is common. Intimal hyperplasia is a nonspecific response to injury regardless of the device used and accounts for about 80% of cases of restenosis. Smooth muscle cell proliferation and phenotypic modulation toward a contractile phenotype are early events and largely completed by the time of clinical presentation of restenosis. Restenotic lesions may be predominantly cellular, matrix or a combination at a particular time after a coronary procedure.     

Restenosis following coronary balloon angioplasty Role of smooth muscle cell proliferation

Restenosis following successful coronary balloon angioplasty remains one of major limitations of this procedure. It is now known that intimal hyperplasia is the primary cause of restenosis. Angioplasty injury of arteries causes activation of platelets, injury and necrosis of smooth muscle and endothelial cells, and leukocyte infiltration. These events result in the production and release of factors that stimulate smooth muscle cell proliferation and subsequently lead to intimal hyperplasia. A number of antiproliferative agents have been found to be effective in inhibiting intimal hyperplasia. It is hoped that an effective pharmacologic approach toward preventing restenosis may be found in the near future.     

The role of c-jun in PDTC-sensitive flow-dependent restenosis after angioplasty and stenting

Restenosis after balloon angioplasty and stenting is exacerbated by low flow. Flow-dependent restenosis after angioplasty but not stenting is prevented by the antioxidant pyrrolidine dithiocarbamate (PDTC). c-jun may play a role in these events as AP-1 activity is both flow and redox sensitive. Carotid arteries of cholesterol fed rabbits underwent stenting or balloon injury in the presence of low or normal flow. c-jun mRNA expression was enhanced by low flow and injury (stent>balloon) and inhibited by the antioxidant PDTC irrespective of the injury type. The effect of locally delivered DZ13 (a DNAzyme specific for c-jun) or scrambled DZ13 (inactive DNAzyme) was assessed by histomorphometry at 28 days. Low flow significantly increased intimal hyperplasia in B and S relative to normal flow (P<0.05). The active DNAzyme DZ13 markedly reduced intimal hyperplasia (P<0.001) and increased lumen size (P<0.05) in balloon-injured but not in stented segments, and abrogated the effect of low flow on restenosis after angioplasty, similar to the morphological effects of PDTC. We conclude that c-jun expression is enhanced by low flow and by injury (stent>balloon) and markedly attenuated by PDTC, and that c-jun is an important mediator of flow-dependent restenosis in balloon-injured but not stented vessels.     

Update on Pharmacology for Restenosis

Coronary restenosis remains a major limitation of percutaneous coronary intervention and has become epidemic in the developed countries. Because almost 80% of the contemporary interventional procedures are performed with the use of coronary stents, strategies aimed at eradicating neointimal hyperplasia are the current research focus. Antiproliferative agents, such as rapamycin, tranilast, and trapidil, are undergoing phase III clinical trials to determine the efficacy of these drugs in preventing restenosis. Stent-based pharmacologic therapy to enhance local delivery of the drug has emerged as a promising anti-restenosis strategy. This article provides an update on the development of the pharmacologic therapy for coronary restenosis.     

Controlled Release of Heparin Reduces Neointimal Hyperplasia in Stented Rabbit Arteries: Ramifications for Local Therapy

Percutaneous coronary angioplasty is limited by neointimal hyperplasia and restenosis. Endovascular stenting has been proposed as a possible means of limiting this process. In practice stents have achieved early patency but are beset by early thrombosis and late restenosis. Heparin administered locally or systemically reduces smooth muscle cell hyperplasia following arterial injury in animals. Balloon-expandable stainless steel stents were placed in de-endothelialized rabbit iliac arteries to determine whether heparin released locally from perivascular matrices could reduce stent induced thrombosis and intimal hyperplasia. All animals received oral aspirin beginning 1 day prior to implantation and an IV bolus of heparin at balloon injury and stent placement. Heparin releasing ethylene-vinyl acetate copolymer matrices were placed adjacent to the stented portion of the artery in the treated group of rabbits. Thrombosis was evident in 30% of ten control arteries 14 days after stent placement and was reduced to 0% in nine segments receiving local heparin therapy (P < 0.05). Intimal hyperplasia was present in all experimental arterial sections, but total intimal area normalized for induced injury was reduced at 14 days from 12.6 ± 0.9 mm² in controls, to 6.8 ± 1.0 mm² in treated arteries (P < 0.001). Our results with perivascular drug administration may shed some light on the pathobiology of the vascular response to endovascular stent insertion and might assist in the design of novel means for enhancing the utilization of angioplasty and other interventional procedures.     

Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis

Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidated. betagamma subunits of heterotrimeric G proteins (Gbetagamma) are known to activate mitogen-activated protein (MAP) kinases after stimulation of certain G protein-coupled receptors; however, their relevance in VSM mitogenesis in vitro or in vivo is not known. Using adenoviral-mediated transfer of a transgene encoding a peptide inhibitor of Gbetagamma signaling (betaARKct), we evaluated the role of Gbetagamma in MAP kinase activation and proliferation in response to several mitogens, including serum, in cultured rat VSM cells. Our results include the striking finding that serum-induced proliferation of VSM cells in vitro is mediated largely via Gbetagamma. Furthermore, we studied the effects of in vivo adenoviral-mediated betaARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the betaARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, Gbetagamma plays a critical role in physiological VSM proliferation, and targeted Gbetagamma inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.     

Adrenomedullin receptor antagonism by calcitonin gene-related peptide(8-37) inhibits carotid artery neointimal hyperplasia after balloon injury

Intimal injury by angioplasty results in a series of changes, including smooth muscle cell hyperplasia, that lead to vascular restenosis. Adrenomedullin, a potent vasodilator peptide, has natriuretic effects, and its plasma concentration is elevated in cardiovascular diseases. Adrenomedullin is secreted by endothelial and vascular smooth muscle cells, but its role in neointimal hyperplasia after balloon injury has not been previously described. We investigated the role of endogenous adrenomedullin in neointimal hyperplasia using an in vivo rat model of postinjury vascular restenosis. In the injured rats, bromodeoxyuridine-labeled nuclei in the media of untreated common carotid arteries were increased 2 days after injury, which were suppressed by in vivo treatment with the adrenomedullin receptor antagonist calcitonin gene-related peptide (CGRP)(8-37). Inhibition of neointimal hyperplasia by CGRP(8-37) was distinct at 7 and 14 days, whereas CGRP(1-37) had no effect. The expression of adrenomedullin in the media of both untreated and treated common carotid arteries was elevated at 2 days and further enhanced in hyperplastic intima of untreated common carotid arteries at 7 days. Our findings suggest a novel role for endogenous adrenomedullin in balloon injury-induced restenosis and indicate that CGRP(8-37) may be useful for the prevention of vascular restenosis.     

Effect of local heating on restenosis and in-stent neointimal hyperplasia in the atherosclerotic rabbit model: a dose-ranging study.

AIMS: In-stent restenosis is related to neointimal hyperplasia. Heating reduces neointimal hyperplasia but promotes constrictive remodeling after balloon angioplasty. We aimed to assess the ability of local heating in inhibiting restenosis and in-stent neointimal hyperplasia and its potential side effects on arterial thrombosis. METHODS AND RESULTS: Atherosclerotic-like lesions were induced in iliac rabbit arteries. One month later, both iliac rabbit arteries were stented. In each animal, one artery was randomized to local heating at four temperatures (50, 60, 80, and 100 degrees C). The contra lateral artery was used as control. Angiographic and histomorphometric analysis were performed 42 days after angioplasty. Immunohistochemistry was performed 3, 15, and 42 days after angioplasty. Angiographic significant reduction of in-stent restenosis after moderate heating (50 degrees C) was related to in-stent neointimal hyperplasia trend to be lower after moderate local heating when compared with controls. In contrast, in-stent thrombosis was similar to controls. Higher temperatures (i.e. 80 and 100 degrees C) also reduced in-stent neointimal hyperplasia but were most frequently associated with severe in-stent thrombosis. Local heating was associated with decreased cell proliferation, collagen density, and increased smooth muscle cell apoptosis and heat shock protein expression. CONCLUSION: Moderate heating represents a promising approach to prevent in-stent restenosis via the limitation of the proliferative response without thrombosis induction.     

Novel NAD(P)H oxidase inhibitor suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat carotid artery

Neointimal proliferation occurring after vascular or endovascular procedures is a major complication leading to end-organ or limb ischemia. In experimental models, balloon injury has been shown to induce NAD(P)H oxidase to produce vascular superoxide anion (O2*-) production, which has been implicated in cell proliferation, but a direct link is still unclear. We postulated that inhibition of arterial NAD(P)H oxidase, resulting in decreased O2*-, would lessen the neointimal hyperplasia caused by balloon injury to the common carotid artery (CCA). Sprague-Dawley rats were implanted with osmotic minipumps containing either vehicle, a cell-permeant peptide that inhibits NAD(P)H oxidase (gp91ds-tat, 10 mg/kg per day), or a scrambled peptide control (scrmb-tat). Two days after pump implantation, the left CCA was injured using an intravascular balloon embolectomy catheter (2F Fogarty). Systolic blood pressure was monitored by tail cuff. Fourteen days after injury, CCAs were harvested and analyzed by digital morphometry. Rats in both groups remained normotensive, with no significant differences in systolic blood pressure. Reactive oxygen species measurements after injury indicated a significant reduction in vascular O2*- in rats infused with gp91ds-tat, and the neointima/media area and thickness ratios were significantly lower in their arteries compared with control. On the contrary, no significant change in overall CCA diameter was observed in any group. Our data indicate that in response to balloon injury of the rat carotid artery, NAD(P)H oxidase activity contributes to neointimal hyperplasia and is involved in vascular cell proliferation and migration during restenosis.