HiCAR is a robust and sensitive method to analyze open-chromatin-associated genome organization.

The long-range interactions of cis-regulatory elements (cREs) play a central role in gene regulation. cREs can be characterized as accessible chromatin sequences. However, it remains technically challenging to comprehensively identify their spatial interactions. Here, we report a new method HiCAR (Hi-C on accessible regulatory DNA), which utilizes Tn5 transposase and chromatin proximity ligation, for the analysis of open-chromatin-anchored interactions with low-input cells. By applying HiCAR in human embryonic stem cells and lymphoblastoid cells, we demonstrate that HiCAR identifies high-resolution chromatin contacts with an efficiency comparable with that of in situ Hi-C over all distance ranges. Interestingly, we found that the "poised" gene promoters exhibit silencer-like function to repress the expression of distal genes via promoter-promoter interactions. Lastly, we applied HiCAR to 30,000 primary human muscle stem cells and demonstrated that HiCAR is capable of analyzing chromatin accessibility and looping using low-input primary cells and clinical samples.

Current Status and Principles for the Treatment and Prevention of Diabetic Foot Ulcers in the Cardiovascular Patient Population: A Scientific Statement From the American Heart Association.

Despite the known higher risk of cardiovascular disease in individuals with type 2 diabetes, the pathophysiology and optimal management of diabetic foot ulcers (DFUs), a leading complication associated with diabetes, is complex and continues to evolve. Complications of type 2 diabetes, such as DFUs, are a major cause of morbidity and mortality and the leading cause of major lower extremity amputation in the United States. There has recently been a strong focus on the prevention and early treatment of DFUs, leading to the development of multidisciplinary diabetic wound and amputation prevention clinics across the country. Mounting evidence has shown that, despite these efforts, amputations associated with DFUs continue to increase. Furthermore, due to increasing patient complexity of management secondary to comorbid conditions, such as cardiovascular disease, the management of peripheral artery disease associated with DFUs has become increasingly difficult, and care delivery is often episodic and fragmented. Although structured, process-specific approaches exist at individual institutions for the management of DFUs in the cardiovascular patient population, there is insufficient awareness of these principles in the general medicine communities. Furthermore, there is growing interest in better understanding the mechanistic underpinnings of DFUs to better define personalized medicine to improve outcomes. The goals of this scientific statement are to provide salient background information on the complex pathogenesis and current management of DFUs in cardiovascular patients, to guide therapeutic and preventive strategies and future research directions, and to inform public policy makers on health disparities and other barriers to improving and advancing care in this expanding patient population.

Risk factors and consequences of wound complications following sartorius flap reconstruction.

OBJECTIVE: Groin wound complications are common following vascular surgery and can lead to significant patient morbidity. Sartorius muscle flap coverage may help to prevent vascular graft infection in the setting of wound dehiscence or infection. However, risk factors and consequences of wound complications following sartorius flap reconstruction remain incompletely investigated. METHODS: We retrospectively queried all patients who underwent sartorius flap reconstruction at a tertiary academic medical center. Data collected included patient demographics, medical comorbidities, surgical indication, index vascular procedure, and postoperative outcomes. The primary outcome was wound complication following sartorius flap procedure, which was defined as groin wound infection, dehiscence, or lymphocutaneous fistula. RESULTS: From 2012 to 2022, a total of 113 patients underwent sartorius flap reconstruction. Of these, 66 (58.4%) were performed after the development of a prior groin complication, and 47 (41.6%) were prophylactic. A total of 88 patients (77.9%) had a prosthetic bypass graft adjacent to the flap. Twenty-nine patients (25.7%) suffered a wound complication following sartorius flap reconstruction, including 14 (12.4%) with wound dehiscence, 13 (11.5%) with wound infection, and two (1.8%) with lymphocutaneous fistula. Patients with wound complications had a higher body mass index (28.8 vs 26.4 kg/m2; P =.03) and more frequently active smokers (86.2% vs 66.7%; P = .04). Additionally, patients with wound complications had a higher unplanned 30-day hospital readmission rates (72.4% vs 15.5%; P < .001), reintervention rates (75.9% vs 8.3%; P < .001), and re-do flap reconstruction rates (13.8% vs 2.4%; P = .02). On multivariable analysis, higher body mass index was independently associated with post-flap wound complications (adjusted odds ratio [aOR], 1.01; 95% confidence interval [CI], 1.001-1.03; P = .037). Consequently, wound complications were associated with both surgical reintervention (aOR, 35.4; 95% CI, 9.9-126.3; P < .001) and unplanned hospital readmission (aOR, 17.8; 95% CI, 5.9-54.1; P < .001). CONCLUSIONS: Sartorius flap reconstruction is an effective adjunct in facilitating wound healing of groin wounds. However, wound complications are common following sartorius flap reconstruction and may be associated with reintervention and unplanned hospital readmission. These data support the judicious and thoughtful utilization of sartorius flap procedures among high-risk patients.

Prosthetic Conduit Use Does Not Adversely Impact Outcomes after Open Repair of Popliteal Artery Aneurysms.

BACKGROUND: Single segment, greater saphenous vein (GSV) conduit is considered the optimal bypass conduit among patients undergoing bypass surgery for peripheral artery disease (PAD). While this data has been extrapolated to patients undergoing bypass for popliteal artery aneurysms (PAAs), the pathophysiology of PAA is inherently different when compared to PAD, and the impact of conduit type on long-term outcomes after open repair of PAA remains unclear. METHODS: A multicenter database of five regional hospitals was retrospectively reviewed for all patients with PAA undergoing open surgical repair. Data were collected on demographic information, operative details, medications, and postoperative outcomes. Kaplan-Meier curves were used to compare freedom from major adverse limb events (MALE) following GSV versus prosthetic bypass. Cox proportional hazards model was used to identify patient-level characteristics associated with MALE, which was defined as major ipsilateral limb amputation or reintervention for graft patency. RESULTS: From 1999 to 2020, a total of 101 patients with PAA underwent open exclusion and bypass surgery. Median follow-up period was 4.2 years (interquartile range, 1.3-7.4 years), and complete data were available for 99 (98.0%) patients. The majority of patients were male (99.0%) and Caucasian (93.9%). Only 11.1% of procedures were emergent, with the remainder (88.9%) being elective. All patients underwent medial exposure with a below-knee popliteal bypass target (100%). Bypass conduits included GSV (69.7%), prosthetic conduit (28.3%), and 2 (2.0%) alternative conduits (one spliced arm vein, one cryopreserved vein). Patients undergoing prosthetic bypass were older (72 vs. 66 years, P = 0.001) and had similar rates of medical comorbidities. Compared with the GSV group, patients with prosthetic conduits were more frequently placed on postoperative anticoagulation (60.7% vs. 23.2%, P < 0.001). Conduit type did not impact postoperative complication rates (P = NS each). MALE rates were low overall (19.2% at 2 years), and similar when stratified by conduit type (log rank P = 0.47). On multivariable analysis, emergent bypass was associated with MALE (hazard ratio [HR] 5.73, 95% confidence interval [CI] 2.07-15.85, P < 0.001). Prosthetic conduit usage (HR 1.00, 95% CI, 0.40-2.51, P = 0.99) and postoperative anticoagulation (HR 1.02, 95% CI 0.42-2.50, P = 0.97) were not associated with MALE. CONCLUSIONS: Open repair of PAA is associated with excellent long-term outcomes. Prosthetic bypass is a comparable alternative to autogenous conduit for below-knee popliteal bypass targets, and lack of suitable GSV should not prohibit open surgical repair when indicated.

Feasibility and Intermediate Results of Transcarotid Revascularization with a Prosthetic Conduit.

BACKGROUND: Transcarotid artery revascularization (TCAR) is a hybrid technique with excellent initial outcomes. The technical success and safety of TCAR is heavily dependent on an anatomically suitable common carotid artery (CCA). Many patients do not meet anatomic criteria and therefore are not eligible for this therapy. We sought to extend the eligibility of TCAR to patients with unfavorable CCA anatomy via the adoption of a prosthetic arterial conduit. METHODS: A single-center retrospective study of patients with critical carotid artery stenosis who underwent TCAR via a prosthetic conduit between June 2019 and October 2021 was performed. All patients in the study were considered high-risk for carotid endarterectomy based on anatomic features, such as restenosis post-carotid endarterectomy and neck radiation. Unfavorable CCA anatomy was defined as a clavicle to carotid bifurcation distance <5 cm, a CCA diameter <6 mm, and/or significant atherosclerotic disease at the intended arterial access site. The primary outcome of interest was technical success. Secondary outcomes included perioperative complications, intermediate and long-term patency, intermediate and long-term stroke and/or mortality and in-hospital length of stay. Follow-up ranged from 1 to 29 months. RESULTS: Eight patients underwent 10 TCAR procedures via a prosthetic conduit. A total of 2 procedures (20%) were performed on female patients and 8 procedures (75%) were performed on male patients. The mean age was 65 years old (standard deviation 11 years). Technical success was 100%. The 30-day ipsilateral stroke rate was 0%. The 30-day patency was 90%. There was no re-exploration for hemorrhage and 30 day mortality was 0%. CONCLUSIONS: TCAR is an excellent option for carotid artery revascularization. Unfavorable CCA anatomy has limited its applicability. TCAR via a prosthetic conduit has the potential to expand eligibility for this promising therapy.

A national analysis of vascular surgery resident operative experience in peripheral artery disease.

BACKGROUND: Endovascular and hybrid interventions have played an increasingly prominent role in the treatment of peripheral arterial disease (PAD) in the past decade. This shift has prompted concerns about the adequacy of open surgical training for current surgical residents. Moreover, the recent Best Surgical Therapy in Patients With Critical Limb Ischemia trial has further emphasized the importance of open surgical techniques in the treatment of peripheral arterial disease. The purpose of this study was to examine national temporal trends in peripheral operative volume among integrated vascular surgery residents. METHODS: Data was obtained from the Accreditation Council for Graduate Medical Education national data reports for integrated vascular surgery residents. Case volumes for surgeon chief or surgeon junior cases were collected from academic years 2012 to 2013 and 2021 to 2022. Trends in case-mix and volume were evaluated using linear regression analysis. RESULTS: The mean total vascular operative volume increased from 851.2 to 914.3 cases among graduating chief residents, with an annual growth of 8.5 ± 1.7 cases/year (R2 = 0.77; P < .0001). Major vascular case volume also increased at a rate of 5.7 ± 1.2 cases/year (R2 = 0.74; P < .001). Among operative categories, peripheral cases were the most frequent (n = 232.2 [26.6%]) and demonstrated the greatest annual growth (+8.0 ± 0.8 cases/year, R2 = 0.93; P < .001). No changes were seen in volume of open peripheral cases, including suprainguinal bypass (+0.1 ± 0.2 cases/year; R2 = 0.08; P = .40) or femoropopliteal bypass procedures (-0.1 ± 0.2 cases/year; R2 = 0.17; P = .20). Infrapopliteal bypass (+0.4 ± 0.1 cases/year; R2 = 0.48; P = .006), iliac/femoral endarterectomy (+1.3 ± 0.2 cases/year; R2 = 0.82; P < .001), and leg thromboembolectomy (+0.4 ± 0.1 cases/year; R2 = 0.64; P < .001) all demonstrated annual growth. For endovascular peripheral cases, aortoiliac revascularization (+3.4 ± 0.3 cases/year; R2 = 0.94; P < .001), femoropopliteal revascularization (+5.4 ± 0.2 cases/year; R2 = 0.98; P < .001), and tibioperoneal revascularization (+2.0 ± 0.2 cases/year; R2 = 0.92; P < .001) all increased in volume. Lower extremity amputations, including above-knee amputation (+0.6 ± 0.2 cases/year; R2 = 0.65; P < .001) and below-knee amputation (+0.9 ± 0.2 cases/year; R2 = 0.72; P < .001) also demonstrated an increase in volume. CONCLUSIONS: Current graduating residents have higher open and endovascular case volumes for peripheral artery disease on a national level, despite the increasing popularity of endovascular techniques. Further studies are needed to identify how these trends may impact current vascular surgery milestones. These trends may also influence the rising interest in competency-based training programs.

First experience of evaluation of the impact of high-matrix size reconstruction in image quality in arterial CT runoff studies of the lower extremities.

OBJECTIVES: To determine whether image reconstruction with a higher matrix size improves image quality for lower extremity CTA studies. METHODS: Raw data from 50 consecutive lower extremity CTA studies acquired on two MDCT scanners (SOMATOM Flash, Force) in patients evaluated for peripheral arterial disease (PAD) were retrospectively collected and reconstructed with standard (512 × 512) and higher resolution (768 × 768, 1024 × 1024) matrix sizes. Five blinded readers reviewed representative transverse images in randomized order (150 total). Readers graded image quality (0 (worst)-100 (best)) for vascular wall definition, image noise, and confidence in stenosis grading. Ten patients' stenosis scores on CTA images were compared to invasive angiography. Scores were compared using mixed effects linear regression. RESULTS: Reconstructions with 1024 × 1024 matrix were ranked significantly better for wall definition (mean score 72, 95% CI = 61-84), noise (74, CI = 59-88), and confidence (70, CI = 59-80) compared to 512 × 512 (wall = 65, CI = 53 × 77; noise = 67, CI = 52 × 81; confidence = 62, CI = 52 × 73; p = 0.003, p = 0.01, and p = 0.004, respectively). Compared to 512 × 512, the 768 × 768 and 1024 × 1024 matrix improved image quality in the tibial arteries (wall = 51 vs 57 and 59, p < 0.05; noise = 65 vs 69 and 68, p = 0.06; confidence = 48 vs 57 and 55, p < 0.05) to a greater degree than the femoral-popliteal arteries (wall = 78 vs 78 and 85; noise = 81 vs 81 and 84; confidence = 76 vs 77 and 81, all p > 0.05), though for the 10 patients with angiography accuracy of stenosis grading was not significantly different. Inter-reader agreement was moderate (rho = 0.5). CONCLUSION: Higher matrix reconstructions of 768 × 768 and 1024 × 1024 improved image quality and may enable more confident assessment of PAD. CLINICAL RELEVANCE STATEMENT: Higher matrix reconstructions of the vessels in the lower extremities can improve perceived image quality and reader confidence in making diagnostic decisions based on CTA imaging. KEY POINTS: • Higher than standard matrix sizes improve perceived image quality of the arteries in the lower extremities. • Image noise is not perceived as increased even at a matrix size of 1024 × 1024 pixels. • Gains from higher matrix reconstructions are higher in smaller, more distal tibial and peroneal vessels than in femoropopliteal vessels.

Preoperative Anemia is Associated with Poorer Postoperative Outcomes in Patients Undergoing Infrainguinal Bypass Surgery.

BACKGROUND: Preoperative anemia is an important, modifiable risk factor among surgical patients. However, data are scarce on the impact of preoperative anemia on postoperative outcomes after infrainguinal bypass. METHODS: In this multi-institutional analysis, data were retrospectively collected on all infrainguinal bypass procedures performed between 2010 and 2020. Patients were grouped by preoperative hemoglobin as per the National Cancer Institute anemia scale (mild, 10 g/dL-lower limit of normal; moderate, 8.0-9.9 g/dL; severe, 6.5-7.9 g/dL). Multivariable comparisons were performed using logistic regression analysis. RESULTS: A total of 492 patients underwent bypass for peripheral artery disease over the 10-year study period. Median preoperative hemoglobin was 11.0 g/dL (interquartile range 9.5-12.7) and median follow-up was 1.7 years. Preoperative anemia was prevalent among bypass patients (mild 52.4% [n = 258], moderate 26.4% [n = 130], and severe 5.1% [n = 25]). Women were more likely to have moderate (49.2% [women] vs. 50.8% [men]) or severe anemia (52.0% [women] vs. 48.0% [men]) compared with normal hemoglobin (17.7% [women] vs. 82.3% [men]) (P < 0.001). Patients with preoperative anemia were more likely to present with tissue loss (22.8% [normal] vs. 47.7% [moderate] vs. 52.0% [severe], P = 0.01). Bypass target and conduit types were similar between groups. Anemic patients had longer median hospital length of stay compared with nonanemic patients (4 days [normal] vs. 5 days [mild] vs. 6 days [moderate] vs. 7 days [severe], P < 0.001). Postoperative mortality at 30 days was similar across anemia groups (2.5% [normal] vs. 4.6% [moderate] vs. 8.0% [severe], P = 0.23). On multivariable analysis, however, postoperative mortality was independently associated with severe anemia (odds ratio 7.5 [1.2-48.8], P = 0.04) and male gender (odds ratio 7.5 [1.2-26.4], P = 0.03). CONCLUSIONS: Preoperative anemia is common among patients undergoing infrainguinal bypass surgery and is an independent risk factor for postoperative mortality. Future investigation is needed to determine whether correction of anemia improves postoperative outcomes in these high-risk patients.

Study protocol of a randomized controlled trial of fistula vs. graft arteriovenous vascular access in older adults with end-stage kidney disease on hemodialysis: the AV access trial.

BACKGROUND: Treatment of end-stage kidney disease (ESKD) with hemodialysis requires surgical creation of an arteriovenous (AV) vascular access-fistula (AVF) or graft (AVG)-to avoid (or limit) the use of a central venous catheter (CVC). AVFs have long been considered the first-line vascular access option, with AVGs as second best. Recent studies have suggested that, in older adults, AVGs may be a better strategy than AVFs. Lacking evidence from well-powered randomized clinical trials, integration of these results into clinical decision making is challenging. The main objective of the AV Access Study is to compare, between the two types of AV access, clinical outcomes that are important to patients, physicians, and policy makers. METHODS: This is a prospective, multicenter, randomized controlled trial in adults ≥ 60 years old receiving chronic hemodialysis via a CVC. Eligible participants must have co-existing cardiovascular disease, peripheral arterial disease, and/or diabetes mellitus; and vascular anatomy suitable for placement of either type of AV access. Participants are randomized, in a 1:1 ratio, to a strategy of AVG or AVF creation. An estimated 262 participants will be recruited across 7 healthcare systems, with average follow-up of 2 years. Questionnaires will be administered at baseline and semi-annually. The primary outcome is the rate of CVC-free days per 100 patient-days. The primary safety outcome is the cumulative incidence of vascular access (CVC or AV access)-related severe infections-defined as access infections that lead to hospitalization or death. Secondary outcomes include access-related healthcare costs and patients' experiences with vascular access care between the two treatment groups. DISCUSSION: In the absence of studies using robust and unbiased research methodology to address vascular access care for hemodialysis patients, clinical decisions are limited to inferences from observational studies. The goal of the AV Access Study is to generate evidence to optimize vascular access care, based on objective, age-specific criteria, while incorporating goals of care and patient preference for vascular access type in clinical decision-making. TRIAL REGISTRATION: This study is being conducted in accordance with the tenets of the Helsinki Declaration, and has been approved by the central institutional review board (IRB) of Wake Forest University Health Sciences (approval number: 00069593) and local IRB of each participating clinical center; and was registered on Nov 27, 2020, at ClinicalTrials.gov (NCT04646226).

A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.

Underutilization of Guideline-based Abdominal Aortic Aneurysm Screening in an Academic Health System.

OBJECTIVES: The US Preventive Services Task Force (USPSTF) recommends a 1 time screening for AAA with ultrasonography in men aged 65-75 who have ever smoked. Our objectives were to identify the AAA screening rates in a large academic health system and assess factors associated with receipt of screening. METHODS: Data were extracted from electronic health records from the Duke University Health System and the US Census Bureau. Index screening eligibility date was defined as the 65th birthdate for male patients with a history of smoking. Patients with an index screening eligibility date between January 1, 2016 and December 31, 2018 were included in the study population and followed through December 31, 2019. Screened patients were identified by procedure codes for ultrasonography, CT or MRI. RESULTS: Among 6,682 eligible patients who turned 65 years old between January 1, 2016 and December 31, 2018 with at least 1 year of follow-up, only 463 (6.9%) received AAA screening during the study period. The odds of receiving AAA screening within 1 year of index eligibility were 27% lower for Black patients compared to whites [OR = 0.73, 95% CI (0.58,0.93)]. Patients who visited a PCP or were diagnosed with hypertension had 75% and 41% greater odds of receiving screening, respectively [OR 1.75, 95% CI (1.36,2.25)] and [OR 1.41 95% CI (1.11,1.80)] compared with patients who did not. Among 4,580 men with 2 years of follow-up, AAA screening rate increased to 13.0%. Patients who visited a PCP had 64% greater odds of receiving screening within 2 years of index eligibility compared to those who did not [OR = 1.64, 95% CI (1.30,2.06)]. CONCLUSIONS: Screening for AAA per USPSTF guidelines is underutilized with evidence of a racial disparity. Although PCP visit is the most consistent predictor of screening, provider screening rates are low.

Cerebral monitoring during transcarotid artery revascularization with flow reversal via transcranial doppler ultrasound examination.

OBJECTIVE: Transcarotid artery revascularization (TCAR) is a hybrid technique for carotid artery revascularization that relies on proximal carotid occlusion with flow reversal for distal embolic protection. The hemodynamic response of the intracranial circulation to flow reversal is unknown. In addition, the rate and pattern of cerebral embolization during flow reversal has yet to be investigated. The aim of this study was to characterize cerebral hemodynamic and embolization patterns during TCAR. METHODS: A single-institution retrospective study of patients with carotid artery stenosis undergoing TCAR with intraoperative transcranial Doppler (TCD) monitoring of the middle cerebral artery (MCA) was performed. Primary outcomes included changes in MCA velocity and MCA embolic signals observed throughout TCAR. RESULTS: Eleven patients underwent TCAR with TCD monitoring of the ipsilateral MCA. The average MCA velocity at baseline was 50.6 ± 16.4 cm/s. MCA flow decreased significantly upon initiation of flow reversal (50.5 ± 16.4 cm/s vs 19.1 ± 18.4 cm/s; P = .02). The reinitiation of antegrade flow resulted in a significant increase in the number of embolic events compared with baseline (P = .003), and embolic events were observed in two patients during flow reversal. CONCLUSIONS: TCD monitoring of patients undergoing TCAR revealed that the initiation of flow reversal results in a decrement in ipsilateral MCA velocity. Furthermore, embolic events can occur during flow reversal and are significantly associated with the reinitiation of antegrade flow in the internal carotid artery. However, both of these hemodynamic events were well-tolerated in our cohort. These findings suggest that TCAR remains a safe neuroprotective strategy for carotid revascularization.

An analysis of the vascular injuries and attempted resuscitation surrounding the assassination of Martin Luther King Jr.

Martin Luther King Jr was the most prominent civil rights leader in the United States in the 1960s. He was shot by an assassin in Memphis, Tennessee, on April 4, 1968. After the shooting he was taken to a local hospital where he had an unsuccessful resuscitation for a right subclavian artery transection. Despite the fact that the circumstances around the assassination have been frequently reported and reviewed in the past 50 years, the specific vascular care of the traumatic injury has not been analyzed. This paper reviews the medical aspects of the King assassination and the management of his subclavian injury.

BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.

BACKGROUND: Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. METHODS: We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia. RESULTS: We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6-Lsq1-3). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3Ile81, but not BAG3Met81, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3Ile81 (n=9), but not BAG3Met81 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. CONCLUSIONS: Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.

The impact of femoral arterial thrombosis in paediatric cardiac catheterisation: a national study.

BACKGROUND: Previous studies have identified risk factors for femoral arterial thrombosis after paediatric cardiac catheterisation, but none of them have evaluated the clinical and economic significance of this complication at the population level. Therefore, we examined the national prevalence and economic impact of femoral arterial thrombosis after cardiac catheterisation in children. METHODS: Patients⩽18 years of age who underwent cardiac catheterisation were identified in the 2003-2009 Kids' Inpatient Database. Patients were stratified by age as follows: <1 year of age or 1-18 years of age. The primary outcome was arterial thrombosis of the lower extremity during the same hospitalisation as cardiac catheterisation. Propensity score matching was used to determine the impact of femoral arterial thrombosis on hospital length of stay, cost, and mortality. RESULTS: Among the 11,497 paediatric cardiac catheterisations identified, 4558 catheterisations (39.6%) were performed in children <1 year of age. This age group experienced a higher prevalence of reported femoral arterial thrombosis, compared with children aged 1-18 years (1.3 versus 0.3%, p<0.001). After matching, femoral arterial thrombosis in children <1 year of age was associated with similar mortality (5.4 versus 1.8%, p=0.28), length of stay (8 versus 5 days, p=0.11), and total hospital cost ($27,135 versus $28,311, p=0.61), compared with absence of thrombosis. CONCLUSIONS: Femoral arterial thrombosis is especially prevalent in children <1 year of age undergoing cardiac catheterisation. Clinicians should be vigilant in monitoring femoral arterial patency in neonates and infants after cardiac catheterisation.

Elevated Cardiac Troponin I in Preservation Solution Is Associated With Primary Graft Dysfunction.

BACKGROUND: Although primary graft dysfunction (PGD) is a leading cause of mortality and morbidity early post-heart transplant, relatively little is known regarding mechanisms involved in PGD development. METHODS AND RESULTS: We examined the relationship between cardiac troponin I (cTnI) concentrations in the preservation solution from 43 heart transplant procedures and the development of PGD. Donor hearts were flushed with cold preservation solution (University of Wisconsin [UW] or Custodiol) and stored in the same solution. cTnI concentrations were measured utilizing the i-STAT System and normalized to left ventricular mass. Recipient medical records were reviewed to determine PGD according to the 2014 ISHLT consensus conference. Nineteen patients developed PGD following cardiac transplantation. For both UW and Custodiol, normalized cTnI levels were significantly increased (P = .031 and .034, respectively) for those cases that developed PGD versus no PGD. cTnI levels correlated with duration of ischemic time in the UW group, but not for the Custodiol group. Donor age and donor cTnI (obtained prior to organ procurement) did not correlate with preservation cTnI levels in either UW or Custodiol. CONCLUSIONS: Increased preservation solution cTnI is associated with the development of PGD suggesting preservation injury may be a dominant mechanism for the development of PGD.

Surgical outcomes of patients with inferior vena cava leiomyosarcoma.

INTRODUCTION: Primary vascular leiomyosarcomas are incredibly rare and have a poor prognosis. The purpose of this study was to analyze the surgical outcomes of patients with primary inferior vena cava (IVC) leiomyosarcoma. METHODS: We performed a retrospective review of IVC leiomyosarcoma resections performed at a single tertiary care hospital from 2014 to 2023. A total of 13 cases were analyzed, including 10 women and 3 men. The presenting symptoms, tumor characteristics, operative management, postoperative complications, and survival rates were assessed for each patient. RESULTS: The median patient age was 59 years (quartile [Q]1, 52 years; Q3, 68 years). The median tumor size was 7.0 cm (Q1, 6 cm; Q3, 12 cm). The median mitotic rate was 6 per 10 high-power fields (Q1, 2.5; Q3, 15.5). All 13 patients underwent grossly negative tumor resection, with 9 (69%) having microscopically negative margins (R0). No patient had lymph node involvement. The IVCs were managed with ligation in four patients for tumors already occluding the IVC and bovine pericardial patch angioplasty in seven patients or primary repair in two patients for patent IVCs. Concomitant right nephrectomy was performed in seven patients. Left renal vein ligation was performed in three patients, but no left nephrectomies were performed. Significant postoperative complications included one patient with lower extremity compartment syndrome, two patients with severe leg swelling, and one patient with arm swelling. The 30-day mortality rate was zero. Using the Kaplan-Meier product limit method, disease-specific survival was estimated to be 93%. CONCLUSIONS: Surgical resection is a feasible and effective oncologic treatment option for patients with IVC leiomyosarcoma. The IVC can be safely managed by ligation, primary repair, or patch angioplasty, depending on the prior patency of the IVC.

Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response.

Vasculopathies occur 15 years earlier in individuals with diabetes mellitus (DM) as compared to those without, but the underlying mechanisms driving diabetic vasculopathy remain incompletely understood. Endothelial cells (ECs) and macrophages (MΦ) are critical players in vascular wall and their crosstalk is crucial in diabetic vasculopathy. In diabetes, EC activation enables monocyte recruitment, which transmigrate into the intima and differentiate into macrophages (MΦ). Beyond this established model of diapedesis, EC-MΦ interplay is highly intricate and heterogenous. To capture these highly context dependent EC-MΦ interactions, we leveraged single-cell (sc)RNA-seq in conjunction with spatial transcriptome (ST)-seq profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We provide in this study a transcriptomic map encompassing major arterial vascular cells, e.g., EC, mononuclear phagocyte (MP), and T cells, and their interactions associated with human T2D. Furthermore, we identified Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2) as a top T2D-induced gene in MP, with concomitant increase of TREM2 ligands in ECs. TREM2 induction was confirmed in mouse models of T2D and monocyte/MΦ subjected to DM-mimicking stimuli. Perturbing TREM2 with either an antibody or silencing RNA in MPs led to decreased pro-inflammatory responses in MPs and ECs and increased EC migration in vitro . In a mouse model of diabetes, TREM2 expression and its interaction with ECs are increased in the ischemic, as compared to non-ischemic muscles. Importantly, neutralization of TREM2 using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in the diabetic mice, suggesting a role of TREM2 in promoting diabetic PAD. Finally, we verified that both TREM2 expression and the TREM2-EC-interaction are increased in human patients with DM-PAD. Collectively, our study presents the first atlas of human diabetic vessels with a focus on EC-MP interactions. Exemplified by TREM2, our study provides valuable insights into EC-MΦ interactions, key processes contributing to diabetic vasculopathies and the potential of targeting these interactions for therapeutic development.

The Opportunity for Impactful Integration of Vascular and Podiatric Care.

BACKGROUND: The importance of collaboration between vascular and podiatric surgeons has been well-established. High-level partnerships are integral to the development of multidisciplinary programs and wound care centers, ultimately resulting in improved patient outcomes. This vascular-podiatric integration is not universal, however, and podiatric surgery may not be aligned within a vascular surgery division at many institutions. As one such institution, we reviewed our single-center experience in order to identify opportunities for the impactful integration of vascular-podiatric patient care. METHODS: Institutional electronic medical records were retrospectively reviewed for all procedures performed by vascular surgeons at a high volume, safety-net academic medical center. Data were collected on all primary and additional procedures, current procedural terminology (CPT) codes, case type (elective, urgent, emergent), surgeon specialty, and date/time of the procedures performed. CPT codes were linked to the Centers for Medicare & Medicaid Services' Physician Fee Schedule to estimate the work relative value unit (wRVU) per procedure. RESULTS: From 2018 to 2022, vascular surgeons performed a total of 12,206 operations, of which 1102 (9.9%) involved podiatric procedures. The most common vascular-performed podiatry procedures performed were toe amputations (38.1%, n = 420), transmetatarsal foot amputations (20.1%, n = 222), and ankle/foot debridement (16.2%, n = 178). Foot/ankle-specific procedures were identified as the primary procedure in 726 (65.9%) cases and as the adjunct procedure in 376 (34.1%) cases. A substantial proportion of podiatric procedures occurred on an urgent (n = 278, 25.2%) or emergent (n = 28, 2.5%) basis. A total of 163 (14.8%) cases occurred after hours (either before 0600 or after 1800), and 133 (12.1%) cases were performed on a holiday or weekend. Procedure-specific revenue included 4243.39 wRVU for primary procedures and 2108.08 wRVU for additional procedures performed. CONCLUSIONS: We report our single-center experience in which vascular surgeons provide a significant proportion of podiatric procedures. Our study underscores the potential for integrating podiatric surgeons within a vascular surgical division and presents opportunities for collaboration and enhanced patient care.

Epigenetic Regulation of Angiogenesis in Peripheral Artery Disease.

Peripheral arterial disease (PAD) represents a global health concern with a rising prevalence attributed to factors such as obesity, diabetes, aging, and smoking. Among patients with PAD, chronic limb-threatening ischemia (CLTI) is the most severe manifestation, associated with substantial morbidity and mortality. While revascularization remains the primary therapy for CLTI, not all patients are candidates for such interventions, highlighting the need for alternative approaches. Impaired angiogenesis, the growth of new blood vessels, is a central feature of PAD, and despite decades of research, effective clinical treatments remain elusive. Epigenetics, the study of heritable changes in gene expression, has gained prominence in understanding PAD pathogenesis. Here, we explore the role of epigenetic regulation in angiogenesis within the context of PAD, with a focus on long non-coding RNAs and fibroblast-endothelial cell transdifferentiation. Additionally, we discuss the interplay between metabolic control and epigenetic regulation, providing insights into potential novel therapeutic avenues for improving PAD treatments. This review aims to offer a concise update on the application of epigenetics in angiogenesis and PAD research, inspiring further investigations in this promising field.