良性中心气道狭窄支气管镜介入治疗术后近远期再狭窄相关因素分析

目的探讨良性中心气道狭窄支气管镜介入治疗术后近远期再狭窄相关因素。方法对2011年2月~2015年2月我院收治的60例良性中心气道狭窄患者经支气管镜下介入治疗,治疗方式包括高频电刀、冷冻、球囊扩张、金属覆膜支架置入等。治疗后对患者的治疗时机、局部感染情况、治疗方法、气道狭窄病因、年龄、性别、基础疾病等情况进行分析,随访观察评估术后疗效、出现再狭窄的时间,探讨近远期再狭窄的危险因素。结果 Cox回归分析表明,患有基础疾病(高血压、糖尿病)、球囊扩张、支架置入、治疗时机不当(溃疡坏死增值阶段)、局部感染是良性气管狭窄支气管镜下腔内介入治疗术后近期再狭窄的相关危险因素,其对再狭窄影响的风险比(OR值)依次为6.715、2.197、5.820、6.914、5.345。支架置入和治疗时机不当(溃疡坏死增值阶段)是良性气管狭窄支气管镜下腔内介入治疗术后远期再狭窄的相关危险因素,其对再狭窄影响的风险比(OR值)分别为6.706,7.154。结论良性中心气道狭窄患者支气管镜下腔内介入治疗术后近期再狭窄的危险因素是基础疾病、球囊扩张、支架置入、局部感染、治疗时机不当,远期再狭窄危险因素是支架置入和治疗时机不当。     

Stent‐mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight

This review concisely recapitulates the different existing modes of stent‐mediated gene/drug delivery, their considerable advancement in clinical trials and a rationale for other merging new technologies such as nanotechnology and microRNA‐based therapeutics, in addition to addressing the limitations in each of these perpetual stent platforms. Over the past decade, stent‐mediated gene/drug delivery has materialized as a hopeful alternative for cardiovascular disease and cancer in contrast to routine conventional treatment modalities. Regardless of the phenomenal recent developments achieved by coronary interventions and cancer therapies that employ gene and drug‐eluting stents, practical hurdles still remain a challenge. The present review highlights the limitations that each of the existing stent‐based gene/drug delivery system encompasses and therefore provides a vision for the future with respect to discovering an ideal stent therapeutic platform that would circumvent all the practical hurdles witnessed with the existing technology. Further study of the improvisation of next‐generation drug‐eluting stents has helped to overcome the issue of restenosis to some extent. However, current stent formulations fall short of the anticipated clinically meaningful outcomes and there is an explicit need for more randomized trials aiming to further evaluate stent platforms in favour of enhanced safety and clinical value. Gene‐eluting stents may hold promise in contributing new ideas for stent‐based prevention of in‐stent restenosis through genetic interventions by capitalizing on a wide variety of molecular targets. Therefore, the central consideration directs us toward finding an ideal stent therapeutic platform that would tackle all of the gaps in the existing technology.     

Celastrol ameliorates vascular neointimal hyperplasia through Wnt5a-involved autophagy

Neointimal hyperplasia caused by the excessive proliferation of vascular smooth muscle cells (VSMCs) is the pathological basis of restenosis. However, there are few effective strategies to prevent restenosis. Celastrol, a pentacyclic triterpene, has been recently documented to be beneficial to certain cardiovascular diseases. Based on its significant effect on autophagy, we proposed that celastrol could attenuate restenosis through enhancing autophagy of VSMCs. In the present study, we found that celastrol effectively inhibited the intimal hyperplasia and hyperproliferation of VSMCs by inducing autophagy. It was revealed that autophagy promoted by celastrol could induce the lysosomal degradation of c-MYC, which might be a possible mechanism contributing to the reduction of VSMCs proliferation. The Wnt5a/PKC/mTOR signaling pathway was found to be an underlying mechanism for celastrol to induce autophagy and inhibit the VSMCs proliferation. These observations indicate that celastrol may be a novel drug with a great potential to prevent restenosis.     

A fibronectin-fibrinogen-tropoelastin coating reduces smooth muscle cell growth but improves endothelial cell function

Reendothelialization of the stent surface after percutaneous coronary intervention (PCI) is known to be an important determinant of clinical outcome. We compared the effects of biological stent coatings, fibronectin, fibrinogen and tropoelastin, on human umbilical vein endothelial cell (HUVEC) and vascular smooth muscle cell (VSMC) characteristics. Umbilical cord arterial segments were cultured on coated surfaces and VSMC outgrowth (indicating proliferation and migration) was measured after 12 days. mRNA was isolated from HUVEC and VSMC cultured on these coatings and gene expression was profiled by QPCR. Procoagulant properties of HUVEC were determined by an indirect chromogenic assay which detects tissue factor activity. The varying stent coatings influence VSMC outgrowth: 31.2 ± 4.0 mm(2) on fibronectin, 1.6 ± 0.3 mm(2) on tropoelastin and 8.1 ± 1.5 mm(2) on a mixture of fibronectin/fibrinogen/tropoelastin, although HUVEC migration remains unaffected. Culturing HUVEC on tropoelastin induces increased expression of VCAM-1 (13.1 ± 4.4 pg/ml), ICAM-1 (5.1 ± 1.3 pg/ml) and IL-8 (11.6 ± 3.1 pg/ml) compared to fibronectin (0.7 ± 0.2, 0.8 ± 0.2, 2.3 ± 0.5 pg/ml, respectively), although expression levels on fibronectin/fibrinogen/tropoelastin remain unaltered. No significant differences in VCAM-1, ICAM-1 and IL-8 mRNA expression are found in VSMC. Finally, HUVEC cultured on tropoelastin display a fivefold increased tissue factor activity (511.6 ± 26.7%), compared to cells cultured on fibronectin (100 ± 3.9%) or fibronectin/fibrinogen/tropoelastin (76.3 ± 25.0%). These results indicate that tropoelastin inhibits VSMC migration but leads to increased inflammatory and procoagulant markers on endothelial cells. Fibronectin/fibrinogen/tropoelastin inhibits VSMCs while compensating the inflammatory and procoagulant effects. These data suggest that coating a mixture of fibronectin/fibrinogen/tropoelastin on a stent may promote reendothelialization, while keeping unfavourable processes such as restenosis and procoagulant activity limited.     

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。     

Human internal mammary artery (IMA) transplantation and stenting: a human model to study the development of in-stent restenosis

Preclinical in vivo research models to investigate pathobiological and pathophysiological processes in the development of intimal hyperplasia after vessel stenting are crucial for translational approaches (1,2). The commonly used animal models include mice, rats, rabbits, and pigs (3-5). However, the translation of these models into clinical settings remains difficult, since those biological processes are already studied in animal vessels but never performed before in human research models (6,7). In this video we demonstrate a new humanized model to overcome this translational gap. The shown procedure is reproducible, easy, and fast to perform and is suitable to study the development of intimal hyperplasia and the applicability of diverse stents. This video shows how to perform the stent technique in human vessels followed by transplantation into immunodeficient rats, and identifies the origin of proliferating cells as human.     

血清白细胞介素-18、氧化低密度脂蛋白与急性心肌梗死患者急诊PCI术后支架内再狭窄的关系

目的:探讨血清白细胞介素-18(IL-18)、氧化低密度脂蛋白(ox-LDL)与急诊经皮冠状动脉介入治疗(PCI)术后支架内再狭窄的关系。方法:75例急性心梗急诊介入术后8～12个月内接受冠状动脉造影复查,其中9例有再狭窄作为再狭窄组,66例无再狭窄作为对照组。2组术后均接受阿司匹林、氯吡格雷、他汀类等药物治疗。取2组患者PCI术前、术后冠状动脉造影复查时血清标本,采用酶联免疫吸附法(EL ISA)检测血清IL-18、ox-LDL水平。结果:①再狭窄组PCI术后IL-18、ox-LDL水平较术前均明显升高[(2.37±0.22):(0.85±0.19)mg/L、(6.99±0.98):(2.38±1.06)mg/L],均P<0.01;对照组PCI后IL-18、ox-LDL水平较术前明显下降[(0.48±0.11):(1.23±0.09)mg/L、(1.39±0.54):(4.45±0.87)mg/L],P<0.05。②再狭窄组和对照组PCI术前IL-18、ox-LDL水平差异无统计学意义,再狭窄组PCI术后IL-18、ox-LDL水平显著高于对照组(均P<0.01)。④再狭窄组和对照组术前、术后IL-18和o...     

Numerical Simulation of Physiological Blood Flow in 2-way Coronary Artery Bypass Grafts

The Coronary Artery Bypass Graft (CABG) yields excellent results and remains the modern standard of care for treatment of occlusive disease in the cardiovascular system. However, the development of anastomotic Intimal Hyperplasia (IH) and restenosis can compromise the medium-and-long term effects of the CABG. This problem can be correlated with the geometric configuration and hemodynamics of the bypass graft. A novel geometric configuration was proposed for the CABG with two symmetrically implanted grafts for the purpose of improving the hemodynamics. Physiological blood flows in two models of bypass grafts were simulated using numerical methods. One model was for the conventional bypass configuration with a single graft (1-way model); the other model was for the proposed bypass configuration with two grafts (2-way model). The temporal and spatial distributions of hemodynamics, such as flow patterns and Wall Shear Stress (WSS) in the vicinity of the distal anastomoses, were analyzed and compared. Calculation results showed that the 2-way model possessed favorable hemodynamics with uniform longitudinal flow patterns and WSS distributions, which could decrease the probability of restenosis and improve the effect of the surgical treatment. Concerning the limitations of the 2-way bypass grafts, it is necessary to perform animal experiments to verify the viability of this novel idea for the CABG.     

Upregulation of connexin43 gap junctions between neointimal smooth muscle cells

Increased expression of connexin43 gap junctions in smooth muscle cells (SMC) is implicated in the response to primary arterial injury and in the early stages of human coronary atherosclerosis, but the relevance of these findings to restenosis is unknown. Here we investigated the expression of connexin43 gap junctions in restenotic aortas of cholesterol-fed double injured rabbits. Immunofluorescence confocal microscopy was used to evaluate temporal and spatial expression patterns and to characterize the major expressing cell type. Parallel studies were conducted by electron microscopy, in situ hybridization and Northern blot analysis. Connexin43 gap junctions- and connexin43 mRNA-expressing cells were abundant in the media of non-injured control aorta. Following primary injury and 6 weeks cholesterol diet, connexin43 gap junctions were found distributed throughout the primary intimal layer; although medial expression was reduced, the overall mRNA expression level remained similar to that of non-injured controls. After secondary injury, no major change in distribution pattern of connexin43 gap junctions occurred up to day 10, when marked neointimal labeling was observed. This overall pattern persisted, though with some diminution, at later stages. On the mRNA level total connexin43 mRNA expression declined to about 40% of control values within 4 days after secondary injury (P < 0.05), but subsequently increased four-fold, attaining levels double that of non-injured controls in the 10-day group (P < 0.005 versus control and 4 days). At later stages mRNA expression levels returned to values similar to those of non-injured controls. At all stages, connexin43 gap junctions were localized to the SMC, not to macrophages. We conclude that the enhanced gap junction formation may contribute to the coordination of the response of SMC after secondary injury, particularly in the early phase of restenosis.