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Abstract Clinical outcomes of arteriovenous fistulae (AVF) for hemodialysis remain inadequate since biological mechanisms of AVF maturation and failure are still poorly understood. Aortocaval fistula creation (AVF group) or a sham operation (sham group) was performed in C57BL/6 mice. Venous limbs were collected on postoperative day 7 and total RNA was extracted for high throughput RNA sequencing and bioinformatic analysis. Genes in metabolic pathways were significantly downregulated in the AVF, whereas significant sex differences were not detected. Since gene expression patterns among the AVF group were heterogenous, the AVF group was divided into a ‘normal’ AVF (nAVF) group and an ‘outliers’ (OUT) group. The gene expression patterns of the nAVF and OUT groups were consistent with previously published data showing venous adaptive remodeling, whereas enrichment analyses showed significant upregulation of metabolism, inflammation and coagulation in the OUT group compared to the nAVF group, suggesting the heterogeneity during venous remodeling reflects early gene expression changes that may correlate with AVF maturation or failure. Early detection of these processes may be a translational strategy to predict fistula failure and reduce patient morbidity.

Arterial stiffening is associated with adverse cardiovascular patient outcomes; stiffness may also be associated with postsurgical events and has been suggested to be a fundamental mechanism in the pathogenesis of aortic aneurysms. Although open repair of aneurysms decreases aortic stiffness, implantation of a rigid endograft is associated with increased aortic stiffness after endovascular aneurysm repair (EVAR). This review provides an overview of aortic wall physiology and the contemporary understanding of aortic stiffness and its implications for patients undergoing abdominal aortic aneurysm repair. Recent data suggests that increased central arterial stiffness, estimated preoperatively using the pulse wave velocity (PWV), may predict aneurysm sac behavior after EVAR, with elevated preoperative PWV associated with less sac shrinkage, and even sac enlargement, after EVAR. With the development of several simple noninvasive methods to measure PWV, such as brachial-ankle PWV and single cuff brachial oscillometry, there may be a role for monitoring ambulatory PWV to predict outcomes after EVAR. Additionally, because aortic stiffness is associated with adverse cardiovascular outcomes, and EVAR increases aortic stiffness, assessment of aortic stiffness before aortic interventions may help to guide therapeutic decisions as well as surveillance protocols, leading to optimized patient outcomes.

Background: Peripheral artery disease (PAD) impacts more than 200 million people worldwide. The understanding of the genetics of the disease and its clinical implications continue to evolve. This systematic review provides a comprehensive summary of all DNA variants that have been studied in association with the diagnosis and progression of PAD, with a meta-analysis of the ones replicated in the literature. Methods: A systematic review of all studies examining DNA variants associated with the diagnosis and progression of PAD was performed. Candidate gene and genome-wide association studies (GWAS) were included. A meta-analysis of 13 variants derived from earlier smaller candidate gene studies of the diagnosis of PAD was performed. The literature on the progression of PAD was limited, and a meta-analysis was not feasible because of the heterogeneity in the criteria used to characterize it. Results: A total of 231 DNA variants in 112 papers were studied for the association with the diagnosis of PAD. There were significant variations in the definition of PAD and the selection of controls in the various studies. GWAS have established 19 variants associated with the diagnosis of PAD that were replicated in several large patient cohorts. Only variants in intercellular adhesion molecule-1 (rs5498), IL-6 (rs1800795), and hepatic lipase (rs2070895) showed significant association with the diagnosis of PAD. However, these variants were not noted in the published GWAS. Conclusions: Genetic research in the diagnosis of PAD has significant heterogeneity, but recent GWAS have demonstrated variants consistently associated with the disease. More research focusing on the progression of PAD is needed to identify patients at risk of adverse events and develop strategies that would improve their outcomes.

The role of the fractional flow reserve to guide lower extremity peripheral vascular intervention, specifically in chronic limb-threatening ischemia, has remained unclear. This series presents a novel use of the fractional flow reserve in four patients to guide lower extremity endovascular interventions in patients with chronic limb-threatening ischemia.

Hydrogel is a nature scaffold that can degraded in animal body and can be used as a drug delivery system, we hypothesized that patch made of three layers of hydrogel with different PLGA nanoparticle drugs (bio-patch) can be used to decrease venous neointimal hyperplasia. Rat inferior vena cava (IVC) patch venoplasty model was used. Samples from rat IVC direct suture (DS), decellularized thoracic artery patch (TA) venoplasty and bovine pericardial patch (BPP) venoplasty were examined at day 14 after implantation. Sodium alginate and hyaluronic acid (SA/HA) hydrogel was used, three layers hydrogel patch (control) and three layers hydrogel patch with PLGA nanoparticle drugs (bio-patch) were used in rat IVC venoplasty. Patches were harvested at day 14 and analyzed. In rats, TA and BPP patch showed a thicker neointima and adventitia compared to the DS, there were larger numbers of CD68 and PCNA positive cells in both groups. The control hydrogel patch showed much thinner neointima and adventitia compared to TA and BPP patches. In both of the neointima and peri-patch area, bio-patch showed significantly fewer smooth muscle cells, fewer CD68, fewer PCNA positive cells, fewer collagen-1 positive cells, fewer p-smad2 positive cells, fewer TNF-α positive cells compared to control hydrogel patch. Bio-patch made of hydrogel and PLGA nanoparticle drugs showed a thinner neointimal thickness, and is biocompatible to the animal body. These results showed the potential application of hydrogel patch in vascular surgery.

Objectives: High-intensity focused ultrasound (HIFU) is a noninvasive therapeutic modality with a variety of applications. It is approved for the treatment of essential tremors, ablation of prostate, hepatic, breast, and uterine tumors. Although not approved for use in the treatment of atherosclerotic arterial disease, there is a growing body of evidence investigating applications of HIFU. Currently, percutaneous endovascular techniques are predominant for the treatment of arterial pathology; however, there are no endovascular techniques of HIFU available. This study aims to review the state of current evidence for the application of HIFU in atherosclerotic arterial disease. Methods: All English-language articles evaluating the effect of HIFU on arterial occlusive and thrombotic disease until 2021 were reviewed. Both preclinical and human clinical studies were included. Study parameters such as animal or clinical model and outcomes were reviewed. In addition, details pertaining to settings on the HIFU device used were also reviewed. Results: In preclinical models, atherosclerotic plaque progression was inhibited by HIFU, through decreases in oxidized low-density lipoprotein cholesterol and increases in macrophage apoptosis. Additionally, HIFU promotes angiogenesis in hindlimb ischemic models by the upregulation of angiogenic and antiapoptotic factors, with increased angiogenesis at higher line densities of HIFU. HIFU also promotes thrombolysis and conversely induces platelet activation at low frequencies and higher intensities. Various clinical studies have attempted to translate some of these properties and demonstrated positive clinical outcomes for arterial recanalization after thrombotic stroke, decreased atherosclerotic plaque burden in carotid arteries, increase in tissue perfusion and a decrease in diameter stenosis in patients with atherosclerotic arterial disease. Conclusions: In current preclinical and clinical data, the safety and efficacy of HIFU shows great promise in the treatment of atherosclerotic arterial disease. Future focused studies are warranted to guide the refinement of HIFU settings for more widespread adoption of this technology.

The 2023 Vascular Research Initiatives Conference (VRIC) was held in Boston, Massachusetts, and coincided with the first day of Vascular Discovery 2023, hosted by the American Heart Association. VRIC attracts vascular clinicians, surgeon-scientists, and basic science researchers to a common arena to facilitate the exchange of basic and translational science to stimulate and inspire participants to study and find solutions to vascular conditions. The theme of the conference this year was “Structural and Immune Cells in Vascular Disease.” Abstract sessions focused on venous disease, vascular regeneration, stem cells and wound healing, aortopathies, and the role of the immune system in atherosclerosis. A moderated translational science panel included talks from Dr Chiara Giannarelli and Dr Bhama Ramkhelawon. Recipients of Society for Vascular Surgery partner grants and National Institutes of Health K08 awardees presented their progress reports, and the Resident Research and VRIC Trainee Awardees were acknowledged. The Alexander W. Clowes Distinguished Lecture, entitled “Co-stimulatory Immune Checkpoints in Atherosclerosis: Novel Immunotherapeutic Targets to Combat Atherosclerotic Cardiovascular Disease” was given by Dr Ester Lutgens. VRIC continues to foster interdisciplinary collaborations across the translational field of vascular disease.

T cells and macrophages play an important role in the formation of allograft vasculopathy, which is the predominant form of chronic rejection in cardiac transplants. Arteries express Ephrin-B2 as a marker of arterial identity, whereas circulating monocytes express the cognate receptor EphB4, which facilitates monocyte adhesion to the endothelial surface. Adherent monocytes transmigrate and differentiate into macrophages that activate T cells and are a main source of tissue damage during rejection. We hypothesized that inhibition of Ephrin-B2-EphB4 binding would decrease immune cell accumulation within a transplanted graft and prevent allograft vasculopathy. We used EphB4 monomer to inhibit Ephrin-B2-EphB4 binding in a rat infrarenal aortic transplant model. Rats treated with EphB4 monomer had fewer macrophages and T cells in the aortic allografts at 28 days, as well as significantly less neointima formation. These data show that the Ephin-B2-EphB4 axis may be an important target for prevention or treatment of allograft vasculopathy.

Bai et al. employ a fish bladder-derived decellularized matrix for the engineering of vascular grafts. The authors show that rapamycin-coated bladder-derived vascular grafts can be implanted as an interposition graft in rats, and that these vascular grafts showed decreased neointimal thickness both in artery and veins.

Secondary aortoenteric fistula is a potentially lethal complication after aortic surgery. Traditional treatment consists of open graft excision with extra-anatomic bypass or in situ reconstruction. Patients who present in extremis, however, are generally poor candidates for re-do open aortic surgery. Endovascular repair has emerged as an alternative treatment modality for patients who would otherwise be unable to tolerate an extended operation. We report here a case of urgent endovascular repair of a juxtarenal secondary aortoenteric fistula via endovascular aneurysm repair with a renal artery chimney in a patient with a solitary kidney who presented in hemorrhagic and septic shock.

ObjectiveThis study aimed to summarize the long-term experience of using the chimney technique in thoracic endovascular aortic repair (TEVAR) for aortic arch diseases.MethodsFrom November 2007 to June 2021, a total of 345 consecutive patients (mean age 56 ± 11.3 years, range 28–83, 302 men) with aortic arch pathologies underwent TEVAR combined with chimney technique (cTEVAR). Their medical data and follow-up results were retrospectively reviewed and analyzed.ResultsAmong the 345 patients, 278 (80.6%) received single chimneys, 53 (15.4%) received double chimneys, 7 (2%) received triple chimneys, and 7 (2%) underwent cTEVAR accompanied by other techniques (two with extra-anatomical bypass, two with in situ fenestration, and three with physician modified fenestration). A total of 412 chimney stents were used, including 27 in the innominate artery (IA), 113 in the left common carotid artery, 270 in the left subclavian artery, and two in the aberrant right subclavian artery. Early type IA endoleaks were found in 38 (11%) patients, including 12 with the double or triple chimney technique. Early type II endoleak was found in nine (2.6%) patients. Early re-intervention occurred in two patients with double chimney technique, one for chimney stent migration and the other for compression of chimney stent. The 30-day mortality was 1.2% (4 in 345). During a mean follow-up of 42 ± 22 months (range 1–108 months), major stroke occurred in nine (2.6%) patients, chimney occlusion or stenosis occurred in six (1.7%), and retrograde type A aortic dissection occurred in four (1.2%). Fourteen (4.1%) patients received the secondary intervention. The all-cause mortality was 6.7% (23 in 345). Additionally, the total adverse event rate after cTEVAR was 13.9% (48 in 345).ConclusionTEVAR with chimney technique provides a minimally invasive alternative with good chimney graft patency and low postoperative mortality during follow-up. However, the double and triple chimney techniques should be used cautiously as they seem to have a higher risk for type IA endoleak and adverse events after the operation.

Background: Patches are commonly used to close blood vessels after vascular surgery. Most currently used materials are either prosthetics or animal-derived; although natural materials, such as a leaf, can be used as a patch, healing of these natural materials is not optimal; rhodamine and rapamycin have been used to show that coating patches with drugs allow drug delivery to inhibit neointimal hyperplasia that may improve patch healing. Wood is abundant, and its stiffness can be reduced with processing; however, whether wood can be used as a vascular patch is not established. We hypothesized that wood can be used as a vascular patch and thus may serve as a novel plant-based biocompatible material.Method: Male Sprague–Dawley rats (aged 6–8 weeks) were used as an inferior vena cava (IVC) patch venoplasty model. After softening, wood patches coated with rhodamine and rapamycin were implanted into the rat subcutaneous tissue, the abdominal cavity, or the IVC. Samples were explanted on day 14 for analysis.Result: Wood patches became soft after processing. Patches showed biocompatibility after implantation into the subcutaneous tissue or the abdominal cavity. After implantation into the IVC, the patches retained mechanical strength. There was a significantly thinner neointima in wood patches coated with rapamycin than control patches (146.7 ± 15.32 μm vs. 524.7 ± 26.81 μm; p = 0.0001). There were CD34 and nestin-positive cells throughout the patch, and neointimal endothelial cells were Eph-B4 and COUP-TFII-positive. There was a significantly smaller number of PCNA and α-actin dual-positive cells in the neointima (p = 0.0003), peri-patch area (p = 0.0198), and adventitia (p = 0.0004) in wood patches coated with rapamycin than control patches. Piezo1 was expressed in the neointima and peri-patch area, and there were decreased CD68 and piezo1 dual-positive cells in wood patches coated with rapamycin compared to control patches.Conclusion: Wood can be used as a novel biomaterial that can be implanted as a vascular patch and also serve as a scaffold for drug delivery. Plant-derived materials may be an alternative to prosthetics or animal-based materials in vascular applications.

The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.

Loeys-Dietz syndrome (LDS) type 3 results from a SMAD3 mutation and is a phenotypically milder variant of LDS with frequent aortic, visceral, and cerebral vascular pathologies and osteoarthritis. Historically, endovascular treatment (endovascular aortic repair [EVAR]) of LDS-related aortic aneurysmal disease with traditional modular bifurcated devices has been limited owing to concerns regarding continued aortic dilation at proximal fixation sites. Furthermore, associated dissection pathology has also precluded traditional modular bifurcated EVAR owing to inadequate proximal infrarenal necks and narrow distal aortic domains leading to compromised contralateral gate opening and cannulation as well as limb flow compromise. To address these barriers to EVAR, we present our approach for the endovascular treatment of a dissecting pararenal abdominal aortic aneurysm using an anatomically fixated, bifurcated, unibody aortic stent graft in a patient with LDS-3.

OBJECTIVE: This study examined the psychological impact of the coronavirus disease 2019 (COVID-2019) outbreak on medical staff in China. MATERIALS AND METHODS: In February 2020, an online survey was carried out by using an online survey tool (WeChat) to evaluate the effects of the outbreak on the mental health of medical staff in China. RESULTS: A total of 11,118 medical staff responded to the survey. About 4.98% of the respondents reported middle and high levels of anxiety, while 13.47% of the respondents reported middle and high levels of depression since the COVID-19 outbreak. Nurses, frontline medical staff, and younger medical staff were more likely to have anxiety and depression than physicians, nonfrontline medical staff, and older medical staff. CONCLUSIONS: Although the serious psychological impact of COVID-19 is not so common in medical staff in China, programs are needed to protect them against the negative impacts of COVID-19.

Objective: Arteriovenous fistulae (AVF) placed for hemodialysis have high flow rates that can stimulate left ventricular (LV) hypertrophy. LV hypertrophy generally portends poor cardiac outcomes, yet clinical studies point to superior cardiac-specific outcomes for patients with AVF when compared with other dialysis modalities. We hypothesize that AVF induce physiologic cardiac hypertrophy with cardioprotective features. Methods: We treated 9- to 11-week-old C57Bl/6 male and female mice with sham laparotomy or an aortocaval fistula via a 25G needle. Cardiac chamber size and function were assessed with serial echocardiography, and cardiac computed tomography angiography. Hearts were harvested at 5 weeks postoperatively, and the collagen content was assessed with Masson's trichrome. Bulk messenger RNA sequencing was performed from LV of sham and AVF mice at 10 days. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis (Qiagen) to identify affected pathways and predict downstream biological effects. Results: Mice with AVF had similar body weight and wet lung mass, but increased cardiac mass compared with sham-operated mice. AVF increased cardiac output while preserving LV systolic and diastolic function, as well as indices of right heart function; all four cardiac chambers were enlarged, with a slight decrement in the relative LV wall thickness. Histology showed preserved collagen density within each of the four chambers without areas of fibrosis. RNA sequencing captured 19 384 genes, of which 857 were significantly differentially expressed, including transcripts from extracellular matrix-related genes, ion channels, metabolism, and cardiac fetal genes. The top upstream regulatory molecules predicted include activation of angiogenic (Vegf, Akt1), procardiomyocyte survival (Hgf, Foxm1, Erbb2, Lin9, Areg), and inflammation-related (CSF2, Tgfb1, TNF, Ifng, Ccr2, IL6) genes, as well as the inactivation of cardiomyocyte antiproliferative factors (Cdkn1a, FoxO3, α-catenin). The predicted downstream effects include a decrease in heart damage, and increased arrhythmia, angiogenesis, and cardiogenesis. There were no significant sex-dependent differences in the AVF-stimulated cardiac adaptation. Conclusions: AVF stimulate adaptive cardiac hypertrophy in wild-type mice without heart failure or pathologic fibrosis. Transcriptional correlates suggest AVF-induced cardiac remodeling has some cardioprotective, although also arrhythmogenic features. (JVS–Vascular Science 2021;2:110-28.) Clinical Relevance: Arteriovenous fistulae (AVF) are commonly used as access for hemodialysis in patients with end-stage renal disease. AVF induce a high-output state that is associated with long-term structural cardiac remodeling, including left ventricle hypertrophy, but this element has uncertain clinical significance. Although left ventricle hypertrophy has traditionally been associated with an increased risk of cardiovascular disease, clinical studies have suggested that cardiac-specific outcomes of patients with end-stage renal disease were better with AVF compared with other dialysis modalities. This study uses a mouse model of AVF to study the structural, functional, and molecular correlates of AVF-induced cardiac remodeling. It finds that AVF causes an adaptive cardiac hypertrophy without functional decline or fibrosis. Transcriptional correlates suggest an electrical remodeling and the upregulation of proangiogenic, procardiogenic, and prosurvival factors, implying that AVF-induced cardiac hypertrophy is potentially cardioprotective, but also arrhythmogenic.

Surgical repair of iatrogenic femoral pseudoaneurysms in the setting of distorted anatomy, multiple prior interventions, and ongoing hemorrhage requires extensive proximal and distal dissection for control. Furthermore, profunda femoral and other arterial branch control may not always be feasible and can lead to considerable blood loss at the time of surgical exploration. We present a simple, safe, and effective hybrid approach for inflow, outflow, and branch control for treatment of a proximally located, actively expanding, iatrogenic common femoral artery pseudoaneurysm recalcitrant to multiple sessions of percutaneous thrombin injection.

As the general population ages, there will be an increasing number of vascular patients in their 90s and older. However, geriatric patients have historically been turned down for abdominal aortic aneurysm repair despite high aneurysm-related mortality in the unrepaired. Herein, we describe the perioperative considerations and the successful, uncomplicated operative course of a 100-year-old woman who underwent an elective endovascular aortic aneurysm repair for an expanding 5.3-cm abdominal aortic aneurysm. Given a suitable patient, there is acceptable risk profile of an endovascular approach, even in centenarians.

Anomalous marginal veins of the trunk or extremities are congenitally incompetent entities found in association with phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth syndromes, such as Klippel-Trénaunay syndrome and congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal deformities (CLOVES) syndrome. When present, they can be a major source of venous hypertension-related morbidity and potentially lethal thromboembolic events. Herein, we describe a rare case of an upper extremity marginal vein in a patient with CLOVES syndrome. Through a multimodal therapeutic approach, we identified a somatic PIK3CA mutation in the excised anomalous vein. This finding questions the validity of commonly employed terminology, such as persistent embryonic vein, in reference to these anomalous entities.

Stenosis due to neointimal hyperplasia (NIH) is among the major causes of peripheral graft failure. Its link to abnormal hemodynamics in the graft is complex, and isolated use of hemodynamic markers is insufficient to fully capture its progression. Here, a computational model of NIH growth is presented, establishing a link between computational fluid dynamics simulations of flow in the lumen and a biochemical model representing NIH growth mechanisms inside the vessel wall. For all three patients analyzed, NIH at proximal and distal anastomoses was simulated by the model, with values of stenosis comparable to the computed tomography scans.

Symptomatic carotid artery disease caused by hyoid bone compression is rare, although scant reports describe cerebrovascular events due to this mechanical interference leading to entrapment, embolism, dissection, atherosclerotic stenosis, and pseudoaneurysm formation. This report describes a patient presenting with left-sided paresis and paresthesia who was found to have focal right carotid stenosis secondary to impingement of the carotid bulb by an elongated hyoid bone. Whereas previous cases describe hyoid bone resection, we describe successful management with endarterectomy and carotid mobilization without hyoid resection, with long-term follow-up demonstrating a widely patent carotid system without recurrent impingement. Keywords: Hyoid bone, Carotid artery, Carotid stenosis, Atherosclerosis, Cerebral infarction

Objective: The arteriovenous fistula (AVF) is the preferred method of dialysis access because of its proven superior long-term outcomes. However, women have lower rates of AVF patency and utilization than men. We used a novel mouse AVF 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.

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. : Clinical Relevance: A mouse model of venous stenosis distal to an arteriovenous fistula shows similar Doppler waveforms as those observed in a human case of central venous stenosis. These mice retain disturbed shear stress in the vein distal to the fistula, characterized by a sustained increase of the spectral broadening index and diminished expression of proteins upregulated by laminar shear stress. This novel mouse model will enable investigation of the physiology and downstream molecular pathways involved in central venous stenosis in humans.

Patients with end-stage renal failure depend on hemodialysis indefinitely without renal transplantation, requiring a long-term patent vascular access. Although an arteriovenous fistula (AVF) remains the preferred vascular access for hemodialysis because of its longer patency and fewer complications compared with other vascular accesses, the primary patency of AVF is only 50% to 60%, presenting a clinical need for improvement. AVF mature by developing a thickened vascular wall and increased diameter to adapt to arterial blood pressure and flow volume. Inflammation plays a critical role during vascular remodeling and fistula maturation; increased shear stress triggers infiltration of T cells and macrophages that initiate inflammation, with involvement of several different subsets of T cells and macrophages. We review the literature describing distinct roles of the various subsets of T cells and macrophages during vascular remodeling. Immunosuppression with sirolimus or prednisolone decreases neointimal hyperplasia during AVF maturation, suggesting novel approaches to enhance vascular remodeling. However, M2 macrophages and CD4+ T cells play essential roles during AVF maturation, suggesting that total immunosuppression may suppress adaptive vascular remodeling. Therefore, it is likely that regulation of inflammation during fistula maturation will require a balanced approach to coordinate the various inflammatory cell subsets. Advances in immunosuppressive drug development and delivery systems may allow for more targeted regulation of inflammation to improve vascular remodeling and enhance AVF maturation. (JVS–Vascular Science 2020;1:207-18.) : Clinical Relevance: Patients with end-stage renal failure depend on successful AVF maturation to have a useful access. Inflammation occurs during fistula maturation and may be a therapeutic target to improve fistula maturation and utilization. Inflammation is mainly caused by T cells and macrophages, which have several subsets with distinct phenotypes and roles during vascular remodeling. Regulation of inflammation during fistula maturation requires a balanced approach to coordinate the various inflammatory cell subsets.

Internal mammary artery aneurysms are rare but serious clinical entities. Rupture results in hemothorax and can be life threatening. Most reported cases are pseudoaneurysms secondary to iatrogenic or traumatic causes. Noniatrogenic, nontraumatic, true internal mammary artery aneurysms have most commonly been associated with vasculitides or connective tissue disorders; rare cases have been deemed idiopathic. We describe a rare case of bilateral internal mammary artery aneurysms—successfully treated with coil embolization—in the setting of heterozygosity for a missense variant of unknown significance in the COL5A1 gene and multifocal fibrodysplastic changes on angiography. Keywords: Internal mammary artery aneurysm, Coil embolization, Fibromuscular dysplasia

Despite scientific advances, vascular diseases are responsible for one third of deaths. Understanding the biology of stem cells and cell therapy can mean an important advance in reducing this mortality.

Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte‐specific glucocorticoid receptor knockout (GRPKO) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GRPKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor‐βR1 and β‐catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin‐positive cells were found in the kidneys of diabetic GRPKO mice. Podocytes isolated from diabetic GRPKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GRPKO mice. The glomerular endothelium of diabetic GRPKO mice demonstrated the features of endothelial‐to‐mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α‐smooth muscle actin, transforming growth factor‐βR1 and β‐catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte–endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

Vascular disorders frequently have differing clinical presentations among women and men. Sex differences exist in vascular access for hemodialysis; women have reduced rates of arteriovenous fistula (AVF) maturation as well as fistula utilization compared with men. Inflammation is increasingly implicated in both clinical studies and animal models as a potent mechanism driving AVF maturation, especially in vessel dilation and wall thickening, that allows venous remodeling to the fistula environment to support hemodialysis. Sex differences have long been recognized in arterial remodeling and diseases, with men having increased cardiovascular events compared with pre-menopausal women. Many of these arterial diseases are driven by inflammation that is similar to the inflammation during AVF maturation. Improved understanding of sex differences in inflammation during vascular remodeling may suggest sex-specific vascular therapies to improve AVF success.

Advances in endovascular therapy have exponentially increased the number of procedures performed for peripheral artery disease, but public concerns of overuse have placed the vascular community under scrutiny. The appropriateness of care has thus become a focus of discussion within several professional societies, but literature on the topic is limited. This report presents two cases of patients with peripheral artery disease, one patient who did not need revascularization and underwent an intervention and the other who required additional intervention that was not recognized owing to an incomplete diagnostic workup. Keywords: Appropriateness of care, Peripheral arterial disease, National guidelines

Femoral endarterectomy with iliac stenting is a safe and effective minimally invasive alternative to aortobifemoral bypass. However, TransAtlantic Inter-Society Consensus D lesions with contiguous iliofemoral occlusion are challenging cases for hybrid repair. Herein, we present a unique approach for iliofemoral revascularization by on-table modification of self-expanding covered stents. Keywords: Aortoiliac occlusive disease, Endarterectomy, Covered stent, Hybrid vascular surgery

In conjunction with traditional modular bifurcated aortic endografts, bilateral iliac branch endoprostheses have been safely and effectively used for treatment of bilateral iliac artery aneurysms. However, anatomic constraints, such as inadequate renal artery to iliac bifurcation lengths and unfavorable aortic anatomy, can preclude deployment in certain configurations and limit use in many patients. We present an innovative technique to overcome such anatomic constraints and to extend the reach of iliac branch endoprosthesis technology in patients with iliac artery aneurysms. Keywords: Iliac aneurysm, Endovascular aneurysm repair, Iliac branch endoprosthesis, Aortic aneurysm

Abstract Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products; however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells; they are harvested non-invasively and can be transplanted autologously, reducing immune rejection; and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies.

The increasing prevalence of chronic and end-stage renal disease creates an increased need for reliable vascular access; although arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, 60% fail to mature and only 50% remain patent at 1 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 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 and insufficient diameter expansion in a previously functional fistula. In recent years, the molecular basis of AVF maturation and failure are becoming understood to develop potential therapeutic targets to aid maturation and prevent access loss. Erythropoietin-producing hepatocellular (Eph) carcinoma receptors, along with their ligands and 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.

Abstract Background Diabetic foot ulcer (DFU) is a severe complication of diabetes, preceding most diabetes-related amputations. DFUs require over US$9 billion for yearly treatment and are now a global public health issue. DFU occurs in the setting of ischemia, infection, neuropathy, and metabolic disorders that result in poor wound healing and poor treatment options. Recently, stem cell therapy has emerged as a new interventional strategy to treat DFU and appears to be safe and effective in both preclinical and clinical trials. However, variability in the stem cell type and origin, route and protocol for administration, and concomitant use of angioplasty confound easy interpretation and generalization of the results. Methods The PubMed, Google Scholar, and EMBASE databases were searched and 89 preclinical and clinical studies were selected for analysis. Results There was divergence between preclinical and clinical studies regarding stem cell type, origin, and delivery techniques. There was heterogeneous preclinical and clinical study design and few randomized clinical trials. Granulocyte-colony stimulating factor was employed in some studies but with differing protocols. Concomitant performance of angioplasty with stem cell therapy showed increased efficiency compared to either therapy alone. Conclusions Stem cell therapy is an effective treatment for diabetic foot ulcers and is currently used as an alternative to amputation for some patients without other options for revascularization. Concordance between preclinical and clinical studies may help design future randomized clinical trials.

Abstract Background For patients with thromboangiitis obliterans (TAO), revascularization with bypass or angioplasty is frequently not feasible due to the poor outflow of the distal small vessels. We evaluated the long-term results of our experience treating patients with TAO with autologous bone marrow-derived mononuclear cells (ABMMNCs) to determine the safety and efficacy of ABMMNC therapy in patients with critical limb ischemia due to TAO. Methods This was a retrospective chart review from a single university hospital vascular surgery center between January 2005 and July 2006. Patients were treated with smoking cessation and either aspirin (100 mg/day) alone or aspirin and ABMMNC injection according to patient preference. Groups were compared for demographics, clinical characteristics, and short-term and long-term results. Results Of 59 patients with TAO who were treated, 19 patients elected aspirin alone and 40 patients elected aspirin and ABMMNC injection. No patients suffered perioperative complications and 49 (83%) patients remained smoke-free for 10 years. The 10-year amputation-free survival was 85.3% (29/34) in patients treated with ABMMNCs compared to 40% (6/15) in patients treated with aspirin alone (p = 0.0019). Ulcer area (p