Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.

BACKGROUND: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. METHODS: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas. RESULTS: Single-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. CONCLUSIONS: This reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD. METHODS: AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHRmKO (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD. RESULTS: PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared with either muscle from the PAD condition with normal renal function (P<0.05 for all 3 genes) or nonischemic controls. AHRmKO significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. CONCLUSIONS: These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.

N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.

The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.

National Institutes of Health funding among vascular surgeons is rare.

BACKGROUND: The National Institutes of Health (NIH) is an essential source of funding for vascular surgeons conducting research. NIH funding is frequently used to benchmark institutional and individual research productivity, help determine eligibility for academic promotion, and as a measure of scientific quality. We sought to appraise the current scope of NIH funding to vascular surgeons by appraising the characteristics of NIH-funded investigators and projects. In addition, we also sought to determine whether funded grants addressed recent Society for Vascular Surgery (SVS) research priorities. METHODS: In April 2022, we queried the NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) database for active projects. We only included projects that had a vascular surgeon as a principal investigator. Grant characteristics were extracted from the NIH Research Portfolio Online Reporting Tools Expenditures and Results database. Principal investigator demographics and academic background information were identified by searching institution profiles. RESULTS: There were 55 active NIH awards given to 41 vascular surgeons. Only 1% (41/4037) of all vascular surgeons in the United States receive NIH funding. Funded vascular surgeons are an average of 16.3 years out of training; 37% (n = 15) are women. The majority of awards (58%; n = 32) were R01 grants. Among the active NIH-funded projects, 75% (n = 41) are basic or translational research projects, and 25% (n = 14) are clinical or health services research projects. Abdominal aortic aneurysm and peripheral arterial disease are the most commonly funded disease areas and together accounted for 54% (n = 30) of projects. Three SVS research priorities are not addressed by any of the current NIH-funded projects. CONCLUSIONS: NIH funding of vascular surgeons is rare and predominantly consists of basic or translational science projects focused on abdominal aortic aneurysm and peripheral arterial disease research. Women are well-represented among funded vascular surgeons. Although the majority of SVS research priorities receive NIH funding, three SVS research priorities are yet to be addressed by NIH-funded projects. Future efforts should focus on increasing the number of vascular surgeons receiving NIH grants and ensuring all SVS research priorities receive NIH funding.

Assessing the quality of reporting of studies using Vascular Quality Initiative (VQI) data.

OBJECTIVE: The Society for Vascular Surgery Vascular Quality Initiative (VQI) has become an increasingly popular data source for retrospective observational vascular surgery studies. There are published guidelines on the reporting of data in such studies to promote transparency and rigor, but these have not been used to evaluate studies using VQI data. Our objective was to appraise the methodological reporting quality of studies using VQI data by evaluating their adherence to these guidelines. METHODS: The Society for Vascular Surgery VQI publication repository was queried for all articles published in 2020. The REporting of studies Conducted using Observational Routinely-collected Health Data (RECORD) statement and the Journal of American Medical Association-Surgical Section (JAMA-Surgery) checklist were utilized to assess the quality of each article's reporting. Five and three items from the RECORD statement and JAMA-Surgery checklist were excluded, respectively, because they were either inapplicable or nonassessable. Journal impact factor (IF) was queried for each article to elucidate any difference in reporting standards between high and low IF journals. RESULTS: Ninety studies were identified and analyzed. The median score on the RECORD checklist was 6 (of 8). The most commonly missed item was discussing data cleaning methods (93% missed). The median score on the JAMA-Surgery checklist was 3 (of 7). The most commonly missed items were the identification of competing risks (98% missed), the use of a flow chart to clearly define sample exclusion and inclusion criteria (84% missed), and the inclusion of a solid research question and hypothesis (81% missed). There were no differences in JAMA-Surgery checklist or RECORD statement median scores among studies published in low vs high IF journals. CONCLUSIONS: Studies using VQI data demonstrate a poor to moderate adherence to reporting standards. Key areas for improvement in research reporting include articulating a clear hypothesis, using flow charts to clearly define inclusion and exclusion criteria, identifying competing risks, and discussing data cleaning methods. Additionally, future efforts should center on creating tailored instruments to better guide reporting in studies using VQI data.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

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

Metabolomic profiling reveals muscle metabolic changes following iliac arteriovenous fistula creation in mice.

End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis.NEW & NOTEWORTHY Creation of an arteriovenous fistula (AVF) is the preferred approach for dialysis access, but some patients experience hand dysfunction after AVF creation. In this study, we provide a detailed metabolomic analysis of the limb muscle in a murine model of AVF. AVF creation resulted in metabolite changes associated with an energetic crisis and myosteatosis that associated with limb function.

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.

BACKGROUND: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. METHODS: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. RESULTS: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. CONCLUSIONS: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Analyses of hemodialysis arteriovenous fistula geometric configuration and its associations with maturation and reintervention.

OBJECTIVE: An arteriovenous fistula (AVF) is the preferred vascular access for chronic hemodialysis; however, the rates of AVF maturation failure and reintervention remain high. We investigated the AVF geometric parameters and their associations with AVF physiologic maturation and reintervention in a prospective multicenter study. METHODS: From 2011 to 2016, patients undergoing vein end-to-artery side upper extremity AVF creation surgery were recruited. Contrast-free dark blood and phase-contrast magnetic resonance imaging (MRI) scans were performed using 3.0T scanners to obtain the AVF lumen geometry and flow rates, respectively, at postoperative day 1, week 6, and month 6. The arteriovenous anastomosis angle, nonplanarity, and tortuosity of the fistula were calculated according to the lumen centerlines. AVFs were considered physiologically matured if, using the week 6 MRI data, the flow rate was ≥500 mL/min and the minimum vein lumen diameter was ≥5 mm. The associations of these geometric parameters with AVF maturation and reintervention due to perianastomotic and mid-vein stenosis within 1 year were assessed. RESULTS: A total of 111 patients had a usable day 1 MRI scan, with most having upper arm AVFs (n = 73). Compared with the forearm AVFs, upper arm AVFs had greater anastomosis angles (P < .001), larger deviations from a plane (nonplanarity; P = .002), and more prominent tortuosity (P = .038) at day 1. These parameters significantly increased between day 1 and week 6 in upper arm AVFs. In contrast, significant changes in these parameters in forearm AVFs were not observed. The rate of maturation was 54% and 86% for forearm and upper arm AVFs, respectively. None of the geometric parameters at day 1 were associated with AVF maturation in either location. The rate of reintervention was 24% and 30% for forearm and upper arm AVFs, respectively, with a larger nonplanarity angle at day 1 associated with less reintervention (30° ± 15° vs 21° ± 10°; P = .034) in upper arm AVFs only. This relationship was unchanged after adjusting for age, sex, race, dialysis status, or diabetes. CONCLUSIONS: In our study, upper arm fistulas had a larger anastomosis angle, were more nonplanar, and had more tortuous veins than forearm fistulas. For upper arm fistulas, a larger nonplanarity angle is associated with a lower rate of reintervention within 1 year. Once confirmed, vascular surgeons could consider increasing the nonplanarity angle by incorporating a tension-free gentle curvature in the proximal segment of the mobilized vein to reduce reinterventions when creating an upper arm fistula.

Contemporary management and outcomes of complex vascular surgical groin wound infections.

OBJECTIVE: Vascular surgical groin wound infection (VS-GWI) has multiple causes and frequently is manifested as a limb- or life-threatening problem, resulting in significant morbidity and mortality. For patients undergoing operative extirpation, in situ repair, extra-anatomic bypass, or ligation can be used; however, limited data exist describing comparative results of the different operative choices or conduit subtypes. Therefore, we sought to describe our experience with management of VS-GWI and to detail outcomes of the different strategies. METHODS: Patients (2003-2017) undergoing surgical treatment of VS-GWI (Szilagyi grade III) secondary to primary infectious arteritis or infected pseudoaneurysm after percutaneous intervention as well as previous prosthetic graft placement were reviewed. The primary end point was major adverse limb events (MALEs; major amputation, graft occlusion, or unplanned reintervention). Secondary end points included 30-day mortality, wound healing, amputation-free survival (AFS), and all-cause mortality. Cox proportional hazards modeling was used to determine relative risk of end points; Kaplan-Meier methodology was employed to estimate freedom from outcomes. RESULTS: There were 149 patients (age, 65 ± 11 years; body mass index, 27 ± 6 kg/m2; 70% male; 32% diabetes) identified, of whom 120 (81%) had unilateral and 29 (19%) had bilateral VS-GWI. Indications included infected prosthetic bypass (88% [n = 131]; infrainguinal, 107; suprainguinal, 24) and primary infectious femoral artery complications (12% [n = 18]). A majority underwent single-stage operations (87% [n = 129]). In situ reconstruction occurred in 87% (n = 129); 9% (n = 13) underwent ligation, and 6% (n = 7) received extra-anatomic revascularization. Autogenous conduit was used most commonly (68% [n = 101/149]; 88% single stage), of which 81% (n = 80) were femoral vein. The remaining patients received cadaveric (15% [n = 23]; 87% single stage) or prosthetic (8% [n=12]; 67% single stage) grafts. Adjunctive myocutaneous flap was used in 37% (n = 54). Length of stay was 19 ± 15 days and 30-day mortality was 7% (n = 10), with no difference between conduit repair types. All femoral wounds healed (mean follow-up, 17 ± 11 months); however, 33% (n = 49) underwent reoperation (unplanned graft reintervention, 33%; graft occlusion, 16%; wound débridement, 15%; major amputation, 11%). Reinfection occurred in 17% (n = 27), with no difference between groups. MALE rate was 22% (n = 33; most were arterial reinterventions, 19%), with no difference in single-stage vs multistage, in situ vs extra-anatomic, or autogenous vs nonautogenous conduit strategies Predictors of MALE included younger age (hazard ratio [HR], 1.6 per decade; 95% confidence interval [CI], 1.1-2.5; P = .02) and lower body mass index (<25 kg/m2; HR, 1.6 per BMI category; 95% CI, 1.1-2.5; P = .02). Overall, 1- and 3-year freedom from MALE, AFS, and survival were as follows: MALE, 74% ± 5% and 63% ± 6%; AFS, 68% ± 4% and 58% ± 5%; survival, 78% ± 3% and 70% ± 4%. Autogenous conduit use was associated with better survival (HR, 0.5; 95% CI, 0.3-0.8; 1-year: 83% ± 4% vs nonautogenous, 78% ± 4%; 3-year: 68% ± 8% vs 53% ± 9%; log-rank, P = .006). CONCLUSIONS: An individualized approach to operative strategy and conduit choice leads to comparable outcomes in this challenging group of patients. VS-GWI can be safely managed with in situ, autogenous reconstruction in a majority of patients with acceptable mortality, excellent wound healing rates, and improved overall survival. However, a significant proportion of patients experience reinfection and MALEs, the preponderance of which are arterial reintervention, mandating need for close follow-up and graft surveillance.

Surgeon experience versus volume differentially affects lower extremity bypass outcomes in contemporary practice.

BACKGROUND: Calls for minimum case thresholds to guide surgeon credentialing paradigms are increasing in contemporary practice. To date, the volume-outcome relationship and the role of surgeon experience as a proxy for quality have remained primarily focused on nonvascular extirpative surgery and aneurysm repair. However, it is unclear whether these data can be rightly extrapolated to predict lower extremity bypass (LEB) outcomes. Thus, the purpose of the present study was to examine whether the annualized case volume vs surgeon experience is more consequential in predicting for successful LEB reconstruction. METHODS: A total of 25,852 procedures with sufficient 1-year follow-up data from the Society for Vascular Surgery Vascular Quality Initiative infrainguinal bypass registry (2003-2019) were reviewed for chronic limb threatening ischemia among patients undergoing infrageniculate reconstruction. The procedures were categorized according to surgeon years of practice experience at surgery (ie, 0-5, 6-10, 11-15, >15 years) and the number of LEB procedures performed by the surgeon during the year of surgery (volume quartiles: 1-8, 9-14, 15-21, and >21). Mixed effects logistic and Cox regression models were used to assess the effects of experience, volume, and their interaction on outcomes. RESULTS: Increasing practice experience was more significantly associated with a reduction of in-hospital complications (odds ratio, 0.97; 95% confidence interval [CI], 0.96-0.99; P = .002) and the risk of major adverse limb events (odds ratio, 0.94; 95% CI, 0.92-0.97; P < .0001) compared with the volume. Increasing experience and volume were both associated with increased freedom from thrombosis (hazard ratio, 0.95; 95% CI, 0.93-0.98; P = .001). In contrast, neither experience nor volume had any significant association with early mortality. However, a higher volume was associated with diminished long-term survival (hazard ratio, 1.04; 95% CI, 1.0-1.1; P = .01). The most experienced surgeons (>15 years' experience) were significantly more likely to perform LEB for rest pain (P < .0001). No significant differences were found in the bypass rates among patients with tissue loss. The most experienced and highest volume surgeons were more likely to use an autogenous and/or composite conduit, in situ reconstruction, and/or pedal targets (P < .05). Similarly, more experienced and higher volume surgeons had less blood loss and shorter procedure times (P < .0001). Overall, the most experienced surgeons (>15 years' experience) were significantly more likely to have a higher volume with a diminished risk for all LEB outcomes. CONCLUSIONS: Surgeon experience appears to have the most important role in predicting for overall LEB performance with improved in-hospital outcomes and major adverse limb events. The more experienced surgeons performed more complex reconstructions with fewer complications. These findings have significant clinical and educational implications as our most experienced surgeons approach retirement. Mentorship strategies to facilitate ongoing technical development among less experienced surgeons are imperative to sustain optimal limb salvage outcomes and have significant ramifications regarding expectations for regulatory and credentialing paradigms.

Effect of ischemia-reperfusion on outcomes after open mesenteric bypass for chronic mesenteric ischemia.

OBJECTIVE: Significant physiologic perturbations can occur in patients with chronic mesenteric ischemia (CMI) undergoing open mesenteric bypass (OMB). These events have frequently been attributed to ischemia-reperfusion events and have been directly implicated in the occurrence of multiple organ dysfunction (MOD). Scoring systems (MOD score [MODS] and sequential organ failure assessment [SOFA]) have been derived within the critical care field to provide a composite metric for these pathophysiologic changes. The purpose of the present study was to describe the early pathophysiologic changes that occur after OMB for CMI and determine whether these are predictive of the outcomes. METHODS: Patients with CMI who had undergone elective OMB from 2002 to 2018 at a single institution were reviewed. Changes in the hemodynamic, pulmonary, hepatic, renal, and hematologic parameters in the first 96 hours postoperatively were analyzed. The MODSs and SOFA scores were calculated. Cox regression was used to determine the association of the MODSs and SOFA scores with the outcomes. RESULTS: The use of OMB was analyzed for 72 patients (age, 66 ± 11 years; 68% women; body mass index, 23.8 ± 6 kg/m2; 48 ± 34-lb weight loss in 59%). Previous mesenteric stent placement or bypass had been performed in 39% [stenting in 21; bypass in 8; (one patient had both)]. An antegrade configuration (93%) was most common (retrograde configuration, 7%), with revascularization of the superior mesenteric artery/celiac vessels in 85% (superior mesenteric artery only in 15%). Postoperative pathophysiologic and metabolic changes were common, and the mean MODSs and SOFA scores were 3.6 ± 2.4 (range, 1-10) and 4.0 ± 2.7 (range, 1-13), respectively. The median length of stay was 14 days (interquartile range, 9-21). The 30-day mortality was 4% (n = 3) and in-hospital morbidity was 53% (n = 38; gastrointestinal, 25%; infectious, 22%; cardiac, 18%; pulmonary, 18%; renal, 11%). The clinical follow-up period was 16 ± 20 months. The MODSs and SOFA scores correlated linearly with overall mortality (MODS: odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.7; P < .01; SOFA score: OR, 1.4; 95% CI, 1.2-1.7; P < .01 per unit), with a score of ≥5 the inflection point most predictive of mortality (MODS: OR, 3.9; 95% CI, 1.6-9.9; P ≤ .01; SOFA score: OR, 2.8; 95% CI, 1.2-6.6; P = .02). The 1- and 3-year primary bypass patency and freedom from reintervention was 91% ± 5% and 83% ± 7%, respectively, with no association with the MODSs or SOFA scores. The 1- and 3-year survival was 86% ± 4% and 71% ± 6% with significantly worse outcomes for patients with higher MODSs and/or SOFA scores. CONCLUSIONS: Most CMI patients undergoing OMB will experience significant metabolic derangements resulting from sequelae of the ischemia-reperfusion phenomenon postoperatively. These can be objectively assessed in the early postoperative period using simply applied scoring systems to reliably predict the early and long-term outcomes. A derivation of the MODS and/or SOFA score after OMB for CMI can identify the most vulnerable patients at the greatest risk of mortality.

Association between surgeon case volume and years of practice experience with open abdominal aortic aneurysm repair outcomes.

BACKGROUND: Widespread adoption of endovascular aneurysm repair has led to a consequential decline in the use of open aneurysm repair (OAR). This evolution has had significant ramifications on vascular surgery training paradigms and contemporary practice patterns among established surgeons. Despite being the subject of previous analyses, the surgical volume-outcome relationship has remained a focus of controversy. At present, little is known about the complex interaction of case volume and surgeon experience with patient selection, procedural characteristics, and postoperative complications of OAR. The purpose of the present analysis was to examine the association between surgeon annual case volume and years of practice experience with OAR. METHODS: All infrarenal OARs (n = 11,900; elective, 70%; nonelective, 30%) included in the Society for Vascular Surgery Vascular Quality Initiative from 2003 to 2019 were examined. Surgeon experience was defined as years in practice after training. The experience level at repair was categorized chronologically (≤5 years, n = 1667; 6-10 years, n = 1887; 11-15 years, n = 1806; ≥16 years, n = 6540). The annual case volume was determined by the number of OARs performed by the surgeon annually (median, five cases). Logistic regression was used to perform risk adjustment of the outcomes across surgeon experience and volume (five or fewer vs more than five cases annually) strata for in-hospital major complications and 30-day and 1-year mortality. RESULTS: Practice experience had no association with unadjusted mortality (30-day death: elective, P = .2; nonelective, P = .3; 1-year death: elective, P = .2; nonelective, P = .2). However, more experienced surgeons had fewer complications after elective OAR (25% with ≥16 years vs 29% with ≤5 years; P = .004). A significant linear correlation was identified between increasing surgeon experience and performance of a greater proportion of elective OAR (P-trend < .0001). Risk adjustment (area under the curve, 0.776) revealed that low-volume (five or fewer cases annually) surgeons had inferior outcomes compared with high-volume surgeons across the experience strata for all presentations. In addition, high-volume, early career surgeons (≤5 years' experience) had outcomes similar to those of older, low-volume surgeons (P > .1 for all pairwise comparisons). Early career surgeons (≤5 years) had operated on a greater proportion of elective patients with American Society of Anesthesiologists class ≥4 (35% vs 30% [≥16 years' experience]; P = .0003) and larger abdominal aortic aneurysm diameters (mean, 62 vs 59 mm [≥16 years' experience]; P < .0001) compared with all other experience categories. Similarly, the use of a suprarenal cross-clamp occurred more frequently (26% vs 22% [≥16 years' experience]; P = .0009) but the total procedure time, estimated blood loss, and renal and/or visceral ischemia times were all greater for less experienced surgeons (P-trend < .0001). CONCLUSIONS: Annual case volume appeared to be more significantly associated with OAR outcomes compared with the cumulative years of practice experience. To ensure optimal OAR outcomes, mentorship strategies for "on-boarding" early career, as well as established, low-volume, aortic aneurysm repair surgeons should be considered. These findings have potential implications for widespread initiatives surrounding regulatory oversight and credentialing paradigms.

Expression of a Functional IL-2 Receptor in Vascular Smooth Muscle Cells.

Many nonlymphoid cell types express at least two, if not all three, subunits of the IL-2R; although, compared with lymphocytes, relatively little is known about how IL-2 affects the function of nonlymphoid cells. The limited information available suggests that IL-2 has a substantial impact on cells such as gastrointestinal epithelial cells, endothelial cells, and fibroblasts. In a previous report from our laboratory, we noted that IL-2 and IL-2Rß-deficient mice lose smooth muscle cells over time, eventually resulting in aneurysmal aortas and ectatic esophagi. This finding, combined with our work showing that IL-2 surrounds vascular smooth muscle cells by association with perlecan, led us to ask whether vascular smooth muscle cells express an IL-2R. Toward this end, we reported the expression of IL-2Rß on human and murine vascular smooth muscle cells. We now report that vascular smooth muscle cells express all three subunits of the IL-2R, and that expression of IL-2Rα varies with vascular smooth muscle cell phenotype. Furthermore, we show that, through a functional IL-2R, IL-2 initiates signaling pathways and impacts vascular smooth muscle cell function. Finally, we demonstrate that IL-2 expression increases upon initiation of conditions that promote intimal hyperplasia, suggesting a mechanism by which the IL-2/IL-2R system may impact this widespread vascular pathology.

Heterogeneous and dynamic lumen remodeling of the entire infrainguinal vein bypass grafts in patients.

OBJECTIVE: To examine the regional variation and temporal change in lumen size along the entire autogenous vein bypass graft used for treating arterial occlusive disease in lower extremity and to explore the factors associated with graft expansive or constrictive remodeling. METHODS: Patients were prospectively scanned using contrast-enhanced computed tomography at 1 week and 1, 6, and 12 months postoperatively to obtain lumen cross-sectional areas at 1-mm intervals along the entire grafts. Graft lumen remodeling characteristics and the associated demographic and clinical factors were examined. RESULTS: Fifty-six patients with at least two consecutive computed tomography scans were analyzed. Patients with a composite or longer graft, or with diabetes, had a larger lumen cross-sectional area variation along the graft. The mean lumen cross-sectional areas of all the grafts demonstrated no significant changes through 12 months. However, individually, graft remodeling was time dependent and there was a more dramatic change in lumen cross-sectional area within the first postoperative month. At 12 months, a near equal distribution between expansive and constrictive grafts existed. A negative relation between the initial lumen diameters and the subsequent lumen diameter changes was observed. Eleven grafts failed within 12 months; failed and patent grafts had similar mean lumen cross-sectional areas at all four time points, but failed grafts had a larger maximal local cross-sectional area reduction from 1 week to 1 month (58.0 ± 6.7% vs 38.1 ± 3.1%, mean ± standard error of the mean, failed vs patent, P = .004). Black patients had a smaller mean lumen cross-sectional area than white patients at all four time points and also had a higher early percent mean area reduction (-20.5 ± 6.3% vs -1.0 ± 3.7%, black vs white, P = .018). Cilostazol use was associated with early expansive graft remodeling. CONCLUSIONS: Vein grafts remodel heterogeneously and dynamically. Remodeling is associated with initial graft lumen size, race, and cilostazol use. It is found that remodeling that produces some critical minimum area or maximal percent reduction during the first postoperative month may predispose to vein graft failure. These findings offer insight into further investigation to examine the underlying mechanisms and opportunities to improve graft remodeling and durability.

Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1.

Recent recognition that TGF-ß signaling disruption is involved in the development of aortic aneurysms has led to renewed investigations into the role of TGF-ß biology in the aortic wall. We previously found that the type I receptor of TGF-ß (TGFBR2) receptor contributes to formation of ascending aortic aneurysms and dissections (AADs) induced by smooth muscle cell (SMC)-specific, postnatal deletion of Tgfbr1 (Tgfbr1iko). Here, we aimed to decipher the mechanistic signaling pathway underlying the pathogenic effects of TGFBR2 in this context. Gene expression profiling demonstrated that Tgfbr1iko triggers an acute inflammatory response in developing AADs, and Tgfbr1iko SMCs express an inflammatory phenotype in culture. Comparative proteomics profiling and mass spectrometry revealed that Tgfbr1iko SMCs respond to TGF-ß1 stimulation via robust up-regulation of cyclophilin A (CypA). This up-regulation is abrogated by inhibition of TGFBR2 kinase activity, small interfering RNA silencing of Tgfbr2 expression, or inhibition of SMAD3 activation. In mice, Tgfbr1iko rapidly promotes CypA production in SMCs of developing AADs, whereas treatment with a CypA inhibitor attenuates aortic dilation by 56% (P = 0.003) and ameliorates aneurysmal degeneration (P = 0.016). These protective effects are associated with reduced aneurysm-promoting inflammation. Collectively, these results suggest a novel mechanism, wherein loss of type I receptor of TGF-ß triggers promiscuous, proinflammatory TGFBR2 signaling in SMCs, thereby promoting AAD formation.-Zhou, G., Liao, M., Wang, F., Qi, X., Yang, P., Berceli, S. A., Sharma, A. K., Upchurch, G. R., Jr., Jiang, Z. Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1.

Haemodynamics of Different Configurations of a Left Subclavian Artery Stent Graft for Thoracic Endovascular Aortic Repair.

OBJECTIVE: Branched stent grafts represent a viable option for left subclavian artery (LSA) revascularisation in patients treated by thoracic endovascular aortic repair (TEVAR) for Zone 2 lesions. This study investigated the haemodynamic performance of different LSA branched stent graft configurations as potential determinants of thrombotic and stroke risks. METHODS: A three dimensional aortic arch geometry extracted from post-operative computed tomography images of a TEVAR patient using a single LSA branched aortic endograft was modified in silico to obtain ten potential LSA branched stent graft configurations: five down facing (0-5 - 10 mm aortic protrusion with 10-12 mm internal diameter), four curved (30-60° with antegrade/retrograde orientation), and one LSA orifice misalignment. The 0 mm down facing stent graft was considered base configuration. Computational fluid dynamic analyses were performed to identify differences in pressure, energy, and wall shear stress (WSS) based parameters. RESULTS: Total pressure drop and energy loss variations among configurations were not greater than 5 mmHg (6% of mean arterial pressure) and 5.7 mW (0.7% of cardiac power), respectively. Protrusions up to 5 mm created clinically insignificant flow disturbances. However, stent graft protrusions further into the aortic lumen created more complex haemodynamics, characterised by larger energy loss and more prominent flow recirculation. Protrusion greater than 5 mm into the lumen was associated with larger areas of elevated maximum WSS (>20 Pa) along the outer surface of the branched stent graft. CONCLUSION: Arterial haemodynamic characteristics are affected by LSA branched stent graft configurations, with pressure drops and energy losses likely to be clinically insignificant. The length of the stent graft protrusion into the aortic lumen generated the largest haemodynamic variations in the aortic system. Protrusions up to 5 mm have smaller risk of potential thrombus generation. Conversely, larger protrusions into the aortic lumen showed more disturbed haemodynamics, suggesting a greater risk of potential thrombus formation, which may be clinically important over time.

Impact of secondary interventions on mortality after fenestrated branched endovascular aortic aneurysm repair.

BACKGROUND: Fenestrated and branched endovascular aortic repair (F/BEVAR) is increasingly used to manage pararenal and thoracoabdominal aortic disease (TAAA). Device-related reintervention after F/BEVAR is common, but little is known about its impact on postoperative mortality. The purpose of this analysis was to describe secondary intervention (SI) after F/BEVAR and determine the impact of these procedures on patient survival. METHODS: A single-center review was done on all consecutive F/BEVARs performed from 2010 to 2016. Primary end points were incidence of secondary aortic, branch, and/or access vessel‒related SI, and survival. SI was categorized as minor endovascular (branch restenting, access vessel treatment, or percutaneous coil embolization), major endovascular (new aortic graft placement), or open (bleeding, access vessel, and/or aortic). Kaplan-Meier methodology was used to estimate freedom from SI and survival. Multivariable analysis was used to identify predictors of SI. RESULTS: A total of 308 F/BEVAR procedures were performed (75% physician-modified, 18% custom, 7% Zfen), with 1022 vessels revascularized (celiac, 228; superior mesenteric artery [SMA], 263; renal, 525). There were 117 (39%) extent I-III TAAA, 132 (44%) extent IV TAAA/4-vessel pararenal, and 54 (18%) <4-vessel pararenal repairs performed. Any type of SI occurred in 24% (74) of patients during the mean follow-up of 20 ± 21 months. The majority of reinterventions were endovascular (minor, 53% [n = 39]; major, 32% [n = 24]), whereas 12% (n = 9) were open and 3% (n = 2) hybrid. Primary indication for SI included: 22 (29%) with branch-related endoleaks (1C or III); 15 (22%) with proximal or distal aortic degeneration; 8 (12%) with branch vessel thrombosis/stenosis; 10 (11%) with aortic device type III endoleak/loss of overlap; 4 (6%) with postoperative mesenteric or renal bleeding events; 5 (5%) with type II endoleak; 3 (5%) with access vessel complication; and 2 (3%) with graft infection. Most SIs were elective (65%; n = 48) with the remainder occurring emergently (24%; n = 18) or for symptoms/urgently (11%; n = 8). Compared with endovascular remediation, open SI was more likely to be emergent (89%, 8 of 9; P = .001). Freedom from SI was 80 ± 3% and 64 ± 4% at 1 and 3 years, respectively. One- and 5-year survival with or without SI was: 1 year, 88 ± 4% vs 81 ± 3%; 5 years, 76 ± 5% vs 59 ± 4% (log rank test, P = .06). There was no survival difference based on type of SI (log rank test, P = .3). Extent I-III TAAA (HR, 1.6; 95% CI, 0.98-3.3; P = .06) and history of cerebrovascular disease (HR, 1.8; 95% CI, 0.97-2.6; P = .07) were predictive of SI. CONCLUSIONS: SIs after F/BEVAR most frequently involve branch vessel or aortic device remediation procedures; however, they do not negatively impact out-of-hospital survival. These results further highlight the crucial role of imaging surveillance after F/BEVAR to maintain durability. Discussions with patients, periprocedural planning, and the next generation of device design must focus on issues surrounding the risk of device-related SI events.

Interaction between frailty and sex on mortality after elective abdominal aortic aneurysm repair.

BACKGROUND: Controversy exists surrounding gender outcome disparity and abdominal aortic aneurysm (AAA) repair. Previous reports have demonstrated worse outcomes for women undergoing open aneurysm repair (OAR); however, these differences are less evident with endovascular aneurysm repair (EVAR). Epidemiologic studies have documented that women score higher on most frailty assessment scales but paradoxically have longer life expectancy compared to men. The interaction of gender/frailty and the influence on outcomes and practice patterns surrounding EVAR and OAR is poorly described. This analysis characterizes the association of frailty/sex interactions on mortality as well as patient selection surrounding elective AAA repair in the Society for Vascular Surgery Vascular Quality Initiative. METHODS: All elective infrarenal AAA (EVAR + OAR; 2003-2017) cases were queried from the Vascular Quality Initiative database. Each patient was assigned a previously published modified frailty index (mFI) score derived from comorbidity and preoperative functional status data. Cox proportional hazard models, adjusted for statistically significant covariates, including procedural complexity, determined associations within full models and sex-stratified models. RESULTS: A total of 20,750 elective AAA cases were analyzed (EVAR 15,893 [77%]; OAR 4857 [23%]). Thirty-day mortality for EVAR and OAR was 0.7% (n = 115) and 3.5% (n = 169), respectively. Patients who died were significantly more likely to be older (EVAR, 78 vs 73 years; OAR, 74 vs 69 years; P < .0001), have larger AAA diameters (EVAR, 59 vs 56 mm; P = .005; OAR, 62 vs 59 mm; P = .001), higher mFI scores (EVAR, 3.2 vs 2.4; OAR, 3.1 vs 2.2; P < .0001), and be of female sex (EVAR hazard ratio = 1.66 [95% confidence interval, 1.10-2.52]; P = .007; OAR-1.43 [1.02-1.99]; P = .003). Significant differences in the gender distribution of frailty scores among EVAR patients were evident (mean mFI: male 2.42 vs female 2.34; P = .02), but no difference was detected for OAR (male 2.17 vs female 2.22; P = .38). The mFI was a strong independent predictor of mortality (30 days: EVAR hazard ratio = 1.36 [1.22-1.53] and OAR 1.46 [1.32-1.60]; 1 year: EVAR 1.32 [1.25-1.39] and OAR-1.38 [1.28-1.48]). There was no interaction between mFI and gender on the association with mortality. Across frailty strata, male patients were nearly twofold more likely to undergo either elective EVAR or OAR for an AAA below recommended minimum diameter thresholds (male, <5.5 cm; female, <5.0 cm). Greater mFI score did not alter OAR selection but was associated with less frequent EVAR of small AAA. CONCLUSIONS: Given the strong association between frailty and postoperative mortality, mFI can be used as a predictive tool to aid in surgical planning of patients undergoing elective AAA repair. While mFI can predict postoperative mortality for both men and women, it does not account for the survival disparity between sexes, and further research is warranted to explain this difference. There appear to be significant gender differences in patient selection based on current Society for Vascular Surgery-endorsed treatment thresholds that may have important implications on the appropriateness of AAA care delivery nationally.

Contemporary outcomes of thoracofemoral bypass.

OBJECTIVE: Thoracofemoral bypass (TFB) is an alternative to aortofemoral bypass (AFB) or extra-anatomic bypass for severe aortoiliac occlusive disease (AIOD). TFB may be particularly useful in select patients with concurrent visceral aortic branch vessel disease, infrarenal aortic occlusions, or after failed AFB. However, there are few contemporary series describing the indications and outcomes for TFB. Therefore, the purpose of this analysis was to review our experience with TFB. METHODS: All patients undergoing TFB for occlusive disease from 2002 to 2017 were reviewed. All patients underwent left thoracoretroperitoneal exposure of the supraceliac aorta with division of the diaphragmatic crus and supraceliac cross-clamping. An end-to-side aortic anastomosis was created and each graft limb was tunneled in the retroperitoneum to the femoral bifurcation. Adjunctive visceral/infrainguinal revascularization was performed selectively based on symptoms, end-organ function, and/or preoperative imaging. The primary end points were major complications and 30-day mortality. Secondary end points included limb patency, freedom from major adverse limb events, and survival. Kaplan-Meier methodology was used to characterize the end points. RESULTS: Forty-one patients (age 61 ± 9 years; 54% female; 7% in a hypercoaguable state) underwent TFB. The mean preoperative ankle-brachial index was 0.4 bilaterally. Indications included critical limb ischemia (56%), claudication (30%), acute limb ischemia (7%), and combined AIOD and mesenteric ischemia (7%). Seven patients (17%) had previously undergone AFB and 15 (38%) had previously undergone any prior aortic operation. Adjunctive visceral bypass occurred in 8 patients (20%; N = 14 grafts, n = 6 renal, n = 5 superior mesenteric artery, and n = 3 celiac). The postoperative duration of stay was 11 days (interquartile range [IQR], 7-16 days) and the 30-day mortality was 5% (n = 2). Major complications occurred in 34% of patients (N = 14; pulmonary, 15%; cardiac, 12%; bleeding, 7%; accidental splenectomy, 5%; renal, 5%; wound, 2%). The mean postoperative ankle-brachial index was 0.9 bilaterally. At a median follow-up of 7 months (IQR, 1-17 months), 5 patients (12%) underwent some form of reintervention (graft/limb related, n = 4 [n = 2 graft thrombosis, n = 2 graft infection], n = 1 mesenteric bypass revision). The estimated 3-year primary limb patency and freedom from major adverse limb events were 80 ± 10%, and 70 ± 10%, respectively. The estimated 5-year survival was 93 ± 5% (median, 27.3; IQR, 14.5-35.2; 95% confidence interval, 17.9-32.8). CONCLUSIONS: This experience represents one of the largest and most current series of retroperitoneal TFB. We demonstrate that TFB can be performed with good outcomes for patients with severe AIOD, especially if concomitant visceral/infrainguinal reconstruction is warranted. These results support a continued role for TFB in select patients.