内皮祖细胞在支架术后再内皮化中应用的研究进展

经皮冠状动脉介入治疗的应用改善了冠心病患者的临床症状及预后,但现在困扰人们的问题是作为其术后并发症之一的支架内再狭窄发病率仍然很高。大量的研究证实,内膜增生在支架内再狭窄的形成中起主导作用,所以提高受损内膜再内皮化的速度是防止支架内再狭窄的一个重要措施。新近的研究表明,内皮祖细胞能参与损伤后血管内皮修复,促进受损血管内膜的再内皮化,因此,在防止支架内再狭窄中将得到进一步的研究与应用。因此,本文就内皮祖细胞在支架术后再内皮化中应用的研究进展做一综述。     

DES早期支架内血栓的形成和防治

目前,冠状动脉内支架植入术是冠心病血运重建的主要方法,支架置入可显著减少再狭窄和靶血管血运重建.虽然支架术后支架内血栓形成少见,但预后差,临床上可表现为急性心肌梗死或猝死.是药物洗脱支架的潜在危险,预防支架内血栓形成是冠状动脉粥样硬化性心脏病介入领域的研究热点和难点,因此,支架内血栓的形成、防治问题仍然值得我们关注与探讨.本文阐明了早期支架内血栓的影响因素,预防,观察方法及治疗措施.使用新一代的药物洗脱支架有望减少支架内血栓的发生.     

药物洗脱支架植入后再狭窄的研究进展

随着药物洗脱支架(Drug Eluting Stent,DES)的出现,再狭窄的问题得到进一步的有效控制.然而,药物洗脱支架也存在较低的再狭窄率,由于应用药物洗脱支架治疗人数非常多,这一比率就不容忽视.本文将阐述DES支架内再狭窄发生的病理生理学机制、临床表现、形态学特征以及处理策略.     

冠脉支架内再狭窄发生机制及防治研究进展

冠心病介入治疗已经成为冠心痛的重要治疗方法.但是支架内再狭窄是冠心病介入医师不得不面对的一个问题.近年来随着关于ISR发生的病理生理学基础研究细胞信号转导等基础研究的深入,有关各种针对其发生机制的相关防治方法不断发展.各种涂层支架、冠脉内放射治疗、基因治疗以及口服药物治疗为解决ISR提供了各种方法.本文就冠脉支架术后支架内再狭窄的发生机制及诊治进展进行了综述.     

形状记忆合金超弹性自扩张血管支架的优化设计

自扩张型镍钛合金血管支架由于其良好的生物相容性与超弹性,可以很好地解决支架植入后的再狭窄问题。利用有限元软件ANSYS对支架在血管中的自扩张行为进行模拟,并对支架的网格形状与尺寸进行优化设计。     

可降解冠状动脉支架的研究进展

冠脉内支架植入是临床上预防PTCA术后再狭窄并发症的有效措施,但金属支架仅在植入早期发生作用,在冠脉内壁修复完成后则成为多余的负担,可能激活血小板及多种凝血因子聚集导致血栓形成及刺激血管壁造成心脏事件及再狭窄的发生。针对上述问题,生物可降解冠状动脉支架的研究得到了相当的发展。本文就可降解支架的发展及现状作一简要综述。     

瑞舒伐他汀强化治疗对支架置入术后患者血管再狭窄的影响

目的:探究瑞舒伐他汀强化治疗对行冠状动脉支架置入术后患者再狭窄率、血管内皮功能和血脂水平的影响。方法:选择2013年1月~2015年12月90例于我院行冠状动脉支架置入术后的患者。按照治疗方法的不同将患者随机分为观察组及对照组,每组45例。观察组患者术后给予20 mg/天瑞舒伐他汀强化治疗,对照组患者术后给予常规剂量(5~10 mg/天)瑞舒伐他汀治疗,连续服用6个月。比较两组患者治疗前后的血脂、C反应蛋白(CRP)、白介素8(IL-8)、一氧化氮合酶(e NOS)、内皮素-1(ET-1)水平及术后6个月支架内再狭窄率(ISR)。结果:治疗后,两组患者的胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)水平均较治疗前显著降低(P0.05),且观察组患者以上指标均显著低于对照组(P0.05);观察组患者高密度脂蛋白(HDL-C)水平较治疗前增加明显(P0.05),而对照组该指标无明显改善(P0.05)。治疗后,两组患者的CRP、IL-8水平均较治疗前显著降低(P0.05),且观察组患者以上指标显著低于对照组(P0.05);观察组患者的一氧化氮合酶(e NOS)水平较治疗前显著提高,血管内皮素-1(ET-1)水平显著降低(P0.05),但对照组以上指标与治疗前相比无明显差异(P0.05)。术后6个月,观察组患者支架内再狭窄率(ISR)显著低于对照组(P0.05)。结论:瑞舒伐他汀强化治疗可通过显著改善患者血脂水平,减轻患者机体炎症状态,积极恢复内皮组织损伤,进而预防ISR的发生。     

骨髓间充质干细胞捕获支架对犬冠状动脉再狭窄影响的研究

目的:观察骨髓间充质(MSCs)干细胞捕获支架能否预防和减少犬冠状动脉支架植入术后再狭窄.方法:①用乙基纤维素作为包被底物对支架进行包被,然后再包被骨髓间充质干细胞抗体.②以球囊损伤法建立犬冠状动脉狭窄模型,应用标准球囊导管技术,将包被有抗体的支架植入犬(n=20)冠状动脉前将支损伤段远端,再以相同方法在损伤段近端植入裸支架作为对照组(n=20).4w后处死动物,取出支架段血管行血管内超声(IVUS)及血管形态学检测分析血管管腔面积和内膜增生面积.结果:术后4周,骨髓间充质干细胞捕获支架组较裸支架组的最小管腔直径和新生内膜面积较明显减少(P<0.05),而最小管腔面积则明显增加(P<0.05).结论:骨髓间充质干细胞捕获支架能快速修复损伤的血管内膜,降低再狭窄的发生.     

血管内支架成形术治疗大脑中动脉狭窄

目的:探讨血管内支架成形术治疗大脑中动脉狭窄的疗效及安全性.方法:对22例大脑中动脉狭窄患者行血管内支架成形术,回顾性分析其临床特点、疗效及治疗经验.结果:22例患者共植入22枚支架,均获得成功.术后即刻造影狭窄率为(11.2±4.5)%,较术前(79±15)%明显改善.术后残余狭窄程度均小于20%.临床随访无TIA发作或脑卒中再发,DSA随访除1例外均无再狭窄发生.结论:血管内支架成形术治疗大脑中动脉狭窄安全有效,但远期疗效还需进一步观察.     

载基因洗脱支架防治再狭窄的研究进展

药物洗脱支架(DES)在冠状动脉疾病的治疗中起到巨大作用,不但能机械支撑血管狭窄区,而且可以通过持续释放药物显著降低病灶处再狭窄率。然而,长期临床研究表明,载药DES在后期有引发血栓的风险。在DES表面载入基因药物,通过表面涂层输送系统局部缓慢释放治疗基因,能针对引起再狭窄的细胞过程进行修改。选择合适的治疗基因,可以抑制内膜增生,促进再内皮化,提高洗脱支架的有效性和安全性,是非常有前途的抗再狭窄方法。同时,良好的涂层材料不仅改善了支架表面的生物相容性,更能通过不同的基因药物输送系统有效控制治疗基因的释放速率。本文首先介绍了一部分针对再狭窄的治疗基因,在此基础上,综合阐述了基因缓释系统中使用的材料和技术,分析提炼了基因缓释系统的释放机理,举例分析了载基因洗脱支架的研究进展,并展望了该领域的发展前景。     

Efficiency of endovascular re-interventions for evolving restenosis of different types of stents

The paper compares the results of different treatment options (balloon angioplasty and restenting) for in-stent restenosis in case of evolving restenosis of drug- and nondrug eluting stents. The investigation enrolled 496 coronary heart disease patients with clinical presentation of angina pectoris and/or signs of myocardial ischemia, as well as hemodynamic restenosis of a previously implanted stent. Of them, 216 and 280 patients had restenosis of previously implanted drug- and nondrug-eluting stents, respectively. In the patients with non-drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis were significantly more frequently observed after balloon dilatation than after drug-eluting stent implantation (28.4 and 10.2%; p < 0.05; 19.9 and 8.7%; p < 0.05). In those with drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis did not differ significantly between balloon dilatation of restenosis and implantation of a second drug-eluting stent.     

Release of TNF-alpha during stent implantation into saphenous vein aortocoronary bypass grafts and its relation to plaque extrusion and restenosis

The reduction in plaque volume during stent implantation is associated with the release of particulate debris and plaque-derived soluble substances. We studied the potential release of the proinflammatory cytokine TNF-alpha into the coronary circulation and whether such release is related to the reduction in plaque volume and, possibly, a predictor for restenosis. In 18 male patients (n = 24 stents) with severe stenosis in a saphenous vein aortocoronary bypass graft (SVG), we used a distal balloon occlusion-aspiration device during stent implantation. The aspirate TNF-alpha levels were determined before and after stent implantation and related to the angiographic and intravascular ultrasound-assessed severity of stenosis and restenosis. We found that TNF-alpha is, indeed, released into the aspirate of stented SVG (9 +/- 1 and 28 +/- 3 pg/ml before and after stent implantation, respectively, P < 0.0001) and that such release is related to the reduction in plaque volume (r = 0.88, P < 0.0001) and associated with restenosis after 5 mo (r = 0.71, P = 0.001). The periprocedural release of plaque-derived TNF-alpha possibly represents the amount and activity of the atherosclerotic process and might be a predictor for restenosis.     

Biodegradable stents as a platform to drug loading

Despite technical and mechanical improvement in coronary stents the incidence of restenosis caused by in-stent neointimal hyperplasia remains high. Oral administration of numerous pharmacological agents has failed to reduce restenosis after coronary stenting in humans, possibly owing to insufficient local drug concentration. Therefore, drug-eluting stents were developed as a vehicle for local drug administration. The authors developed a new drug-eluting polymer stent that is made of poly-l-lactic acid polymer mixed with tranilast, an anti-allergic drug that inhibits the migration and proliferation of vascular smooth muscle cells induced by platelet-derived growth factor and transforming growth factor->1. Polymer stents might be superior to polymer-coated metallic stents as local drug delivery stents in terms of biodegradation and the amount of loaded drug. Drug-mixed polymer stents can be loaded with a larger amount of drug than can drug-coated metallic stents because the polymer stent struts can contain the drug. Clinical application is required to assess the safety and efficacy of drug-eluting polymer stents against stent restenosis.     

Alterations in wall shear stress predict sites of neointimal hyperplasia after stent implantation in rabbit iliac arteries

Restenosis resulting from neointimal hyperplasia (NH) limits the effectiveness of intravascular stents. Rates of restenosis vary with stent geometry, but whether stents affect spatial and temporal distributions of wall shear stress (WSS) in vivo is unknown. We tested the hypothesis that alterations in spatial WSS after stent implantation predict sites of NH in rabbit iliac arteries. Antegrade iliac artery stent implantation was performed under angiography, and blood flow was measured before casting 14 or 21 days after implantation. Iliac artery blood flow domains were obtained from three-dimensional microfocal X-ray computed tomography imaging and reconstruction of the arterial casts. Indexes of WSS were determined using three-dimensional computational fluid dynamics. Vascular histology was unchanged proximal and distal to the stent. Time-dependent NH was localized within the stented region and was greatest in regions exposed to low WSS and acute elevations in spatial WSS gradients. The lowest values of WSS spatially localized to the stented area of a theoretical artery progressively increased after 14 and 21 days as NH occurred within these regions. This NH abolished spatial disparity in distributions of WSS. The results suggest that stents may introduce spatial alterations in WSS that modulate NH in vivo.     

Endovascular stent configuration affects intraluminal flow dynamics and in vitro endothelialization

Neointimal hyperplasia influenced by intravascular hemodynamics is considered partly responsible for restenosis after endovascular stenting. To evaluate the effect of stent configuration on fluid flow behavior, we visualized flow near stents, and measured the proliferation of cultured endothelial cells (ECs). A single-coil stent (coil pitch; CP = 2.5, 5, or 10 mm) was inserted into a glass tube and perfused at 30-90 ml/min, while the flow pattern was determined by particle imaging velocimetry. The reduction of the flow velocity near the wall was correlated with the decrease in the coil interval of the stent. In perfusion cultures with stents, the proliferation of ECs was influenced by the local flow velocity distribution. When a stent with a CP value of 10 mm was used, the doubling time of ECs was 30.7 h, while the doubling time was 38.5 h when the CP was 5 mm. The doubling time of ECs was shorter at sites upstream of the stent wire where the velocity was higher than downstream of the wire. In conclusion, a single-coil stent can be used to modify hemodynamic factors, suggesting that improved stent design may facilitate rapid endothelialization after stent implantation.     

Cardiovascular stent design and vessel stresses: a finite element analysis

Intravascular stents of various designs are currently in use to restore patency in atherosclerotic coronary arteries and it has been found that different stents have different in-stent restenosis rates. It has been hypothesized that the level of vascular injury caused to a vessel by a stent determines the level of restenosis. Computational studies may be used to investigate the mechanical behaviour of stents and to determine the biomechanical interaction between the stent and the artery in a stenting procedure. In this paper, we test the hypothesis that two different stent designs will provoke different levels of stress within an atherosclerotic artery and hence cause different levels of vascular injury. The stents analysed using the finite-element method were the S7 (Medtronic AVE) and the NIR (Boston Scientific) stent designs. An analysis of the arterial wall stresses in the stented arteries indicates that the modular S7 stent design causes lower stress to an atherosclerotic vessel with a localized stenotic lesion compared to the slotted tube NIR design. These results correlate with observed clinical restenosis rates, which have found higher restenosis rates in the NIR compared with the S7 stent design. Therefore, the testing methodology outlined here is proposed as a pre-clinical testing tool, which could be used to compare and contrast existing stent designs and to develop novel stent designs.     

A multi-scale mechanobiological model of in-stent restenosis: deciphering the role of matrix metalloproteinase and extracellular matrix changes

Since their first introduction, stents have revolutionised the treatment of atherosclerosis; however, the development of in-stent restenosis still remains the Achilles' heel of stent deployment procedures. Computational modelling can be used as a means to model the biological response of arteries to different stent designs using mechanobiological models, whereby the mechanical environment may be used to dictate the growth and remodelling of vascular cells. Changes occurring within the arterial wall due to stent-induced mechanical injury, specifically changes within the extracellular matrix, have been postulated to be a major cause of activation of vascular smooth muscle cells and the subsequent development of in-stent restenosis. In this study, a mechanistic multi-scale mechanobiological model of in-stent restenosis using finite element models and agent-based modelling is presented, which allows quantitative evaluation of the collagen matrix turnover following stent-induced arterial injury and the subsequent development of in-stent restenosis. The model is specifically used to study the influence of stent deployment diameter and stent strut thickness on the level of in-stent restenosis. The model demonstrates that there exists a direct correlation between the stent deployment diameter and the level of in-stent restenosis. In addition, investigating the influence of stent strut thickness using the mechanobiological model reveals that thicker strut stents induce a higher level of in-stent restenosis due to a higher extent of arterial injury. The presented mechanobiological modelling framework provides a robust platform for testing hypotheses on the mechanisms underlying the development of in-stent restenosis and lends itself for use as a tool for optimisation of the mechanical parameters involved in stent design.     

Methods to improve dose uniformity for radioactive stents in endovascular brachytherapy

Intravascular brachytherapy (IVBT) has rapidly gained acceptance as a new treatment modality for reducing restenosis and improving the success rate of percutaneous transluminal coronary angioplasty (PTCA). Recent clinical results on patients treated with beta-emitting 32P stents suggest that radiation reduces in-stent restenosis but may exacerbate neointimal growth at the edges of the stents. This has been referred to as the "candy wrapper effect." It is well known that radioactive stents yield extremely inhomogeneous dose distributions, with low doses delivered to tissues in between stent struts, at the ends of the stent, and also at depth. Some animal model studies suggest that low doses of radiation may stimulate rather than inhibit neointimal growth in an injured vessel, and it is hypothesized that dose inhomogeneity at the ends of a stent may contribute to the candy wrapper effect. We present here a theoretical study comparing dose distributions for beta stents vs. gamma stents; "dumbbell" radioactive loaded stents vs. uniformly loaded stents; and stents with alternate strut design. Calculations demonstrate that dose inhomogenieties between stent struts, at the ends of stents, and at depth can be reduced by better stent design and isotope selection. Prior to the introduction of radioactive stents, criteria for stent design included factors such as trackability, flexibility, strength, etc. We show here that if stent design also includes criteria for strut shape and spacing that improved dose distributions are possible, which in turn could reduce the candy wrapper effect.     

In silico prediction of the mechanobiological response of arterial tissue: application to angioplasty and stenting

One way to restore physiological blood flow to occluded arteries involves the deformation of plaque using an intravascular balloon and preventing elastic recoil using a stent. Angioplasty and stent implantation cause unphysiological loading of the arterial tissue, which may lead to tissue in-growth and reblockage; termed "restenosis." In this paper, a computational methodology for predicting the time-course of restenosis is presented. Stress-induced damage, computed using a remaining life approach, stimulates inflammation (production of matrix degrading factors and growth stimuli). This, in turn, induces a change in smooth muscle cell phenotype from contractile (as exists in the quiescent tissue) to synthetic (as exists in the growing tissue). In this paper, smooth muscle cell activity (migration, proliferation, and differentiation) is simulated in a lattice using a stochastic approach to model individual cell activity. The inflammation equations are examined under simplified loading cases. The mechanobiological parameters of the model were estimated by calibrating the model response to the results of a balloon angioplasty study in humans. The simulation method was then used to simulate restenosis in a two dimensional model of a stented artery. Cell activity predictions were similar to those observed during neointimal hyperplasia, culminating in the growth of restenosis. Similar to experiment, the amount of neointima produced increased with the degree of expansion of the stent, and this relationship was found to be highly dependant on the prescribed inflammatory response. It was found that the duration of inflammation affected the amount of restenosis produced, and that this effect was most pronounced with large stent expansions. In conclusion, the paper shows that the arterial tissue response to mechanical stimulation can be predicted using a stochastic cell modeling approach, and that the simulation captures features of restenosis development observed with real stents. The modeling approach is proposed for application in three dimensional models of cardiovascular stenting procedures.     

Drug-eluting stents: from bench to bed

The introduction of stents to clinical practice in 1987 was the major breakthrough in the field of percutaneous coronary intervention (PCI). The use of stenting has drastically improved the outcomes of traditional PCI. First stents were approved for bailout and treatment of dissections, reducing dramatically the need for emergent coronary artery bypass grafting (CABG) as a result of vessel closure during PCI. Later stents were proven to reduce the restenosis rate of PCI from 30%-40% with balloon angioplasty to 15%-20% with stents, primarily by eliminating elastic recoil and vascular remodeling as shown by intravascular ultrasound (IVUS) studies. These outcomes have led to a wide acceptance of stenting as the strategy of choice for more than 80% of all PCI procedures performed. The current review focuses on the following topics: (1) strategies in drug selection to reduce neointimal proliferation, (2) stent designs and polymer selection as a platform for drug-eluting stents, (3) review of major preclinical and clinical experimental work performed in the field, and (4) a discussion of the potential and limitations of the technology.