Utility of Closed Suction Drains in Groin Incisions after Femoral Artery Exposure.

BACKGROUND: Surgical groin wounds are at risk of delayed healing and infection, leading to costly and prolonged postoperative recoveries. This study assesses the use of closed suction drains (CSDs) as a wound care adjunct in groin incisions to prevent surgical site infections (SSI). METHODS: A single-center retrospective review was performed on 210 consecutive patients after vascular surgery with common femoral artery exposure from 2016 to 2021. The cohort was divided into 2 groups, groins with and without CSD, looking for surgical site complications. A subgroup analysis comparing postoperative outcomes between complicated and uncomplicated groin incisions within both groups was also performed. RESULTS: Of 293 surgical groins, 20% (n = 59) had drains. Overall, the CSD group had higher SSI rates (14% vs. 5.6%), but also had higher proportion of smokers (92% vs. 83%; P = 0.019), diabetes (56% vs. 36%; P = 0.005), coronary artery disease (69% vs. 46%; P = 0.001), hyperlipidemia (69% vs. 51%; P = 0.01), and previous groin surgery (54% vs. 17%; P < 0.001). The higher risk of SSI was not significant after adjustment of these confounders. A separate analysis within each group showed SSI groins with CSD had lower reintervention rates (37.5%) than those without CSD (69%), as well as shorter length of hospital stay (7 [5-11] vs. 22 [7-25] days). CONCLUSIONS: Our study suggests that CSDs can be a beneficial adjunct for groin wounds after common femoral artery exposure in patients with comorbidities cited above. CSDs decrease the risk of reintervention and length of hospital stay.

Effect of Body Mass Index on Early Outcomes of Endovascular Abdominal Aortic Aneurysm Repair.

BACKGROUND: This study compares the presentation, management, and outcomes of patients undergoing endovascular abdominal aortic aneurysm repair (EVAR), based on their weight status as defined by their body mass index (BMI). METHODS: Patients with primary EVAR for ruptured and intact abdominal aortic aneurysm (AAA) were identified in the National Surgical Quality Improvement Program database (2016-2019). Patients were categorized by weight status (underweight: BMI < 18.5 kg/m2, normal weight: 18.5-24.9 kg/m2, overweight: 25-29.9 kg/m2, Obese I: 30-34.9 kg/m2, Obese II: 35-39.9 kg/m2, Obese III: > 40 kg/m2). Preoperative characteristics and 30-day outcomes were compared. RESULTS: Of 3,941 patients, 4.8% were underweight, 24.1% normal weight, 37.6% overweight, and 22.5% with Obese I, 7.8% Obese II, and 3.3% Obese III status. Underweight patients presented with larger (6.0 [5.4-7.2] cm) and more frequently ruptured (25.0%) aneurysms than normal weight patients (5.5 [5.1-6.2] cm and 4.3%, P < 0.001 for both). Pooled 30-day mortality was worse for underweight (8.5%) compared to all other weight status (1.1-3.0%, P < 0.001), but risk-adjusted analysis demonstrated that aneurysm rupture (odds ratio [OR] 15.9, 95% confidence interval [CI] 8.98-28.0) and not underweight status (OR 1.75, 95% CI 0.73-4.18) accounted for increased mortality in this population. Obese III status was associated with prolonged operative time and respiratory complications after ruptured AAA, but not 30-day mortality (OR 0.82, 95% CI 0.25-2.62). CONCLUSIONS: Patients at either extreme of the BMI range had the worst outcomes after EVAR. Underweight patients represented only 4.8% of all EVARs, but 21% of mortalities, largely attributed to higher incidence of ruptured AAA at presentation. Severe obesity, on the other hand, was associated with prolonged operative time and respiratory complications after EVAR for ruptured AAA. BMI, as an independent factor, was however not predictive of mortality for EVAR.

Outcomes and role of shunting during carotid endarterectomy for symptomatic patients.

OBJECTIVE: Shunt placement during carotid endarterectomy (CEA) has often been advocated to protect the ischemic penumbra in patients with symptomatic carotid stenosis. In the present study, we assessed the effect of shunt placement during CEA on postoperative stroke risk in symptomatic patients. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database (2016-2019) for CEA cases with complete CEA procedure-targeted data available. Symptomatic patients were identified as those with a preoperative diagnosis of stroke on presentation (DS), transient ischemic attack, amaurosis fugax, or temporary monocular blindness. The DS patients were further analyzed according to the severity of their stroke using the modified Rankin scale scores. To better assess the effect of shunt placement on the stroke rate, we compared cases of CEA with the patch angioplasty technique stratified by the use of an intraoperative shunt. Patients who had undergone carotid eversion or primary closure were excluded. The baseline demographics and perioperative outcomes were compared using the χ2 and Mann-Whitney U tests. Multivariate analysis was performed to identify the independent risk factors for postoperative stroke and cranial nerve injury. RESULTS: We identified 4652 cases of CEA with patch angioplasty in symptomatic patients, including 1889 with (40.6%) and 2763 without (59.4%) shunt placement. The distribution of age, race, and sex was similar for both procedures. Compared with patients without a shunt, those with a shunt had significantly higher rates of emergency surgery (9.1% vs 7.0%; P = .010), nonelective surgery (40.3% vs 37.2%; P = .035), general anesthesia (97.0% vs 86.3%; P < .001), and bleeding disorders (27.2% vs 22.7%; P < .001). The 30-day incidence of postoperative stroke was similar between the patients with (3.2%) and without (2.6%) shunt placement (P = .219). Additionally, a subgroup analysis failed to show any benefit from shunt placement on the incidence of postoperative stroke, regardless of the preoperative symptoms or neurologic disability. In contrast, shunt placement was associated with an increased rate of cranial nerve injury (4.1% vs 2.4%; P = .001). Multivariate analysis revealed that nonelective surgery (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.36-2.91; P < .001) and DS (vs transient ischemic attack, amaurosis fugax, or temporary monocular blindness; OR, 1.64; 95% CI, 1.12-2.41; P = .012) were predictive of 30-day postoperative stroke. After adjusting for confounders, shunt placement had no effect on stroke risk at 30 days but remained an independent risk factor for cranial nerve injury (adjusted OR, 1.87; 95% CI, 1.32-2.64; P < .001). CONCLUSIONS: For symptomatic patients undergoing CEA with patch angioplasty, shunt placement was associated with an increased risk of cranial nerve injury without a reduction in postoperative stroke risk.

COVID-19-related thrombotic complications experience before and during delta wave.

OBJECTIVE: Hypercoagulability and thrombotic complications seen in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as the associated pathophysiology, have been reported extensively. However, there is limited information regarding the factors related to this phenomenon and its association with the Coronavirus disease 2019 (COVID-19) Delta variant. METHODS: A retrospective review including patients admitted to a tertiary center with a COVID-19 positive test and at least one acute thrombotic event confirmed by imaging between June 2020 and August 2021 was performed. We compared the rates of thrombotic events in patients with COVID-19 before and during the Delta peak. We also analyzed the association of the thrombotic complications with demographic characteristics, comorbidities, anticoagulation strategies, and prothrombotic markers while describing other complications secondary to COVID-19 infection. RESULTS: Of 964 patients admitted with COVID-19 diagnosis, 26.5% (n = 256) had a thrombotic event evidenced by ultrasound or computed tomography scan. Venous thromboembolism was found in 60% (n = 153), arterial thrombosis in 23% (n = 60), and both venous and arterial thromboses in 17% (n = 17) of the study cohort. Of all patients, 94% were not vaccinated. Delta variant wave (DW) patients had thrombotic episodes in 34.7% (n = 50/144) of cases compared with 25% (n = 206/820) of non-Delta wave (NDW) patients, posing an estimated risk 1.36 times higher in patients infected with COVID-19 during the DW than NDW. Overall, DW subjects were significantly younger (P < .001) with lower body mass index (P = .021) compared with NDW patients. Statistical analyses showed African American patients were more likely to have arterial thrombosis compared with the other groups when testing positive for COVID-19 (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.04-3.05; P = .035, whereas immunosuppressed patients had less risk of arterial thrombosis (OR, 0.38; 95% CI, 0.15-0.96; P = .042). Female gender (OR, 2.15; 95% CI, 1.20-3.85; P = .009) and patients with active malignancy (OR, 5.99; 95% CI, 2.14-16.78; P = .001) had an increased risk of having multiple thrombotic events at different locations secondary to COVID-19. CONCLUSIONS: COVID-19 infection is associated with elevated rates of thrombotic complications and an especially higher risk in patients infected during the Delta variant peak. We highlight the importance of vaccination and the development of new anticoagulation strategies for patients with COVID-19 with additional hypercoagulable risk factors to prevent thrombotic complications caused by this disease.

Echocardiographic changes after arteriovenous fistula creation in hemodialysis patients.

BACKGROUND: Pulmonary hypertension (PH) is common in end-stage renal disease (ESRD) patients and is associated with increased all-cause and cardiovascular mortality in this group. There is scarce data on the long-term effect of arteriovenous fistula (AVF) creation on pulmonary hypertension (PH) and the reflected changes in echocardiographic measurements. MATERIALS AND METHODS: This is a retrospective study of 54 patients who underwent AVF creation between 2009 and 2014 and with echocardiographic evaluations before and after surgery. We analyzed pairwise changes in right ventricular systolic pressure (RVSP), right atrial pressure (RAP) during systole, left ventricular mass (LVM), tricuspid regurgitation (TR), mitral E/E' ratio, and ejection fraction (EF), as well as the factors that predicted change in RVSP after surgery. RESULTS: The median time for the preoperative echocardiogram was 0.3 years (interquartile range (IQR) 0.2 - 0.7 years) prior to AVF creation, while the follow-up echo was done 1.3 (0.6 - 2.1) years after surgery. 67% of the patients had RVSP > 37 mmHg at baseline. There was a significant reduction in RVSP after AVF creation compared to baseline (median 33 (IQR 26 - 43) vs. 46 mmHg, p = 0.0015), with 59% of the patients experiencing a decrease and 19% remaining stable. There were also significant decreases in LVM (201 (143 - 256) vs. 215 (163 - 276), p = 0.045) and RAP systole (10 (10 - 15) vs. 3 (3 - 8); p < 0.001) after surgery. Higher preoperative weight (p = 0.038) and RVSP (p = 0.006), and use of loop diuretics (p = 0.015) were significantly associated with improvement in RVSP after AVF creation. CONCLUSION: Our results suggest that AVF creation is associated with a significant reduction or stable measurements of RVSP in the ESRD population, likely due to an improvement in volume status.

Transcriptomics of Human Arteriovenous Fistula Failure: Genes Associated With Nonmaturation.

RATIONALE & OBJECTIVE: Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. PREDICTOR: RNA expression in native veins and AVFs. OUTCOME: Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6mm. ANALYTICAL APPROACH: Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. RESULTS: Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate < 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r=0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. LIMITATIONS: Small sample size, analysis of only upper-arm veins and transposed fistulas. CONCLUSIONS: Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.

Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas.

The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P=0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population's median value (OR, 2.63; 95% CI, 1.07 to 6.46; P=0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P=0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH.

Comparison of Ultrasound-Guided Thrombin Injection of Iatrogenic Pseudoaneurysms Based on Neck Dimension.

BACKGROUND: Ultrasound-guided thrombin injection (UGTI) of femoral artery pseudoaneurysms after endovascular procedures is an effective therapy. There is controversy in the literature regarding injecting pseudoaneurysms with short and/or wide necks. This article reports our experience in UGTI of pseudoaneurysms in 1 hospital regarding the efficacy of this treatment in all pseudoaneurysms regardless of the size of the necks. METHODS: A retrospective review of 46 patients diagnosed between 2011 and 2016 with groin pseudoaneurysms using established duplex ultrasound criteria. Mean age was 68 years (range 27-87). Ten pseudoaneurysms thrombosed spontaneously, 5 were thrombosed by ultrasound-guided compression, and 2 were treated surgically due to disqualifying criteria. In this retrospective review, we analyzed the remaining 29 pseudoaneurysms regarding the dimensions of their neck lengths and outcomes after attempting thrombin injection. RESULTS: The mean aneurysm neck length and width were 1.03 ± 0.9 cm and 0.30 ± 0.1 cm, respectively. All 29 patients were evaluated with respect to pseudoaneurysm size, neck length, neck width, and complexity. Successful treatment of 29 pseudoaneurysms (2 external iliac, 20 common femoral, 2 deep femoral, and 5 superficial femoral) with UGTI was achieved without complications in 100% of the cases, regardless of pseudoaneurysm size, neck dimensions, or complexity. Anticoagulation status did not affect the efficacy of the procedure. Nine of the 29 pseudoaneurysms (31.0%) had neck length less than 0.5 cm. CONCLUSIONS: This study demonstrates the safety and efficacy of UGTI in treating iatrogenic pseudoaneurysm in 29 of 29 patients, even in patients with pseudoaneurysm with short neck lengths. Our experiences support injecting all pseudoaneurysms irrespective of dimension.

Dialysis Arteriovenous Fistula Failure and Angioplasty: Intimal Hyperplasia and Other Causes of Access Failure.

The arteriovenous fistula (AVF) is the preferred hemodialysis access type because it has better patency rates and fewer complications than other access types. However, primary failure remains a common problem impeding AVF maturation and adding to patients' morbidity and mortality. Juxta-anastomotic (or inflow) stenosis is the most common reason leading to primary failure, and percutaneous transluminal angioplasty continues to be the gold-standard treatment with excellent success rates. Intimal hyperplasia (IH) has been traditionally blamed as the main pathophysiologic culprit, but new evidence raises doubts regarding the contribution of IH alone to primary failure. We report a 64-year-old man with a 2-stage brachiobasilic AVF that was complicated by failure 4 months after creation. An angiogram showed multiple juxta-anastomotic and midfistula stenotic lesions. Percutaneous transluminal angioplasty was successful in assisting maturation and subsequently cannulating the AVF for hemodialysis treatment. We failed to identify the underlying cause of stenosis because biopsy specimens from fistula tissue obtained at the time of transposition revealed no occlusive IH. This case emphasizes the need for additional research on factors contributing to AVF failure besides IH and highlights the need for more therapeutic options to reduce AVF failure rate.

Pre-existing and Postoperative Intimal Hyperplasia and Arteriovenous Fistula Outcomes.

BACKGROUND: The contribution of intimal hyperplasia (IH) to arteriovenous fistula (AVF) failure is uncertain. This observational study assessed the relationship between pre-existing, postoperative, and change in IH over time and AVF outcomes. STUDY DESIGN: Prospective cohort study with longitudinal assessment of IH at the time of AVF creation (pre-existing) and transposition (postoperative). Patients were followed up for up to 3.3 years. SETTING & PARTICIPANTS: 96 patients from a single center who underwent AVF surgery initially planned as a 2-stage procedure. Veins and AVF samples were collected from 66 and 86 patients, respectively. Matched-pair tissues were available from 56 of these patients. PREDICTORS: Pre-existing, postoperative, and change in IH over time. OUTCOMES: Anatomic maturation failure was defined as an AVF that never reached a diameter > 6mm. Primary unassisted patency was defined as the time elapsed from the second-stage surgery to the first intervention. MEASUREMENTS: Maximal intimal thickness in veins and AVFs and change in intimal thickness over time. RESULTS: Pre-existing IH (>0.05mm) was present in 98% of patients. In this group, the median intimal thickness increased 4.40-fold (IQR, 2.17- to 4.94-fold) between AVF creation and transposition. However, this change was not associated with pre-existing thickness (r(2)=0.002; P=0.7). Ten of 96 (10%) AVFs never achieved maturation, whereas 70% of vascular accesses remained patent at the end of the observational period. Postoperative IH was not associated with anatomic maturation failure using univariate logistic regression. Pre-existing, postoperative, and change in IH over time had no effects on primary unassisted patency. LIMITATIONS: The small number of patients from whom longitudinal tissue samples were available and low incidence of anatomic maturation failure, which decreased the statistical power to find associations between end points and IH. CONCLUSIONS: Pre-existing, postoperative, and change in IH over time were not associated with 2-stage AVF outcomes.

The impact of arteriovenous fistulae on the myocardium: the impact of creation and ligation in the transplant era.

Cardiac hypertrophy is a relatively common complication seen in patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD). Moreover, cardiac hypertrophy is even more frequently seen in patients with ESRD who have an arteriovenous (AV) access. There has been substantial evidence pertaining to the effects of AV access creation on the heart structure and function. Similarly, there is increasing evidence on the effects of AV access closure, flow reduction, transplantation, and immunosuppressive medication on both endpoints. In this review, we present the evidence available in the literature on these topics and open the dialog for further research in this interesting field.

A meta-analysis of randomized clinical trials assessing hemodialysis access thrombosis based on access flow monitoring: where do we stand?

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommends the routine use of hemodialysis arteriovenous (AV) access surveillance to detect hemodynamically significant stenoses and appropriately correct them to reduce the incidence of thrombosis and to improve accesses patency rates. Access blood flow monitoring is considered as one of the preferred surveillance method for both AV fistulas (AVF) and AV grafts (AVG); however, published studies have reported conflicting results of its utility that led healthcare professionals to doubt the benefits of this surveillance method. We performed a meta-analysis of the published randomized controlled trials (RCTs) of AV access surveillance using access blood flow monitoring. Our hypothesis was that access blood flow monitoring lowers the risk of AV access thrombosis and that the outcome differs between AVF and AVG. The estimated overall pooled risk ratio (RR) of thrombosis was 0.87 (95% confidence interval [CI], 0.67-1.13) favoring access blood flow monitoring. The pooled RR of thrombosis were 0.64 (95% CI, 0.41-1.01) and 1.06 (95% CI, 0.77-1.46) in the subgroups of only AVF and only AVG, respectively. Our results added to the uncertainty of access blood flow monitoring as a surveillance method of hemodialysis accesses.

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae.

Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae.

The intricate cellular ecosystem of human peripheral veins as revealed by single-cell transcriptomic analysis.

The venous system has been historically understudied despite its critical roles in blood distribution, heart function, and systemic immunity. This study dissects the microanatomy of upper arm veins at the single cell level, and how it relates to wall structure, remodeling processes, and inflammatory responses to injury. We applied single-cell RNA sequencing to 4 non-diseased human veins (3 basilic, 1 cephalic) obtained from organ donors, followed by bioinformatic and histological analyses. Unsupervised clustering of 20,006 cells revealed a complex ecosystem of endothelial cell (EC) types, smooth muscle cell (SMCs) and pericytes, various types of fibroblasts, and immune cell populations. The venous endothelium showed significant upregulation of cell adhesion genes, with arteriovenous zonation EC phenotypes highlighting the heterogeneity of vasa vasorum (VV) microvessels. Venous SMCs had atypical contractile phenotypes and showed widespread localization in the intima and media. MYH11+DESlo SMCs were transcriptionally associated with negative regulation of contraction and pro-inflammatory gene expression. MYH11+DEShi SMCs showed significant upregulation of extracellular matrix genes and pro-migratory mediators. Venous fibroblasts ranging from secretory to myofibroblastic phenotypes were 4X more abundant than SMCs and widely distributed throughout the wall. Fibroblast-derived angiopoietin-like factors were identified as versatile signaling hubs to regulate angiogenesis and SMC proliferation. An abundant monocyte/macrophage population was detected and confirmed by histology, including pro-inflammatory and homeostatic phenotypes, with cell counts positively correlated with age. Ligand-receptor interactome networks identified the venous endothelium in the main lumen and the VV as a niche for monocyte recruitment and infiltration. This study underscores the transcriptional uniqueness of venous cells and their relevance for vascular inflammation and remodeling processes. Findings from this study may be relevant for molecular investigations of upper arm veins used for vascular access creation, where single-cell analyses of cell composition and phenotypes are currently lacking.

Single-Cell Analyses Offer Insights into the Different Remodeling Programs of Arteries and Veins.

Arteries and veins develop different types of occlusive diseases and respond differently to injury. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts human peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Upper arm arteries (brachial) and veins (basilic/cephalic) from 30 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a 7.8× higher proportion of contractile smooth muscle cells (SMCs) in arteries and a trend toward more modulated SMCs. In contrast, veins showed a higher abundance of endothelial cells, pericytes, and macrophages, as well as an increasing trend in fibroblasts. Activated fibroblasts had similar proportions in both types of vessels but with significant differences in gene expression. Modulated SMCs and activated fibroblasts were characterized by the upregulation of MYH10, FN1, COL8A1, and ITGA10. Activated fibroblasts also expressed F2R, POSTN, and COMP and were confirmed by F2R/CD90 flow cytometry. Activated fibroblasts from veins were the top producers of collagens among all fibroblast populations from both types of vessels. Venous fibroblasts were also highly angiogenic, proinflammatory, and hyper-responders to reactive oxygen species. Differences in wall structure further explain the significant contribution of fibroblast populations to remodeling in veins. Fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with the above, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. The distinct cellular compositions and transcriptional programs of reparative populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information may be relevant for the development of antistenotic therapies.

A snapshot of early venous remodeling in a 7-day-old arteriovenous fistula.

Early remodeling of the arteriovenous fistula (AVF) determines maturation outcomes. However, the cellular response of the venous wall early after AVF creation remains largely enigmatic because of the lack of venous biopsies obtained shortly after anastomosis. This report presents a detailed immunohistochemistry analysis of a pre-access cephalic vein and the resulting seven-day-old AVF that required ligation due to steal syndrome. We test for markers of mature and progenitor endothelial cells (CD31, CD34, VWF), contractile smooth muscle cells and myofibroblasts (MYH11, SMA), and immune cell populations (CEACAM8, CD3, CD20, CD11b, CD45, CD68, CD163, tryptase). We demonstrated near complete endothelial coverage of the fistula at 7 days, a high degree of wall neovascularization, pronounced loss of myofibroblasts and smooth muscle cells, and significant infiltration of mast cells, neutrophils, monocytes, and macrophages. Of interest, the presence of CD163+ macrophages in the AVF suggests a reactive response to increased intramural oxygenation. In conclusion, these images provide for the first time a glimpse of early remodeling in a human AVF by immunohistochemistry. This case demonstrates the possibility to obtain additional precious samples of this early stage through future multicenter collaborative efforts.

The anatomical sources of neointimal cells in the arteriovenous fistula.

Neointimal cells are an elusive population with ambiguous origins, functions, and states of differentiation. Expansion of the venous intima in arteriovenous fistula (AVF) is one of the most prominent remodeling processes in the wall after access creation. However, most of the current knowledge about neointimal cells in AVFs comes from extrapolations from the arterial neointima in non-AVF systems. Understanding the origin of neointimal cells in fistulas may have important implications for the design and effective delivery of therapies aimed to decrease intimal hyperplasia (IH). In addition, a broader knowledge of cellular dynamics during postoperative remodeling of the AVF may help clarify other transformation processes in the wall that combined with IH determine the successful remodeling or failure of the access. In this review, we discuss the possible anatomical sources of neointimal cells in AVFs and their relative contribution to intimal expansion.

The outcomes of a novel two-stage proximal brachial artery to proximal basilic/brachial vein arteriovenous graft extension for dialysis access.

BACKGROUND: We describe a technique to mature a basilic/brachial vein in the mid-arm in preparation for a second stage loop proximal brachial artery to basilic/brachial vein arteriovenous graft (BBAVG). This can occur after a failed basilic/brachial vein transposition or a lack of adequate veins in the distal arm. This allows a mature vein to be used in an end-to-end configuration as an outflow to a BBAVG while preserving proximal vessels for the future. METHODS: This single-center retrospective study was performed from 2015 to 2021, including 104 AVG patients divided into three groups: (1) Patients who failed a basilic vein transposition and had an enlarged vein suitable for an AVG outflow; (2) Patients who had a small caliber basilic/brachial vein after the transposition, requiring a mid-arm brachial artery to brachial/basilic arteriovenous fistula (AVF) creation with a subsequent AVG extension; (3) and lastly, patients who had no distal arm veins available and required a primary brachial artery to basilic/brachial AVF with AVG extension. A survival analysis was performed looking at time to loss of primary and secondary patency, calculated with Kaplan-Meier estimates and Cox regression models adjusted for covariates. RESULTS: The median follow-up time was 11 months (IQ = 11-30 months). The survival analysis showed 28% lost primary patency at a median time of 9 months, and 14% lost secondary patency at a median time of 61 months. Overall secondary patency of the vascular access measured at 12 months was 85.6%. Loss of primary (p = 0.008) and secondary patency (p = 0.017), as well as patency during the first 12 months (p = 0.036), were all significantly associated with increased age when adjusting for covariates. CONCLUSIONS: Our results suggest that the graft extension technique using a mature vein from a previous fistula can result in reliable and durable access. This is important for patients with limited access for hemodialysis, as the axillary vein is preserved for future use if needed.

Chronic Kidney Disease Transdifferentiates Veins into a Specialized Immune-Endocrine Organ with Increased MYCN-AP1 Signaling.

Most patients with end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) choose hemodialysis as their treatment of choice. Thus, upper-extremity veins provide a functioning arteriovenous access to reduce dependence on central venous catheters. However, it is unknown whether CKD reprograms the transcriptome of veins and primes them for arteriovenous fistula (AVF) failure. To examine this, we performed transcriptomic analyses of bulk RNA sequencing data of veins isolated from 48 CKD patients and 20 non-CKD controls and made the following findings: (1) CKD converts veins into immune organs by upregulating 13 cytokine and chemokine genes, and over 50 canonical and noncanonical secretome genes; (2) CKD increases innate immune responses by upregulating 12 innate immune response genes and 18 cell membrane protein genes for increased intercellular communication, such as CX3CR1 chemokine signaling; (3) CKD upregulates five endoplasmic reticulum protein-coding genes and three mitochondrial genes, impairing mitochondrial bioenergetics and inducing immunometabolic reprogramming; (4) CKD reprograms fibrogenic processes in veins by upregulating 20 fibroblast genes and 6 fibrogenic factors, priming the vein for AVF failure; (5) CKD reprograms numerous cell death and survival programs; (6) CKD reprograms protein kinase signal transduction pathways and upregulates SRPK3 and CHKB; and (7) CKD reprograms vein transcriptomes and upregulates MYCN, AP1, and 11 other transcription factors for embryonic organ development, positive regulation of developmental growth, and muscle structure development in veins. These results provide novel insights on the roles of veins as immune endocrine organs and the effect of CKD in upregulating secretomes and driving immune and vascular cell differentiation.

The Transcriptomics of the Human Vein Transformation After Arteriovenous Fistula Anastomosis Uncovers Layer-Specific Remodeling and Hallmarks of Maturation Failure.

Introduction: The molecular transformation of the human preaccess vein after arteriovenous fistula (AVF) creation is poorly understood. This limits our ability to design efficacious therapies to improve maturation outcomes. Methods: Bulk RNA sequencing (RNA-seq) followed by paired bioinformatic analyses and validation assays were performed in 76 longitudinal vascular biopsies (veins and AVFs) from 38 patients with stage 5 chronic kidney disease or end-stage kidney disease undergoing surgeries for 2-stage AVF creation (19 matured, 19 failed). Results: A total of 3637 transcripts were differentially expressed between veins and AVFs independent of maturation outcomes, with 80% upregulated in fistulas. The postoperative transcriptome demonstrated transcriptional activation of basement membrane and interstitial extracellular matrix (ECM) components, including preexisting and novel collagens, proteoglycans, hemostasis factors, and angiogenesis regulators. A postoperative intramural cytokine storm involved >80 chemokines, interleukins, and growth factors. Postoperative changes in ECM expression were differentially distributed in the AVF wall, with proteoglycans and fibrillar collagens predominantly found in the intima and media, respectively. Interestingly, upregulated matrisome genes were enough to make a crude separation of AVFs that failed from those with successful maturation. We identified 102 differentially expressed genes (DEGs) in association with AVF maturation failure, including upregulation of network collagen VIII in medial smooth muscle cells (SMCs) and downregulation of endothelial-predominant transcripts and ECM regulators. Conclusion: This work delineates the molecular changes that characterize venous remodeling after AVF creation and those relevant to maturation failure. We provide an essential framework to streamline translational models and our search for antistenotic therapies.