Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Drug-coated balloon therapy for in-stent restenosis in patients with iliofemoral deep vein thrombosis: A single-arm observational study.

BACKGROUND: Iliofemoral deep vein thrombosis (IFDVT) causes severe symptoms and affect the quality of life to a great extent. Endovascular thrombectomy and stent implantation have been a feasible strategie to alleviate the signs and symptoms of IFDVT. However, venous in-stent restenosis (ISR) has become an emerging non-negligible problem. METHODS: To evaluate the histological characteristics of venous ISR, neointima of arterial and venous ISR patients were collected and examed. To explore the effect of drug-coated balloon (DCB) on venous ISR lesions, we conducted a single-center retrospective case series study involving IFDVT patients with ISR after venous stenting who were treated with paclitaxel-coated balloon dilatation. RESULTS: We found a collagen-rich matrix but not elastin, as well as fewer cells and less neovascularization in venous intimal hyperplasia compared with neointima in arteries. Thirteen IFDVT patients were involved in the study, with average preoperative stenosis degree of 87.69% ± 13.48%. After intervention, the stenosis degree was significantly reduced to 14.6% ± 14.36% immediately (p < 0.0001) and to 16.54% ± 15.73% during follow-up (p < 0.0001). During follow-up, the VEINES-QOL scores (p < 0.0001), VEINES-Sym scores (p < 0.0001), and Villalta scores (p = 0.04) of patients was improved significantly compared with those before intervention. No major adverse events were observed. CONCLUSIONS: The use of DCB may have a positive effect in the treatment of venous ISR by targeting intimal hyperplasia. Moreover, the application of DCB dilatation in IFDVT stenting patients with ISR is deemed safe and effective.

Clinical efficacy of sodium aescinate administration following endovenous laser ablation for varicose veins.

BACKGROUND: Endovenous interventions and minimally invasive procedures are effective in the management of varicose veins. However, they can cause postoperative discomfort. OBJECTIVE: To evaluate the clinical efficacy of sodium aescinate (SA) in improving edema, pain, vein-specific symptoms, and quality of life in patients following endovenous laser ablation (EVLA) for varicose veins. METHODS: In this single-center randomized controlled trial (RCT), patients were allocated into two groups: in Group A, 60 mg SA was administered twice daily for 20 days, and in Group B (control), no venoactive drug was prescribed. The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification system for chronic venous disorders was used to assess the varicose veins. The circumferences of the calf and ankle were recorded for evaluating edema. The 10-point Visual Analog Scale (VAS), Venous Clinical Severity Score (VCSS), and Aberdeen Varicose Veins Questionnaire (AVVQ) were used to measure the pain intensity, overall varicose vein severity, and patient's quality of life, respectively. RESULTS: The study included 87 patients (mean age, 59.9 ± 10.7 years; 54 men) with CEAP class C2-C5 varicose veins who underwent EVLA and phlebectomy or foam sclerotherapy. The calf circumference recovered quicker in Group A than in Group B by days 10, 21, and 30 (difference from baseline was 1.04 ± 0.35 vs 2.39 ± 1.15 [p < .001], 0.48 ± 0.42 vs1.73 ± 1.00 [p < .001], and 0.18 ± 0.64 vs 0.82 ± 0.96 [p < .001], respectively). The ankle circumference recovered quicker in Group A than in Group B by days 10 and 21 (the difference from baseline was 1.37 ± 0.52 vs 2.36 ± 0.93 [p < .001] and 0.58 ± 0.60 vs 1.14 ± 0.88 [p = .002], respectively). Pain relief was achieved quicker in Group A than in Group B (0.257 ± 1.097 [p = .0863] vs 0.506 ± 1.250 [p = .0168] by day 21). There were no significant differences in the VCSS and AVVQ scores between both groups. There were no drug-related adverse effects. CONCLUSIONS: SA, in combination with compression therapy, can relieve edema and alleviate pain in patients following EVLA for varicose veins.

CDKN2B-AS1 mediates proliferation and migration of vascular smooth muscle cells induced by insulin.

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the intimal hyperplasia in type 2 diabetes mellitus (T2DM) patients after percutaneous coronary intervention. We aimed to investigate the role of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in VSMC proliferation and migration, as well as the underlying mechanism. T2DM model mice with carotid balloon injury were used in vivo and mouse aortic vascular smooth muscle cells (MOVAS) stimulated by insulin were used in vitro to assess the role of CDKN2B-AS1 in VSMC proliferation and migration following vascular injury in T2DM state. To investigate cell viability and migration, MTT assay and Transwell assay were conducted. To elucidate the underlying molecular mechanisms, the methylation-specific polymerase chain reaction, RNA immunoprecipitation, RNA-pull down, co-immunoprecipitation, and chromatin immunoprecipitation were performed. In vivo, CDKN2B-AS1 was up-regulated in common carotid artery tissues. In vitro, insulin treatment increased CDKN2B-AS1 level, enhanced MOVAS cell proliferation and migration, while the promoting effect was reversed by CDKN2B-AS1 knockdown. CDKN2B-AS1 forms a complex with enhancer of zeste homolog 2 (EZH2) and DNA methyltransferase (cytosine-5) 1 (DNMT1) to regulate smooth muscle 22 alpha (SM22α) methylation levels. In insulin-stimulated cells, SM22α knockdown abrogated the inhibitory effect of CDKN2B-AS1 knockdown on cell viability and migration. Injection of lentivirus-sh-CDKN2B-AS1 relieved intimal hyperplasia in T2DM mice with carotid balloon injury. Up-regulation of CDKN2B-AS1 induced by insulin promotes cell proliferation and migration by targeting SM22α through forming a complex with EZH2 and DNMT1, thereby aggravating the intimal hyperplasia after vascular injury in T2DM.

Internal iliac artery preservation during endovascular aortic repair using in situ laser fenestration.

OBJECTIVE: The purpose of the present study was to evaluate the technical and short-term clinical outcomes of internal iliac artery (IIA) reconstruction during endovascular aortic repair (EVAR) with in situ laser-assisted fenestration in cases of abdominal aortic aneurysm (AAA) in which the iliac artery is unfit for an internal branched device (IBD). METHODS: In the present single-institution retrospective study, we analyzed patients with AAAs who had undergone EVAR with in situ laser-assisted fenestration for IIA reconstruction between January 2018 and April 2021. The study included patients with iliac artery anatomy unfit for the use of commercial IBDs. The primary safety end point was freedom from major adverse events and unplanned reinterventions within 30 days. The primary efficacy end point was freedom from IIA restenosis, reintervention, and symptoms due to pelvic ischemia at 1 year after the procedure. RESULTS: A total of 20 patients requiring IIA reconstruction but with anatomy unfit for IBD placement were treated with in situ laser-assisted fenestration during EVAR for aortoiliac aneurysms during the study period. The mean age of our patients was 72 years, and 90% were men. The technical success rate was 100%. No patient had died within 30 days after the procedure. A suspicious IIA perforation had occurred in one patient, which was treated with an additional covered stent, for a primary safety end point of 95.0%. After a mean follow-up of 11 months, all except for one of the reconstructed IIAs were patent. Three patients reported symptoms of buttock claudication on the IIA occluded side at their 3-month follow-up after the procedure. However, these symptoms had subsided in two of these patients at 6 months. Type II endoleaks without sac expansion had occurred in two patients owing to retrograde blood flow from the inferior mesenteric artery and lumbar artery. Both patients were kept under close surveillance. The rate of freedom from major adverse events and unplanned reinterventions within 30 days (primary efficacy end point) was 86.3% at 1 year after procedure. CONCLUSIONS: In situ laser-assisted fenestration was found to be a safe and effective alternative method for IIA reconstruction during EVAR for aortoiliac aneurysms in patients with anatomy unfit for IBD.

Assessment of atherectomy treatment for Thromboangiitis Obliterans: A single center experience.

BACKGROUND AND AIMS: Endovascular recanalizaiton (ER) has been proven to be a feasible method for Thromboangiitis Obliterans (TAO). The aims of this study were to evaluate the effectiveness and safety of atherectomy for TAO compared to nonatherectomy ER in our center. METHODS: Patients diagnosed as TAO were reviewed from January 2016 to June 2021 in our center. Basic characteristics of patients before ER and perioperative data were collected and compared between the atherectomy and nonatherectomy groups. The vascular event-free survival and limb salvage were calculated to evaluate the prognosis of TAO patients after ERs. Logistic Regression and Cox Regression were used to identify the risk factors for technical failure and prognosis, respectively. RESULTS: Seventy-two TAO patients with 79 lower limbs who met the criteria were included in this report. Compared with the nonatherectomy group, no significant improvement was identified in ER technical success, vascular event-free survival, or limb salvage in the atherectomy group. The total technical success rate was 91.1% (atherectomy group, 95.2%; nonatherectomy group, 89.7%), and the multiple limb involvement (p = 0.005; odds ratio [OR], 28.16; confidence interval [CI], 3.28-241.55) was the independent risk factor for technical failure. The total vascular event-free survival proportion was 66.05% and 58.40% at 1 and 3 years, respectively. Technical failure (OR, 5.61; 95% CI, 1.57-20.04; p = 0.008), and runoff grade 0 (OR, 3.28; 95% CI, 1.09-9.85; p = 0.034) were independent risk factors for vascular events. The total limb salvage proportion at 1 and 3 years was 95.84% and 92.53%, respectively. Technical failure (OR, 8.54; 95% CI, 1.71-40.73; p = 0.02) was identified as an independent risk factor for above ankle amputation. CONCLUSIONS: No significant difference in prognosis was found between the atherectomy group and the nonatherectomy group during a midterm follow-up. The technical success of ER was crucial for TAO prognosis.

Covered Stents vs Bare Metal Stents for Aortoiliac Arterial Diseases: A Systematic Review and Meta-Analysis.

PURPOSE: Covered stents and bare metal stents (BMS) have been regarded as viable treatment options for aortoiliac arterial diseases. We performed this systematic review and meta-analysis to compare the efficacy of covered stents with BMS for aortoiliac arterial diseases. MATERIALS AND METHODS: The Cochrane Library, Embase, and Medline databases were searched by 2 authors (C.Z. and Z.W.) to retrieve all studies comparing the outcomes of covered stents vs BMS for aortoiliac arterial diseases. The Cochrane tool and the Newcastle-Ottawa scale were used to assess the risk of bias in randomized controlled trials and observational studies, respectively. The outcomes at the same stage reported in at least 2 studies were pooled together. The fixed effects model combined the data when I2<50%, otherwise the random effects model was applied. The results for dichotomous variables were presented as odds ratio (OR) or risk difference and 95% confidence interval (CI); continuous variables were reported as mean difference and 95% CI. RESULTS: Herein, 10 studies with a total of 1695 limbs were included. The covered stents significantly increased the freedom from target lesion revascularization (OR 2.85, 95% CI: 1.28-6.33, p=0.010) compared to the BMS during a 24-month follow-up. However, no statistically significant difference was found in the technical success, primary patency, secondary patency, major adverse events (MAEs), ankle-brachial index (ABI) improvement, limb salvage, and survival between the two groups. CONCLUSION: Compared to BMS, covered stents appear to have similar technical success, primary patency, secondary patency, MAEs, ABI improvement, limb salvage, and survival but may have advantages in reducing target lesion revascularization. More well-designed, prospective studies are warranted to determine such findings. CLINICAL IMPACT: Covered stents may increase freedom from target lesion revascularization (TLR) compared to bare metal stents (BMS) in the treatment of aortoiliac arterial diseases. However, technical success, primary patency, secondary patency, major adverse events (MAEs), ABI improvement, limb salvage, and survival were similar. The aforementioned results are still not sufficient to draw a solid conclusion about the selection of stents for aortoiliac arterial diseases. More well-designed, prospective studies are warranted to determine such findings.

Assessing outcomes after thrombectomy with or without iliac vein stenting for young provoked DVT patients with iliac vein stenosis.

BACKGROUND: This study aimed to assess the outcomes of thrombectomy with/without iliac vein stenting for young and transiently provoked DVT patients with iliac vein stenosis. METHODS: This is a retrospective analysis of a prospectively collected multicenter database. Acute, transiently provoked DVT patients between 18 and 45 years old with iliac vein stenosis were included. All patients underwent thrombectomy. Outcomes including the Villalta score, the VEINES-QOL score, and adverse events were evaluated. RESULTS: The data of 522 patients were collected of whom 75 were included, 58 underwent thrombectomy alone (nonstenting group) and 17 underwent thrombectomy and stenting (stenting group). Within 6 months, the Villalta score of patients in stenting group is lower than that of patients in nonstenting group (6 mo: 0.73 ± 0.77 vs. 1.41 ± 0.56, p = .0004), and the VEINES-QOL score of stenting group is higher than that of nonstenting group (6 mo: 89.00 ± 2.94 vs. 87.47 ± 3.72, p = .2141). At the following follow-ups, the Villalta score (12 mo: 0.56 ± 0.49 vs. 0.60 ± 0.58, p = .8266) and VEINES-QOL score (12 mo: 88.36 ± 2.29 vs. 88.31 ± 3.36, p = .9604) between the two groups are similar. CONCLUSION: The stenting group had better efficacy within 6 months after intervention, while there was no significant difference in the symptom, signs, and quality of life between two groups after 6 months within a 2-year follow-up. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR2200056073).

Safety and Efficacy of the Passeo-18 Lux Drug-Coated Balloon Catheter in Atherosclerotic Femoropopliteal Lesions: The Multicenter BIOLUX P-IV China Study.

BACKGROUND: The purpose of this trial was to assess the safety and effectiveness of a paclitaxel-coated balloon catheter in Chinese patients with de novo or nonstented restenotic femoropopliteal atherosclerotic lesions. METHODS: BIOLUX P-IV China is a prospective, independently adjudicated, multicenter, single-arm trial conducted in China. Patients with Rutherford class 2-4 were eligible, excluded were patients in which predilation resulted in severe (≥ grade D) flow-limiting dissection or residual stenosis > 70%. Follow-up assessments were conducted at 1, 6, and 12 months. The primary safety end point was 30-day major adverse event rate and the primary effectiveness end point was primary patency at 12 months. RESULTS: We enrolled 158 patients with 158 lesions. Mean age was 67.6 ± 9.6 years, diabetes was present in 53.8% (n = 85), and previous peripheral intervention/surgeries in 17.1% (n = 27). Lesions were 4.1 ± 0.9 mm in diameter and 74 ± 50 mm long with a mean diameter stenosis of 91 ± 13%; 58.2% (n = 92) were occluded (core laboratory analysis). Device success was achieved in all patients. The rate of major adverse events was 0.6% (95% confidence interval: 0.0; 3.5) at 30 days, consisting of 1 target lesion revascularization. At 12 months, binary restenosis was present in 18.7% (n = 26) and target lesion revascularization was performed in 1.4% (n = 2, all clinically driven), resulting in a primary patency of 80.0% (95% confidence interval: 72.4, 85.8); no major target limb amputation occurred. Clinical improvement at 12 months, defined as improvement of at least 1 Rutherford class, was 95.3% (n = 130). The median walking distance per 6-minute walk test was 279 m at baseline and improved by 50 m at 30 days and by 60 m at 12 months; the visual analogue scale changed from 76.6 ± 15.6 at baseline to 80.0 ± 15.0 at 30 days and 78.6 ± 14.6 at 12 months. CONCLUSIONS: Our results confirmed the clinical effectiveness and safety of a paclitaxel-coated peripheral balloon dilatation catheter for the treatment of de novo and nonstented restenotic lesion of the superficial femoral and proximal popliteal artery in Chinese patients (NCT02912715).

TNFα activation and TGFß blockage act synergistically for smooth muscle cell calcification in patients with venous thrombosis via TGFß/ERK pathway.

Venous calcification has been observed in post-thrombotic syndrome (PTS) patients; yet, the cell types and possible mechanisms regulating this process are still unclear. We evaluated the calcium deposition within the venous wall, the cell type involved in the calcified remodelling of the venous wall after thrombosis and explored possible mechanisms in vitro. Calcium deposition was found in human specimens of superficial thrombotic veins and was co-localized with VSMCs markers αSMA and TAGLN (also known as SM22α). Besides, the expression of osteogenesis-related genes was dramatically changed in superficial thrombotic veins. Moreover, the inhibition of the TGFß signalling pathway after TNFα treatment effectively induced the expression of osteogenic phenotype markers, the calcium salt deposits and the obvious phosphorylation of ERK1/2 and JNK2 in the VSMCs calcification model. Supplementing TGFß2 or blocking the activation of the ERK/MAPK signalling pathway prevented the transformation of VSMCs into osteoblast-like cells in vitro. Taken together, VSMCs have an important role in venous calcification after thrombosis. Supplementing TGFß2 or inhibiting the ERK/MAPK signalling pathway can reduce the appearance of VSMCs osteogenic phenotype. Our findings may present a novel therapeutic approach to prevent of vascular calcification after venous thrombosis.

Meta-analysis suggests statins reduce mortality after abdominal aortic aneurysm repair.

OBJECTIVE: The necessity and efficacy of statin treatment for abdominal aortic aneurysm (AAA) remains controversial. This systematic review and meta-analysis was conducted to investigate the effects of statin therapy on the outcomes of patients with AAA. METHODS: The Cochrane library, Embase, and MedLine were searched comprehensively to identify relevant cohort studies and randomized controlled trials. The primary outcomes included short- and long-term mortality after AAA repair, and secondary outcomes included the incidence of perioperative cardiovascular complications, sac shrinkage after endovascular aneurysm repair, and the growth rate of the aneurysms. Short-term mortality was defined as all-cause 30-day or in-hospital postoperative mortality. Long-term mortality was defined as the all-cause mortality at the end of follow-up period (≥1 year). A random effects model was used to combine the results of included studies. Forest plots were created to show the pooled results of each outcome. RESULTS: One post hoc analysis of a randomized trial and 36 cohort studies (n = 134,290 patients) were included in this systematic review. The average score of included studies by Newcastle-Ottawa Scale was 7.76. Patients taking or not taking statin therapy were all diagnosed with unruptured AAA, and 59.9% of these patients were given statin therapy. Compared with statin nonusers, patients in statin therapy had significantly lower long-term mortality (odds ratio, 0.67; 95% confidence interval, 0.59-0.75; P < .001; I2 = 71.7%), and short-term mortality after aneurysmal repair (odds ratio, 0.51; 95% confidence interval, 0.36-0.73; P < .001; I2 = 81.4%). No significant difference was found between patients taking or not taking statin treatment on perioperative cardiovascular complications or sac shrinkage after endovascular aneurysm repair or growth rate of AAA under surveillance. CONCLUSIONS: These findings suggest that statin use is associated with a significant decrease in long- and short-term mortality in patients after AAA repair. Based on these results, statin therapy is worth being used in clinical practice for the management of AAA.

A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans.

OBJECTIVE: Atherosclerosis obliterans (ASO) is a chronic occlusive arterial disease and the most common type of peripheral arterial disease. Current treatment options like medication and vascularization have limited effects for "no-option" patients, and stem cell therapy is considered a viable option, although its application and efficacy have not been standardized. The objective of this review was to assess the safety and efficacy of autologous stem cell therapy in patients with ASO. METHODS: We performed a literature search of published randomized controlled trials (RCTs) for patients with ASO receiving stem cell therapy without a revascularization option. PubMed, Embase, and the Cochrane Library were searched. This study was conducted by a pair of authors independently and audited by a third author. Data were synthesized with a random-effects model. RESULTS: A total of 630 patients in 12 RCTs were included. The results showed that cell therapy significantly improved total amputation (relative risk [RR], 0.64; 95% confidence interval [CI], 0.47-0.87; P = .004), major amputation (RR, 0.69; 95% CI, 0.50-0.94; P = .02), ankle-brachial index (mean difference [MD], 0.08; 95% CI, 0.02-0.13; P = .004), transcutaneous oxygen tension (MD, 11.52; 95% CI, 3.60-19.43; P = .004), and rest pain score (MD, -0.64; 95% CI, -1.10 to -0.17; P = .007) compared with placebo or standard care. However, current studies showed cell therapy was not superior to placebo or standard care in all-cause death (RR, 0.75; 95% CI, 0.41-1.36; P = .34) and ulcer size (MD, -8.85; 95% CI, -29.05 to 11.36; P = .39). The number of trials included was limited. Moreover, most trials were designed for "no-option" patients, and thus the results should be applied with caution to other patients with peripheral arterial disease. CONCLUSIONS: Patients with ASO can benefit from autologous cell therapy in limb salvage, limb blood perfusion, and rest pain alleviation.

Local versus general anesthesia for endovascular aneurysm repair in ruptured abdominal aortic aneurysm: A systematic review and meta-analysis.

OBJECTIVES/BACKGROUND: In the endovascular treatment of ruptured abdominal aortic aneurysm (RAAA), there is no effective evidence to show preference for a specific anesthetic option. A meta-analysis was conducted to assess the result of different anesthesia in endovascular aneurysm repair (EVAR) of RAAA. METHODS: Randomized controlled trials (RCTs) and cohort studies were searched in PubMed, Embase, Ovid, and the Cochrane Library. Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool were applied to evaluate the quality of cohort studies and RCTs, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to express differences for primary and secondary outcomes. Subgroup analyses and sensitivity analyses were applied in the primary outcome to illustrate the results further. Significance was set at p < 0.05. Random-effects models were used considering limited research regardless of I2 < 50%. RESULTS: Ten cohort studies were included in this meta-analysis. Perioperative mortality was presented as the primary outcome by analyzing eight of these research. Among the included patients, local anesthesia (LA) was considered as a better choice considering perioperative mortality (n = 156/902) rather than general anesthesia (n = 907/3434) with significant difference (OR: 0.49; 95% CI: 0.35-0.67; p < 0.00001; I2 = 42%). However, no significant difference was found in the secondary outcome: the complication rate, ICU admission rate, postoperative morbidity of pneumonia, myocardial infarction, leg ischemia, and wound complication. CONCLUSIONS: There exists some evidence in this review that LA appears to improve perioperative mortality, especially in hemodynamically stable patients and should be recommended for patients undergoing EVAR with RAAA when appropriate.

Allogeneic adipose-derived stem cells promote ischemic muscle repair by inducing M2 macrophage polarization via the HIF-1α/IL-10 pathway.

Adipose-derived mesenchymal stem cells (ASCs) are multipotent stromal cells that possess considerable therapeutic potential for tissue remodeling. However, their protective mechanism in critical limb ischemia has not been fully defined. After the occlusion of blood vessels, hypoxia becomes a prominent feature of the ischemic limb. This study investigated the immunomodulatory effect of ASCs on ischemic muscle repair and explored the specific mechanism. We found that the ability of RAW264.7 cells to migrate was impaired in hypoxia, whereas coculturing with ASCs could enhance the migration capacity. In addition, under hypoxic conditions, the paracrine effect of ASCs was enhanced and ASCs could induce RAW264.7 macrophages toward the anti-inflammatory M2 phenotype. We further demonstrated that ASCs-derived interleukin 10 (IL-10), mediated by hypoxia inducible factor-1α (HIF-1α), played a crucial role in the induction of M2 macrophages by activating the signal transducer and activator of transcription 3 (STAT3)/Arginase (Arg-1) pathway. Our in vivo experiments revealed that transplanted ASCs exhibited an immunomodulatory effect by recruiting macrophages to ischemic muscle and increasing the density of M2 macrophages. The transplantation of ASCs into ischemic limbs induced increased blood flow reperfusion and limb salvage rate, whereas the depletion of tissue macrophages or transplanting HIF-1α-silenced ASCs inhibited the therapeutic effect. These findings elucidated the critical role of macrophages in ASCs-mediated ischemic muscle repair and proved that allogeneic ASCs could exert the protective effect by enhancing the recruitment of macrophages and inducing macrophages toward M2 phenotype through HIF-1α/IL-10 pathway.

Drug-Coated Balloon Angioplasty Compared With Uncoated Balloons in the Treatment of Infrapopliteal Artery Lesions (AcoArt II-BTK).

PURPOSE: To compare the safety and efficacy of drug-coated balloon (DCB) vs uncoated balloon angioplasty in the treatment of de novo and restenotic infrapopliteal lesions in patients with chronic limb-threatening ischemia (CLTI). MATERIALS AND METHODS: The prospective, multicenter, randomized study AcoArt II-BTK study (ClinicalTrials.gov identifier NCT02137577) enrolled 120 patients who were randomly assigned to angioplasty with either a DCB (n=61; mean age 70.7±7.4 years; 36 men) or a conventional balloon catheter (n=59; mean age 70.8±9.0 years; 36 men). There were no significant differences observed in baseline clinical or target lesion characteristics between the groups. The target lesion length was 169.95±86.35 mm in the DCB group vs 179.93±80.16 mm in the control group, and approximately three-quarters of the lesions were chronic occlusions. Primary patency was assessed by angiography at 6 months, and mortality and clinically-driven target lesion revascularization (CD-TLR) were evaluated at 12 months. RESULTS: Primary patency at 6 months was 75.0% in the DCB group and 28.3% in the control group (p<0.001), while late lumen loss was 0.43±0.62 mm for DCBs vs 0.99±0.55 mm for controls (p<0.001). Freedom from CD-TLR at 12 months was 91.5% in the DCB group vs 76.8% in the controls (p=0.03); there was no significant difference in mortality (1.7% DCB vs 3.6% controls; p=0.53). CONCLUSION: This study demonstrated that the Litos/Tulip DCBs are safe and effective in treating infrapopliteal lesions, with improved angiographic and clinical outcomes vs plain balloon angioplasty. The DCBs demonstrated significantly higher primary patency with fewer CD-TLRs than conventional angioplasty. The safety of the DCBs was noninferior to that of the uncoated balloons after 1 year of follow-up.

Outcomes of Drug-Coated Balloon Angioplasty for Isolated Chronic Occlusion of the Popliteal Artery: A Retrospective Single-Institution Study.

PURPOSE: To assess the 12-month safety and effectiveness of paclitaxel drug-coated balloon (DCB) for the treatment of patients with isolated chronic occlusions in popliteal arteries and evaluate the risk factors of lesion reocclusion. MATERIALS AND METHODS: From January 2018 to December 2019, DCB angioplasty was performed in 54 limbs with isolated chronic popliteal artery occlusion of 48 patients (32 men) with a mean age of 71.5 ± 12.1 (range, 50-97) years, mean occlusive length of 6.3 ± 3.0 (range, 1-15) cm, and mean preoperative ankle-brachial index (ABI) of 0.42 ± 0.12 (range, 0.19-0.58). A total of 18.5% (10/54) of lesions were long-segment occlusions involving the entire popliteal artery from P1 to P3. Twenty seven of 54 limbs presented with critical limb ischemia (CLI) with a mean ABI of 0.33 ± 0.10 (range, 0.19-0.51). The primary endpoint was primary patency rate at 12 months. The secondary endpoints included technical success rate, 1-year secondary patency rate, limb salvage rate, and improvement in clinical symptoms. Univariate Cox regression analysis was used to determine the predictors of lesion reocclusion. RESULTS: The technical success rate was 85.2% (46/54), and bailout stenting was performed in 14.8% (8/54) of lesions. The 12-month primary and secondary patency rates by the Kaplan-Meier estimate were 72.6% and 88.3%, respectively. Two thirds of the reocclusions occurred within 6 months after intervention. No 30-day mortality was observed. The limb salvage rate was 100% during a mean follow-up period of 13 months, and all minor amputations occurred in the limbs presented with CLI. The mean ABI increased from 0.42 before the procedure to 0.73 after the procedure. Patients younger than 60 years and the lesions exhibiting long-segment occlusions present as trending risk factors for lesion reocclusion. CONCLUSIONS: Paclitaxel DCB angioplasty is safe and effective in managing isolated chronic occlusion of popliteal arteries. Younger patients and long-segment occlusions of the popliteal artery are associated with a relatively higher reocclusion rate after the procedure.

Comparing Safety and Efficacy of Rivaroxaban with Warfarin for Patients after Successful Stent Placement for Chronic Iliofemoral Occlusion: A Retrospective Single Institution Study.

OBJECTIVE: The aim was to compare the safety and effectiveness of rivaroxaban and warfarin as anticoagulants for treating patients with post-thrombotic syndrome (PTS) with chronic iliofemoral venous occlusion undergoing iliofemoral venous stenting. METHODS: This single institution retrospective study analysed patients with PTS with chronic iliofemoral venous occlusion who were prescribed rivaroxaban or warfarin for one year after successfully undergoing iliofemoral venous stenting. The primary safety and efficacy endpoints were bleeding complication rate and primary patency rate at one year. Secondary outcomes included Villalta score, symptom recurrence rate, ulcer healing rate, and clinically driven target lesion revascularisation (CD-TLR) rate during follow up. RESULTS: From January 2016 to December 2017, 154 legs from 154 patients were included in this study (69 in rivaroxaban group and 85 in warfarin group). The groups were well matched for patient demographics, clinical characteristics, and procedural details. There was no significant difference between the rivaroxaban group and warfarin group in bleeding complication rate (10% vs. 16%, p = .23, hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.25 - 1.37) at one year, as well as major bleeding complication rate (0% vs. 2%, p = .20, HR 0.16, 95% CI 0.01 - 2.61) and minor bleeding complication rate (10% vs. 14%, p = .40, HR 0.67, 95% CI 0.27 - 1.66). The primary patency rate was higher in the rivaroxaban group at one year (84% vs. 71%, p = .049, HR 0.50, 95% CI 0.26 - 0.96) and at two years (79% vs. 63%, p = .037, HR 0.52, 95% CI 0.29 - 0.93). At a mean follow up of 24 months (range 1 - 42 months), the rivaroxaban group had a significantly lower post-operative Villalta score (4.87 ± 3.51 vs. 6.88 ± 5.85, p = .010, t = 2.64, 95% CI 0.50 - 3.52), lower rate of symptom recurrence (4% vs. 32%, p < .001), lower CD-TLR rates (3% vs. 13%, p = .039), and higher ulcer healing rate (90% vs. 59%, p = .004) than the warfarin group. CONCLUSION: For PTS patients with chronic iliofemoral venous occlusion undergoing iliofemoral venous stenting, rivaroxaban probably exhibited similar safety but superior efficacy to warfarin. However, further prospective control studies with large sample size are necessary to confirm the results.

Atherectomy Combined with Balloon Angioplasty versus Balloon Angioplasty Alone for de Novo Femoropopliteal Arterial Diseases: A Systematic Review and Meta-analysis of Randomised Controlled Trials.

OBJECTIVE: The efficacy and cost effectiveness of atherectomy for femoropopliteal (FP) arterial diseases have not been determined yet. A systematic review and meta-analysis were performed to compare the efficacy and safety between atherectomy combined with balloon angioplasty (BA) and BA alone for patients with de novo FP steno-occlusive lesions. METHODS: The Cochrane Library, Medline, and Embase were used to search for studies evaluating outcomes of atherectomy combined with BA compared with BA alone in FP arterial diseases from inception to July 2020. The methodological quality of the included studies was evaluated with the Cochrane Risk of Bias Tool. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to assess the level of evidence for each outcome. The fixed effects model was chosen to combine the data when I2 < 50%; otherwise, the random effects model was used. Subgroup and sensitivity analyses were performed to further analyse the results. RESULTS: Four RCTs were included. The meta-analysis showed that atherectomy combined with BA was associated with improved technical success rate (risk ratio [RR] 0.22, 95% confidence interval [CI] 0.13-0.38, p < .001; I2 = 0; high quality), reduced bailout stenting (RR 0.15, 95% CI 0.07-0.32, p < .001; I2 = 16%; high quality), and flow limiting dissection (RR 0.24, 95% CI 0.13-0.47, p < .001; I2 = 0; high quality). No statistically significant difference was found in target lesion revascularisation (TLR), primary patency, mortality, major adverse event (MAE), or ankle brachial index (ABI) after one year follow up. CONCLUSION: Compared with BA alone, atherectomy combined with BA may not improve primary patency, TLR, mortality rate, or ABI, but may reduce the need for bailout stenting and the incidence of flow limiting dissection and increase the technical success rate in FP arterial diseases. More studies are warranted to further confirm the conclusion.

Clinical Outcomes of Distal Tapered Restrictive Covered Stent Applied in Endovascular Treatment of Aortic Dissection Involving Zone 0.

OBJECTIVE: The safety and efficacy of a distal tapered restrictive covered stent (RCS) applied in the endovascular treatment of aortic dissection involving Zone 0 was evaluated. METHODS: This study retrospectively analysed 43 patients with acute aortic dissection involving Zone 0 who received in situ laser fenestrated thoracic endovascular aortic repair with distal tapered RCS from January 2015 to February 2019. The indication for the distal tapered RCS procedure was an inappropriate distal size of the main stent graft. Technical success, aortic remodelling, and clinical outcomes were evaluated. RESULTS: Technical success was achieved in all patients. The 30 day post-operative mortality rate was 0%. All patients had complete false lumen thrombosis in the stent coverage segment. True lumen volume increased significantly (p < .001) with an average change of 87.0% ± 34.3%, while false lumen volume decreased significantly (p < .001) with an average change of -71.0% ± 13.5% between baseline and 12 months. During the follow up period (mean 28.7 months, range 12-63 months), no distal stent graft induced new entry (SINE) was observed. The average distance between the distal end of the RCS and the coeliac trunk was 57.5 mm. Two (4.7%) patients had spinal cord ischaemia (SCI) and recovered without permanent paraplegia after undergoing conservative treatment. CONCLUSION: The distal tapered RCS applied in the endovascular treatment of aortic dissection involving Zone 0 is considered to be a feasible and effective approach along with satisfactory aortic remodelling, a low risk of SINE, and SCI. The favourable results are partly explained by selection. No patients had an entry tear near the coronary artery, nor were the coronary arteries, pericardium, or aortic valve involved at the time of repair.

A meta-analysis of combined proximal stent grafting with or without adjunctive distal bare stent for the management of aortic dissection.

BACKGROUND: The efficacy and safety of placement of a proximal covered stent graft combined with a distal bare stent are controversial because of the lack of evidence. This systematic review and meta-analysis compared the outcomes of combined proximal covered stent grafting with distal bare stenting (BS group) and proximal covered stent grafting without distal bare stenting (non-BS group). METHODS: The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and key references were searched up to January 26, 2019. Predefined outcomes of interest were mortality, morbidity, and postoperative assessment of aortic remodeling. We pooled risk ratios (RRs) of the outcomes of interest using fixed effects model or random effects model. RESULTS: Overall, eight observational studies involving 914 patients were included. There were no significant differences in overall aorta-related mortality (RR, 0.54; confidence interval [CI], 0.24-1.24; P = .15), complete thoracic false lumen (FL) thrombosis rate (RR, 1.23; CI, 0.83-1.81; P = .30), or complete abdominal FL thrombosis rate (RR, 1.96; CI, 0.68-5.69; P = .21) between the BS group and the non-BS group. The BS group had a lower rate of partial thoracic FL thrombosis (RR, 0.40; CI, 0.25-0.65; P = .0002), a lower stent graft-induced new entry rate (RR, 0.08; CI, 0.02-0.41; P = .003), and a lower reintervention rate (RR, 0.42; CI, 0.26-0.69; P = .0005). CONCLUSIONS: Combined proximal covered stent grafting with distal adjunctive bare stenting had the potential to reduce the partial thoracic FL thrombosis rate and the rates of stent graft-induced new entry and reintervention but was not associated with lower aorta-related mortality or the complete FL thrombosis rate. Further research with a stricter methodology is needed.