Xinrui Yang

Systematic review and meta-analysis of balloon angioplasty versus primary stenting in the infrapopliteal disease.

Objectives: We performed a systematic review and meta-analysis of comparing balloon angioplasty and primary stenting for symptomatic infrapopliteal disease to evaluate the clinical value of primary stenting in treating infrapopliteal diseases. Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. PubMed (1984-present), ScienceDirect (1980-present), Embase (1990-present), and CBM (1988-present) databases were searched for relevant articles. Finally, 16 studies (published between 2001 and 2013) satisfying the inclusion criteria were identified. The outcome parameters were immediate technical success, 1-year primary patency rate, 1-year limb salvage rate, and 1-year target vessel revascularization (TVR)-free rate. Comparisons were made with balloon angioplasty and primary stenting, and based on the different types of stents, we divided the primary stent group into the bare metal stent (BMS) group and drug-eluting stent (DES) group. Results: A total of 3789 patients and 4339 limbs constituted our final study population. The technical success rate of balloon angioplasty was 92.29% (95% confidence interval [CI] 88.75%-94.78%). Only 2 study reported the technical failure rates as 4% and 5.2% in the primary stent group. The pooled estimates of 1-year primary patency and TVR-free rate were similarly low in the balloon angioplasty group and BMS group (primary patency: 57.65%, 95% CI 53.54%-61.67% vs 60.95%, 95% CI 48.31%-72.28%, P = .38; TVR-free rate: 73.41%, 95% CI 66.51%-80.08% vs 73.66%, 95% CI 63.58%-81.75%, P = .91). The pooled estimates of 1-year primary patency and TVR-free rate in DES group were 81.10% (95% CI 75.48%-85.67%) and 90.30% (95% CI 85.30%-93.73%), respectively, which were better than those of the BMS and balloon angioplasty groups (P < .001 for both). The pooled estimate of 1-year limb salvage in the balloon angioplasty, BMS, and DES groups was 88.61% (95% CI 85.01%-91.43%), 94.41% (95% CI 89.52%-97.1%), and 95.20% (95% CI 86.97%-98.33%), respectively (P < .001). The BMS and DES groups had higher limb salvage rates than the balloon angioplasty group (P < .001 for both comparisons). The rates of severe complications were low both in the balloon angioplasty and in the primary stent groups. Conclusion: Primary BMS implantation had no advantage over balloon angioplasty in reducing restenosis or revascularization for infrapopliteal disease. Primary DES implantation seems to be a promising treatment for focal infrapopliteal lesions. Publication bias could not be ruled out, and the results should be treated with caution.

Technical details and clinical outcomes of transpopliteal venous stent placement for postthrombotic chronic total occlusion of the iliofemoral vein.

PURPOSE To evaluate the technical aspects and early clinical results of stent placement for managing postthrombotic chronic total occlusion (CTO) of the iliofemoral vein through ipsilateral popliteal access. MATERIALS AND METHODS A retrospective analysis of 110 patients (44 men; mean age, 51 y; 118 limbs; 102 left limbs) with postthrombotic CTO of the iliofemoral vein treated with stent placement in a single institution from January 2007-December 2011 was conducted. All occlusions were initially accessed via ipsilateral popliteal veins under the guidance of venography or ultrasonography. Technical aspects, quality of life, stent patency, and Villalta scores were recorded at follow-up evaluation. Risk factors of in-stent restenosis and early in-stent thrombosis were evaluated using Cox proportional hazards regression model. RESULTS Percutaneous recanalization was successful in 112 of 118 limbs (95%). The mean duration of the procedure was 43 minutes (range, 10-120 min). The quality of life and Villalta scores were significantly improved (P < .01). The 3-year primary, assisted primary, and secondary cumulative stent patency rates were 70%, 90%, and 94%. During a median follow-up period of 25 months (range, 1-52 mo), the relief rates of severe leg pain (visual analog scale > 5) and severe leg swelling (grade 3) were 72% (49 of 68) and 70% (64 of 91), respectively, and the healing of ulcers was successful in 78% (36 of 46) of the cases. After stent placement, the limbs with visible remaining collateral circulation had a higher rate of early in-stent thrombosis (22.5% vs 6.1%; P = .007). The patients with long stents extending below the inguinal ligament had a higher rate of in-stent restenosis (hazard ratio = 1.77-6.5; P = .0146). CONCLUSIONS Transpopliteal venous stent placement is an effective, safe, and feasible method of managing postthrombotic CTO of the iliofemoral vein. The stent extending below the inguinal ligament is the major risk factor of in-stent restenosis. The visible remaining collateral circulation after stent placement may indicate persistent hemodynamically significant stenosis.

Noninvasive detection of macrophages in atherosclerotic lesions by computed tomography enhanced with PEGylated gold nanoparticles

Macrophages are becoming increasingly significant in the progression of atherosclerosis (AS). Molecular imaging of macrophages may improve the detection and characterization of AS. In this study, dendrimer-entrapped gold nanoparticles (Au DENPs) with polyethylene glycol (PEG) and fluorescein isothiocyanate (FI) coatings were designed, tested, and applied as contrast agents for the enhanced computed tomography (CT) imaging of macrophages in atherosclerotic lesions. Cell counting kit-8 assay, fluorescence microscopy, silver staining, and transmission electron microscopy revealed that the FI-functionalized Au DENPs are noncytotoxic at high concentrations (3.0 μM) and can be efficiently taken up by murine macrophages in vitro. These nanoparticles were administered to apolipoprotein E knockout mice as AS models, which demonstrated that the macrophage burden in atherosclerotic areas can be tracked noninvasively and dynamically three-dimensionally in live animals using micro-CT. Our findings suggest that the designed PEGylated gold nanoparticles are promising biocompatible nanoprobes for the CT imaging of macrophages in atherosclerotic lesions and will provide new insights into the pathophysiology of AS and other concerned inflammatory diseases.

MRI of iron oxide nanoparticle-labeled ADSCs in a model of hindlimb ischemia.

Adipose-derived stem cells (ADSCs) exhibit tremendous potential for repair of ischemic diseases. However, studies on the fate, migration, differentiation, and body distribution of the labeled ADSCs are rarely reported. In this study, magnetic iron oxide nanoparticles were designed, synthesized, and coated with meso-2,3-dimercaptosuccinic acid (DMSA) to produce DMSA nanoparticles (DMSA-NPs). The properties, size distribution, and characterization of DMSA-NPs were evaluated. Green fluorescent protein expressing ADSCs (GFP-ADSCs) were obtained and labeled with DMSA-NPs. The viability, cytotoxicity and multi-differentiation capacity of labeled GFP-ADSCs were evaluated in vitro. Labeled and non-labeled GFP-ADSCs were injected into a mouse model of hindlimb ischemia, and 3T magnetic resonance imaging (MRI) was acquired. The synthesized DMSA-NPs efficiently labeled the GFP-ADSCs in vitro and in vivo without affecting cell viability, proliferation, cell cycle, and multi-differentiation capacity. The MRI showed hypointense spots in the labeled GFP-ADSCs that lasted up to 8 weeks. Prussian blue staining and immunofluorescence assay at 4 and 8 weeks indicated that the labeled GFP-ADSCs were in and around the ischemic sites and some differentiated into capillaries. This observation is identical to that seen for transplants of unlabeled cells. Labeled cells were also identified mainly in the liver and spleen, with significantly smaller amounts in the lungs, intestines, heart, and kidney. Developed DMSA-NPs were shown to exhibit a considerable potential for use as nanoprobes for MRI of stem cells, which will enhance our understanding of cell-based therapeutic strategies for ischemic diseases.

In vivo MRI tracking of iron oxide nanoparticle-labeled human mesenchymal stem cells in limb ischemia.

Background Stem cell transplantation has been investigated for repairing damaged tissues in various injury models. Monitoring the safety and fate of transplanted cells using noninvasive methods is important to advance this technique into clinical applications. Methods In this study, lower-limb ischemia models were generated in nude mice by femoral artery ligation. As negative-contrast agents, positively charged magnetic iron oxide nanoparticles (aminopropyltriethoxysilane-coated Fe2O3) were investigated in terms of in vitro labeling efficiency, effects on human mesenchymal stromal cell (hMSC) proliferation, and in vivo magnetic resonance imaging (MRI) visualization. Ultimately, the mice were sacrificed for histological analysis three weeks after transplantation. Results With efficient labeling, aminopropyltriethoxysilane-modified magnetic iron oxide nanoparticles (APTS-MNPs) did not significantly affect hMSC proliferation. In vivo, APTS-MNP-labeled hMSCs could be monitored by clinical 3 Tesla MRI for at least three weeks. Histological examination detected numerous migrated Prussian blue-positive cells, which was consistent with the magnetic resonance images. Some migrated Prussian blue-positive cells were positive for mature endothelial cell markers of von Willebrand factor and anti-human proliferating cell nuclear antigen. In the test groups, Prussian blue-positive nanoparticles, which could not be found in other organs, were detected in the spleen. Conclusion APTS-MNPs could efficiently label hMSCs, and clinical 3 Tesla MRI could monitor the labeled stem cells in vivo, which may provide a new approach for the in vivo monitoring of implanted cells.

Periostin enhances adipose-derived stem cell adhesion, migration, and therapeutic efficiency in Apo E deficient mice with hind limb ischemia.

IntroductionTherapeutic angiogenesis by transplantation of autologous/allogeneic adipose-derived stem cells (ADSCs) is a potential approach for severe ischemic diseases. However, poor viability, adhesion, migration and differentiation limit the therapeutic efficiency after the cells were transplanted into the targeted area. Periostin, an extracellular matrix protein, exhibits a critical role in wound repair as well as promotes cell adhesion, survival, and angiogenesis.MethodADSCs were obtained and genetically engineered with periostin gene (P-ADSCs). The viability, proliferation, migration, and apoptosis of P-ADSCs under hypoxia were analyzed. Moreover, P-ADSCs were implanted into Apo E deficient mice with hind limb ischemia. The Laser Doppler perfusion index, immunofluorescence, and histological pathology assay were tested to evaluate the therapeutic effects. The associated molecular mechanism of periostin on the proliferation, adhesion, migration, and differentiation of ADSCs was also analyzed.ResultsThe in vitro studies have shown that periostin-transfected ADSCs (P-ADSCs) promoted viability, proliferation, and migration of ADSCs. Apoptosis of ADSCs was inhibited under hypoxic conditions. The Laser Doppler perfusion index was significantly higher in the P-ADSCs group compared with that in the ADSC and control groups after 4 weeks. Immunofluorescence and histological pathology assay showed that the P-ADSCs were in and around the ischemic sites, and some cells differentiated into capillaries and endothelium. Microvessel densities were significantly improved in P-ADSCs group compared with those in the control group. The molecular mechanisms that provide the beneficial effects of periostin were connected with the upregulated expression of integrinβ1/FAK/PI3K/Akt/eNOS signal pathway and the increased secretion of growth factors.ConclusionOverexpression of periostin by gene transfection on ADSCs promotes survival, migration, and therapeutic efficiency, which will bring new insights into the treatment of critical limb ischemia.

Glyoxalase-1 Overexpression Reverses Defective Proangiogenic Function of Diabetic Adipose-Derived Stem Cells in Streptozotocin-Induced Diabetic Mice Model of Critical Limb Ischemia

Adipose‐derived stem cell (ADSC)‐based therapy is promising for critical limb ischemia (CLI) treatment, especially in patients with diabetes. However, the therapeutic effects of diabetic ADSCs (D‐ADSCs) are impaired by the diabetes, possibly through intracellular reactive oxygen species (ROS) accumulation. The objective of the present study was to detect whether overexpression of methylglyoxal‐metabolizing enzyme glyoxalase‐1 (GLO1), which reduces ROS in D‐ADSCs, can restore their proangiogenic function in a streptozotocin‐induced diabetic mice model of CLI. GLO1 overexpression in D‐ADSCs (G‐D‐ADSCs) was achieved using the lentivirus method. G‐D‐ADSCs showed a significant decrease in intracellular ROS accumulation, increase in cell viability, and resistance to apoptosis under high‐glucose conditions compared with D‐ADSCs. G‐D‐ADSCs also performed better in terms of migration, differentiation, and proangiogenic capacity than D‐ADSCs in a high‐glucose environment. Notably, these properties were restored to the same level as that of nondiabetic ADSCs under high‐glucose conditions. G‐D‐ADSC transplantation induced improved reperfusion and an increased limb salvage rate compared D‐ADSCs in a diabetic mice model of CLI. Histological analysis revealed higher microvessel densities and more G‐D‐ADSC‐incorporated microvessels in the G‐D‐ADSC group than in the D‐ADSC group, which was comparable to the nondiabetic ADSC group. Higher expression of vascular endothelial growth factor A and stromal cell‐derived factor‐1α and lower expression of hypoxia‐induced factor‐1α were also detected in the ischemic muscles from the G‐D‐ADSC group than that of the D‐ADSC group. The results of the present study have demonstrated that protection from ROS accumulation by GLO1 overexpression is effective in reversing the impaired biological function of D‐ADSCs in promoting neovascularization of diabetic CLI mice model and warrants the future clinical application of D‐ADSC‐based therapy in diabetic patients. Stem Cells Translational Medicine 2017;6:261–271

In Situ Laser Fenestration Is a Feasible Method for Revascularization of Aortic Arch During Thoracic Endovascular Aortic Repair

Background Reconstruction of the aortic major branches during thoracic endovascular aortic repair is complicated because of the complex anatomic configuration and variation of the aortic arch. In situ laser fenestration has shown great potential for the revascularization of aortic branches. This study aims to evaluate the feasibility, effectiveness, and safety of in situ laser fenestration on the three branches of the aortic arch during thoracic endovascular aortic repair. Methods and Results Before clinical application, the polytetrafluoroethylene and Dacron grafts were fenestrated by an 810‐nm laser system ex vivo, which did not damage the bare metal portion of the endografts and created a clean fenestration while maintaining the integrity of the endografts. In vivo, 6 anesthetized female swine survived after this operation, including stent‐graft implantation in the aortic arches, laser fenestration, and conduit implantation through the innominate arteries and the left carotid arteries. Based on the animal experiments, in situ laser fenestration during thoracic endovascular aortic repair was successively performed on 24 patients (aged 33–86 years) with aortic artery diseases (dissection type A: n=4, type B: n=7, aneurysm: n=2, mural thrombus: n=7). Fenestration of 3 aortic branches was performed in 2 (8.3%) patients. Both the left carotid artery and the left subclavian artery were fenestrated in 6 (25%) patients. Only left subclavian artery fenestration surgery was done in 16 (66.7%) patients. Among these patients, 1 fenestration was abandoned secondary to an acute takeoff of the innominate artery in a type III aortic arch. The average operative time was 137±15 minutes. The technical success rate was 95.8% (n=23). No fenestration‐related complications or neurological morbidity occurred after this operation. During a mean postoperative 10‐month follow‐up (range: 2–17 months), 1 patient died of severe pneumonia, and all the left subclavian artery and carotid artery stents were patent with no fenestration‐related endoleaks upon computed tomography angiography images. Conclusions In situ laser fenestration is a feasible, effective, rapid, repeatable, and safe option for the reconstruction of aortic arch during thoracic endovascular aortic repair, which might be available to revascularize the 3 branches. However, follow‐up periods should be extended to evaluate the robustness of this technique.

Endovascular treatment for symptomatic stent failures in long-segment chronic total occlusion of femoropopliteal arteries

OBJECTIVE The objective of this study was to evaluate the outcomes of the secondary endovascular treatment (SEVT) for symptomatic recurrences in long-segment chronic total occlusion (CTO) of femoropopliteal arteries (FPAs) and to investigate the factors affecting the outcomes. METHODS Data of patients undergoing FPA stent implantation for primary, long-segment (>10 cm) CTO lesions and receiving endovascular intervention for symptomatic recurrences more than once in our institution from July 1, 2008, to September 1, 2012, were reviewed. Follow-up results referring to SEVT procedures were analyzed, including primary patency, limb salvage (LS) rate, technical success rate, and prevalence of procedure-related complications. Primary patency and LS were analyzed with Kaplan-Meier curves. Univariate and multivariable analyses were performed to identify factors associated with recurrent restenosis with a Cox proportional hazards model. RESULTS Ninety-one patients (mean age, 75.1 years) were included. The indications for SEVT were claudication (38.5%) and critical limb ischemia (61.5%). Preprocedural ankle-brachial index was 0.37 ± 0.16. The median time between initial endovascular treatment and SEVT was 6.5 months (range, 1.0-24.4 months). The arteries in 63 limbs were totally occluded. Fractures were found in 30 (18.8%) of the initially placed stents. Successful recanalization was achieved in 82 limbs (90.1%). The mean postprocedural ankle-brachial index was 0.84 ± 0.15 in those limbs that were successfully recanalized. The complication rate was 9.9%. One patient died of cerebral hemorrhage during catheter-directed thrombolysis. Other complications included the development of a groin hematoma (n = 5), distal embolization (n = 1), formation of a femoral pseudoaneurysm (n = 1), and development of acute heart failure (n = 1). The mean follow-up period was 11.0 ± 5.6 months. The cumulative primary patency rate after SEVT was 66.9% and 52.0% at 12 and 24 months. The LS rate since SEVT was 91.2% and 81.1% at 12 and 24 months. The multivariate analysis showed that stent fracture and stent overlap were independent predictors of recurrent restenosis (hazard ratio, 3.07; 95% confidence interval, 1.40-6.74; P = .005; hazard ratio, 4.75; 95% confidence interval, 1.77-12.75; P = .002). CONCLUSIONS Endovascular treatment is feasible for FPA stent failure in long-segment CTO. However, SEVT does not achieve durable patency. Stent fracture and overlap are related to recurrent restenosis.

Functional blocking of Ninjurin1 as a strategy for protecting endothelial cells in diabetes mellitus

Ongoing efforts to remove pathological inflammatory stimuli are crucial for the protection of endothelial cells in diabetes. Nerve injury-induced protein 1 (Ninj1) is an adhesion molecule that not only contributes to inflammation but also regulates the apoptosis of endothelial cells. In the present study, Ninj1 was found highly expressed in endothelial cells in Type 2 diabetic mice and increased in high-glucose (HG) cultured HUVECs. Furthermore, we found that Ninj1 levels are up-regulated in endothelial cells in clinical specimens of diabetic patients when compared with nondiabetic tissues, indicating a biological correlation between Ninj1 and endothelial pathophysiology in diabetic condition. Functional blocking of Ninj1 promoted endothelial tube formation and eNOS phosphorylation in the HG condition. Additionally, blocking Ninj1 inhibited the activation of caspase-3 and increased the Bcl-2/Bax ratio, thus inhibiting HUVECs apoptosis induced by HG. HG-induced ROS overproduction, p38 MAPK and NF-κB activation, and the overexpression of VCAM-1, ICAM-1, MCP-1, and IL-6 genes were ameliorated after Ninj1 was blocked. Using the signaling pathway inhibitor LY294002, we found that Bcl-2 expression and eNOS phosphorylation after Ninj1 blockade were regulated via PI3K/Akt signaling pathway. The in vivo endothelial contents, α-SMA+PECAM-1+ vascular numbers, and blood perfusion in the hindlimb were markedly up-regulated after Ninj1 was blocked. According to our findings, functional blocking of Ninj1 shows protective effects on diabetic endothelial cells both in vitro and in vivo Thus, we consider Ninj1 to be a potential therapeutic target for preventing endothelial dysfunction in diabetes mellitus.