Long-term inhibition of intimal hyperplasia using vascular photodynamic therapy in balloon-injured carotid arteries

Flexible treatments for intimal hyperplasia after angioplasty are still needed. The aim of this study was to demonstrate the long-term effects of vascular photodynamic therapy with talaporfin sodium on intimal hyperplasia following interventional injury. Intimal hyperplasia was induced by balloon distension injury to the carotid artery in 31 rabbits. Talaporfin, 5.0 mg/kg, was delivered systemically immediately after balloon injury. The injury site was irradiated with a diode laser light of wavelength 664 nm using a fluence of 50 J/cm² after 30 min. At day 3 and weeks 3, 6, 9, 15, and 25 after photodynamic therapy, the treated artery of each rabbit was excised and examined immunohistochemically. Thirty minutes after talaporfin administration, drug fluorescence was found only in the balloon-injured carotid artery wall. At 3 days, no smooth muscle cells were seen in the media of the photodynamic therapy-treated arterial segments. Intimal hyperplasia developed progressively in the balloon-injured and untreated segments; however, in the segments treated with photodynamic therapy, intimal hyperplasia was markedly suppressed until 25 weeks and the media was repopulated by smooth muscle cells without macrophages. Vascular photodynamic therapy with talaporfin may be used to inhibit restenosis after vascular intervention. An erratum to this article is available at .     

The effect of oestrogen on intimal hyperplasia in cultured human ovarian veins

The beneficial effect of oestrogen on blood vessels may include modulation of vascular response to injury. In this experiment we set out to develop an in-vitro model, using all human materials, for the study of vascular changes in culture, and their response to oestrogen treatment. Human ovarian vein segments were obtained from 15 hysterectomy specimens, and cultured with and without the addition of 17beta-oestradiol. Paired control veins were cultured with the inert 17alpha-oestradiol. The veins were stained with anti-alpha-smooth muscle actin and Miller's elastin, and intimal thickness measured. Cultured veins developed a significant degree of intimal thickening [15.7 versus 8.25 microm in fresh veins, 95% confidence intervals (CI) 13.6, 17.8 and 6.3, 10.2 respectively; P = 0.0001]. The addition of 17beta-oestradiol, but not 17alpha-oestradiol, led to a significant reduction in intimal hyperplasia (intimal thickness 8.85 microm; 95% CI 6.9, 10.8; P = 0.008). The mean number of nuclei per high-power field was also significantly lower in the intima of oestrogen-treated compared to untreated veins (11.6; 95% CI 9.9, 13.26 versus 14.05; 95% CI 12.5, 15.6; P = 0.001). Our data suggest that intimal hyperplasia in cultured ovarian veins is effectively reduced by oestrogen.      

小鼠血管内皮损伤/再生伴内膜增生模型的建立

目的： 探讨如何建立稳定的小鼠血管内皮损伤/再生及内膜增生模型。方法： 用改良的空气干燥法造成小鼠颈总动脉内皮剥脱损伤模型。术后活体灌注Evans蓝染料以评估受损内皮再生情况，并取受损部分动脉作纵向切片，行CD31内皮细胞标志抗原检测。术后4周常规组织学检测内膜增生肥厚情况。结果： 内皮损伤术后内皮完全剥脱，Evans蓝染色完全，未见CD31抗原表达，随着术后时间延长，Evans蓝染色部分从损伤边缘开始，逐渐向中心区缩小，CD31抗原表达逐渐增多。术后7 d仍可见部分损伤血管未再内皮化。术后4周可见明显新生内膜增生。结论： 用改良的空气干燥法可以建立稳定的小鼠动脉内皮损伤/再生模型，并且伴有明显的新生内膜增生。     

A novel polymer-free paclitaxel-eluting stent with a nanoporous surface for rapid endothelialization and inhibition of intimal hyperplasia: Comparison with a polymer-based sirolimus-eluting stent and bare metal stent in a porcine model

Hypersensitivity and inflammatory responses to polymers may be responsible for late stent thrombosis after implantation of a drug-eluting stent (DES). Polymer-free DES may reduce the prevalence of these adverse reactions in vessels. We evaluated a polymer-free paclitaxel-eluting-stent with a nanoporous surface (nano-PES) for endothelialization and inhibition of neointimal hyperplasia by optical coherence tomography (OCT) and pathology in a porcine model. Nano-PES with high-dose (HD) and low-dose (LD) paclitaxel (1.0 μg/mm(2) and 0.4 μg/mm(2), respectively) was compared with a sirolimus-eluting stent (SES) and bare-metal stent (BMS) in a porcine model. Fifty-three stents (14 HD, 14 LD, 14 SES, 11 BMS) were implanted in 18 minipigs. At 14 days, nano-PES with HD and LD showed more complete endothelialization compared with SES. BMS had 100% endothelial coverage. At 28 days, a significant reduction in neointimal hyperplasia was detected by OCT in the nano-PES HD group compared with BMS. No benefit in prevention of the neointimal hyperplasia was observed in the nano-PES LD group. Nano-PES stents showed decreased deposition of fibrin and inflammation compared with SES. Pharmacokinetic studies revealed that nano-PES could effectively deliver the drug to the local coronary artery and it released the drug more rapidly than SES. Such a release profile was favorable for rapid endothelialization of nano-PES. The present study showed the nano-PES to be a new drug-delivery technology; that it used a nanoporous stent surface; that it offered desirable drug-elution properties without the use of polymers; that it may translate into an improved safety profile for next-generation DES.     

大蒜素包被支架术后冠状动脉管壁原癌基因c-fos表达的变化

目的：探讨大蒜素（DT）包被支架置入后对血管内膜增生及管壁原癌基因c-fos表达的影响。方法：直接支架置入术建立犬冠状动脉内膜损伤模型，观察血管形态学变化，并用RT-PCR方法检测不同时点冠状动脉壁内c-fos基因的表达丰度。结果：单纯蛋白包被支架置入后4周管壁内膜明显增生，DT包被支架明显抑制内膜增生。对照组c-fos基因在术后1 d有大量的表达，7 d达高峰，以后随时间的推移表达逐渐下降,28 d仍可检出。与对照组相比，各时点DT包被支架均显著抑制c-fos mRNA的表达。结论：DT包被支架具有抑制c-fos基因的表达与内膜增生的作用。     

Smooth muscle cell proliferation but not neointimal formation is dependent on alloantibody in a murine model of intimal hyperplasia

Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2(h2)) donor mice and B-cell deficient muMT(-/-) knockout or wild-type C57BL/6 (H-2(b)) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to muMT(-/-) recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent.     

Neuroform EZ支架及Solitaire AB支架在颅内动脉粥样硬化性重度狭窄治疗中的应用

目的:探讨Neuroform EZ支架及Solitaire AB支架治疗症状性颅内动脉粥样硬化性重度狭窄(ICAS)的疗效和安全性。方法:回顾性队列研究。纳入2018年7月—2019年12月解放军总医院第一医学中心神经内科行Neuroform EZ支架或Solitaire AB支架植入治疗的症状性ICAS患者142例,...     

反义凝血酶受体基因表达抑制大鼠动脉内膜损伤后内膜增生

目的 了解凝血酶及其受体在血管损伤后动脉内膜增生中的作用,以进一步阐明经皮冠状动脉血管腔内成形术（PTCA）后再狭窄的发生机制,为寻找再狭窄的防治途径提供线索。方法 采用球囊导管损伤动脉内膜的方法建立大鼠颈动脉球囊损伤模型。用纳米粒子包装凝血酶受体重组反义基因质凿pLXSN/ATR,用保护灌注的方法局部定位转染损伤后的大鼠颈动脉。结果 PCR检测发现重组基因整合,RNA斑点杂交观察到实验组大鼠颈动脉壁内有重组反义凝血酶受体基因表达,正义凝血酶受体基因的表达受到明显抑制,反义基因转染组新生内膜,中膜比例降低了40．9％。结论 反义凝因酶受体重组基因转基因表达对大鼠颈动脉球囊损伤后动脉内膜的增生具有抑制作用,提示凝血酶及其受体在PTCA后再狭窄过程中有重要作用,为再狭窄的防治提供了新的线索。     

Angiographic density averaging in a case of renal artery intimal fibroplasia and recanalized thrombus

The angiographic appearance of renal artery, intimal fibroplasia with recanalized luminal thrombus is presented. Criteria for diagnosis are discussed.     

Development of microporous self-expanding stent grafts for treating cerebral aneurysms: designing micropores to control intimal hyperplasia

Treatment of large (diameter 12–25 mm) or giant (diameter >25 mm) cerebral aneurysms with a broad neck in the cranio-cervical area is difficult and carries relatively high risks, even with surgical and/or endovascular methods. To this end, we have been developing a high-performance, self-expanding stent graft which consists of a commercially available NiTi stent (diameter 5 mm, length 20 mm) initially covered with a thin microporous segmented polyurethane membrane fabricated by the dip-coating method. Micropores are then created by the excimer laser ablation technique, and the outer surface is coated with argatroban. There are 2 types of micropore patterns: circular-shaped pore type (pore: diameter 100 μm, opening ratio 12.6%) and the bale-shaped pore type (pore: size 100 × 268 μm, opening ratio 23.6%). This self-expanding stent graft was tested on side-wall aneurysms of both canine carotid arteries that were experimentally induced using the venous pouches from the external jugular veins, with the self-expanding stent graft on one side and a bare self-expanding stent on the other side. All carotid arteries were patent and free of marked stenosis after 1 month. All aneurysms were occluded by stent grafts, while patent in those treated with bare stents. Histologically, the stent grafts with bale-shaped micropores and a high opening ratio were associated with less intimal hyperplasia (187 ± 98 μm) than the bare stents (341 ± 146 μm) or the stent grafts with circular micropores and a low opening ratio (441 ± 129 μm). A pore ratio of 23.6% was found to control intimal growth.     

Hemodynamic parameters and early intimal thickening in branching blood vessels

Intimal thickening due to atherosclerotic lesions or intimal hyperplasia in medium to large blood vessels is a major contributor to heart disease, the leading cause of death in the Western World. Balloon angioplasty with stenting, bypass surgery, and endarterectomy (with or without patch reconstruction) are some of the techniques currently applied to occluded blood vessels. On the basis of the preponderance of clinical evidence that disturbed flow patterns play a key role in the onset and progression of atherosclerosis and intimal hyperplasia, it is of interest to analyze suitable hemodynamic wall parameters that indicate susceptible sites of intimal thickening and/or favorable conditions for thrombi formation. These parameters, based on the wall shear stress, wall pressure, or particle deposition, are applied to interpret experimental/clinical observations of intimal thickening. Utilizing the parameters as "indicator" functions, internal branching blood vessel geometries are analyzed and possibly altered for different purposes: early detection of possibly highly stenosed vessel segments, prediction of future disease progression, and vessel redesign to potentially improve long-term patency rates. At the present time, the focus is on the identification of susceptible sites in branching blood vessels and their subsequent redesign, employing hemodynamic wall parameters. Specifically, the time-averaged wall shear stress (WSS), its spatial gradient (WSSG), the oscillatory shear index (OSI), and the wall shear stress angle gradient (WSSAG) are compared with experimental data for an aortoceliac junction. Then, the OSI, wall particle density (WPD), and WSSAG are segmentally averaged for different carotid artery bifurcations and compared with clinical data of intimal thickening. The third branching blood vessel under consideration is the graft-to-vein anastomosis of a vascular access graft. Suggested redesigns reduce several hemodynamic parameters (i.e., the WSSG, WSSAG, and normal pressure gradient [NPG]), thereby reducing the likelihood of restenosis, especially near the critical toe region.     

Arg—Gly—Asp—Ser序列肽抗血小板聚集及抑制血栓形成的作用

本研究采集精氨酰－甘氨酰－天冬氨酸（Ａｒｇ－Ｇｌｙ－Ａｓｐ，ＲＧＤ）序列肽精氨酰－甘氨酰－天冬氨酰－丝氨酸四肽（Ａｒｇ－Ｇｌｙ－Ａｓｐ－Ｓｅｒ，ＲＧＤＳ）观察其小血板聚集功能，实验性血栓形成以及对纤维蛋白溶解系统的影响，结果表明ＲＧＤＳ显著抑制了血小板聚集功能，一分钟聚集抑制率，最大聚集抑制率随药物体外作用浓度增加而增加（０．０５～１．０ｍｍｏｌ／Ｌ）同时聚集速率显著下降，体内给予ＲＧＤＳ（８μｍ     

The effect of a polypeptide complex isolated from the animal prostate on thrombus formation]

The authors studied the effect of polypeptides, which were obtained from the prostate of cattle and were related to the class of cytomedines, on the formation of thrombi in the venules of the mesentery in rats. Thrombosis of the venules was induced by laser irradiation, the thrombogenesis parameters were measured with a TV microscope. Intramuscular injection of the preparation and its local action on the mesenteric vessels reduced the time of growth and the size of the thrombi in the experimental animals as compared to that in the controls. The obtained data are evidenced that the preparation produces an inhibiting effect on the thrombocyte-vascular mechanism of hemostasis by increasing the thromboresistance of the vascular wall.     

Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries

Endogenous hydrogen sulfide (H(2)S), generated from homocysteine metabolism mainly catalyzed by cystathionine gamma-lyase (CSE), possesses important functions in the cardiovascular system. In this study, we investigated the role of H(2)S during the pathogenesis of neointimal formation induced by balloon injury in rats. CSE mRNA levels were reduced by 86.5% at 1 week and 64.0% at 4 weeks after balloon injury compared with the uninjured controls. CSE activity was also correspondingly reduced. Endogenous production of H(2)S in the injured carotid artery was significantly inhibited at 1 week and 4 weeks after balloon injury. Treatment with NaHS (a donor of H(2)S) enhanced methacholine-induced vasorelaxation of balloon-injured artery. More importantly, treatment with NaHS significantly inhibited neointima formation (0.15 +/- 0.01 mm(2) versus 0.21 +/- 0.01 mm(2), P < 0.001) of the balloon-injured carotid arteries and reduced the intima/media ratio (1.05 +/- 0.07 versus 1.43 +/- 0.06, P < 0.001). A significant decrease in vascular smooth muscle cell proliferation was demonstrated by bromodeoxyuridine incorporation at day 7 after injury. In conclusion, CSE expression and H(2)S production are reduced during the development of balloon injury-induced neointimal hyperplasia, and treatment with NaHS significantly reduces neointimal lesion formation.     

The effect of high-density-lipoprotein on thrombus formation on and endothelial cell attachement to biomaterial surfaces

Cardiovascular implants such as vascular grafts fail frequently because they lack genuine blood-compatibility. The blood-contacting surface should simultaneously prevent thrombus formation and promote formation of a confluent endothelial cell layer, to achieve sustained haemostasis. Contact activation and endothelialization are known to be determined by the plasma proteins which adsorb onto virtually all synthetic surfaces almost immediately upon contact with blood. A common approach in blood-compatibility research is, therefore, to use hydrophilic biomaterials, which are sometimes claimed to be "protein-repellent". We report here that, for synthetic polymeric surfaces, hydrophilicity is by no means synonymous to protein-repellency. We discovered that significant amounts of proteins, especially high-density lipoprotein, adsorb to hydrophilic surfaces. Pre-incubation of hydrophilic synthetic surfaces with high-density lipoprotein provides a blood-biomaterial interface, which inhibits thrombin generation and subsequent thrombus formation, and also accommodates overgrowth with a confluent endothelial layer. This approach may open the way to truly functional small-caliber arterial prostheses, and may also be relevant to cardiovascular tissue engineering in which de novo vascular tissues are cultured on or within a biomaterial scaffold.     

Limb immobilization and intimal hyperplasia - an echo-Doppler study in man

Summary The authors studied the circulatory alterations observed in the upper limbs of patients showing muscular atrophy due to flaccid paralysis of traumatic origin. Ten patients who had suffered avulsion of the nerve roots from C4 to D1 that occurred 9 to 216 months previously, presented a significant degree of muscular atrophy of the affected upper limb, despite physiotherapy. We performed echo-doppler examinations of the patients to measure the lumen of the subclavian, axillary, brachial, radial and ulnar arteries and also of the veins of both upper limbs. The measurements from both upper limbs in each patient were statistically compared. The data revealed a significant reduction of the width of the lumen of the arteries and veins and a reduced arterial blood flow in the affected limb in comparison with the normal one. The greater echogenicity and the abnormal Doppler waves of the affected vessels suggest that they presented an increased thickness and a hardened wall. The authors propose that this finding may be related to an intimal hyperplasia brought about by muscular atrophy or by the observed blood flow reduction.

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Immobilisation de membre et hyperplasie intimale -Etude écho-Doppler chez l'homme

Résumé Les auteurs ont étudiés les altérations circulatoires observées au niveau des membres supérieurs chez les patients présentant une atrophie musculaire due à une paralysie flasque d'origine traumatique. 10 patients ont subi un traumatisme des racines nerveuses de C4 à D1 entre 9 à 216 mois auparavant et présenté une atrophie musculaire significative au niveau du membre supérieur malgré la kinésithérapie. Nous avons réalisé des examens écho-Doppler chez ces patients pour mesurer la lumière des artères subclavière, axillaire, brachiale, radiale et ulnaire et des veines des deux membres supérieurs. Les mesures de l'ensemble des membres supérieurs de chaque patient ont été comparées statistiquement en utilisant le test de Wilcoxon. Cette analyse a montré une réduction significative du calibre de la lumière des artères et des veines ainsi qu'une réduction du débit artériel sanguin au niveau des membres atteints en comparaison au membre normal. La plus grande échogénicité et le flux anormal au Doppler des membres atteints suggèrent un épaississement et un durcissement de la paroi. Les auteurs expliquent ce fait par une hyperplasie intimale liée à l'atrophie musculaire ou à la réduction du flux sanguin.