Bypass Surgery Provides Better Outcomes Compared with Endovascular Therapy in Patients with Chronic Limb-Threatening Ischemia Classified as Indeterminate Category According to the Global Vascular Guidelines.

BACKGROUND: The present study aimed to determine the preferred initial revascularization procedure between bypass surgery and endovascular therapy (EVT) in patients with chronic limb-threatening ischemia (CLTI) categorized as indeterminate according to the Global Vascular Guidelines (GVG). METHODS: We retrospectively analyzed the multicenter data of patients who underwent infrainguinal revascularization for CLTI categorized as indeterminate according to the GVG between 2015 and 2020. The end point was the composite of relief from rest pain, wound healing, major amputation, reintervention, or death. RESULTS: A total of 255 patients with CLTI and 289 limbs were analyzed. Of the 289 limbs, 110 (38.1%) and 179 (61.9%) underwent bypass surgery and EVT, respectively. The 2-year event-free survival rates with respect to the composite end point were 63.4% and 28.7% in the bypass and EVT groups, respectively (P < 0.01). Multivariate analysis revealed that increased age (P = 0.03); decreased serum albumin level (P = 0.02); decreased body mass index (P = 0.02); dialysis-dependent end-stage renal disease (P < 0.01); increased Wound, Ischemia, and foot Infection (WIfI) stage (P < 0.01); Global Limb Anatomic Staging System (GLASS) III (P = 0.04); increased inframalleolar grade (P < 0.01); and EVT (P < 0.01) were independent risk factors for the composite end point. In the WIfI-GLASS 2-III and 4-II subgroups, bypass surgery was superior to EVT with regard to 2-year event-free survival (P < 0.01). CONCLUSIONS: Bypass surgery is superior to EVT in terms of the composite end point in patients classified as indeterminate according to the GVG. Bypass surgery should be considered an initial revascularization procedure, especially in the WIfI-GLASS 2-III and 4-II subgroups.

Left Renal Vein Division during Open Surgical Repair for Abdominal Aortic Aneurysm May Cause Long-Term Kidney Remodeling.

BACKGROUND: Left renal vein division (LRVD) is a maneuver performed during open surgical repair for abdominal aortic aneurysms. Even so, the long-term effects of LRVD on renal remodeling are unknown. Therefore, we hypothesized that interrupting the venous return of the left renal vein might cause renal congestion and fibrotic remodeling of the left kidney. METHODS: We used a murine left renal vein ligation model with 8-week-old to 12-week-old wild-type male mice. Bilateral kidneys and blood samples were harvested postoperatively on days 1, 3, 7, and 14. We assessed the renal function and the pathohistological changes in the left kidneys. In addition, we retrospectively analyzed 174 patients with open surgical repairs between 2006 and 2015 to assess the influence of LRVD on clinical data. RESULTS: Temporary renal decline with left kidney swelling occurred in a murine left renal vein ligation model. In the pathohistological assessment of the left kidney, macrophage accumulation, necrotic atrophy, and renal fibrosis were observed. In addition, Myofibroblast-like macrophage, which is involved in renal fibrosis, was observed in the left kidney. We also noted that LRVD was associated with temporary renal decline and left kidney swelling. LRVD did not, however, impair renal function in long-term observation. Additionally, the relative cortical thickness of the left kidney in the LRVD group was significantly lower than that of the right kidney. These findings indicated that LRVD was associated with left kidney remodeling. CONCLUSIONS: Venous return interruption of the left renal vein is associated with left kidney remodeling. Furthermore, interruption in the venous return of the left renal vein does not correlate with chronic renal failure. Therefore, we suggest careful follow-up of renal function after LRVD.

Treatment outcomes between bypass surgery and endovascular therapy in patients with chronic limb-threatening ischemia classified as bypass-preferred category based on Global Vascular Guidelines.

OBJECTIVE: The aim of this study was to examine outcomes between bypass surgery and endovascular therapy (EVT) in patients with chronic limb-threatening ischemia (CLTI), classified as bypass-preferred according to the Global Vascular Guidelines (GVG). METHODS: We retrospectively analyzed the multi-center data of patients who underwent infrainguinal revascularization for CLTI with Wound, Ischemia, and foot Infection (WIfI) Stage 3 to 4 and Global Limb Anatomical Staging System (GLASS) Stage III, which is classified as bypass-preferred category by the GVG between 2015 and 2020. The endpoints were limb salvage and wound healing. RESULTS: We analyzed 301 patients and 339 limbs following 156 bypass surgeries and 183 EVTs. The 2-year limb salvage rates were 92.2% in the bypass surgery group and 76.3% in the EVT group, respectively (P < .01). The 1-year wound healing rates were 86.7% in the bypass surgery group and 67.8% in the EVT group (P < .01). Multivariate analysis shows decreased serum albumin level (P < .01), increased wound grade (P = .04), and EVT (P < .01) were risk factors for major amputation. Decreased serum albumin level (P < .01), increased wound grade (P < .01), GLASS infrapopliteal grade (P = .02), inframalleolar (IM) P grade (P = .01), and EVT (P < .01) were risk factors for impaired wound healing. Subgroup analysis of limb salvage in patients after EVT, decreased serum albumin level (P < .01), increased wound grade (P = .03), increased IM P grade (P = .04), and congestive heart failure (P < .01) were risk factors for major amputation. According to scoring by existence of these risk factors, 2-year limb salvage rates following EVT were 83.0% and 42.8% for the total score of 0 to 2 and of 3 to 4, respectively (P < .01). CONCLUSIONS: Bypass surgery provides better limb salvage and wound healing in patients with WIfI Stage 3 to 4 and GLASS Stage III, which is classified as bypass-preferred category by the GVG. In patients after EVT, serum albumin level, wound grade, IM P grade, and congestive heart failure were related to major amputation. Although bypass surgery may be considered as initial revascularization procedure in patients classified as bypass-preferred category, in case that EVT has to be selected, relatively acceptable outcomes can be expected in patients with less of these risk factors.

Impact of ambulatory status change on survival in patients with chronic limb-threatening ischemia undergoing infrainguinal surgical or endovascular revascularization.

OBJECTIVE: This study aimed to evaluate the influence of change in ambulatory status on the prognosis of patients with chronic limb-threatening ischemia (CLTI) undergoing infrainguinal bypass surgery or endovascular therapy (EVT). METHODS: We retrospectively analyzed data from two vascular centers for patients who underwent revascularization for CLTI between 2015 and 2020. The primary endpoint was overall survival (OS), and the secondary endpoints were changes in ambulatory status and postoperative complications. RESULTS: Throughout the study, 377 patients and 508 limbs were analyzed. In the preoperative nonambulation cohort, the average body mass index (BMI) was lower in the postoperative nonambulatory group than in the postoperative ambulatory group (P < .01). The percentage of cerebrovascular disease (CVD) was higher in the postoperative nonambulatory group than in the postoperative ambulatory group (P = .01). In the preoperative ambulation cohort, the average controlling nutritional status (CONUT) score was higher in the postoperative nonambulatory group than in the postoperative ambulatory group (P < .01). There was no difference in the bypass percentage and the EVT in the preoperative nonambulation (P = .32) and ambulation (P = .70) cohorts. According to the change in ambulatory status before and after revascularization, the 1-year OS rates were 86.8% in the ambulatory → ambulatory group, 81.1% in the nonambulatory → ambulatory group, 54.7% in the nonambulatory → nonambulatory group, and 23.9% in the ambulatory → nonambulatory group (P < .01). On multivariate analysis, increased age (P = .04), higher Wound, Ischemia, and foot Infection stage (P = .02), and increased CONUT score (P < .01) were independent risk factors for the decline in ambulatory status in patients with preoperative ambulation. In patients with preoperative nonambulation, increased BMI (P < .01) and absence of CVD (P = .04) were independent factors related to the improved ambulatory status. The percentages of postoperative complications were 31.0% and 17.0% in the preoperative nonambulation and the preoperative ambulation in the overall cohort (P < .01). Preoperative nonambulatory status (P < .01), CONUT score (P < .01), and bypass surgery (P < .01) were risk factors for postoperative complications. CONCLUSIONS: Improved ambulatory status is associated with better OS in patients with preoperative nonambulatory status after infrainguinal revascularization for CLTI. Although patients with preoperative nonambulatory status have a risk of postoperative complication, some may benefit from revascularization if they have no factors such as low BMI and CVD, improving their ambulatory status.

Risk Factors for Major Amputation in Chronic Limb-Threatening Ischemia Patients Classified as Wound, Ischemia, and Foot Infection Stage 4 following Infrainguinal Revascularization.

BACKGROUND: To evaluate limb salvage outcomes and risk factors for major amputation in chronic limb-threatening ischemia (CLTI) patients classified as stage 4 per the wound, ischemia, and foot infection (WIfI) classification following infrainguinal revascularization. METHODS: We retrospectively analyzed multicenter data of patients who had undergone infrainguinal revascularization for CLTI between 2015 and 2020. The endpoint was secondary major amputation defined as an above- or below-knee amputation following infrainguinal revascularization. RESULTS: We analyzed 243 patients with CLTI and 267 limbs. Bypass surgery was performed in 14 (25.5%) and 120 (56.6%) limbs from the secondary major amputation and limb salvage groups, respectively (P < 0.01). Endovascular therapy (EVT) was performed in 41 limbs (74.5%) in the secondary major amputation group and 92 limbs (43.4%) in the limb salvage group (P < 0.01). The average serum albumin levels were 3.0 ± 0.6 and 3.4 ± 0.5 g/dL in the secondary major amputation and limb salvage groups, respectively (P < 0.01). The percentage of congestive heart failure (CHF) was 36.4% and 14.2% in secondary major amputation and limb salvage groups, respectively (P < 0.01). The number of limbs with infra-malleolar (IM) P0, P1, and P2 were 4 (7.3%), 37 (67.3%), and 14 (25.5%), respectively, in the secondary major amputation group and 58 (27.4%), 140 (66.0%), and 14 (6.6%), respectively, in the limb salvage group (P < 0.01). Limb salvage rates at 1 year were 91.0% and 68.6% in the bypass and EVT groups, respectively (P < 0.01). Limb salvage rates at 1 year in patients with IM P0, P1, and P2 were 91.8%, 79.9%, and 53.1%, respectively (P < 0.01). Multivariate analysis revealed that serum albumin level [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.36-0.89; P = 0.01], hypertension (HR, 0.39; 95% CI, 0.21-0.75; P < 0.01), CHF (HR, 2.10; 95% CI, 1.09-4.05; P = 0.03), wound grade (HR, 1.72; 95% CI, 1.03-2.88; P = 0.04), IM P (HR, 2.08; 95% CI, 1.27-3.42; P < 0.01), and EVT (HR, 3.31; 95% CI, 1.77-6.18; P < 0.01) as independent risk factors for secondary major amputation being required. CONCLUSIONS: Among CLTI patients with WIfI stage 4, the limb salvage rate was poor in those with IM P1-2 following infrainguinal EVT. Low serum albumin levels, CHF, high wound grade, IM P1-2, and EVT were independent risk factors for CLTI patients requiring major amputation.

Perioperative therapeutic antibiotics are beneficial to prevent exacerbation of limb-associated infection after bypass surgery in patients with critical limb-threatening ischemia and foot infection score of ≥1.

OBJECTIVE: Postoperative limb infection is associated with a poor prognosis and a low amputation-free survival rate after surgical revascularization in patients with critical limb-threatening ischemia. The Global Vascular Guidelines 2019 recommend antibiotic therapy for patients with deep space foot infection or wet gangrene; however, no study is cited as evidence for this recommendation. The present study was performed to offer new evidence supporting the use of perioperative therapeutic antibiotics in patients with critical limb-threatening ischemia (CLTI) undergoing surgical revascularization. METHODS: This single-center retrospective study was performed in Kyushu University Hospital and involved patients with CLTI who underwent surgical revascularization from 2003 to 2021. Ampicillin/sulbactam and cefazolin were defined as preventive antibiotics, and other types were defined as therapeutic antibiotics. Postoperative limb-associated infection was defined as an increased foot infection (fI) score in the Wound, Ischemia, and foot Infection (WIfI) classification system after surgical revascularization. The association between perioperative antibiotic therapy and postoperative limb-associated infection was assessed. RESULTS: Among 286 limbs of 263 patients with CLTI, 27 (9%) limbs developed postoperative limb-associated infection after surgical revascularization. The fI scores were significantly higher in the patients with than without postoperative limb-associated infection (1.0 ± 0.2 vs 0.4 ± 0.1, respectively; p = 0.0033), indicating that an fI score of ≥1 was a risk factor for postoperative limb-associated infection. Perioperative therapeutic antibiotics significantly reduced the incidence of postoperative limb-associated infection compared with preventive antibiotics (0.0% vs. 44.8%, respectively; p = 0.0028) in the patients with CLTI who had an fI score of ≥1 after bypass surgery, although perioperative therapeutic antibiotics were not effective for patients with an fI score of 0. CONCLUSION: Perioperative therapeutic antibiotics for patients with an fI score of ≥1 are beneficial for reducing the incidence of postoperative limb-associated infection after surgical revascularization.

Interleukin-38 suppresses abdominal aortic aneurysm formation in mice by regulating macrophages in an IL1RL2-p38 pathway-dependent manner.

Macrophages play crucial roles in abdominal aortic aneurysm (AAA) formation through the inflammatory response and extracellular matrix degradation; therefore, regulating macrophages may suppress AAA formation. Interleukin-38 (IL-38) is a member of the IL-1 family, which binds to IL-36 receptor (IL1RL2) and has an anti-inflammation effect. Because macrophages express IL1RL2, we hypothesized that IL-38 suppresses AAA formation by controlling macrophages. We assessed a C57BL6/J mouse angiotensin II-induced AAA model with or without IL-38 treatment. RAW 264.7 cells were cultured with tumor necrosis factor-α and treated with or without IL-38. Because p38 has important roles in inflammation, we assessed p38 phosphorylation in vitro and in vivo. To clarify whether the IL-38 effect depends on the p38 pathway, we used SB203580 to inhibit p38 phosphorylation. IL1RL2+ macrophage accumulation along with matrix metalloproteinase (MMP)-2 and -9 expression was observed in mouse AAA. IL-38 reduced the incidence of AAA formation along with reduced M1 macrophage accumulation and MMP-2 and -9 expression in the AAA wall. Macrophage activities including inducible nitric oxide, MMP-2, and MMP-9 production and spindle-shaped changes were significantly suppressed by IL-38. Furthermore, we revealed that inhibition of p38 phosphorylation diminished the effects of IL-38 on regulating macrophages to reduce AAA incidence, indicating the protective effects of IL-38 depend on the p38 pathway. IL-38 plays protective roles against AAA formation through regulation of macrophage accumulation in the aortic wall and modulating the inflammatory phenotype. Using IL-38 may be a novel therapy for AAA patients.

Global Limb Anatomic Staging System Inframalleolar Modifier Predicts Limb Salvage and Wound Healing in Patients with Chronic Limb Threatening Ischaemia Undergoing Endovascular Infrainguinal Revascularisation.

OBJECTIVE: This study aimed to analyse the influence of the Global Anatomic Staging System (GLASS) and inframalleolar (IM) disease on the treatment outcomes of patients with chronic limb threatening ischaemia (CLTI) who undergo endovascular treatment (EVT) METHODS: Data of patients who underwent infrainguinal endovascular therapy (EVT) for CLTI between 2015 and 2019 at two centres were analysed retrospectively. The endpoints were major amputation, major adverse limb events (MALE), and wound healing. RESULTS: Overall, 276 patients and 340 limbs were analysed. The number of revascularisations for an infrapopliteal lesion was 48 (70.6%), 63 (63.0%), and 142 (82.6%) in the GLASS I, GLASS II, and GLASS III stages, respectively (p < .001). There was no statistically significant difference in limb salvage among the GLASS stages (p = .78). The limb salvage rates at one year were 94.6%, 88.0%, and 70.0% in the IM P0 P1, and P2 groups, respectively (p < .001). Multivariable analysis showed that Wound, Ischemia, and foot Infection (WIfI) stage, and IM grade were risk factors for major amputation. The freedom from MALE rates at two years were 60.5%, 45.3%, and 41.1% in the GLASS I, II, and III stages, respectively (p = .003) and 64.1%, 43.5%, and 18.4% in the IM P0, P1, and P2 groups, respectively (p < .001). Multivariable analysis demonstrated that WIfI stage, GLASS stage, IM grade, and infrapopliteal revascularisation were risk factors for MALE. There was no significant difference in wound healing among GLASS I - III (p = .75). The wound healing rates at 365 days were 78.6%, 68.6%, and 42.0% in the IM P0, P1, and P2 groups, respectively (p = .065). Multivariable analysis showed that WIfI stage and IM P2 were risk factors for incomplete wound healing. CONCLUSION: GLASS IM was associated with major amputation, MALE, and wound healing, while GLASS stage was associated with only MALE.

Evaluation of three nutritional indices as predictors of 2-year mortality and major amputation in patients with chronic limb-threatening ischemia.

OBJECTIVE: The present study aimed to examine which nutritional index, such as the controlling nutritional status (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI), is better for predicting prognosis in patients with chronic limb-threatening ischemia (CLTI) following revascularization. METHOD: We retrospectively analyzed data of patients who underwent revascularization for CLTI between 2008 and 2020. The endpoints were 2-year overall survival and limb salvage. The optimal cutoff values of 2-year overall survival and major amputation were determined by receiver operating characteristic curve analyses. RESULT: A total of 238 patients with CLTI and 289 limbs were analyzed. The 2-year overall survival rates were 48.9%, 54.6%, and 53.5% in patients with CONUT score ≥4, PNI score <42.6, and GNRI <98.4 compared with 80.0%, 80.0%, and 78.4% in patients with CONUT score <4, PNI score ≥42.6, and GNRI ≥98.4 (p < 0.01). Age, non-ambulatory status, hemodialysis, and nutritional indices were independent risk factors for 2-year mortality in the multivariate analyses. The 2-year limb salvage rates were 70.1%, 82.2%, and 81.9% in patients with CONUT score ≥7, PNI score <41.9, and GNRI <95.3 compared with 92.8%, 98.3%, and 94.2% in patients with CONUT score <7, PNI score ≥41.9, and GNRI ≥95.3 (p < 0.01). Wound, ischemia, and foot infection stage and each nutritional index (CONUT and PNI) were independent risk factors for major amputation in multivariate analyses. The overall survival and limb salvage rates of patients with malnutrition diagnosed by CONUT score were poor compared with those of normal nutrition or malnutrition diagnosed by PNI and/or GNRI scores. CONCLUSION: The CONUT, PNI, and GNRI scores can predict the 2-year overall survival in patients with CLTI after revascularization. The CONUT and PNI scores were associated with major amputation.

Gut dysbiosis and bacterial translocation in the aneurysmal wall and blood in patients with abdominal aortic aneurysm.

Inflammation plays a part in the development of abdominal aortic aneurysm (AAA), and the gut microbiota affects host inflammation by bacterial translocation. The relationship between abdominal aortic aneurysm and the gut microbiota remains unknown. This study aimed to detect bacterial translocation in the aneurysmal wall and blood of patients with abdominal aortic aneurysm, and to investigate the effect of the gut microbiota on abdominal aortic aneurysm. We investigated 30 patients with abdominal aortic aneurysm from 2017 to 2019. We analysed the aneurysmal wall and blood using highly sensitive reverse transcription-quantitative polymerase chain reaction, and the gut microbiota was investigated using next-generation sequencing. In the 30 patients, bacteria were detected by reverse transcription- quantitative polymerase chain reaction in 19 blood samples (detection rate, 63%) and in 11 aneurysmal wall samples (detection rate, 37%). In the gut microbiota analysis, the Firmicutes/Bacteroidetes ratio was increased. The neutrophil-lymphocyte ratio was higher (2.94 ± 1.77 vs 1.96 ± 0.61, P < 0.05) and the lymphocyte-monocyte ratio was lower (4.02 ± 1.25 vs 5.86 ± 1.38, P < 0.01) in the bacterial carrier group than in the bacterial non-carrier group in blood samples. The volume of intraluminal thrombus was significantly higher in the bacterial carrier group than in the bacterial non-carrier group in aneurysmal wall samples (64.0% vs 34.7%, P < 0.05). We confirmed gut dysbiosis and bacterial translocation to the blood and aneurysmal wall in patients with abdominal aortic aneurysm. There appears to be a relationship between the gut microbiota and abdominal aortic aneurysm.

A systematic review of management of ureteroarterial fistula.

OBJECTIVE: Ureteroarterial fistula (UAF) is lethal condition. However, no consensus has been reached regarding the diagnosis and treatment of UAF owing to its rarity. The aim of our report was to present an actual case of UAF and systematically review the symptoms, risk factors, diagnosis, and treatment of this condition. METHODS: The case study was of a 52-year-old woman who had experienced a massive hemorrhage during urinary stent replacement. For the systematic review of studies of UAF, those written in English and reported from 1939 to 2020 were searched for on PubMed using the keywords "uretero-arterial fistula," "arterio-ureteral fistula," and "hematuria." RESULTS: We included 121 studies with 235 patients (mean age, 66.0 years; 139 women [59.1%]) in our review. UAF had occurred most frequently in the common iliac artery (n = 112; 47.7%). Almost all patients (n = 232; 98.7%) had complained of hematuria. The risk factors for UAF were pelvic surgery (n = 205; 87.2%), the long-term use of urinary stents (n = 170; 72.3%), oncologic radiotherapy (n = 107; 45.5%), and malignancy (n = 159; 67.7%). Although computed tomography can detect various useful findings such as extravasation, pseudoaneurysm, hydronephrosis, and opacification of ureters, it was diagnostically useful for only one third of the cases. Angiography was useful for the diagnoses of UAF for 124 (66.3%) of the 187 patients (79.6%) who had undergone angiography. With regard to treatment, endovascular approaches have been widely used in recent years because their invasiveness is lesser than that of open surgical repair. In the era of endovascular therapy, the indications for open surgical repair include ureteral-intestinal fistula, abscess formation, and graft infection after endovascular therapy. CONCLUSIONS: Computed tomography can be recommended as the first examination for patients with risk factors for UAF because of its usefulness. Subsequently, angiography should be considered because UAF can be treated using an endovascular approach after diagnostic angiography. The diagnosis and treatment of UAF can often be difficult; therefore, the important first step of diagnosis is suspecting the occurrence of UAF and using a multidisciplinary approach.

Bioinformatics identifies predictors of arteriovenous fistula maturation.

BACKGROUND: Arteriovenous fistulae (AVF) are the preferred access for hemodialysis but still have poor rates of maturation and patency limiting their clinical use. The underlying mechanisms of venous remodeling remain poorly understood, and only limited numbers of unbiased approaches have been reported. METHODS: Biological Gene Ontology (GO) term enrichment analysis and differentially expressed genes (DEG) analysis were performed for three AVF datasets. A microRNA enrichment analysis and L1000CDS2 query were performed to identify factors predicting AVF patency. RESULTS: The inflammatory and immune responses were activated during both early and late phases of AVF maturation, with upregulation of neutrophil and leukocyte regulation, cytokine production, and cytokine-mediated signaling. In men with failed AVF, negative regulation of myeloid-leukocyte differentiation and regulation of macrophage activation were significantly upregulated. Compared to non-diabetic patients, diabetic patients had significantly reduced immune response-related enrichment such as cell activation in immune response, regulation of immune-effector process, and positive regulation of defense response; in addition, diabetic patients showed no enrichment of the immune response-regulating signaling pathway. CONCLUSIONS: These data show coordinated, and differential regulation of genes associated with AVF maturation, and different patterns of several pathways are associated with sex differences in AVF failure. Inflammatory and immune responses are activated during AVF maturation and diabetes may impair AVF maturation by altering these responses. These findings suggest several novel molecular targets to improve sex specific AVF maturation.

Sex differences in arterial identity correlate with neointimal hyperplasia after balloon injury.

BACKGROUND: Endovascular treatment of atherosclerotic arterial disease exhibits sex differences in clinical outcomes including restenosis. However, sex-specific differences in arterial identity during arterial remodeling have not been described. We hypothesized that sex differences in expression of the arterial determinant erythropoietin-producing hepatocellular receptor interacting protein (Ephrin)-B2 occur during neointimal proliferation and arterial remodeling. METHODS AND RESULTS: Carotid balloon injury was performed in female and male Sprague-Dawley rats without or 14 days after gonadectomy; the left common carotid artery was injured and the right carotid artery in the same animal was used as an uninjured control. Arterial hemodynamics were evaluated in vivo using ultrasonography pre-procedure and post-procedure at 7 and 14 days and wall composition examined using histology, immunofluorescence and Western blot at 14 days after balloon injury. There were no significant baseline sex differences. 14 days after balloon injury, there was decreased neointimal thickness in female rats with decreased smooth muscle cell proliferation and decreased type I and III collagen deposition, as well as decreased TNFα- or iNOS-positive CD68+ cells and increased CD206- or TGM2-positive CD68+ cells. Female rats also showed less immunoreactivity of VEGF-A, NRP1, phosphorylated EphrinB2, and increased Notch1, as well as decreased phosphorylated Akt1, p38 and ERK1/2. These differences were not present in rats pretreated with gonadectomy. CONCLUSIONS: Decreased neointimal thickness in female rats after carotid balloon injury is associated with altered arterial identity that is dependent on intact sex hormones. Alteration of arterial identity may be a mechanism of sex differences in neointimal proliferation after arterial injury.

Endothelial Cell TGF-ß (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.

BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-ß (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation-critical components of wall thickness-we hypothesized that disruption of TGF-ß signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542-an inhibitor of TGF-ß receptor I-was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-ß receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-ß signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-ß signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-ß signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell-targeted TGF-ß inhibition may be a translational strategy to improve AVF patency.

Effect of abdominal aortic aneurysm sac shrinkage after endovascular repair on long-term outcomes between favorable and hostile neck anatomy.

OBJECTIVE: The aim of the present study was to analyze the influence of abdominal aortic aneurysm sac shrinkage on the long-term outcomes after endovascular aneurysm repair (EVAR) between patients with favorable and hostile neck anatomy. METHODS: In the present study, we retrospectively analyzed data from 268 patients with fusiform aneurysm and sac behavior who had been evaluated for ≥1 year after EVAR. Hostile neck anatomy was defined as a proximal aneurysmal neck length of <10 mm or proximal neck angle of ≥60°. The primary end point was sac shrinkage, and the secondary end points included reintervention and a composite of rupture, type Ia endoleak, and late open conversion. RESULTS: No differences were found in sac shrinkage between the patients with favorable and hostile neck anatomy (P = .47). Multivariate analysis revealed that an occluded inferior mesenteric artery (P = .04), the presence of posterior thrombus (P < .01), and no antiplatelet therapy (P = .01) were positive factors for sac shrinkage. The reintervention-free survival rate was better for patients with sac shrinkage compared with those without sac shrinkage regardless of the proximal neck anatomy (P < .01). The event-free survival rate of the composite end point at 5 and 10 years was 97.5% and 83.5% for patients with favorable neck anatomy and 86.8% and 81.0% for those with hostile neck anatomy, respectively (P = .02). In the subgroup with sac shrinkage, the event-free survival rates at 5 and 10 years were 98.7% and 98.7% for those with favorable neck anatomy and 92.7% and 82.4% for those with hostile neck anatomy, respectively (P = .02). In contrast, the event-free survival for patients without sac shrinkage did not differ between those with favorable and hostile neck anatomy (P = .08). Multivariate analysis showed that a hostile neck anatomy (hazard ratio, 3.32; 95% confidence interval, 1.26-8.80; P = .02) and no sac shrinkage (hazard ratio, 3.88; 95% confidence interval, 1.25-12.0; P = .02) were significant risk factors for the composite end point of rupture, type Ia endoleak, and late open conversion. CONCLUSIONS: Proximal neck anatomy did not affect sac shrinkage after EVAR. Sac shrinkage has been a good surrogate marker of better long-term outcomes after EVAR for patients with favorable neck anatomy. In contrast, critical events such as rupture and type Ia endoleak can occur even after sac shrinkage has been achieved in patients with hostile neck anatomy.

Bypass Surgery Provides Better Outcomes Compared with Endovascular Therapy in the Composite Endpoint Comprising Relief from Rest Pain, Wound Healing, Limb Salvage, and Survival after Infra-inguinal Revascularisation in Patients with Chronic Limb Threatening Ischaemia.

OBJECTIVE: The present study aimed to determine the factors related to relief from rest pain, wound healing, major adverse limb events (MALEs), and prognosis after infrainguinal revascularisation in patients with chronic limb threatening ischaemia (CLTI). METHODS: The data of patients who underwent infrainguinal revascularisation for CLTI between 2010 and 2020 was analysed retrospectively. The endpoint was the composite of relief from rest pain, wound healing, MALE, or death. RESULTS: A total of 234 limbs in 187 patients with CLTI were analysed. Of the 234 limbs, 149 (63.7%) underwent bypass surgery and 85 (36.3%) underwent endovascular therapy (EVT). The event free survival rates with respect to the composite endpoint at two years were 30.4% in the EVT and 48.5% in the bypass groups, respectively (p = .005). The event free survival rates at two years were 56.7% in bypass surgery and 29.5% in EVT in the indeterminate subgroup (p = .051). Multivariable analysis revealed that age (hazard ratio [HR] 1.03; 95% confidence interval [CI] 1.01 - 1.05; p < .001), coronary artery disease (CAD) (HR 1.45; 95% CI 1.01 - 2.07; p = .042), haemodialysis (HR 1.74; 95% CI 1.22 - 2.48; p = .002), Wound, Ischaemia and foot Infection stage (HR 1.34; 95% CI 1.07 - 1.68; p = .012), Global Limb Anatomical Staging System stage (HR 1.31; 95% CI 1.01 - 1.72; p = .043), EVT (HR 1.90; 95% CI 1.31 - 2.74; p < .001), Geriatric Nutritional Risk Index (HR 0.98; 95% CI 0.97 - 0.99; p = .021), and non-ambulatory status (HR 1.89; 95% CI 1.31 - 2.74; p < .001) were risk factors for the composite endpoint. CONCLUSION: Bypass surgery is superior to EVT with respect to the composite endpoint including relief from rest pain, wound healing, MALE, or death. Bypass surgery may be considered as the treatment of choice, instead of EVT, in patients in the indeterminate group according to the Global Vascular Guidelines preferred revascularisation method.

Validation of the GLASS Staging Systems in Patients With Chronic Limb-Threatening Ischemia Undergoing De Novo Infrainguinal Revascularization.

OBJECTIVES: The Global Limb Anatomic Staging System (GLASS) was proposed for evaluating the anatomic complexity of arterial disease in patients with chronic limb-threatening ischemia (CLTI). We aimed to examine the relationship between GLASS stage and treatment outcomes after infrainguinal revascularization in patients with CLTI. METHODS: We retrospectively analyzed data of patients undergoing infrainguinal revascularization for CLTI between 2010 and 2018 to examine whether GLASS stage affects the limb salvage, wound healing, and overall survival (OS). RESULTS: Throughout the study period, 153 CLTI patients and 190 limbs with Fontaine classification III and IV were analyzed for major amputation and OS, and 125 patients and 157 limbs of Fontaine classification IV were analyzed for wound healing. The number of patients with WIfI stage 1, 2, 3, and 4 was 14 (7.4%), 44 (23.2%), 65 (34.2%), and 67 (53.3%), respectively. The number of patients with GLASS stage I, II, and III was 23 (12.1%), 48 (25.3%), and 119 (62.6%), respectively. Among the 190 limbs, the number subject to bypass surgery, endovascular therapy, and hybrid therapy was 132 (69.5%), 39 (20.5%), and 19 (10.0%), respectively. A multivariate analysis showed that only WIfI stage and inframalleolar (IM) disease were risk factors for major amputation and impaired wound healing. There was no relationship between GLASS stage and limb salvage or wound healing. A multivariate analysis revealed that age, geriatric nutritional risk index and GLASS stage were risk factors for 2-year OS (P < 0.01). Patients with all risk factors had a poor prognosis (35.3% at 2 years). CONCLUSION: WIfI stage and IM disease predicted limb salvage and wound healing after infrainguinal revascularization in patients with CLTI. Although GLASS stage did not affect limb salvage or wound healing, it was a prognostic factor for poor OS. The GLASS staging could be useful for deciding between bypass surgery and endovascular therapy in prediction of prognosis.

Iliac Artery Aneurysms Expand in Quadratically Proportion to the Diameter.

BACKGROUND: Iliac artery aneurysms (IAAs) are life-threatening once ruptured. Although some studies have revealed the pathology of IAAs, clinical information on IAAs is still limited. Moreover, previous studies were conducted in Western countries; thus, we aimed to identify the natural history of iliac artery aneurysms in a Japanese cohort. The purpose of this study was to investigate the IAA expansion rate in a Japanese cohort to consider the management of small IAAs and to identify indications for surgical intervention. METHODS: Patients with iliac artery aneurysms were retrospectively reviewed. The primary outcome was the expansion rate of IAAs. We also investigated the correlation between expansion rate and patients' characteristics. Natural histories, including surgical interventions and rupture, were also assessed. RESULTS: The mean expansion rate in our study was 1.59 ± 1.16 mm/year. There was a positive correlation between expansion rate and aneurysm diameter, which was estimated by y = 0.0052 × (X - 23.270)2 + 0.0632 × X - 0.0517, where y is the expansion rate, and X is aneurysm diameter. The freedom from surgical intervention rate of IAAs was 85.5% at 1 year, 54.0% at 3 years, and 41.5% at 5 years. No factors, except initial aneurysm diameter, were revealed as independent predictors of surgical intervention. We experienced one ruptured IAA, which showed unexpected rapid growth from 30.1 mm to 56.3 mm over 15 months during conservative management. This case demonstrated that IAAs ≥30 mm should be carefully followed up and considered for surgical intervention. CONCLUSIONS: We conclude that larger aneurysms have greater expansion rates. Because IAAs ≥30 mm carry a risk of rapid expansion resulting in rupture, careful follow-up, and surgical intervention should be performed if iliac artery aneurysms are ≥30 mm in diameter.

Effects of Antithrombotic Therapy on Abdominal Aortic Aneurysm Sac Size after Endovascular Repair in Patients with Favorable Neck Anatomy.

PURPOSE: To evaluate the influence of antiplatelet or anticoagulant therapy on sac behavior after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: This study retrospectively analyzed data from patients with favorable neck anatomy who underwent EVAR between 2007 and 2019. Patients with ruptured AAA and ≤1 year of sac behavior evaluation were excluded. Sac shrinkage after 1 year, persistent type II endoleak, and late sac expansion were examined. RESULTS: In total, 182 patients with favorable neck anatomy were included in this study. A multivariable analysis identified an occluded inferior mesenteric artery (IMA; P = .049), the presence of a posterior thrombus (P = .009), and no antiplatelet therapy (P = .012) as factors positively associated with sac shrinkage at 1 year. Persistent type II endoleak was detected in 56 (30.8%) patients, with patent IMA (P = .006), the lack of a posterior thrombus (P = .004), the number of patent lumbar arteries (P = .004), and antiplatelet therapy (P = .039) being identified as significant risk factors. The multivariable analysis identified a larger initial AAA diameter (P < .001), the lack of a posterior thrombus (P = .038), and antiplatelet and anticoagulant therapies (P = .038 and P = .003, respectively) as risk factors for late sac expansion. CONCLUSIONS: After EVAR in patients with favorable neck anatomy, antiplatelet therapy is associated with the lack of sac regression at 1 year, whereas antiplatelet and anticoagulant therapies are risk factors for late sac expansion.