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.     

Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation following arterial injury plays a critical role in a variety of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. In this study, we tested the hypothesis that localized arterial infection at the time of balloon angioplasty with an adenovirus (ADV-tk) encoding the herpes simplex virus thymidine kinase gene (HSV-tk), followed by systemic ganciclovir administration, can inhibit VSMC proliferation and neointima formation in a well-characterized model of arterial injury and restenosis. MATERIALS AND METHODS: The left carotid arteries of 31 male Sprague-Dawley rats were subjected to balloon angioplasty and immediately infected with 2 x 10(9) pfu of either ADV-tk or a control adenovirus that does not encode a recombinant protein (ADV-delta E1). Twenty-four hours after injury, animals from each experimental group were randomized to receive a course of systemic ganciclovir (ADV-tk/+GC, ADV delta E1/+GC) or saline (ADV-tk/-GC, ADV-delta E1/-GC). VSMC DNA synthesis was measured by 5'-bromodeoxuridine (BrdU) incorporation 2-4 days after balloon injury. The extent of restenosis, expressed as the neointima to media (I/M) area ratio was determined by digital planimetry 20 days after balloon injury in each of the four treatment groups. Immunohistochemistry using a mAb to von Willebrand factor (vWF) was used to determine the effects of ADV-tk infection and ganciclovir treatment on re-endothelialization of the carotid arteries 20 days following balloon angioplasty. RESULTS: Forty-one percent of the medial VSMCs in the ADV-tk/-GC arteries were labeled with BrdU 4 days after balloon injury. In contrast, ADV-tk infected animals that were treated with systemic ganciclovir (ADV-tk/+GC) displayed a 40% reduction in BrdU-staining medial VSMCs (p < 0.03). I/M area ratios of the three control groups were 1.17 +/- 0.18 (ADV-tk/-GC, n = 5), 1.15 +/- 0.10 (ADV-delta E1/+GC, n = 6), and 0.91 +/- 0.08 (ADV-delta E1/-GC, n = 6). These differences were not statistically significant (p > 0.05). In contrast, the ADV-tk/+GC animals (n = 6) displayed an I/M area ratio of 0.49 +/- 0.13 which was significantly lower than that seen in each of the three control groups (p < 0.02). None of the treated animals showed evidence of significant organ toxicity at autopsy. A regenerated endothelium was observed in the ADV-tk/+GC animals 20 days after balloon injury. CONCLUSIONS: Localized arterial infection with ADV-tk at the time of balloon angioplasty followed by systemic ganciclovir therapy reduces VSMC proliferation and neointimal expansion in the rat carotid artery injury model. Moreover, combined treatment with ADV-tk and systemic ganciclovir does not result in systemic toxicity and appears to selectively eliminate proliferating VSMCs, while preserving the capacity of the injured arterial segments to re-endothelialize within 3 weeks of injury. Taken together, these results support the feasibility of using this gene therapy approach for the treatment of human vascular proliferative disorders.     

Aging exacerbates negative remodeling and impairs endothelial regeneration after balloon injury

Many older patients, because of their high prevalence of coronary artery disease, are candidates for percutaneous coronary interventions (PCI), but the effects of vascular aging on restenosis after PCI are not yet well understood. Balloon injury to the right carotid artery was performed in adult and old rats. Vascular smooth muscle cell (VSMC) proliferation, apoptotic cell death, together with Akt induction, telomerase activity, p27kip1, and endothelial nitric oxide synthase (eNOS) expression was assessed in isolated arteries. Neointima hyperplasia and vascular remodeling along with endothelial cell regeneration were also measured after balloon injury. Arteries isolated from old rats exhibited a significant reduction of VSMC proliferation and an increase in apoptotic death after balloon injury when compared with adult rats. In the vascular wall of adult rats, balloon dilation induced Akt phosphorylation, and this was barely present in old rats. In arteries from old rats, Akt-modulated cell cycle check points like telomerase activity and p27kip1 expression were decreased and increased, respectively, compared with adults. After balloon injury, old rats showed a significant reduction of neointima formation and an increased vascular negative remodeling compared with adults. These results were coupled by a marked delay in endothelial regeneration in aged rats, partially mediated by a decreased eNOS expression and phosphorylation. Interestingly, chronic administration of L-arginine prevented negative remodeling and improved reendothelialization after balloon injury in aged animals. A decreased neointimal proliferation, an impaired endothelial regeneration, and an increase in vascular remodeling after balloon injury were observed in aged animals. The molecular mechanisms underlying these responses seem to be a reduced Akt and eNOS activity.     

The kinase inhibitor fasudil (HA-1077) reduces intimal hyperplasia through inhibiting migration and enhancing cell loss of vascular smooth muscle cells.

Smooth muscle cell (SMC) migration plays an important role in restenosis after angioplasty. Myosin phosphorylation is necessary for cell migration. Fasudil is an inhibitor of protein kinases, including myosin light chain kinase and Rho associated kinase, thereby inhibiting myosin phosphorylation, and it has been clinically used to prevent vasospasm following subarachnoid hemorrage. Based on these findings, we examined the anti-migrative action of fasudil. In SMC (SM-3), fasudil (1-100 microM) inhibited SMC migration in a dose-dependent manner (p < 0.001). Fasudil suppressed actin stress fiber formation dose dependently. In rabbit carotid artery, fasudil (10 mg/kg/day) markedly reduced intimal hyperplasia 14 days following balloon injury. Cell kinetic study showed that fasudil did not affect proliferation but enhanced cell loss in the media after injury. We concluded that fasudil reduced neointimal formation after balloon injury through both inhibiting migration and enhancing cell loss of medial SMC.     

Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP

Phosphatidylinositol 3-kinase (PI3K) is required for smooth muscle cell (SMC) proliferation. This study reports that inhibitors of PI3K also prevent SMC migration and block neointimal hyperplasia in an organ culture model of restenosis. Inhibition of neointimal formation by LY-294002 was concentration and time dependent, with 10 muM yielding the maximal effect. Continuous exposure for at least the first 4-7 days of culture was essential for significant inhibition. To assess the role of matrix metalloproteinases (MMPs) in this process, we monitored MMP secretion by injured vessels in culture. Treatment with LY-294002 selectively reduced active MMP-2 in media samples according to zymography and Western blot analysis without concomitant changes in latent MMP-2. Parallel results with wortmannin indicate that MMP-2 activation is PI3K dependent. Previous research has shown a role for both furin and membrane-type 1 (MT1)-MMP (MMP-14) in the activation of MMP-2. The furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone did not prevent MMP-2 activation after balloon angioplasty. In contrast, balloon angioplasty induced a significant increase in the levels of MT1-MMP, which was suppressed by LY-294002. No change in MT1-MMP mRNA was observed with LY-294002, because equivalent amounts of this mRNA were present in both injured and noninjured vessels. These results implicate PI3K-dependent regulation of MT1-MMP protein synthesis and subsequent activation of latent MMP-2 as critical events in neointimal hyperplasia after vascular injury.     

Alterations in regional vascular geometry produced by theoretical stent implantation influence distributions of wall shear stress: analysis of a curved coronary artery using 3D computational fluid dynamics modeling

Background  

The success of stent implantation in the restoration of blood flow through areas of vascular narrowing is limited by restenosis. Several recent studies have suggested that the local geometric environment created by a deployed stent may influence regional blood flow characteristics and alter distributions of wall shear stress (WSS) after implantation, thereby rendering specific areas of the vessel wall more susceptible to neointimal hyperplasia and restenosis. Stents are most frequently implanted in curved vessels such as the coronary arteries, but most computational studies examining blood flow patterns through stented vessels conducted to date use linear, cylindrical geometric models. It appears highly probable that restenosis occurring after stent implantation in curved arteries also occurs as a consequence of changes in fluid dynamics that are established immediately after stent implantation.     

Fabrication of drug-eluting covered stents with micropores and differential coating of heparin and FK506

To reduce in-stent restenosis rates, we developed a novel drug-eluting covered stent with a microporous elastometric covered film, in which its luminal surface was flat and immobilized with heparin for anticoagulation and its outer surface immobilized with FK506 to prevent neointimal hyperplasia. One month after implantation into the bilateral common carotid arteries, all stented arteries were patent and the luminal surfaces were fully covered with a confluent of endothelial cells irrespective of the drug immobilization. In the control group, which consisted of covered stents without drug immobilization, intensive inflammatory cells adjacent to the stents and neointimal hyperplasia, indicating vascular injury, were observed. In contrast, in the developed drug-eluting stents, only a few inflammatory cells around the stent strut and covered film were observed, and there was no significant neointimal thickening.     

Provisional stenting in small vessels

Based on the currently available data, the strategy of routine stent placement in unselected lesions located in small coronary arteries provides good immediate results but is still associated with a high incidence of in-stent restenosis. Randomized trials comparing elective stenting with balloon angioplasty have not provided the demonstration that routine stenting is the best strategy for percutaneous intervention in coronary arteries with a reference diameter smaller than 2.75-3.0 mm. This paper describes the rationale for provisional stenting in this clinical setting and reviews the role of quantitative coronary angiography, intracoronary ultrasound and intracoronary Doppler measurements in the identification of lesions that would benefit from adjunctive stent placement after balloon angioplasty and in guiding stent implantation.     

Expression and function of periostin-like factor in vascular smooth muscle cells

In injured blood vessels activated vascular smooth muscle cells (VSMCs) migrate from the media to the intima, proliferate and synthesize matrix proteins. This results in occlusion of the lumen and detrimental clinical manifestations. We have identified a novel isoform of the periostin family of proteins referred to as periostin-like factor (PLF). PLF expression in VSMCs was increased following treatment with mitogenic compounds, suggesting that PLF plays a role in VSMC activation. Correspondingly, proliferation of the cells was significantly reduced with anti-PLF antibody treatment. PLF expression increased VSMC migration, an essential cellular process leading to vascular restenosis after injury. PLF protein was localized to neointimal VSMC of rat and swine balloon angioplasty injured arteries, as well as in human arteries with transplant restenosis, supporting the hypothesis that PLF is involved in VSMC activation and vascular proliferative diseases. Taken together, these data suggest a role for PLF in the regulation of vascular proliferative disease. migration; proliferation     

Proliferation of neointimal smooth muscle cells after arterial injury. Dependence on interactions between fibroblast growth factor receptor-2 and fibroblast growth factor-9

The growth factor signaling mechanisms responsible for neointimal smooth muscle cell (SMC) proliferation and accumulation, a characteristic feature of many vascular pathologies that can lead to restenosis after angioplasty, remain to be identified. Here, we examined the contribution of fibroblast growth factor receptors (FGFRs) 2 and 3 as well as novel fibroblast growth factors (FGFs) to such proliferation. Balloon catheter injury to the rat carotid artery stimulated the expression of two distinctly spliced FGFR-2 isoforms, differing only by the presence or absence of the acidic box, and two distinctly spliced FGFR-3 isoforms containing the acidic box and differing only by the presence of either the IIIb or IIIc exon. Post-injury arterial administration of recombinant adenoviruses expressing dominant negative mutant forms of these FGFRs were used to assess the roles of the endogenous FGFR isoforms in neointimal SMC proliferation. Dominant negative FGFR-2 containing the acidic box inhibited such proliferation by 40%, whereas the dominant negative FGFR-3 forms had little effect. Expression of FGF-9, known to be capable of binding to all four neointimal FGFR-2/-3 isoforms, was abundant within the neointima. FGF-9 markedly stimulated both the proliferation of neointimal SMCs and the activation of extracellular signal-related kinases 1/2, effects which were abrogated by the administration of antisense FGF-9 oligonucleotides to injured arteries and the expression of the dominant negative FGFR-2 adenovirus in cultured neointimal SMCs. These studies demonstrate that, although multiple FGFRs are induced in neointimal SMCs following arterial injury, specific interactions between distinctly spliced FGFR-2 isoforms and FGF-9 contribute to the proliferation of these SMCs.     

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.     

2-Cyclopenten-1-one and prostaglandin J2 reduce restenosis after balloon angioplasty in rats: role of NF-kappaB

The aim of this study was to evaluate, using a rat model of balloon angioplasty, whether prostaglandin (PG) J(2) and 2-cyclopenten-1-one are able to reduce restenosis. We found that both PGJ(2) and 2-cyclopenten-1-one, administered by local application on carotid arteries, caused a dose-dependent inhibition of neointimal formation. Furthermore, both agents prevented vascular negative remodeling. The effect of these compounds on restenosis was correlated with an inhibition of nuclear factor-kappaB (NF-kappaB) activation as well as of intercellular adhesion molecule-1 (ICAM-1) protein expression in injured carotid arteries of control animals. Our results show that cyclopentenone PGs and their derivatives reduce restenosis and may have therapeutic relevance for the prevention of human restenosis.     

Intravascular brachytherapy to prevent restenosis: dosimetric considerations.

Acute myocardial infarction is often the result of occlusion of one or more coronary arteries. Occlusion and restenosis (re-closing of the vessel) are principal reasons that percutaneous transluminal coronary angioplasty (PTCA) may fail to provide long-term benefit. PTCA has been a popular treatment, which is less invasive than surgeries involving revascularization of the myocardium, promising a better quality of life for patients. Unfortunately, the rate of restenosis after balloon angioplasty is high (approximately 30-50% in the first year after treatment). Recent data suggest that intraluminal irradiation of coronary arteries in conjunction with balloon angioplasty and/or stent implantation reduces the proliferation of smooth muscle cells and neointima formation, thereby inhibiting restenosis. In order to study radiation dosimetry in the patient and for this therapy, dose distributions for electrons and photons, with discrete energies, were simulated for blood vessels of diameter 1.5, 3 and 4.5 mm irradiated with balloon and wire sources. Electron and photon transport was performed in a simple model representing the system used for irradiation using the MCNP 4B code (Monte Carlo N-Particles). Specific calculations for balloon and wire sources were also carried out for a few radionuclides. In this work, strengths and drawbacks conceming the use of each radionuclide simulated, as well as source geometries are discussed. The dosimetry performed in this study will improve understanding of the benefit-to-risk ratio in intracoronary brachytherapy.     

Anti-angiogenesis: A new potential strategy to inhibit restenosis

Microvessels are an integral component of the neointima developing in response to the acute vascular injury resulting from angioplasty. These vessels originate from the vasa vasorum of the adventitia, and as such appear similar to the microvessels present in atherosclerotic plaques. Several angiogenic factors have been found in atherosclerotic plaques and have been associated with increased microvascularity. In addition, most of these agents - either directly or indirectly - also induce smooth muscle cell (SMC) proliferation, an essential component of the developing neointima. We therefore propose: (1) these newly formed blood vessels are necessary for the development, maintenance, and expansion of the neointimal lesions present in restenosis; (2) the initiation, regulation and maintenance of these vessels is, at least in part, due to the coordinate sequential expression of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and/or other angiogenic factors such as the fibroblast growth factor (FGF) family of proteins; (3) targeted disruption of the signal transduction pathways modulated by these molecules may reduce vasa vasorum expansion and SMC proliferation. These effects, in turn, may inhibit neointimal expansion and thus the development of restenosis, especially following stenting.     

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。     

Coronary Injury Score Correlates with Proliferating Cells and Alpha-Smooth Muscle Actin Expression in Stented Porcine Coronary Arteries

Neointimal formation and cell proliferation resulting into in-stent restenosis is a major pathophysiological event following the deployment of stents in the coronary arteries. In this study, we assessed the degree of injury, based on damage to internal elastic lamina, media, external elastic lamina, and adventitia following the intravascular stenting, and its relationship with the degree of smooth muscle cell proliferation. We examined the smooth muscle cell proliferation and their phenotype at different levels of stent injury in the coronary arteries of domestic swine fed a normal swine diet. Five weeks after stent implantation, swine with and without stents were euthanized and coronaries were excised. Arteries were embedded in methyl methacrylate and sections were stained with H&E, trichrome, and Movat’s pentachrome. The expression of Ki67, α-smooth muscle actin (SMA), vimentin, and HMGB1 was evaluated by immunofluorescence. There was a positive correlation between percent area stenosis and injury score. The distribution of SMA and vimentin was correlated with the degree of arterial injury such that arteries that had an injury score >2 did not have immunoreactivity to SMA in the neointimal cells near the stent struts, but these neointimal cells were positive for vimentin, suggesting a change in the smooth muscle cell phenotype. The Ki67 and HMGB1 immunoreactivity was highly correlated with the fragmentation of the IEL and injury in the tunica media. Thus, the extent of coronary arterial injury during interventional procedure will dictate the degree of neointimal hyperplasia, in-stent restenosis, and smooth muscle cell phenotype.