TGFß (Transforming Growth Factor-Beta)-Activated Kinase 1 Regulates Arteriovenous Fistula Maturation.

OBJECTIVE: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFß [transforming growth factor-beta]-activated kinase 1) is a mediator of noncanonical TGFß signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm2) activated noncanonical TGFß signaling including TAK1 phosphorylation in mouse endothelial cells. CONCLUSIONS: TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFß signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.

Reduced patency in left-sided arteriovenous grafts in a porcine model.

OBJECTIVE: The porcine arteriovenous graft model is commonly used to study hemodialysis vascular access failure, with most studies using a bilateral, paired-site approach in either the neck or femoral vessels. In humans, left- and right-sided central veins have different anatomy and diameters, and left-sided central vein catheters have worse outcomes. We assessed the effect of laterality on arteriovenous prosthetic graft patency and hypothesized that left-sided carotid-jugular arteriovenous prosthetic grafts have reduced patency in the porcine model. METHODS: Arteriovenous polytetrafluoroethylene grafts were placed ipsilaterally or bilaterally in 10 Yorkshire male pigs from the common carotid artery to the internal jugular vein. Ultrasound measurements of blood flow velocities and diameters were assessed before graft placement. Animals were sacrificed at 1 week, 2 weeks, or 3 weeks. Patency was determined clinically; grafts and perianastomotic vessels were excised and analyzed with histology and immunostaining. RESULTS: At baseline, left- and right-sided veins and arteries had similar blood flow velocities. Although internal jugular veins had similar diameters at baseline, left-sided carotid arteries had 11% smaller outer diameters (P = .0354). There were 10 left-sided and 8 right-sided polytetrafluoroethylene grafts placed; only 4 of 10 (40%) grafts were patent on the left compared with 7 of 8 (88%) grafts patent on the right (P = .04). Left-sided grafts had increased macrophages at the arterial anastomosis (P = .0007). Left-sided perianastomotic arteries had thicker walls (0.74 vs 0.60 mm; P = .0211) with increased intima-media area (1.14 vs 0.77 mm2; P = .0169) as well as a trend toward 38% smaller luminal diameter (1.6 vs 2.5 mm; P = .0668) and 20% smaller outer diameter (3.0 vs 3.7 mm; P = .0861). Left- and right-sided perianastomotic veins were similar histologically, but left-sided veins had decreased expression of phosphorylated endothelial nitric oxide synthase (P = .0032) and increased numbers of α-actin-positive smooth muscle cells (P = .0022). CONCLUSIONS: Left-sided arteriovenous grafts are associated with reduced short-term patency compared with right-sided grafts in the Yorkshire pig preclinical model of arteriovenous prosthetic grafts. Laterality must be considered in planning and interpreting surgical preclinical models.

Venous Mechanical Properties After Arteriovenous Fistulae in Mice.

BACKGROUND: An arteriovenous fistula (AVF) exposes the outflow vein to arterial magnitudes and frequencies of blood pressure and flow, triggering molecular pathways that result in venous remodeling and AVF maturation. It is unknown, however, how venous remodeling, that is lumen dilation and wall thickening, affects venous mechanical properties. We hypothesized that a fistula is more compliant compared with a vein because of altered contributions of collagen and elastin to the mechanical properties. METHODS: Ephb4+/- and littermate wild-type (WT) male mice were treated with sham surgery or needle puncture to create an abdominal aortocaval fistulae. The thoracic inferior vena cava was harvested 3 wk postoperatively for mechanical testing and histological analyses of collagen and elastin. RESULTS: Mechanical testing of the thoracic inferior vena cava from Ephb4+/- and WT mice showed increased distensibility and increased compliance of downstream veins after AVF compared with sham. Although Ephb4+/- veins were thicker than WT veins at the baseline, after AVF, both Ephb4+/- and WT veins showed similar wall thickness as well as similar collagen and elastin area fractions, but increased collagen undulation compared with sham. CONCLUSIONS: Fistula-induced remodeling of the outflow vein results in circumferentially increased distensibility and compliance, likely due to post-translational modifications to collagen.

Transforming Growth Factor-ß1 Inhibits Pseudoaneurysm Formation After Aortic Patch Angioplasty.

OBJECTIVE: Pseudoaneurysms remain a significant complication after vascular procedures. We hypothesized that TGF-ß (transforming growth factor-ß) signaling plays a mechanistic role in the development of pseudoaneurysms. APPROACH AND RESULTS: Rat aortic pericardial patch angioplasty was associated with a high incidence (88%) of pseudoaneurysms at 30 days, with increased smad2 phosphorylation in small pseudoaneurysms but not in large pseudoaneurysms; TGF-ß1 receptors were increased in small pseudoaneurysms and preserved in large pseudoaneurysms. Delivery of TGF-ß1 via nanoparticles covalently bonded to the patch stimulated smad2 phosphorylation both in vitro and in vivo and significantly decreased pseudoaneurysm formation (6.7%). Inhibition of TGF-ß1 signaling with SB431542 decreased smad2 phosphorylation both in vitro and in vivo and significantly induced pseudoaneurysm formation by day 7 (66.7%). CONCLUSIONS: Normal healing after aortic patch angioplasty is associated with increased TGF-ß1 signaling, and recruitment of smad2 signaling may limit pseudoaneurysm formation; loss of TGF-ß1 signaling is associated with the formation of large pseudoaneurysms. Enhancement of TGF-ß1 signaling may be a potential mechanism to limit pseudoaneurysm formation after vascular intervention.

Magnetic resonance thoracic ductography assessment of serial changes in the thoracic duct after the intake of a fatty meal.

The thoracic duct, a terminal lymph vessel, is thought to dilate after the intake of a fatty meal. However, this physiological change has not been well explored in vivo. Therefore, the present study aimed to assess serial changes in the thoracic duct after the intake of a fatty meal using magnetic resonance thoracic ductography (MRTD). Eight healthy volunteers were subjected to one MRTD scan before a fatty meal and eight serial MRTD scans every hour thereafter. The cross-sectional areas of the thoracic duct were estimated using MRTD measurements of the diameters of the thoracic duct at the upper edge of the aortic arch, the tracheal bifurcation, the mid-point between the tracheal bifurcation and the left part of the diaphragm and the left part of the diaphragm. The change-rates in these areas were calculated before and after the fatty meal intake, and the maximal change-rate and timing of its achievement were determined for each subject. The summed change-rates in the four portions of the thoracic duct ranged from -40.1 to 81.3%, with maximal change-rates for each subject ranging from 22.8 to 81.3% (mean, 50.4%). Although individual variations were observed, most subjects (88.9%) exhibited a maximal change-rate at 4-6 h after meal intake, with subsequent decreases at 7-8 h. In conclusion, MRTD revealed a tendency toward thoracic duct enlargement at 4-6 h after the intake of a fatty meal, followed by contraction.

Improved image quality of helical computed tomography of the head in children by iterative reconstruction.

BACKGROUND AND PURPOSE: Iterative reconstruction (IR) offers noise reduction and improved image quality of computed tomography (CT). Our aim was to assess the imaging quality of non-contrast helical CT of the head in children using IR. MATERIALS AND METHODS: This study recruited 78 consecutive children aged ≤5 years (range: from 3 months to 5 years; mean: 1.7 years) who underwent an emergent non-enhanced helical CT of the head with no abnormal findings. The acquired data were reconstructed using filtered back projection (FBP) and sinogram-affirmed IR (SAFIRE) with strength levels of 2 (IR2) and 4 (IR4). The imaging quality of FBP, IR2 and IR4 was scored by two experienced neuroradiologists in terms of the contrast between the gray-white matter junction and artifacts from the skull at the level of the semioval center, basal ganglia and fourth ventricle. FBP, IR2 and IR4 scores were compared at each slice level. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated for FBP, IR2 and IR4 and were compared among the three reconstruction algorithms. RESULTS: The score of IR2 and IR4 was significantly higher than that of FBP in terms of both the contrast between the gray-white matter junction and artifacts from the skull at each slice level (P<0.001). SNR and CNR on IR4 were the highest followed by those on IR2 and FBP (P<0.001). CONCLUSIONS: IR may improve the image quality of helical CT of the head in children.

Diverse application platform for hard X-ray diffraction in SACLA (DAPHNIS): application to serial protein crystallography using an X-ray free-electron laser.

An experimental system for serial femtosecond crystallography using an X-ray free-electron laser (XFEL) has been developed. It basically consists of a sample chamber, fluid injectors and a two-dimensional detector. The chamber and the injectors are operated under helium atmosphere at 1 atm. The ambient pressure operation facilitates applications to fluid samples. Three kinds of injectors are employed to feed randomly oriented crystals in aqueous solution or highly viscous fluid. Experiments on lysozyme crystals were performed by using the 10 keV XFEL of the SPring-8 Angstrom Compact free-electron LAser (SACLA). The structure of model protein lysozyme from 1 µm crystals at a resolution of 2.4 Šwas obtained.

Optimizing the Approach to STA-MCA Bypass Surgery and Reducing Wound Complications.

BACKGROUND AND OBJECTIVES: The treatment of complex intracranial aneurysms with bypass surgery using 2 branches of the superficial temporal artery (STA) proves to be an effective surgical option. However, the harvest of these 2 STA branches, combined with a pterional craniotomy, carries the potential risk of delayed wound healing of the skin flap. This study undertook a retrospective analysis to examine and identify the factors associated with this delayed wound healing. METHODS: A total of 56 consecutive cases, including both ruptured and unruptured complex intracranial aneurysms, that underwent bypass surgery with 2 branches of the STA, were analyzed retrospectively. RESULTS: Major delayed wound healing was observed in 6 (10.7%) cases. Univariate analysis demonstrated significant associations with the following factors: rupture (P = 0.023), presence of diabetes mellitus (P = 0.028), large craniotomy size (P = 0.012), and the type of skin incision (P ≤ 0.001). Age (P = 0.283), sex (P = 0.558), body mass index (P = 0.221), and other blood test parameters did not demonstrate any statistical significance. Similarly, the presence of a dominant frontal branch (P = 0.515) or a low-positioned frontal branch (P = 0.622) did not reveal statistically significant results. CONCLUSIONS: In the treatment of complex intracranial aneurysms, where harvesting of the 2 STA branches is involved with a pterional craniotomy, producing a smaller skin flap (L- or T-shaped incision) is effective in minimizing the risk of delayed wound healing. The process of harvesting the STA and closing the wound demands meticulous care, taking into consideration the normal anatomical structures and the subdermal vascular plexus of the scalp.

Clinical Significance of Early Venous Filling Detected via Preoperative Angiography in Glioblastoma.

Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between 1 April 2013 and 31 March 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of the 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angiography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, p = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.

Retroperitoneal Hematoma During Prophylactic Dose of Heparin Therapy for Coronavirus Disease 2019.

We report a case of retroperitoneal hematoma during prophylactic heparin therapy for coronavirus disease 2019 (COVID-19). A 79-year-old man was diagnosed with COVID-19 pneumonia with possible exacerbation of fibrotic hypersensitivity pneumonia. He received a prophylactic dose of subcutaneous heparin therapy, methylprednisolone pulse therapy and Intravenous remdesivir but developed a spontaneous iliopsoas muscle hematoma, and transcatheter arterial embolization was performed. Even with a prophylactic dose of subcutaneous heparin therapy, the course should be carefully monitored, especially in patients with preexisting risk factors for hemorrhagic complications. Once retroperitoneal hematoma develops, aggressive procedures, such as transcatheter arterial embolization, should be considered to avoid fatal outcomes.

First reports of clinical effects of transjugular intrahepatic portosystemic shunt in four patients with cirrhotic ascites refractory to tolvaptan.

OBJECTIVE: Ascites in patients with decompensated cirrhosis can lead to abdominal distention and decrease quality of life. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective agent in the treatment of ascites, whereas some patients are refractory to tolvaptan. The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) for these patients is not known. In this study, we performed TIPS for tolvaptan-refractory cirrhotic patients and analysed its efficacy and safety in these patients. DESIGN: This retrospective analysis included patients with liver cirrhosis who received TIPS for ascites or hydrothorax refractory to tolvaptan therapy along with conventional diuretics between January 2015 and May 2018 at Tokai University Hospital. We evaluated the efficacy and safety of TIPS. RESULTS: This study included four patients. All patients presented with Child-Pugh class B liver cirrhosis and model for end-stage liver disease-sodium scores were 10/12/14/16. TIPS was generated successfully without any major complications in all patients. The body weight decreased by a mean of 4.7 (SD=1.0) kg and estimated glomerular filtration rate improved from a mean of 38.2 (SD=10.3) to 59.5 (SD=25.0) mL/min/1.73 m2 in a month after TIPS procedure. CONCLUSION: TIPS is an effective potential treatment for ascites in patients with tolvaptan refractory condition. In appropriate patients who can tolerate TIPS, the treatment may lead towards renal function improvement.

A case of facial nerve palsy caused by severe head injury treated by translabyrinthine approach.

Background: Several treatments for traumatic facial paralysis have been reported, but the role of surgery is still controversial. Case Description: A 57-year-old man was admitted to our hospital with head trauma due to a fall injury. A total body computed tomography (CT) scan showed a left frontal acute epidural hematoma associated with a left optic canal and petrous bone fractures with the disappearance of the light reflex. Hematoma removal and optic nerve decompression were performed immediately. The initial treatment was successful with complete recovery of consciousness and vision. The facial nerve paralysis (House and Brackmann scale grade 6) did not improve after medical therapy, and thus, surgical reconstruction was performed 3 months after the injury. The left hearing was lost entirely, and the facial nerve was surgically exposed from the internal auditory canal to the stylomastoid foramen through the translabyrinthine approach. The facial nerve's fracture line and damaged portion were recognized intraoperatively near the geniculate ganglion. The facial nerve was reconstructed using a greater auricular nerve graft. Functional recovery was observed at the 6-months follow-up (House and Brackmann grade 4), with significant recovery in the orbicularis oris muscle. Conclusion: Interventions tend to be delayed, but it is possible to select a treatment method of the translabyrinthine approach.

Morphometric assessment of the left inferior phrenic vein in patients with portal hypertension.

The left inferior phrenic vein (LIPV) is a major drainage vessel of gastric varices and serves as an important conduit in endovascular treatment for gastric varices. The narrowing of LIPV has been empirically demonstrated and sometimes hinders catheter insertion for the treatment of gastric varices. We herein investigated the morphology of narrowed LIPV in patients with portal hypertension. Venograms of LIPV on 25 patients with gastric varices (15 males; 10 females; age range, 45-79 years with a mean of 67 years) were retrospectively reviewed, the following four parameters were measured: the diameter of LIPV, the diameter of narrowed LIPV, the narrowing rate, and the distance to narrowed LIPV from the left renal vein. On all 25 venograms, a narrowing was detected just above the common trunk with the left adrenal vein. The diameter of LIPV was 9.0 ± 4.2 mm, the diameter of narrowed LIPV was 5.1 ± 2.3 mm, the narrowing rate was 40.6 ± 16.0%, and the distance to narrowed LIPV from the left renal vein was 20.0 ± 7.4 mm. This anatomical information about the narrowing of LIPV may contribute to the safe and efficacious treatment of gastric varices.

Relationship Between Serum Eicosapentaenoic Acid to Arachidonic Acid Ratio and Atherosclerotic Risk Factors in Patients With Peripheral Artery Disease.

BACKGROUND: The eicosapentaenoic acid to arachidonic acid ratio (EPA/AA) is attracting attention as a risk factor for peripheral artery disease (PAD). However, there have been few studies investigating the relationship between the EPA/AA ratio and atherosclerotic risk factors in patients with PAD. The purpose of the present study was to analyze atherosclerotic risk factors in patients with PAD to identify those factors associated with a low EPA/AA ratio. METHODS.: The data of patients treated for symptomatic PAD at Tokyo Medical University Hospital and Eniwa Midorino Clinic between April 2014 and March 2018 were retrospectively analyzed. RESULTS.: A total of 149 patients were tested for blood levels of n-3 and n-6 polyunsaturated fatty acids, including EPA and AA. 73 patients had a low EPA/AA ratio (<0.4) and 76 patients had a high EPA/AA ratio (≥ 0.4). Univariate analysis showed that older age (≥ 75 years), female sex, smoking history, body mass index (BMI), and hemoglobin A1C (HbA1C) were associated with the low EPA/AA ratio. Multivariable analysis showed that older age (odds ratio [OR], 0.34; 95% confidential interval [CI], 0.15-0.76; p = 0.008), BMI (OR, 0.87; 95% CI, 0.77-0.98; p = 0.027), smoking history (OR, 2.67; 95% CI, 1.09-6.55; p = 0.007), and HbA1C (OR, 0.46; 95% CI, 0.29-0.72; p = 0.020) were independently associated with the low EPA/AA ratio. CONCLUSIONS.: The EPA/AA ratio was related to existing arteriosclerotic risk factors in patients with PAD; it was positively correlated with older age, increasing BMI, and higher HbA1C, whereas it was negatively correlated with smoking history. These results suggest that the EPA/AA ratio may be closely intertwined with other atherosclerotic risk factors and have an influence on cardiovascular health.

Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency.

Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, but 60% of conventional [vein-to-artery (V-A)] AVF fail to mature, and only 50% remain patent at 1 year. We previously showed improved maturation and patency in a pilot study of the radial artery deviation and reimplantation (RADAR) technique that uses an artery-to-vein (A-V) configuration. Here, we show that RADAR exhibits higher rates of maturation, as well as increased primary and secondary long-term patencies. RADAR is also protective in female patients, where it is associated with decreased reintervention rates and improved secondary patency. RADAR and conventional geometries were compared further in a rat bilateral carotid artery-internal jugular vein fistula model. There was decreased cell proliferation and neointimal hyperplasia in the A-V configuration in male and female animals, but no difference in hypoxia between the A-V and V-A configurations. Similar trends were seen in uremic male rats. The A-V configuration also associated with increased peak systolic velocity and expression of Kruppel-like factor 2 and phosphorylated endothelial nitric oxide synthase, consistent with improved hemodynamics. Computed tomography and ultrasound-informed computational modeling showed different hemodynamics in the A-V and V-A configurations, and improving the hemodynamics in the V-A configuration was protective against neointimal hyperplasia. These findings collectively demonstrate that RADAR is a durable surgical option for patients requiring radial-cephalic AVF for hemodialysis access.

Altered hemodynamics during arteriovenous fistula remodeling leads to reduced fistula patency in female mice.

OBJECTIVE: The arteriovenous fistula (AVF) is the preferred method of dialysis access because of its proven superior long-term outcomes.However, women havelower rates of AVF patency andutilizationthan men.We used a novel mouseAVF model that recapitulates human AVF maturation to determine whether there are differences in AVF patency in female and male mice. METHODS: Aortocaval fistulas were created in female and male C57BL/6 mice (9-10 weeks). At days 0, 3, 7, and 21, infrarenal inferior vena cava (IVC) and aortic diameters and flow velocity were monitored by Doppler ultrasound and used to calculate the vessel diameter, blood flow, and shear stress. AVF were harvested, and expression of proteins was examined by proteomic analysis and immunofluorescence and of messenger RNA by quantitative polymerase chain reaction analysis. RESULTS: At baseline, female mice weighed less and had lower IVC velocity and smaller magnitudes of shear stress, but there was no significant difference in IVC diameter and thickness. After AVF creation, both female and male mice had similar IVC dilation and thickening with no significant differences in IVC wall thickness at day 21. However, female mice had diminished AVF patency by day 42 (25.7% vs 64.3%; P = .039). During fistula remodeling, female mice had lower IVC mean velocity and shear stress magnitude and increased spectral broadening (days 0-21). Messenger RNA and protein expression of Krüppel-like factor 2, endothelial nitric oxide synthase, and vascular cell adhesion molecule 1 was similar at baseline in female and male mice but increased in the AVF only in male mice but not in female mice (day 21). Proteomic analysis of female and male mice detected 56 proteins expressed at significantly higher levels in the IVC of female mice and 67 proteins expressed at significantly higher levels in the IVC of male mice (day 7); function-specific analysis showed that the IVC of male mice overexpressed proteins that belong to pathways implicated in the regulation of vascular function, thrombosis, response to flow, and vascular remodeling. CONCLUSIONS: AVF in female mice have diminished patency, preceded by lower velocity, reduced magnitudes of shear stress, and less laminar flow during remodeling. There is also sex-specific differential expression of proteins involved in thrombosis, response to laminar flow, inflammation, and proliferation. These findings suggest that hemodynamic changes during fistula maturation may play an important role underlying the diminished rates of AVF utilization in women. CLINICAL RELEVANCE: Women have lower rates of arteriovenous fistula (AVF) utilization than men. Using a mouse AVF model that recapitulates human AVF maturation, we show that female mice have similar AVF remodeling but diminished patency. AVF remodeling in female mice is associated with reduced shear stress and laminar flow; lack of increased transcription and translation of several anti-inflammatory, antiproliferative, and laminar flow response proteins (endothelial nitric oxide synthase, Krüppel-like factor 2, and vascular cell adhesion molecule 1); and different patterns of expression of pathways that regulate thrombosis and venous remodeling. Identifying downstream targets involved in these mechanisms may improve AVF outcomes in female patients.

A mouse model of stenosis distal to an arteriovenous fistula recapitulates human central venous stenosis.

OBJECTIVE: Central venous stenosis (CVS) is a major cause of arteriovenous fistula (AVF) failure. However, central veins are relatively inaccessible to study with conventional Doppler ultrasound methods. To understand mechanisms underlying AVF failure owing to CVS, an animal model was established that creates a stenosis distal to an AVF. We hypothesized that this mouse model will show comparable morphology and physiology to human CVS. METHODS: An aortocaval fistula was created between the distal aorta and inferior vena cava (IVC); a stenosis was then created distal to the fistula by partial IVC ligation. Sham-operated animals, AVF without venous stenosis, and venous stenosis without AVF were used as controls. Physiologic properties of the IVC, both upstream and downstream of the stenosis, or the corresponding sites in models without stenosis, were assessed with ultrasound examination on days 0 to 21. The spectral broadening index was measured to assess the degree of disturbed shear stress. The IVC was harvested at day 21 and specimens were analyzed with immunofluorescence. RESULTS: The IVC diameter of mice with an AVF and stenosis showed increased upstream (P = .013), but decreased downstream diameter (P = .001) compared with mice with an AVF but without a stenosis, at all postoperative times (days 3-21). IVC wall thickness increased in mice with an AVF, compared with IVC without an AVF (upstream of stenosis: 13.9 µm vs 11.0 µm vs 4.5 µm vs 3.9 µm; P = .020; downstream of stenosis: 6.0 µm vs 6.6 µm vs µm 4.5 µm vs 3.8 µm; P = .002; AVF with stenosis, AVF, stenosis, sham, respectively). AVF patency significantly decreased in mice with an AVF and stenosis by day 21 (50% vs 90%; P = .048). The IVC of mice with AVF and stenosis showed a venous waveform with pulsatility as well as enhanced velocity at and downstream of the stenosis; similar waveforms were observed in a human case of CVS. Downstream to the stenosis, the spectral broadening index was significantly higher compared with mice with AVF alone (1.06 vs 0.78; P = .011; day 21), and there was a trend towards less immunoreactivity of both Krüppel-like factor 2 and phosphorylated-endothelial nitric oxide synthase compared with mice with an AVF alone. CONCLUSIONS: Partial IVC ligation distal to a mouse aortocaval fistula alters the fistula diameter and wall thickness, decreases patency, and increases distal disturbed flow compared with fistulae without a distal stenosis. Our mouse model of stenosis distal to an AVF may be a faithful representation of human CVS that shows similar morphology and physiology, including disturbed shear stress.

Author Correction: Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tissue-Engineered Vascular Grafts with Advanced Mechanical Strength from Human iPSCs.

Vascular smooth muscle cells (VSMCs) can be derived in large numbers from human induced pluripotent stem cells (hiPSCs) for producing tissue-engineered vascular grafts (TEVGs). However, hiPSC-derived TEVGs are hampered by low mechanical strength and significant radial dilation after implantation. Here, we report generation of hiPSC-derived TEVGs with mechanical strength comparable to native vessels used in arterial bypass grafts by utilizing biodegradable scaffolds, incremental pulsatile stretching, and optimal culture conditions. Following implantation into a rat aortic model, hiPSC-derived TEVGs show excellent patency without luminal dilation and effectively maintain mechanical and contractile function. This study provides a foundation for future production of non-immunogenic, cellularized hiPSC-derived TEVGs composed of allogenic vascular cells, potentially serving needs to a considerable number of patients whose dysfunctional vascular cells preclude TEVG generation via other methods.

Molecular Targets for Improving Arteriovenous Fistula Maturation and Patency.

The increasing prevalence of chronic and end-stage renal disease creates an increased need for reliable vascular access, and although arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, 60% fail to mature and only 50% remain patent at one year. Fistulae mature by diameter expansion and wall thickening; this outward remodeling of the venous wall in the fistula environment relies on a delicate balance of extracellular matrix (ECM) remodeling, inflammation, growth factor secretion, and cell adhesion molecule upregulation in the venous wall. AVF failure occurs via two distinct mechanisms with early failure secondary to lack of outward remodeling, that is insufficient diameter expansion or wall thickening, whereas late failure occurs with excessive wall thickening due to neointimal hyperplasia (NIH) and insufficient diameter expansion in a previously functional fistula. In recent years, the molecular basis of AVF maturation and failure are becoming understood in order to develop potential therapeutic targets to aide maturation and prevent access loss. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors, along with their ligands, ephrins, determine vascular identity and are critical for vascular remodeling in the embryo. Manipulation of Eph receptor signaling in adults, as well as downstream pathways, is a potential treatment strategy to improve the rates of AVF maturation and patency. This review examines our current understanding of molecular changes occurring following fistula creation, factors predictive of fistula success, and potential areas of intervention to decrease AVF failure.