LncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas.

Arteriovenous fistulas (AVFs) are the most common vascular access points for hemodialysis (HD), but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia (NIH). Our previous studies have revealed a highly conserved LncRNA-LncDACH1 as an important regulator of cardiomyocyte and fibroblast proliferation. Herein, we find that LncDACH1 regulates NIH in AVF in male mice with conditional knockout of smooth muscle cell-specific LncDACH1 and in male mice model of AVF with LncDACH1 overexpression by adeno-associated virus. Mechanistically, silence of LncDACH1 activates p-AKT through promoting the expression of heat shock protein 90 (HSP90) and serine/arginine-rich splicing factor protein kinase 1 (SRPK1). Moreover, LncDACH1 is transcriptionally activated by transcription factor KLF9 that binds directly to the promoter region of the LncDACH1 gene. In this work, during AVF NIH, LncDACH1 is downregulated by KLF9 and promotes NIH through the HSP90/ SRPK1/ AKT signaling axis.

Endothelialization of PTFE-covered stents for aneurysms and arteriovenous fistulas created in canine carotid arteries.

To investigate the endothelialization of covered and bare stents deployed in the canine carotid arteries and subclavian arteries for treating experimental aneurysms and arteriovenous fistulas, twenty aneurysms were created in 10 dogs, and 20 fistulas in another 10 dogs. The Willis balloon-expandable covered stent and a self-expandable covered stent were used to treat these lesions, and a self-expandable bare stent was deployed in the subclavian artery for comparison. Followed up for up to 12 months, the gross observation, pathological staining, and scanning electronic microscopic data were analyzed. Two weeks after creation of animal model, thirty self-expandable covered stents and ten balloon-expandable covered stents were deployed. Fifteen bare stents were deployed within the left subclavian arteries. Twenty days after stenting, the aneurysm significantly shrank. At 6 months, the thrombi within the aneurysm cavity were organized. Three to 12 months later, most covered and bare stents were covered by a thin transparent or white layer of endothelial intima. Layers of intima or pseudomembrane were formed on the stent 20-40 days after stent deployment. Over three months, the pseudomembrane became organized, thinner, and merged into the vascular wall. Under scanning electronic microscopy, the surface of covered and bare stents had only deposition of collagen fibers and rare endothelial cells 20-40 days after stenting. From three to ten months, the endothelial cells on the internal surface of stent became mature, with spindle, stripe-like or quasi round morphology along the blood flow direction. Over time, the endothelial cells became mature. In conclusion, three months after deployment in canines' arteries, the self-expandable bare and covered stents have mostly been covered by endothelial cells which become maturer over time, whereas the balloon-expandable covered stents do not have complete coverage of endothelial cells at three months, especially for protruding stent struts and areas. Over time, the endothelialization will become mature.

Bioresorbable Mesenchymal Stem Cell-Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation in a Rat Model of Chronic Kidney Disease.

Bioresorbable perivascular scaffolds loaded with antiproliferative agents have been shown to enhance arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). These scaffolds, which can mimic the three-dimensional architecture of the vascular extracellular matrix, also have an untapped potential for the local delivery of cell therapies against NIH. Hence, an electrospun perivascular scaffold from polycaprolactone (PCL) to support mesenchymal stem cell (MSC) attachment and gradual elution at the AVF's outflow vein is fabricated. Chronic kidney disease (CKD) in Sprague-Dawley rats is induced by performing 5/6th nephrectomy, then AVFs for scaffold application are created. The following groups of CKD rats are compared: no perivascular scaffold (i.e., control), PCL alone, and PCL+MSC scaffold. PCL and PCL+MSC significantly improve ultrasonographic (i.e., luminal diameter, wall-to-lumen ratio, and flow rate) and histologic (i.e., neointima-to-lumen ratio, neointima-to-media ratio) parameters compared to control, with PCL+MSC demonstrating further improvement in these parameters compared to PCL alone. Moreover, only PCL+MSC significantly reduces 18 F-fluorodeoxyglucose uptake on positron emission tomography. These findings suggest that adding MSCs promotes greater luminal expansion and potentially reduces the inflammatory process underlying NIH. The results demonstrate the utility of mechanical support loaded with MSCs at the outflow vein immediately after AVF formation to support maturation by minimizing NIH.

Spinal Dorsal Intradural Arteriovenous Fistulas: Natural History, Imaging, and Management.

In this review, we describe the pathophysiology, diagnosis, and treatment of spinal dorsal intradural arteriovenous fistulas (DI-AVFs), focusing on novel research areas. DI-AVFs compose the most common subgroup of spinal arteriovenous lesions and most commonly involve the thoracic spine, followed by lumbar and sacral segments. The pathogenesis underlying DI-AVFs is an area of emerging understanding, thought to be attributable to venous congestion and hypertension that precipitate ascending myelopathy. Patients with DI-AVFs typically present with motor, sensory, or urinary dysfunction, although a wide swath of other less common symptoms has been reported. DI-AVFs can be subdivided by spinal region, which in turn is associated with 4 distinct clinical phenotypes: craniocervical junction (CCJ), subaxial cervical, thoracic, and lumbosacral. Patients with CCJ and lumbosacral DI-AVFs have particularly interesting presentations and treatment considerations. High-value diagnostic findings on MRI include flow voids, missing-piece sign, and T2-weighted intramedullary hyperintensity. However, digital subtraction angiography is the gold standard for diagnosis and localization of DI-AVFs and for definitive treatment planning. Surgical disconnection of DI-AVFs is almost universally curative and frontline treatment, especially for CCJ and lumbosacral DI-AVFs. Endovascular techniques evolve in promising ways, such as improved visualization, distal access, and liquid embolic techniques. The pathophysiology of DI-AVFs is better understood using newly identified radiologic diagnostic markers. Despite new techniques and devices introduced in the endovascular field, surgery remains the gold-standard treatment for DI-AVFs.

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

Rates of arteriovenous fistula maturation failure are still high, especially when suboptimal size veins are used. During successful maturation, the vein undergoes lumen dilatation and medial thickening, adapting to the increased hemodynamic forces. The vascular extracellular matrix plays an important role in regulating these adaptive changes and may be a target for promoting fistula maturation. In this study, we tested whether a device-enabled photochemical treatment of the vein prior to fistula creation facilitates maturation. Sheep cephalic veins were treated using a balloon catheter coated by a photoactivatable molecule (10-8-10 Dimer) and carrying an internal light fiber. As a result of the photochemical reaction, new covalent bonds were created during light activation among oxidizable amino acids of the vein wall matrix proteins. The treated vein lumen diameter and media area became significantly larger than the contralateral control fistula vein at 1 week (p = 0.035 and p = 0.034, respectively). There was also a higher percentage of proliferating smooth muscle cells in the treated veins than in the control veins (p = 0.029), without noticeable intimal hyperplasia. To prepare for the clinical testing of this treatment, we performed balloon over-dilatation of isolated human veins and found that veins can tolerate up to 66% overstretch without notable histological damage.

Congestive myelopathy due to craniocervical junction arteriovenous fistulas mimicking transverse myelitis: a multicenter study on 27 cases.

BACKGROUND: The purpose was to clarify diagnostic clues and pitfalls in cranio-cervical junction arteriovenous fistulas (CCJ AVFs) with congestive myelopathy. METHODS: In a multicenter observational study by the Neurospinal Society of Japan, we described the demographics, clinical courses, imaging findings, and outcomes of consecutive patients with CCJ AVFs presenting with congestive myelopathy between 2009 and 2019. RESULTS: Twenty-seven patients were included (mean age, 70 years; male, 96%). Progressive symptoms within one day to one month were more common (63%) than chronic symptoms. Myelopathic symptoms were characterized by ascending paralysis beginning from the legs, involving the trunk and arms, and sometimes ending in the brainstem. Fifteen patients (56%) received a misdiagnosis, including acute transverse myelitis. The most common MRI findings were venous congestive edema of the cervical cord (96%) and the brainstem (63%) and surrounding vascular flow voids (100%). The mean extension of congestive edema was 5.5 ± 2.9 vertebral segments. The most common angiographic findings were a dural AVF (78%) at the C1 level (81%) with descending venous drainage (85%). Seven patients (26%) were administered steroids, which resulted in neurological decline in 3. Neurosurgical obliteration of the AVF led to improvements in MRI findings in 75% and a functional status in 67%; however, 44% remained dependent. CONCLUSIONS: The myelopathy of CCJ AVFs was characterized by acute ascending paralysis in elderly men. A misdiagnosis was common because of the acute presentation due to a longitudinally extensive spinal cord lesion. Dilated vessels on MRI were a key finding for the correct diagnosis. What is already known on this topic? Slowly progressive myelopathy is a well-known symptom that results from impaired spinal venous drainage due to thoracolumbar AVFs. Although cranio-cervical junction arteriovenous fistulas (CCJ AVFs) constitute a treatable cause of congestive myelopathy, detailed information is not currently available due to their rarity. What does this study add? CCJ AVFs often presented with acute ascending myelopathy in elderly men due to a longitudinally extending cervical cord lesion with surrounding flow voids. Steroid pulse therapy was not effective or even harmful to congestive myelopathy, while neurosurgical treatment effectively obliterated AVFs. How might this study affect research, practice or policy? The results obtained revealed diagnostic clues and pitfalls from the largest dataset of patients with CCJ AVFs in a multicenter cohort.

Filum terminale arteriovenous shunt with nidus structure: a report of rare condition and treatment consideration.

BACKGROUND:  In the literature, filum terminale arteriovenous shunts (FTAVSs) always feature a single shunt point. Nidus-type FTAVSs have rarely been reported, and the best treatment strategy is unclear. This is a report of one exceptional case of a nidus-type FTAVS and surgical treatment of the lesion. CASE DESCRIPTION: The patient suffered from cauda equina syndrome for 9 months. Magnetic resonance imaging and spinal angiography revealed a nidus-type FTAVF at the L2 level. Surgical resection was performed in the hybrid operating room, and the nidus was completely resected with the assistance of intraoperative methylene blue angiography and neurophysiological monitoring. The postoperative neurological function was stable. CONCLUSIONS: A nidus-type arteriovenous shunt could originate from the FT, and in such cases, complete surgical resection with intraoperative neurophysiological monitoring in a hybrid operating room should be suggested.

Neurofibromatosis type 1, severe cervical spinal kyphotic deformity, and vertebral arteriovenous fistula presenting with tetraplegia: case report and literature review.

INTRODUCTION: Neurofibromatosis type 1 (NF-1) is an autosomal-dominant disorder affecting 1 in 3000 individuals worldwide. NF-1 is characterized by café-au-lait macules and peripheral nerve sheath tumors. Patients with NF-1 frequently exhibit bony dysplasia, including spinal deformities such as scoliosis or kyphosis, pseudarthrosis of the tibia, and soft tissue tumors. Some patients with NF-1 exhibit spinal changes, including acutely angled cervical kyphosis. Prior studies have also described arteriovenous (AV) fistulas in individuals with NF-1, as well as a predisposition to cervical fistulas which display symptoms secondary to mass effect, rather than hemorrhage. Sometimes, fistulas are incidentally detected during evaluations for cervical kyphotic deformities. CASE PRESENTATION: The case herein describes a patient with NF-1 who exhibited a severe cervical spinal kyphotic deformity and a vertebral AV fistula. The patient initially presented with neck pain that radiated to all four limbs and resulted in limb weakness. DISCUSSION: Spinal kyphosis is common in patients with NF-1, and if dystrophic changes are noted on plain radiographs, MRI should be considered for the further survey of potential spinal vascular lesions.

Heme Oxygenase 1/Peroxisome Proliferator-Activated Receptor Gamma Pathway Protects Intimal Hyperplasia and Mitigates Arteriovenous Fistula Dysfunction by Regulating Oxidative Stress and Inflammatory Response.

Purpose: An arteriovenous fistula (AVF) is the preferred vascular access mode for maintenance hemodialysis, and access stenosis and thrombosis are the primary causes of AVF dysfunction. This study is aimed at exploring the molecular mechanisms underlying AVF development and the roles of the heme oxygenase 1/peroxisome proliferator-activated receptor gamma (HO-1/PPAR-γ) pathway in AVF. Method: AVF model mice were established, and the vascular tissues from the arteriovenous anastomosis site were sent for mRNA sequencing. Differentially expressed mRNAs (DEmRNAs) were screened and subjected to functional analysis. Thereafter, the mice with HO-1 knockdown and coprotoporphyrin IX chloride (COPP) pretreatment were used to investigate the roles of the HO-1/PPAR-γ pathway in AVF. Results: By sequencing, 2514 DEmRNAs, including 1323 upregulated and 1191 downregulated genes, were identified. These DEmRNAs were significantly enriched in the PPAR signaling pathway, AMPK signaling pathway, glucagon signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway. High expression of HO-1 and PPAR-γ reduced endothelial damage and intimal hyperplasia during AVF maturation. After AVF was established, the levels of transforming growth factor-ß (TGF-ß), interleukin-1ß (IL-1ß), interleukin-18 (IL-18), and reactive oxygen species (ROS) were significantly increased (P < 0.05), and HO-1 normal expression and COPP pretreatment evidently decreased their levels in AVF (P < 0.05). Additionally, AVF significantly upregulated HO-1 and PPAR-γ and downregulated MMP9, and COPP pretreatment and HO-1 normal expression further upregulated and downregulated their expression. Conclusion: The HO-1/PPAR-γ pathway may suppress intimal hyperplasia induced by AVF and protect the intima of blood vessels by regulating MMP9 and ROS, thus mitigating AVF dysfunction.

Long-term outcomes of Spetzler-Martin grade IV and V arteriovenous malformations: a single-center experience.

OBJECTIVE: This study aimed to explore whether intervention can benefit Spetzler-Martin (SM) grade IV-V arteriovenous malformations (AVMs). METHODS: Eighty-two patients with SM grade IV-V AVMs were retrospectively reviewed from 2015 to 2018. Patients were divided into two groups: those who received conservative management (22 cases [26.8%]) and intervention (60 cases [73.2%], including 21 cases of microsurgery, 19 embolization, and 20 hybrid surgery). Neurofunctional outcomes were assessed with the modified Rankin Scale (mRS). The primary outcome was long-term neurofunctional status, and the secondary outcomes were short-term neurofunctional status, long-term obliteration rate, seizure control, and risk of subsequent hemorrhage. RESULTS: Regarding the primary outcome, after an average of 4.7 years of clinical follow-up, long-term neurofunctional outcomes were similar after conservative management or intervention (absolute difference -0.4 [95% CI -1.5 to 0.7], OR 0.709 [95% CI 0.461-1.090], p = 0.106), whereas intervention had an advantage over conservative management for avoidance of severe disability (defined as mRS score > 3) (1.7% vs 18.2%, absolute difference 16.5% [95% CI -23.6% to 56.6%], OR 0.076 [95% CI 0.008-0.727], p = 0.025). Regarding the secondary outcomes, intervention was conducive to better seizure control (Engel class I-II) (70.0% vs 0.0%, absolute difference 70.0% [95% CI 8.6%-131.4%], p = 0.010) and avoidance of subsequent hemorrhage (1.4% vs 6.0%, absolute difference 4.6% [95% CI -0.4% to 9.6%], p = 0.030). In the subgroup analysis based on different intervention modalities, microsurgery and hybrid surgery achieved higher complete obliteration rates than embolization (p < 0.001), and hybrid surgery resulted in significantly less intraoperative blood loss than microsurgery (p = 0.041). CONCLUSIONS: Intervention is reasonable for properly indicated SM grade IV-V AVMs because it provides satisfactory seizure control with decreased risks of severe disability and subsequent hemorrhage than conservative management. Clinical trial registration no.: NCT04572568 (ClinicalTrials.gov).

Pathological Analysis of Vascularization of the Arterialized Veins in Failed Arteriovenous Fistulae.

PURPOSE: To assess venous wall vascularization and its correlation with neointimal hyperplasia (NIH) in failed arteriovenous fistulae (AVFs). MATERIALS AND METHODS: A total of 43 uremic patients who underwent de novo AVF creation and 39 patients who underwent reconstruction of failed fistulae were enrolled in the study. A 5-10-mm vein segment adjacent to the future fistula creation or reconstruction site was surgically removed and assessed using histopathological analyses and stained by immunohistochemistry to quantify vasa vasorum density (VVD). RESULTS: Both the intimal thickness (70.68 [28.81-99.54] vs 4.53 [2.69-7.30] µm, P < .001) and the intimal thickness-to-medial thickness ratio (2.20 [0.77-4.36] vs 0.15 [0.10-0.30], P < .001) were higher in failed AVFs than in preaccess veins. CD31- and factor VIII-marked VVDs in both the intima (6.31 [1.62-12.53] vs 0.0 [0.0-0.0], P < .001; 7.82 [3.33-11.61] vs 0.0 [0.0-0.0], P < .001) and media (10.0 [7.59-12.95] vs 3.71 [2.44-4.87], P < .001; 8.33 [5.55-13.0] vs 3.57 [2.53-4.82], P < .001) as well as the intimal VVD:medial VVD ratio (0.67 [0.19-1.08] vs 0.0 [0.0-0.0], P < .001; 0.71 [0.39-1.14] vs 0.0 [0.0-0.0], P < .001) were significantly higher in failed AVFs than in preaccess veins. Moreover, there was a positive relationship between the intimal VVD:medial VVD ratio and the intimal thickness:medial thickness ratio (P < .001). In addition, the vascular endothelial cell growth factor A expression was higher in failed AVFs than in preaccess veins. CONCLUSIONS: Vascularization of the vessel wall was noticeably more developed in the arterialized veins, especially at the NIH regions in failed AVFs.

IN.PACT AV Access Trial: Economic Evaluation of Drug-Coated Balloon Treatment for Dysfunctional Arteriovenous Fistulae Based on 12-Month Clinical Outcomes.

PURPOSE: To study, from a U.S. payer's perspective, the economic consequences of drug-coated balloon (DCB) versus standard percutaneous transluminal angioplasty (PTA) use for the treatment of stenotic lesions in dysfunctional hemodialysis arteriovenous fistulae. MATERIALS AND METHODS: Cost differences between DCBs and PTA at year 1 and beyond were calculated via 2 methods. The first approach used the mean absolute number of trial-observed access circuit reinterventions through 12 months (0.65 ± 1.05 vs 1.05 ± 1.18 events per patient for DCBs and PTA, respectively) and projected treatment outcomes to 3 years. The second approach was based on the trial-observed access circuit primary patency rates at 12 months (53.8% vs 32.4%) and calculated the cost difference on the basis of previously published Medicare cost for patients who maintained or did not maintain primary patency. Assumptions regarding DCB device prices were tested in sensitivity analyses, and the numbers needed to treat were calculated. RESULTS: Using the absolute number of access circuit reinterventions approach, the DCB strategy resulted in an estimated per-patient savings of $1,632 at 1 year and $4,263 at 3 years before considering the DCB device cost. The access circuit primary patency approach was associated with a per-patient cost savings of $2,152 at 1 year and $3,894 at 2.5 years of follow-up. At the theoretical DCB device reimbursement of $1,800, savings were $1,680 and $2,049 at 2.5 and 3 years, respectively. The one-year NNT of DCB compared to PTA was 2.48. CONCLUSIONS: Endovascular therapy for arteriovenous access stenosis with the IN.PACT AV DCB can be expected to be cost-saving if longer follow-up data confirm its clinical effectiveness.

Downregulation of the endothelial histone demethylase JMJD3 is associated with neointimal hyperplasia of arteriovenous fistulas in kidney failure.

Jumonji domain-containing protein-3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase, promotes endothelial regeneration, but its function in neointimal hyperplasia (NIH) of arteriovenous fistulas (AVFs) has not been explored. In this study, we examined the contribution of endothelial JMJD3 to NIH of AVFs and the mechanisms underlying JMJD3 expression during kidney failure. We found that endothelial JMJD3 expression was negatively associated with NIH of AVFs in patients with kidney failure. JMJD3 expression in endothelial cells (ECs) was also downregulated in the vasculature of chronic kidney disease (CKD) mice. In addition, specific knockout of endothelial JMJD3 delayed EC regeneration, enhanced endothelial mesenchymal transition, impaired endothelial barrier function as determined by increased Evans blue staining and inflammatory cell infiltration, and accelerated neointima formation in AVFs created by venous end to arterial side anastomosis in CKD mice. Mechanistically, JMJD3 expression was downregulated via binding of transforming growth factor beta 1-mediated Hes family transcription factor Hes1 to its gene promoter. Knockdown of JMJD3 enhanced H3K27 methylation, thereby inhibiting transcriptional activity at promoters of EC markers and reducing migration and proliferation of ECs. Furthermore, knockdown of endothelial JMJD3 decreased endothelial nitric oxide synthase expression and nitric oxide production, leading to the proliferation of vascular smooth muscle cells. In conclusion, we demonstrate that decreased expression of endothelial JMJD3 impairs EC regeneration and function and accelerates neointima formation in AVFs. We propose increasing the expression of endothelial JMJD3 could represent a new strategy for preventing endothelial dysfunction, attenuating NIH, and improving AVF patency in patients with kidney disease.

Inhibition of ß-catenin signaling attenuates arteriovenous fistula thickening in mice by suppressing myofibroblasts.

BACKGROUND: Arteriovenous fistula (AVF) is the most important vascular access for hemodialysis; however, preventive treatment to maintain the patency of AVFs has not been developed. In endothelium, ß-catenin functions in both the intercellular adherens complex and signaling pathways that induce the transition of endothelial cells to myofibroblasts in response to mechanical stimuli. We hypothesize that mechanical disturbances in the AVF activate ß-catenin signaling leading to the transition of endothelial cells to myofibroblasts, which cause AVF thickening. The present study aimed to test this hypothesis. METHODS: Chronic kidney disease in mice was induced by a 0.2% adenine diet. AVFs were created by aortocaval puncture. Human umbilical vein endothelial cells (HUVECs) were used in the cell experiments. A pressure-culture system was used to simulate mechanical disturbances of the AVF. RESULTS: Co-expression of CD31 and smooth muscle alpha-actin (αSMA), loss of cell-cell adhesions, and the expression of the myofibroblast marker, integrin subunit ß6 (ITGB6), indicated transition to myofibroblasts in mouse AVF. Nuclear translocation of ß-catenin, decreased axin2, and increased c-myc expression were also observed in the AVF, indicating activated ß-catenin signaling. To confirm that ß-catenin signaling contributes to AVF lesions, ß-catenin signaling was inhibited with pyrvinium pamoate; ß-catenin inhibition significantly attenuated AVF thickening and decreased myofibroblasts. In HUVECs, barometric pressure-induced nuclear localization of ß-catenin and increased expression of the myofibroblast markers, αSMA and ITGB6. These changes were attenuated via pretreatment with ß-catenin inhibition. CONCLUSIONS: The results of this study indicate that mechanical disturbance in AVF activates ß-catenin signaling to induce the transition of endothelial cells to myofibroblasts. This signaling cascade can be targeted to maintain AVF patency.

Circulating Interleukin-6 and CD16 positive monocytes increase following angioplasty of an arteriovenous fistula.

Arteriovenous fistulas are the ideal form of vascular access that allows provision of haemodialysis. Stenotic lesions caused by neointimal hyperplasia commonly occur resulting in patients requiring a fistuloplasty. This is effective but there is a high recurrence rate. We sought to investigate the effects of a fistuloplasty on monocyte populations. Blood samples were taken from patients before and after their fistuloplasty procedure. Samples were analysed using flow cytometry, ELISA and Luminex assays. Univariate cox regression was carried out to investigate associations with post fistuloplasty patency. At 1-2 days post fistuloplasty, the proportion of classical (CD14++CD16-) monocytes decreased (p < 0.001), whilst intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocytes increased (both p < 0.01) in a cohort of 20 patients. A time course study carried out in 5 patients showed that this was due to an increase in absolute numbers of non-classical and intermediate monocytes. Higher levels of non-classical monocytes pre-fistuloplasty were associated with an increased risk for patency loss (p < 0.05). We measured 41 soluble factors in plasma samples taken before a fistuloplasty in 54 patients, with paired post-fistuloplasty samples (1-2 days) available in 30 patients. After correcting for false discovery, the only factor with a significant change in level was IL-6 (P = 0.0003, q = 0.0124). In a further time-course study in 6 patients, peak level of IL-6 occurred 2-3 h post fistuloplasty. This study demonstrates that there is a systemic inflammatory response to the fistuloplasty procedure and that monocyte subsets and IL-6 may be important in the pathophysiology of restenosis.

Intimal Hyperplasia and Arteriovenous Fistula Failure: Looking Beyond Size Differences.

The development of venous intimal hyperplasia (IH) has been historically associated with failure of arteriovenous fistulas (AVF) used for hemodialysis. This long-standing assumption, based on histological observations, has been recently challenged by clinical studies indicating that the size of the intima by itself is not enough to explain stenosis or AVF maturation failure. Irrespective of this lack of association, IH is present in most native veins and fistulas, is prominent in many cases, and suggests a role in the vein that may not be reflected by its dimensions. Therefore, the contribution of IH to AVF dysfunction remains controversial. Using only clinical data and avoiding extrapolations from animal models, we critically discuss the biological significance of IH in vein remodeling, vascular access function, and the response of the venous wall to repeated trauma in hemodialysis patients. We address questions and pose new ones such as: What are the factors that contribute to IH in pre-access veins and AVFs? Do cellular phenotypes and composition of the intima influence AVF function? Are there protective roles of the venous intima? This review explores these possibilities, with hopes of rekindling a critical discussion about venous IH that goes beyond thickness and AVF outcomes.

Natural History and Clinical Outcomes of Paravertebral Arteriovenous Shunts.

BACKGROUND AND PURPOSE: Paravertebral arteriovenous shunts (PVAVSs) are rare. Whether the intradural venous system is involved in drainage may lead to differences in clinical characteristics through specific pathophysiological mechanisms. This study aims to comprehensively evaluate the natural history and clinical outcomes of PVAVSs with or without intradural drainage. METHODS: Sixty-four consecutive patients with PVAVSs from 2 institutes were retrospectively reviewed. Lesions were classified as type A (n=28) if the intradural veins were involved in drainage; otherwise, they were classified as type B (n=36). The clinical course from initial presentation to the last follow-up was analyzed. RESULTS: The patients with type A shunts were older at presentation (52.5 versus 35.5 years, P<0.0001) and more likely to have lower spinal segments affected than patients with type B PVAVSs (67.8% versus 13.9%, P=0.00006). After presentation, the deterioration rates related to gait and sphincter dysfunction were significantly higher in patients with type A than type B shunts (gait dysfunction: 71.8%/y versus 17.0%/y, P=0.0006; sphincter dysfunction: 63.7%/y versus 11.3%/y, P=0.0002). According to the angiogram at the end of the latest treatment, 79% of type A and 75% of type B PVAVSs were completely obliterated. If the lesions were partially obliterated, a significantly higher clinical deterioration rate was observed in patients with type A shunts than those with type B shunts (69.9%/y versus 3.2%/y, P=0.0253). CONCLUSIONS: Type A PVAVSs feature rapid progressive neurological deficits; therefore, early clinical intervention is necessary. For complex lesions that cannot be completely obliterated, surgical disconnection of all refluxed radicular veins is suggested.