Evaluating the Effectiveness of Systemic Heparin During Arteriovenous Fistula Creation by Emulating a Target Trial.

Most of the 800,000 people living with end-stage kidney disease in the United States rely on a functioning vascular access to provide life-sustaining hemodialysis, yet one-third of arteriovenous fistulas experience early failures. Determining the safety and effectiveness of systemic heparin during fistula creation could improve the quality and quantity of life for these vulnerable patients. In this paper, a pragmatic randomized trial was emulated to assess the effect of systemic heparin administration (vs. none) during radiocephalic arteriovenous fistula creation on early bleeding and thrombosis using data from two international multicenter randomized trials performed between 2014 and 2019. Marginal risks were estimated using inverse probability weighted parametric survival analysis and confidence intervals were generated with bootstrapping. A total of 914 patients were enrolled and 61% received systemic heparin; median (IQR) age was 58 (49, 67) years and 45% were on hemodialysis at enrollment. No difference in the risk of bleeding events was observed, with a risk difference (95% CI) at 14 days of -0.1% (-1.6, 1.4). The risk of access thrombosis was lower in the heparin group, with a risk of 3.7% (2.6, 4.8) after heparin and 5.3% (3.4, 7.4) without heparin at 14 days (risk ratio 0.72, 95% CI 0.50, 0.98).

Descriptive Analysis of Amputation-Free Survival After First Time Infra-Inguinal Bypass Occlusion.

INTRODUCTION: Occlusion after infra-inguinal bypass surgery for peripheral artery disease is a major complication with potentially devastating consequences. In this descriptive analysis, we sought to describe the natural history and explore factors associated with long-term major amputation-free survival following occlusion of a first-time infra-inguinal bypass. METHODS: Using a prospective database from a tertiary care vascular center, we conducted a retrospective cohort study of all patients with peripheral artery disease who underwent a first-time infra-inguinal bypass and subsequently suffered a graft occlusion (1997-2021). The primary outcome was longitudinal rate of major amputation-free survival after bypass occlusion. Cox proportional hazard models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) to explore predictors of outcomes. RESULTS: Of the 1318 first-time infra-inguinal bypass surgeries performed over the study period, 255 bypasses occluded and were included in our analysis. Mean age was 66.7 (12.6) years, 40.4% were female, and indication for index bypass was chronic limb threatening ischemia (CLTI) in 89.8% (n = 229). 48.2% (n = 123) of index bypass conduits used great saphenous vein, 29.0% (n = 74) prosthetic graft, and 22.8% (n = 58) an alternative conduit. Median (interquartile range) time to bypass occlusion was 6.8 (2.3-19.0) months, and patients were followed for median of 4.3 (1.7-8.1) years after bypass occlusion. Following occlusion, 38.04% underwent no revascularization, 32.94% graft salvage procedure, 25.1% new bypass, and 3.92% native artery recanalization. Major amputation-free survival following occlusion was 56.9% (50.6%-62.8%) at 1 y, 37.1% (31%-43.3%) at 5 y, and 17.2% (11.9%-23.2%) at 10 y. In multivariable analysis, factors associated with lower amputation-free survival were older age, female sex, advanced cardiorenal comorbidities, CLTI at index procedure, CLTI at time of occlusion, and distal index bypass outflow. Initial treatment after occlusion with both a new surgical bypass (HR 0.44, CI: 0.29-0.67) or a graft salvage procedure (HR 0.56, CI: 0.38-0.82) showed improved amputation-free survival. One-year rate of major amputation or death were 59.8% (50.0%-69.6%) for those who underwent no revascularization, 37.9% (28.7%-49.0%) for graft salvage, and 26.7% (17.6%-39.5%) for new bypass. CONCLUSIONS: Long-term major amputation-free survival is low after occlusion of a first-time infra-inguinal bypass. While several nonmodifiable risk factors were associated with lower amputation-free survival, treatment after graft occlusion with either a new bypass or a graft salvage procedure may improve longitudinal outcomes.

Temporal trends in hemodialysis access creation during the fistula first era.

OBJECTIVE: Although forearm arteriovenous fistulas (AVFs) are the preferred initial vascular access for hemodialysis based on national guidelines, there are no population-level studies evaluating trends in creation of forearm vs upper arm AVFs and arteriovenous grafts (AVGs). The purpose of this study was to report temporal trends in first-time permanent hemodialysis access type, and to assess the effect of national initiatives on rates of AVF placement. METHODS: Retrospective cross-sectional study (2012-2022) utilizing the Vascular Quality Initiative database. All patients older than 18 years with creation of first-time upper extremity surgical hemodialysis access were included. Anatomic location of the AVF or AVG (forearm vs upper arm) was defined based on inflow artery, outflow vein, and presumed cannulation zone. Primary analysis examined temporal trends in rates of forearm vs upper arm AVFs and AVGs using time series analyses (modified Mann-Kendall test). Subgroup analyses examined rates of access configuration stratified by age, sex, race, dialysis, and socioeconomic status. Interrupted time series analysis was performed to assess the effect of the 2015 Fistula First Catheter Last initiative on rates of AVFs. RESULTS: Of the 52,170 accesses, 57.9% were upper arm AVFs, 25.2% were forearm AVFs, 15.4% were upper arm AVGs, and 1.5% were forearm AVGs. From 2012 to 2022, there was no significant change in overall rates of forearm or upper arm AVFs. There was a numerical increase in upper arm AVGs (13.9 to 18.2 per 100; P = .09), whereas forearm AVGs significantly declined (1.8 to 0.7 per 100; P = .02). In subgroup analyses, we observed a decrease in forearm AVFs among men (33.1 to 28.7 per 100; P = .04) and disadvantaged (Area Deprivation Index percentile ≥50) patients (29.0 to 20.7 per 100; P = .04), whereas female (17.2 to 23.1 per 100; P = .03), Black (15.6 to 24.5 per 100; P < .01), elderly (age ≥80 years) (18.7 to 32.5 per 100; P < .01), and disadvantaged (13.6 to 20.5 per 100; P < .01) patients had a significant increase in upper arm AVGs. The Fistula First Catheter Last initiative had no effect on the rate of AVF placement (83.2 to 83.7 per 100; P=.37). CONCLUSIONS: Despite national initiatives to promote autogenous vascular access, the rates of first-time AVFs have remained relatively constant, with forearm AVFs only representing one-quarter of all permanent surgical accesses. Furthermore, elderly, Black, female, and disadvantaged patients saw an increase in upper arm AVGs. Further efforts to elucidate factors associated with forearm AVF placement, as well as potential physician, center, and regional variation is warranted.

Short-term Pre-operative Methionine Restriction Induces Browning of Perivascular Adipose Tissue and Improves Vein Graft Remodeling in Mice.

Short-term preoperative methionine restriction (MetR) shows promise as a translatable strategy to modulate the body's response to surgical injury. Its application, however, to improve post-interventional vascular remodeling remains underexplored. Here, we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and adverse vascular remodeling after vein graft surgery. RNA sequencing reveals that MetR enhances the brown adipose tissue phenotype in arterial perivascular adipose tissue (PVAT) and induces it in venous PVAT. Specifically, PPAR-α was highly upregulated in PVAT-adipocytes. Furthermore, MetR dampens the post-operative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro . This study shows for the first time that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in browning of PVAT. Furthermore, we demonstrate the potential of short-term pre-operative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

Staged autogenous to prosthetic hemodialysis access creation strategy to maximize forearm options.

OBJECTIVE: When an adequate cephalic vein is not available for fistula construction, surgeons often turn to basilic vein or prosthetic constructions. Single-stage forearm prosthetic hemodialysis accesses are associated with poor durability, and upper arm non-autogenous access options are often limited by axillary outflow failure, which inevitably drives transition to the contralateral arm or lower extremity. We hypothesized that initial creation of a modest flow proximal forearm arterial-venous anastomosis to dilate ("develop") inflow and outflow vessels, followed by a planned second-stage procedure to create a cannulation zone with a prosthetic graft in the forearm, would result in reliable and durable hemodialysis access in patients with limited options. METHODS: We performed an institutional cohort study from 2017 to 2021 using a prospectively maintained database supplemented with adjudicated chart review. Patients without traditional autogenous hemodialysis access options in the forearm underwent an initial non-wrist arterial-venous anastomosis creation in the forearm as a first stage, followed by a second-stage interposition graft sewn to the existing inflow and venous outflow segments to create a useable cannulation zone in the forearm while leveraging vascular development. Outcomes included time from second-stage access creation to loss of primary and secondary patency, frequency of subsequent interventions, and perioperative complications. RESULTS: The cohort included 23 patients; first-stage radial artery-based (74%) configurations were more common than brachial artery-based (26%). Mean age was 63 years (standard deviation, 14 years), and 65% were female. Median follow-up was 340 days (interquartile range [IQR], 169-701 days). Median time to cannulation from second-stage procedure was 28 days (IQR, 18-53 days). Primary, primary assisted, and secondary patency at 1 year was 16.7% (95% confidence interval [CI], 5.3%-45.8%), 34.6% (95% CI, 15.2%-66.2%), and 95.7% (95% CI, 81.3%-99.7%), respectively. Subsequent interventions occurred at a rate of 3.02 (IQR, 1.0-4.97) per person-year, with endovascular thrombectomy with or without angioplasty/stenting (70.9%) being the most common. There were no cases of steal syndrome. Infection occurred in two cases and were managed with antibiotics alone. CONCLUSIONS: For patients without adequate distal autogenous access options, staged prosthetic graft placement in the forearm offers few short-term complications and excellent durability with active surveillance while strategically preserving the upper arm for future constructions.

Cystathionine-γ-lyase overexpression modulates oxidized nicotinamide adenine dinucleotide biosynthesis and enhances neovascularization.

Objective: Hydrogen sulfide is a proangiogenic gas produced primarily by the transsulfuration enzyme cystathionine-γ-lyase (CGL). CGL-dependent hydrogen sulfide production is required for neovascularization in models of peripheral arterial disease. However, the benefits of increasing endogenous CGL and its mechanism of action have not yet been elucidated. Methods: Male whole body CGL-overexpressing transgenic (CGLTg) mice and wild-type (WT) littermates (C57BL/6J) were subjected to the hindlimb ischemia model (age, 10-12 weeks). Functional recovery was assessed via the treadmill exercise endurance test. Leg perfusion was measured by laser Doppler imaging and vascular endothelial-cadherin immunostaining. To examine the angiogenic potential, aortic ring sprouting assay and postnatal mouse retinal vasculature development studies were performed. Finally, comparative metabolomics analysis, oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) analysis, and quantitative real-time polymerase chain reaction were performed on CGLWT and CGLTg gastrocnemius muscle. Results: The restoration of blood flow occurred more rapidly in CGLTg mice. Compared with the CGLWT mice, the median ± standard deviation running distance and time were increased for the CGLTg mice after femoral artery ligation (159 ± 53 m vs 291 ± 74 m [P < .005] and 17 ± 4 minutes vs 27 ± 5 minutes [P < .05], respectively). Consistently, in the CGLTg ischemic gastrocnemius muscle, the capillary density was increased fourfold (0.05 ± 0.02 vs 0.20 ± 0.12; P < .005). Ex vivo, the endothelial cell (EC) sprouting length was increased in aorta isolated from CGLTg mice, especially when cultured in VEGFA (vascular endothelial growth factor A)-only media (63 ± 2 pixels vs 146 ± 52 pixels; P < .05). Metabolomics analysis demonstrated a higher level of niacinamide, a precursor of NAD+/NADH in the muscle of CGLTg mice (61.4 × 106 ± 5.9 × 106 vs 72.4 ± 7.7 × 106 area under the curve; P < .05). Similarly, the NAD+ salvage pathway gene expression was increased in CGLTg gastrocnemius muscle. Finally, CGL overexpression or supplementation with the NAD+ precursor nicotinamide mononucleotide improved EC migration in vitro (wound closure: control, 35% ± 9%; CGL, 55% ± 11%; nicotinamide mononucleotide, 42% ± 13%; P < .05). Conclusions: Our results have demonstrated that CGL overexpression improves the neovascularization of skeletal muscle on hindlimb ischemia. These effects correlated with changes in the NAD pathway, which improved EC migration.

Evaluating national guideline concordance of recurrent interventions after radiocephalic arteriovenous fistula creation.

OBJECTIVE: Radiocephalic arteriovenous fistulas have been historically perceived as requiring multiple follow-up procedural interventions to achieve maturation and maintain patency. Recent clinical practice guidelines from the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) emphasize a patient-centered hemodialysis access strategy with new maximum targets for intervention rates, potentially conflicting with concomitant recommendations to prioritize autogenous forearm hemodialysis access creation. The present descriptive study seeks to assess whether radiocephalic fistulas can meet the KDOQI guideline benchmarks for interventions following access creation, and to elucidate clinical and anatomic characteristics associated with the timing and frequency of interventions following radiocephalic arteriovenous fistula creation. METHODS: Prospective patient-level data from the multicenter PATENCY-1 and PATENCY-2 randomized trials, which enrolled patients undergoing new radiocephalic arteriovenous fistula creation, was analyzed (ClinicalTrials.govNCT02110901 and NCT02414841). The primary outcome was the rate of interventions at 1 year postoperatively. Incidence rates were calculated, and time to surgical or endovascular intervention following fistula creation was modeled using recurrent event extensions of the Cox proportional hazards model. Confidence intervals at the 95% level were calculated using nonparametric bootstrapping. RESULTS: The cohort consisted of 914 patients; mean age was 57 years (standard deviation, 13 years), and 22% were female. Median follow-up was 707 days (interquartile range, 447-1066 days). The incidence of interventions per person-year was 1.04 (95% confidence interval [CI], 0.95-1.13) overall; 1.10 (95% CI, 0.98-1.21) before fistula use, and 0.96 (95% CI, 0.82-1.11) after fistula use. The most common interventions overall were balloon angioplasty (54.9% of all interventions), venous side-branch ligation (16.4%), and open revisions (eg, proximalization from snuffbox to wrist, 16.4%). The locations requiring balloon angioplasty included the juxta-anastomotic segment (51.7% of angioplasties), the outflow vein (29.2%), the inflow artery (14.8%), the central veins (3.8%), and the cephalic arch (0.5%). Common indications were to restore or maintain patency (75.6% of all interventions), assist maturation (14.9%), improve depth (4.4%), or improve augmentation (3.0%). In the multivariable regression analysis, female sex (adjusted hazard ratio [HR], 1.21; 95% CI, 1.05-1.45), diabetes (HR, 1.21; 95% CI, 1.01-1.46), and intraoperative vein diameter <3.0 mm (vs ≥4.0 mm: HR, 1.33; 95% CI, 1.02-1.66) were associated with earlier and more frequent interventions. Patients not on hemodialysis at the time of fistula creation underwent less frequent interventions (HR, 0.69; 95% CI, 0.59-0.81). CONCLUSIONS: Patients with radiocephalic arteriovenous fistulas can expect to undergo one intervention, on average, in the first year after creation, which aligns with current KDOQI guidelines. Patients already requiring hemodialysis, female patients, patients with diabetes, and patients with intraoperative vein diameters <3.0 mm were at increased risk for repeated intervention. No subgroup exceeded guideline-suggested maximum thresholds for recurrent interventions. Overall, the results demonstrate that creation of radiocephalic arteriovenous fistula remains a guideline-concordant strategy when part of an end-stage kidney disease life-plan in appropriately selected patients.

Radiocephalic Arteriovenous Fistula Patency and Use: A Post Hoc Analysis of Multicenter Randomized Clinical Trials.

We sought to confirm and extend the understanding of clinical outcomes following creation of a common distal autogenous access, the radiocephalic arteriovenous fistula (RCAVF). Background: Interdisciplinary guidelines recommend distal autogenous arteriovenous fistulae as the preferred hemodialysis (HD) access, yet uncertainty about durability and function present barriers to adoption. Methods: Pooled data from the 2014-2019 multicenter randomized-controlled PATENCY-1 and PATENCY-2 trials were analyzed. New RC-AVFs were created in 914 patients, and outcomes were tracked prospectively for 3-years. Cox proportional hazards and Fine-Gray regression models were constructed to explore patient, anatomic, and procedural associations with access patency and use. Results: Mean (SD) age was 57 (13) years; 45% were on dialysis at baseline. Kaplan-Meier estimates of 3-year primary, primary-assisted, and secondary patency were 27.6%, 56.4%, and 66.6%, respectively. Cause-specific 1-year cumulative incidence estimates of unassisted and overall RC-AVF use were 46.8% and 66.9%, respectively. Patients with larger baseline cephalic vein diameters had improved primary (per mm, hazard ratio [HR] 0.89, 95% confidence intervals 0.81-0.99), primary-assisted (HR 0.75, 0.64-0.87), and secondary (HR 0.67, 0.57-0.80) patency; and higher rates of unassisted (subdistribution hazard ratio 1.21, 95% confidence intervals 1.02-1.44) and overall RCAVF use (subdistribution hazard ratio 1.26, 1.11-1.45). Similarly, patients not requiring HD at the time of RCAVF creation had better primary, primary-assisted, and secondary patency. Successful RCAVF use occurred at increased rates when accesses were created using regional anesthesia and at higher volume centers. Conclusions: These insights can inform patient counseling and guide shared decision-making regarding HD access options when developing an individualized end-stage kidney disease life-plan.

Contemporary indications for open abdominal aortic aneurysm repair in the endovascular era.

OBJECTIVE: Despite the emergence of endovascular aneurysm repair (EVAR) as the most common approach to abdominal aortic aneurysm repair, open aneurysm repair (OAR) remains an important option. This study seeks to define the indications for OAR in the EVAR era and how these indicatioxns effect outcomes. METHODS: A retrospective cohort study was performed of all OAR at a single institution from 2004 to 2019. Preoperative computed tomography scans and operative records were assessed to determine the indication for OAR. These reasons were categorized into anatomical contraindications, systemic factors (connective tissue disorders, contraindication to contrast dye), and patient or surgeon preference (patients who were candidates for both EVAR and OAR). Perioperative and long-term outcomes were compared between the groups. RESULTS: We included 370 patients in the analysis; 71.6% (265/370) had at least one anatomic contraindication to EVAR and 36% had two or more contraindications. The most common anatomic contraindications were short aortic neck length (51.6%), inadequate distal seal zone (19.2%), and inadequate access vessels (15.7%). The major perioperative complication rate was 18.1% and the 30-day mortality was 3.0%. No single anatomic factor was identified as a predictor of perioperative complications. Sixty-one patients (16.5%) underwent OAR based on patient or surgeon preference; these patients were younger, had lower incidences of coronary artery disease and chronic obstructive pulmonary disease, and were less likely to require suprarenal cross-clamping compared with patients who had anatomic and/or systemic contraindications to EVAR. The patient or surgeon preference group had a lower incidence of perioperative major complications (8.2% vs 20.1%; P = .034), shorter length of stay (6 days vs 8 days; P < .001) and no 30-day mortalities. The multivariable adjusted risk for 15-year mortality was lower for patient or surgeon preference patients (adjusted hazard ratio, 0.44; 95% confidence interval, 0.24-0.80; P = .007) compared with those anatomic or systemic contraindications. CONCLUSIONS: Within a population of patients who did not meet instruction for use criteria for EVAR, no single anatomic contraindication was a marker for worse outcomes with OAR. Patients who were candidates for both aortic repair approaches but elected to undergo OAR owing to patient or surgeon preference have very low 30-day mortality and morbidity, and superior long-term survival rates compared with those patients who underwent OAR owing to anatomic and/or systemic contraindications to EVAR.

Comparative analysis of open abdominal aortic aneurysm repair outcomes across national registries.

OBJECTIVE: In a recent analysis, we discovered lower mortality after open abdominal aortic aneurysm repair (OAAA) in the Society for Vascular Surgery Vascular Quality Initiative (VQI) database when compared with previously published reports of other national registries. Understanding differentials in these registries is essential for their utility because such datasets increasingly inform clinical guidelines and health policy. METHODS: The VQI, American College of Surgeons National Surgical Quality Improvement Program (NSQIP), and National Inpatient Sample (NIS) databases were queried to identify patients who had undergone elective OAAA between 2013 and 2016. χ2 tests were used for frequencies and analysis of variance for continuous variables. RESULTS: In total, data from 8775 patients were analyzed. Significant differences were seen across the baseline characteristics included. Additionally, the availability of patient and procedural data varied across datasets, with VQI including a number of procedure-specific variables and NIS with the most limited clinical data. Length of stay, primary insurer, and discharge destination differed significantly. Unadjusted in-hospital mortality also varied significantly between datasets: NIS, 5.5%; NSQIP, 5.2%; and VQI, 3.3%; P < .001. Similarly, 30-day mortality was found to be 3.5% in VQI and 5.9% in NSQIP (P < .001). CONCLUSIONS: There are fundamental important differences in patient demographic/comorbidity profiles, payer mix, and outcomes after OAAA across widely used national registries. This may represent differences in outcomes between institutions that elect to participate in the VQI and NSQIP compared with patient sampling in the NIS. In addition to avoiding direct comparison of information derived from these databases, it is critical these differences are considered when making policy decisions and guidelines based on these "real-world" data repositories.

Short-Term Pre-Operative Protein Caloric Restriction in Elective Vascular Surgery Patients: A Randomized Clinical Trial.

(1) Background: Vascular surgery operations are hampered by high failure rates and frequent occurrence of peri-operative cardiovascular complications. In pre-clinical studies, pre-operative restriction of proteins and/or calories (PCR) has been shown to limit ischemia-reperfusion damage, slow intimal hyperplasia, and improve metabolic fitness. However, whether these dietary regimens are feasible and safe in the vascular surgery patient population remains unknown. (2) Methods: We performed a randomized controlled trial in patients scheduled for any elective open vascular procedure. Participants were randomized in a 3:2 ratio to either four days of outpatient pre-operative PCR (30% calorie, 70% protein restriction) or their regular ad-libitum diet. Blood was drawn at baseline, pre-operative, and post-operative day 1 timepoints. A leukocyte subset flow cytometry panel was performed at these timepoints. Subcutaneous/perivascular adipose tissue was sampled and analyzed. Follow-up was one year post-op. (3) Results: 19 patients were enrolled, of whom 11 completed the study. No diet-related reasons for non-completion were reported, and there was no intervention group crossover. The PCR diet induced weight loss and BMI decrease without malnutrition. Insulin sensitivity was improved after four days of PCR (p = 0.05). Between diet groups, there were similar rates of re-intervention, wound infection, and cardiovascular complications. Leukocyte populations were maintained after four days of PCR. (4) Conclusions: Pre-operative PCR is safe and feasible in elective vascular surgery patients.

Plasma Hydrogen Sulfide Is Positively Associated With Post-operative Survival in Patients Undergoing Surgical Revascularization.

Objective: Hydrogen sulfide (H2S) is a gaseous signaling molecule and redox factor important for cardiovascular function. Deficiencies in its production or bioavailability are implicated in atherosclerotic disease. However, it is unknown if circulating H2S levels differ between vasculopaths and healthy individuals, and if so, whether H2S measurements can be used to predict surgical outcomes. Here, we examined: (1) Plasma H2S levels in patients undergoing vascular surgery and compared these to healthy controls, and (2) the association between H2S levels and mortality in a cohort of patients undergoing surgical revascularization. Methods: One hundred and fifteen patients undergoing carotid endarterectomy, open lower extremity revascularization or lower leg amputation were enrolled at a single institution. Peripheral blood was also collected from a matched control cohort of 20 patients without peripheral or coronary artery disease. Plasma H2S production capacity and sulfide concentration were measured using the lead acetate and monobromobimane methods, respectively. Results: Plasma H2S production capacity and plasma sulfide concentrations were reduced in patients with PAD (p < 0.001, p = 0.013, respectively). Patients that underwent surgical revascularization were divided into high vs. low H2S production capacity groups by median split. Patients in the low H2S production group had increased probability of mortality (p = 0.003). This association was robust to correction for potentially confounding variables using Cox proportional hazard models. Conclusion: Circulating H2S levels were lower in patients with atherosclerotic disease. Patients undergoing surgical revascularization with lower H2S production capacity, but not sulfide concentrations, had increased probability of mortality within 36 months post-surgery. This work provides insight on the role H2S plays as a diagnostic and potential therapeutic for cardiovascular disease.

Intracellular H2S production is an autophagy-dependent adaptive response to DNA damage.

Hydrogen sulfide (H2S) is a gasotransmitter with broad physiological activities, including protecting cells against stress, but little is known about the regulation of cellular H2S homeostasis. We have performed a high-content small-molecule screen and identified genotoxic agents, including cancer chemotherapy drugs, as activators of intracellular H2S levels. DNA damage-induced H2S in vitro and in vivo. Mechanistically, DNA damage elevated autophagy and upregulated H2S-generating enzyme CGL; chemical or genetic disruption of autophagy or CGL impaired H2S induction. Importantly, exogenous H2S partially rescued autophagy-deficient cells from genotoxic stress. Furthermore, stressors that are not primarily genotoxic (growth factor depletion and mitochondrial uncoupler FCCP) increased intracellular H2S in an autophagy-dependent manner. Our findings highlight the role of autophagy in H2S production and suggest that H2S generation may be a common adaptive response to DNA damage and other stressors.

Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease: PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development.

BACKGROUND: Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discover therapeutic targets for vein graft failure. METHODS: Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, quantitative polymerase chain reaction, flow cytometry, metabolic assays, and single-cell RNA sequencing on primary human and mouse macrophages. RESULTS: We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, whereas gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. CONCLUSIONS: This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacological treatment for this unmet medical need.

Contemporary outcomes of a "snuffbox first" hemodialysis access approach in the United States.

OBJECTIVE: The Society for Vascular Surgery guidelines for permanent hemodialysis (HD) access creation recommend prioritizing the most distal possible autogenous access to minimize complications and preserve more proximal options. The "snuffbox" arteriovenous fistula (AVF) is the most distal radial artery-cephalic vein AVF. Despite the theoretical benefits of the snuffbox approach, recent trends have been toward upper arm access. Our study sought to investigate the feasibility of a snuffbox-first strategy for HD access in all anatomically appropriate candidates. METHODS: From January 2016 to August 2019, all patients with end-stage renal disease (ESRD) or pre-ESRD under consideration for HD access were evaluated for a snuffbox-first approach by a team of vascular surgeons and nephrologists at a single, urban academic medical center in the United States. Data were collected prospectively and supplemented by medical record review. A survival analysis was performed to evaluate primary unassisted and secondary patency and clinical and functional maturation. Patients were censored if they had received a kidney transplant or had died. Cox proportional hazards regression was used to determine the risk factors for prolonged clinical maturation and functional maturation. RESULTS: A total of 55 snuffbox AVFs were created. The median patient age was 60 years (interquartile range [IQR], 52-70 years), and 52.7% of the patients were men. The median follow-up was 369 days (IQR, 166-509 days). The median survival for primary unassisted patency was 90 days (95% confidence interval [CI], 79-111). Secondary patency at 1 year was 92.3% (95% CI, 85.3%-99.9%). The clinical maturation rate at 1 year was 83.7% (n = 55; 95% CI, 66.8%-91.9%), and the functional maturation rate at 1 year was 85.6% (n = 40; 95% CI, 63.3%-94.4%). Of the patients who were pre-ESRD at AVF creation and had initiated HD during the study period, 87.5% had successfully received incident HD with their snuffbox AVF. Twenty-four patients were receiving HD via a catheter at snuffbox creation. Of those patients, the functional maturation rate at 1 year was 82.5% (95% CI, 44.8%-94.4%). The patients had undergone a median of two interventions (IQR, zero to seven interventions) in the first year. Of these, 46.9% were percutaneous angioplasty and 31.2% were side-branch ligation. Diabetes was associated with slower AVF clinical maturation (multivariate hazard ratio, 0.35; 95% CI, 0.15-0.82; P = .016). A larger artery diameter was associated with earlier AVF clinical maturation (multivariate hazard ratio, 6.64; 95% CI, 2.11-20.9). CONCLUSIONS: A snuffbox-first approach to HD access is a viable option for distal access creation in a cohort of patients requiring HD in the United States. Subsequent ancillary interventions to facilitate access maturation were required for most patients.

A multicenter, prospective randomized trial of negative pressure wound therapy for infrainguinal revascularization with a groin incision.

BACKGROUND: Wound complications after open infrainguinal revascularization are a frequent cause of patient morbidity, resulting in increased healthcare costs. The purpose of the present study was to assess the effects of closed incision negative pressure therapy (ciNPT) on groin wound complications after infrainguinal bypass and femoral endarterectomy. METHODS: A total of 242 patients who had undergone infrainguinal bypass (n = 124) or femoral endarterectomy (n = 118) at five academic medical centers in New England from April 2015 to August 2019 were randomized to ciNPT (PREVENA; 3M KCI, St Paul, Minn; n = 118) or standard gauze (n = 124). The primary outcome measure was a composite endpoint of groin wound complications, including surgical site infections (SSIs), major noninfectious wound complications, or graft infections within 30 days after surgery. The secondary outcome measures included 30-day SSIs, 30-day noninfectious wound complications, readmission for wound complications, significant adverse events, and health-related quality of life using the EuroQoL 5D-3L survey. RESULTS: The ciNPT and control groups had similar demographics (age, 67 vs 67 years, P = .98; male gender, 71% vs 70%, P = .86; white race, 93% vs 93%, P = .97), comorbidities (previous or current smoking, 93% vs 94%, P = .46; diabetes, 41% vs 48%, P = .20; renal insufficiency, 4% vs 7%, P = .31), and operative characteristics, including procedure type, autogenous conduit, and operative time. No differences were found in the primary composite outcome at 30 days between the two groups (ciNPT vs control: 31% vs 28%; P = .55). The incidence of SSI at 30 days was similar between the two groups (ciNPT vs control: 11% vs 12%; P = .58). Infectious (13.9% vs 12.6%; P = .77) and noninfectious (20.9% vs 17.6%; P = .53) wound complications at 30 days were also similar for the ciNPT and control groups. Wound complications requiring readmission also similar between the two groups (ciNPT vs control: 9% vs 7%; P = .54). The significant adverse event rates were not different between the two groups (ciNPT vs control: 13% vs 16%; P = .53). The mean length of the initial hospitalization was the same for the ciNPT and control groups (5.2 vs 5.7 days; P = .63). The overall health-related quality of life was similar at baseline and at 14 and 30 days postoperatively for the two groups. Although not powered for stratification, we found no differences among the subgroups in gender, obesity, diabetes, smoking, claudication, chronic limb threatening ischemia, bypass, or endarterectomy. On multivariable analysis, no differences were found in wound complications at 30 days for the ciNPT vs gauze groups (odds ratio, 1.4; 95% confidence interval, 0.8-2.6; P = .234). CONCLUSIONS: In contrast to other randomized studies, our multicenter trial of infrainguinal revascularization found no differences in the 30-day groin wound complications for patients treated with ciNPT vs standard gauze dressings. However, the SSI rate was lower in the control group than reported in other studies, suggesting other practice patterns and processes of care might have reduced the rate of groin infections. Further study might identify the subsets of high-risk patients that could benefit from ciNPT.

Patient comprehension necessary for informed consent for vascular procedures is poor and related to frailty.

OBJECTIVE: Informed consent is an essential principle of high-quality health care. A core component of surgical informed consent is patient comprehension of basic information such as the diagnosis, risks, benefits, and alternatives of the proposed surgery. We sought to assess informed consent among vascular surgery patients and the association between frailty, education, decisional conflict, and patient comprehension. METHODS: We tested patient comprehension of basic information required for informed consent with a procedure-specific questionnaire in 102 consecutive patients undergoing selected vascular surgery procedures. Two patients who underwent open aortic aneurysm repair were excluded because of small sample size. All patients underwent assessment using the decisional conflict scale and the Frail/Nondisabled questionnaire. Analyses were performed to determine relationships between being informed and frailty, education level, and decisional conflict score. Patients included in this cohort had a median age of 71 years, and 25%, 14%, 28%, and 33% underwent carotid endarterectomy, endovascular aortic aneurysm repair, dialysis access creation, and percutaneous lower extremity procedures. RESULTS: Overall, 14% of patients were classified as "informed" and correctly answered all questions. Procedure type (P = .001), consent obtained by the attending surgeon vs a trainee (P = .04), and frailty score (P = .005) were all associated with whether a patient was informed or not. However, after multivariable adjustment, only frailty score was independently associated with being informed (odds ratio, 0.54; 95% confidence interval, 0.30-0.95; P = .03). The median decisional conflict scale score was 7.8, suggesting that patients feel well informed and supported in spite of poor understanding of procedural indications, risks, benefits, and alternatives. CONCLUSIONS: As a group, patients have a poor comprehension of basic information related to surgical informed consent. These findings have potential ethical and clinical implications, and additional work is required to best determine causes of poor comprehension and strategies to mitigate the same.

Association and interplay of surgeon and hospital volume with mortality after open abdominal aortic aneurysm repair in the modern era.

OBJECTIVE: Operative volume has been used as a marker of quality. Research from previous decades has suggested minimum open abdominal aortic aneurysm (AAA) repair volume requirements for surgeons of 9 to 13 open AAA repairs annually and for hospitals of 18 open AAA repairs annually to purportedly achieve acceptable results. Given concerns regarding the decreased frequency of open repairs in the endovascular era, we examined the association of surgeon and hospital volume with the 30- and 90-day mortality in the Vascular Quality Initiative (VQI) registry. METHODS: Patients who had undergone elective open AAA repair from 2013 to 2018 were identified in the VQI registry. We performed a cross-sectional evaluation of the association between the average hospital and surgeon volume and 30-day postoperative mortality using a hierarchical Bayesian model. Cross-level interactions were permitted, and random surgeon- and hospital-level intercepts were used to account for clustering. The mortality results were adjusted by standardizing to the observed distribution of relevant covariates in the overall cohort. The outcomes were compared to the Society for Vascular Surgery guidelines recommended criteria of <5% perioperative mortality. RESULTS: A total of 3078 patients had undergone elective open AAA repair by 520 surgeons at 128 hospitals. The 30- and 90-day risks of postoperative mortality were 4.1% (n = 126) and 5.4% (n = 166), respectively. The mean surgeon volume and hospital volume both correlated inversely with the 30-day mortality. Averaged across all patients and hospitals, we found a 96% probability that surgeons who performed an average of four or more repairs per year achieved <5% 30-day mortality. Substantial interplay was present between surgeon volume and hospital volume. For example, at lower volume hospitals performing an average of five repairs annually, <5% 30-day mortality would be expected 69% of the time for surgeons performing an average of three operations annually. In contrast, at higher volume hospitals performing an average of 40 repairs annually, a <5% 30-day mortality would be expected 96% of the time for surgeons performing an average of three operations annually. As hospital volume increased, a diminishing difference occurred in 30-day mortality between lower and higher volume surgeons. Likewise, as surgeon volume increased, a diminishing difference was found in 30-day mortality between the lower and higher volume hospitals. CONCLUSIONS: Surgeons and hospitals in the VQI registry achieved mortality outcomes of <5% (Society for Vascular Surgery guidelines), with an average surgeon volume that was substantially lower compared with previous reports. Furthermore, when considering the development of minimal surgeon volume guidelines, it is important to contextualize the outcomes within the hospital volumes.