Decoding the Genomics of Abdominal Aortic Aneurysm.

A key aspect of genomic medicine is to make individualized clinical decisions from personal genomes. We developed a machine-learning framework to integrate personal genomes and electronic health record (EHR) data and used this framework to study abdominal aortic aneurysm (AAA), a prevalent irreversible cardiovascular disease with unclear etiology. Performing whole-genome sequencing on AAA patients and controls, we demonstrated its predictive precision solely from personal genomes. By modeling personal genomes with EHRs, this framework quantitatively assessed the effectiveness of adjusting personal lifestyles given personal genome baselines, demonstrating its utility as a personal health management tool. We showed that this new framework agnostically identified genetic components involved in AAA, which were subsequently validated in human aortic tissues and in murine models. Our study presents a new framework for disease genome analysis, which can be used for both health management and understanding the biological architecture of complex diseases. VIDEO ABSTRACT.

Editor's Choice -- European Society for Vascular Surgery (ESVS) 2024 Clinical Practice Guidelines on the Management of Abdominal Aorto-Iliac Artery Aneurysms.

OBJECTIVE: The European Society for Vascular Surgery (ESVS) has developed clinical practice guidelines for the care of patients with aneurysms of the abdominal aorta and iliac arteries in succession to the 2011 and 2019 versions, with the aim of assisting physicians and patients in selecting the best management strategy. METHODS: The guideline is based on scientific evidence completed with expert opinion on the matter. By summarising and evaluating the best available evidence, recommendations for the evaluation and treatment of patients have been formulated. The recommendations are graded according to a modified European Society of Cardiology grading system, where the strength (class) of each recommendation is graded from I to III and the letters A to C mark the level of evidence. RESULTS: A total of 160 recommendations have been issued on the following topics: Service standards, including surgical volume and training; Epidemiology, diagnosis, and screening; Management of patients with small abdominal aortic aneurysm (AAA), including surveillance, cardiovascular risk reduction, and indication for repair; Elective AAA repair, including operative risk assessment, open and endovascular repair, and early complications; Ruptured and symptomatic AAA, including peri-operative management, such as permissive hypotension and use of aortic occlusion balloon, open and endovascular repair, and early complications, such as abdominal compartment syndrome and colonic ischaemia; Long term outcome and follow up after AAA repair, including graft infection, endoleaks and follow up routines; Management of complex AAA, including open and endovascular repair; Management of iliac artery aneurysm, including indication for repair and open and endovascular repair; and Miscellaneous aortic problems, including mycotic, inflammatory, and saccular aortic aneurysm. In addition, Shared decision making is being addressed, with supporting information for patients, and Unresolved issues are discussed. CONCLUSION: The ESVS Clinical Practice Guidelines provide the most comprehensive, up to date, and unbiased advice to clinicians and patients on the management of abdominal aorto-iliac artery aneurysms.

Most privately insured patients do not receive federally recommended abdominal aortic aneurysm screening.

OBJECTIVE: Since 2005, the United States Preventative Services Task Force has recommended abdominal aortic aneurysm (AAA) ultrasound screening for 65- to 75-year-old male ever-smokers. Integrated health systems such as Kaiser Permanente and the Veterans Affairs (VA) health care system report 74% to 79% adherence, but compliance rates in the private sector are unknown. METHODS: The IBM Marketscan Commercial and Medicare Supplemental databases (2006-2017) were queried for male ever-smokers continuously enrolled from age 65 to 75 years. Exclusion criteria were previous history of AAA, connective tissue disorder, and aortic surgery. Patients with abdominal computed tomographic or magnetic resonance imaging from ages 65 to 75 years were also excluded. Screening was defined as a complete abdominal, retroperitoneal, or aortic ultrasound. A logistic mixed-effects model utilizing state as a random intercept was used to identify patient characteristics associated with screening. RESULTS: Of 35,154 eligible patients, 13,612 (38.7%) underwent screening. Compliance varied by state, ranging from 24.4% in Minnesota to 51.6% in Montana (P < .05). Screening activity increased yearly, with 0.7% of screening activity occurring in 2008 vs 22.2% in 2016 (P <.05). In a logistic mixed-effects model adjusting for state as a random intercept, history of hypertension (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.03-1.13), coronary artery disease (OR, 1.17; 95% CI, 1.10-1.22), congestive heart failure (OR, 1.14; 95% CI, 1.01-1.22), diabetes (OR, 1.1; 95% CI, 1.06-1.16), and chronic kidney disease (OR, 1.4; 95% CI, 1.24-1.53) were associated with screening. Living outside of a census-designated metropolitan area was negatively associated with screening (OR, 0.92; 95% CI, 0.87-0.97). CONCLUSIONS: In a private claims database representing 250 million claimants, 38.7% of eligible patients received United States Preventative Services Task Force-recommended AAA screening. Compliance was nearly one-half that of integrated health systems and was significantly lower for patients living outside of metropolitan areas. Efforts to improve early detection of AAA should include targeting non-metropolitan areas and modifying Medicare reimbursement and incentivization strategies to improve guideline adherence.

Validity of the Global Vascular Guidelines in Predicting Outcomes Based on First-Time Revascularization Strategy.

BACKGROUND: The Global Vascular Guidelines (GVG) recommend selecting an endovascular versus open-surgical approach to revascularization for chronic limb-threatening ischemia (CLTI), based on the Global Limb Anatomic Staging System (GLASS) and wound, ischemia, and foot infection (WIfI) classification systems. We assessed the utility of GVG-recommended strategies in predicting clinical outcomes. METHODS: We conducted a single-center, retrospective review of first-time lower-extremity revascularizations within a comprehensive limb-preservation program from 2010 to 2018. Procedures were stratified by (1) treatment concordance with GVG-recommended strategy (concordant versus nonconcordant groups), (2) GLASS stages I-III, and (3) endovascular versus open strategies. The primary outcome was 5-year freedom from major adverse limb events (FF-MALE), defined as freedom from reintervention or major amputation, and secondary outcomes included 5-year overall survival, freedom from major amputation, freedom from reintervention, and immediate technical failure (ITF) during initial revascularization. Kaplan-Meier (KM) survival analysis and multivariate analysis with Cox proportional hazard models were performed on the primary and secondary outcomes. RESULTS: Of 281 first-time revascularizations for CLTI, 251 (89.3%) were endovascular and 186 (66.2%) were in the concordant group, with a mean clinical follow-up of 3.02 ± 2.40 years. Within the concordant group alone, 167 (89.8%) of revascularizations were endovascular. The concordant group had a higher rate of chronic kidney disease (60.8% vs. 45.3%, P = 0.02), WIfI foot infection grade (0.81 ± 1.1 vs. 0.56 ± 0.80, P = 0.03), and WIfI stage (3.1 ± 0.79 vs. 2.8 ± 1.2, P < 0.01) compared to the non-concordant group. After both KM and multivariate analyses, there were no significant differences in 5-year FF-MALE or overall survival between concordant and non-concordant groups. There was higher freedom from major amputation in the non-concordant group on KM analysis (83.9% vs. 74.2%, P = 0.025), though this difference was non-significant on multivariate analysis (hazard ratio [HR]: 0.49, 95% confidence interval [CI]: 0.21-1.15, P = 0.10). The open group had lower MALE compared to the endovascular group (HR: 0.39, 95% CI: 0.17-0.91, P = 0.029) attributed to a lower reintervention rate in the open group (HR: 0.31, 95% CI: 0.11-0.87, P = 0.026). GLASS stage was not associated with significant differences in outcomes, but the severity of GLASS stage was associated with ITF (2.1% in stage 1, 6.4% in stage 2, and 11.7% in stage 3, P = 0.01). CONCLUSIONS: In this study, CLTI treatment outcomes did not differ significantly based on whether treatment was received in concordance with GVG-recommended strategy. There was no difference in overall survival between the endovascular and open groups, though there was a higher reintervention rate in the endovascular group. The GVG guidelines are an important resource to help guide the management of CLTI patients. However, in this study, both concordance with GVG guidelines and GLASS staging were found to be indeterminate in differentiating outcomes between complex CLTI patients treated primarily with an endovascular-first approach. The revascularization approach for a CLTI patient is a nuanced decision that must take into account patient anatomy and clinical status, as well as physician skill and experience and institutional resources.

Impact of renal chimney intra-aortic stent length on branch and end-stent angle in chimney endovascular aneurysm repair and endovascular aneurysm sealing configurations.

OBJECTIVE: Practice patterns and durability of parallel stent graft techniques in complex endovascular aneurysm repair (EVAR) remain poorly defined. We aimed to quantify and compare the impact of renal chimney intra-aortic stent length (IASL) on geometric deformations of renal arteries in complex EVAR. METHODS: Thirty-eight nonconsecutive patients underwent EVAR utilizing parallel stent graft techniques (chimney EVAR [chEVAR], n = 28; chimney endovascular aneurysm sealing [chEVAS], n = 10) between 2010 and 2016. A total of 59 renal chimney stent grafts were used. Geometric quantification was derived from three-dimensional model-based centerline extraction. Renal chimney intra-aortic stent length (IASL) was defined as the length of chimney stent that extended from the proximal edge of the chimney stent to the ostium of the corresponding renal artery. RESULTS: Mean IASL for both left and right renal arteries in the cohort was 35.7 mm. Renal arteries containing chimney IASL <30 mm trended toward a greater branch angle (135.4 vs. 127.8°, p = .06). Left renal arteries showed significantly greater branch angle among those with IASL <40 mm (135.5 vs. 121.7°, p = .045). Mean IASL for renal arteries in chEVAR was significantly longer compared to chEVAS (39.2 vs. 26.3 mm, p = .003). No difference was noted in overall branch angle or end-stent angle based on procedure type. ChEVAR with IASL <30 mm had significantly greater end-stent angle (48.2 vs. 33.5°, p = .03). In contrast, chEVAS patients showed no difference in end-stent angle based on IASL thresholds, but did have significantly greater branch angle among those with IASL <30 mm when grouped by both all renal arteries (133.5 vs. 113.5°, p = .004) and right renal arteries (134.3 vs. 111.6°, p = .02). CONCLUSIONS: Renal chimney stents with longer IASL appear to exhibit less renal artery deformation, suggesting a more gradual and perpendicular transition of the chimney stent across the renal ostium.

Reintervention does not affect long-term survival after fenestrated endovascular aneurysm repair.

OBJECTIVE: Fenestrated endovascular aneurysm repair (FEVAR) is increasingly used in the treatment of juxtarenal aortic aneurysms and short-neck infrarenal aneurysms. Reinterventions (REIs) occur frequently, contributing to patient morbidity and resource utilization. We sought to determine whether REI affects long-term survival after FEVAR. METHODS: A single-institution retrospective review of all Cook Zenith fenestrated (ZFEN; Cook Medical, Inc, Bloomington, IN) repairs was performed. Patients with ≥6 months of follow-up and without adjunctive branch modifications were included. REI was defined as any aneurysm, device, target branch, or access-related intervention after the index procedure. REIs were categorized as early (<30 days) or late (≥30 days), by indication (ie, branch, endoleak, limb related, access related, other), and by target branch or device components. Patients were stratified into REI vs no REI groups and branch REI vs non-branch REI groups. RESULTS: Of 219 consecutive ZFEN repairs from 2012 to 2021, 158 patients met the inclusion criteria. Of these 158 patients, 41 (26%) required a total of 51 REIs (10 early and 41 late) during a mean follow-up of 33.9 months. The most common indication for REI was branch-related (31 of 51; 61%), with the renal arteries the most frequently affected (26 of 51; 51%). The only differences found in baseline, aneurysm, and device characteristics were a higher mean Society for Vascular Surgery comorbidity score (9.6 vs 7.9; P = .04) and larger suprarenal neck angle (23.3° vs 17.1°; P = .04) in the no REI group. In contrast, the REI group had a larger mean proximal seal zone diameter (26.3 mm vs 25.1 mm; P = .03) and device diameter (31.9 mm vs 30.0 mm; P = .002) compared with the no REI group. Technical success and operative characteristics were similar between the groups, except for a longer mean fluoroscopy time (74.9 minutes vs 60.8 minutes; P = .01) and longer median length of stay (2 vs 2 days; P = .006) for the REI group. Although the rate of early (<30 days) major adverse events was greater for the REI group (24.4% vs 6.0%; P = .001), the difference in 30-day mortality was not statistically significant (4.9% vs 0.9%; P = .10). On Kaplan-Meier analysis, freedom from REI at 1 and 5 years was 85.7% and 62.6%, respectively, for the overall cohort. No difference was found in the estimated 5-year survival between the REI and no REI groups (62.8% vs 63.5%; log-rank, P = .87) and branch REI and non-branch REI groups (71.8% vs 49.9%; log-rank, P = .16). On multivariate analysis, REI was not an independent predictor for mortality. However, age, Society for Vascular Surgery comorbidity score, and preoperative maximum aneurysm diameter each increased the hazard of death (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12 [P = .007]; HR, 1.10; 95% CI, 1.01-1.18 [P = .02]; HR, 1.05; 95% CI, 1.02-1.08 [P = .003], respectively). CONCLUSIONS: After ZFEN, 41 patients (26%) had required a total of 51 REIs, with most occurring ≥30 days after the index procedure, and 61% were branch related, with no influence on 5-year survival. Age, comorbidity, and baseline aneurysm diameter independently predicted mortality. The use of FEVAR mandates lifelong surveillance and protocols to maintain branch patency. Despite their relative frequency, REIs did not influence 5-year postprocedural survival.

The effect of diabetes on abdominal aortic aneurysm growth over 2 years.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a common progressive disease and a significant cause of morbidity and mortality. Prior investigations have shown that diabetes mellitus (DM) may be relatively protective of AAA incidence and growth. The Non-invasive Treatment of Aortic Aneurysm Clinical Trial (N-TA3CT) is a contemporary study of small AAA growth that provides a unique opportunity to validate and explore the effect of DM on AAA. Confirming the effect of DM on AAA growth in this study may present opportunities to explore for clues to potential biologic mechanisms as well as inform current patient management. METHODS: This is a secondary analysis examining the association of diabetes and aneurysm growth within N-TA3CT: a placebo-controlled multicenter trial of doxycycline in 261 patients with AAA maximum transverse diameters (MTDs) between 3.5 and 5 cm. The primary outcome is the change in the MTD from baseline as determined by computed tomography (CT) scans obtained during the trial. Secondary outcome is the growth pattern of the AAA. Baseline characteristics and growth patterns were assessed with t tests (continuous) or χ2 tests (categorical). Unadjusted and adjusted longitudinal analyses were performed with a repeated measures linear mixed model to compare AAA growth rates between patients with and without diabetes. RESULTS: Of 261 patients, 250 subjects had sufficient imaging and were included in this study. There were 56 patients (22.4%) with diabetes and 194 (77.6%) without. Diabetes was associated with higher body mass index and increased rates of hypercholesterolemia and coronary artery disease (P < .05). Diabetes was also associated with increased frequency of treatment for atherosclerosis and hypertension including treatment with statin, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, anti-platelet, and diuretic therapy (P < .05). Baseline MTD was not significantly different between those with (4.32 cm) and without DM (4.30 cm). Median growth rate for patients with diabetes was 0.12 cm/y (interquartile range, 0.07-0.22 cm/y) and 0.19 cm/y (interquartile range, 0.12-0.27 cm/y) in patients without DM, which was significantly different on unadjusted analysis (P < .0001). Diabetes remained significantly associated with AAA growth after adjustment for other relevant clinical factors (coef, -0.057; P < .0001). CONCLUSIONS: Patients with diabetes have more than a 35% reduction in the median growth rates of AAA despite more severe concomitant vascular comorbidities and similar initial sizes of aneurysms. This effect persists and remains robust after adjusted analysis; and slower growth rates may delay the time to reach repair threshold. Rapid growth (>0.5 cm/y) is infrequent in patients with DM.

Cost-effectiveness of computed tomography versus ultrasound-based surveillance following endovascular aortic repair of intact infrarenal abdominal aortic aneurysms.

BACKGROUND: While Society for Vascular Surgery guidelines recommend computed tomography angiography (CTA) or ultrasound for surveillance following infrarenal endovascular aortic repair (EVAR), there is a lack of consensus regarding optimal timing and modalities. We hypothesized that ultrasound-based approaches would be more cost-effective and developed a cost-effectiveness analysis to estimate the lifetime costs and outcomes of various strategies. METHODS: We developed a decision tree with nested Markov models to compare five surveillance strategies: yearly CTA, yearly CDU, yearly CEU, CTA at first year followed by CDU, and CTA at first year followed by CEU. The model accounted for differential sensitivity, specificity, and risk of acute kidney injury after CTA, and was implemented on a monthly cycle with a willingness-to-pay threshold of $50,000 per quality-adjusted life year (QALY) and 3% annual discounting. RESULTS: Under base case assumptions, the CTA-CDU strategy was cost effective with a lifetime cost of $77950 for 7.74 QALYs. In sensitivity analysis, the CTA-CDU approach remained cost-effective when CEU specificity was less than 95%, and risk of acute kidney injury following CTA was less than 20%. At diagnostic sensitivities below 75% for CEU and 55% for CDU, a yearly CTA strategy maximized QALYs. CONCLUSIONS: A hybrid strategy in which CTA is performed in the first year and CDU is performed annually thereafter is the most cost-effective strategy for infrarenal EVAR surveillance in patients with less than a 20% risk of contrast-induced nephropathy. If the sensitivity of CEU and CDU are at the lower end of plausible estimates, a yearly CTA strategy is reasonable. Further research should aim to identify patients who may benefit from alternative surveillance strategies.

Effect of Telmisartan on the Peak Wall Stress and Peak Wall Rupture Index of Small Abdominal Aortic Aneurysms: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: This study was an unplanned exploratory analysis of a subset of participants from the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. It aimed to assess the efficacy of the angiotensin 1 receptor blocker telmisartan in reducing abdominal aortic aneurysm (AAA) peak wall stress (PWS) and peak wall rupture index (PWRI) among individuals with small AAAs. METHODS: Participants with AAAs measuring 35 - 49 mm in maximum diameter were randomised to receive telmisartan 40 mg or identical placebo in the TEDY trial. Participants who had computed tomography angiography performed at entry and at least one other time point during the trial (12 or 24 months) were included in the current study. Orthogonal AAA diameter, PWS, and PWRI were measured using previously validated methods. The annual change in PWS and PWRI from baseline was compared between participants allocated telmisartan or placebo using linear mixed effects models. These models were either unadjusted or adjusted for risk factors that were different in the groups at entry (p < .100) or systolic blood pressure (SBP) at one year. RESULTS: Of the 207 participants recruited to TEDY, 124 were eligible for inclusion in this study. This study included 65 and 59 participants from the telmisartan and placebo groups, respectively. The PWS and PWRI were not significantly different in the two groups at baseline. Participants allocated telmisartan had a slower annual increase in PWS (-4.19; 95% CI -8.24, -0.14 kPa/year; p = .043) and PWRI (-0.014; 95% CI -0.026, -0.001; p = .032) compared with those allocated placebo after adjusting for risk factors. After adjustment for SBP at one year, telmisartan did not significantly reduce annual increases in PWS or PWRI. CONCLUSION: The findings of this study suggest that telmisartan limits the rate of increase in PWS and PWRI of small AAAs by reducing blood pressure.

Athero-occlusive Disease Appears to be Associated with Slower Abdominal Aortic Aneurysm Growth: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). METHODS: Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models; 131 of the 210 participants recruited to TEDY were included. RESULTS: In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm3 and 0.70 (0.19 - 1.22) mm slower than those without AOD, p = .008 and .007 respectively. The association between AOD and significantly slower AAA growth was maintained after adjusting for risk factors and medications, significantly unequally distributed between participants with and without an AOD diagnosis. CONCLUSION: In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.

Treatment with the Prolyl Hydroxylase Inhibitor JNJ Promotes Abdominal Aortic Aneurysm Progression in Diabetic Mice.

OBJECTIVE: Prolyl hydroxylase domain containing proteins (PHD) rigorously regulate intracellular hypoxia inducible factor-1 (HIF-1) protein expression and activity. Diabetes impairs PHD activity and attenuates abdominal aortic aneurysm (AAA) progression. The extent to which dysregulated PHD activity contributes to diabetes mediated AAA suppression remains undetermined. METHODS: AAAs were induced in diabetic and non-diabetic male C57BL/6J mice via intra-aortic elastase infusion. A PHD inhibitor (JNJ-42041935, aka "JNJ", 150 mmol/kg) or vehicle alone was administered daily starting one day prior to AAA induction for 14 days. Influences on AAA progression was assessed via ultrasonography and histopathology. Expression of aortic HIF-1α, three of its target genes and macrophage derived mediators were assayed via quantitative reverse transcription polymerase chain reaction. Aneurysmal sections from AAA patients with and without diabetes (two patients in each group) were immunostained for HIF-1α and vascular endothelial growth factor (VEGF)-A. RESULTS: Expression of HIF-1α target genes (erythropoietin, VEGF-A, and glucose transporter-1) was reduced by 45% - 95% in experimental diabetic aortas. Diameter enlargement was similarly limited, as were mural elastin degradation, leukocyte infiltration, and neo-angiogenesis (reduced capillary density and length) on histopathology. Pre-treatment with JNJ prior to AAA initiation augmented aortic HIF-1α target gene expression and aneurysm progression in diabetic mice, along with macrophage VEGF-A and matrix metalloproteinase 2 mRNA expression. No differences were noted in HIF-1α or VEGF-A expression on aortic immunohistochemical staining of human aortic tissue as a function of diabetes status. CONCLUSION: Small molecule PHD inhibitor treatment reduces or offsets impairment of experimental AAA progression in hyperglycemic mice, highlighting the potential contribution of dysregulated PHD activity to diabetes mediated aneurysm suppression.

Multidisciplinary Extremity Preservation Program Improves Quality of Life for Patients with Advanced Limb Threat.

BACKGROUND: The need for multidisciplinary care of patients with advanced limb threat is well established. We examined patient reported outcomes and health-related quality of life (HR-QoL) for those who completed a multidisciplinary extremity preservation program (EPP) at our institution. METHODS: Patients with advanced limb threat, who had previously failed standard management at a tertiary-care center, were referred to EPP for evaluation by a multidisciplinary panel of vascular, plastic, orthopedic and podiatric surgeons, along with infectious disease, prosthetics, orthotics, imaging, palliative care, social work and wound nursing specialists. HR-QoL was quantified before and after EPP participation with the RAND-36 questionnaire. The validated RAND-36 assesses physical function, role limitations caused by physical and emotional health problems, social functioning, emotional well-being, energy, pain and general health perceptions. RESULTS: From 2018 to 2020, 185 patients were referred to EPP. After review by the multidisciplinary panel, 120 were accepted into the program, 63 of whom completed their course of care; 9 were one-time consultations. The median number of EPP in-person care visits was 23 (13-54) per participant; 87.3% of patients received one or more surgical procedure, including operative debridement (73%), revascularization (44%), soft-tissue reconstruction or transplantation (46%), as well as hyperbaric oxygen therapy (11%) during their course of treatment. 85.7% of patients achieved complete wound healing, 41.5% occurring within 6 months. Ultimately, 14.3% required a major amputation. Graduates noted improvement in all categories of the HR-QoL upon completion, including those undergoing major amputation. On adjusted multivariate regression analysis, patients with immunocompromised status were more likely to show greater improvement in their social function (OR: 10.1; P < 0.044) and emotional role limitation (OR: 8.1; P = 0.042), while, patients with larger wound volume at presentation were more likely to have greater improvement in their general health (OR: 1.1; P < 0.049). Conversely, patients with a smoking history had less improvement in energy level (OR: 0.4; P = 0.044) and patients with dialysis-dependence had less improvement in social function (OR: 0.2; P = 0.034). CONCLUSIONS: Coordinated, multidisciplinary extremity preservation program improves HR-QoL of patients with complex limb threat, including those who are immunocompromised with impaired social function and emotional role limitations. Furthermore, study is warranted to better characterize the generalizability of this approach, including considerations of cost-effectiveness, wound recidivism, and limiting the number of in-person visits required to achieve complete healing.

Angiotensin-converting enzyme 2, coronavirus disease 2019, and abdominal aortic aneurysms.

OBJECTIVE: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiologic agent of the current, world-wide coronavirus disease 2019 (COVID-19) pandemic. Angiotensin-converting enzyme 2 (ACE2) is the SARS-CoV-2 host entry receptor for cellular inoculation and target organ injury. We reviewed ACE2 expression and the role of ACE2-angiotensin 1-7-Mas receptor axis activity in abdominal aortic aneurysm (AAA) pathogenesis to identify potential COVID-19 influences on AAA disease pathogenesis. METHODS: A comprehensive literature search was performed on PubMed, National Library of Medicine. Key words included COVID-19, SARS-CoV-2, AAA, ACE2, ACE or angiotensin II type 1 (AT1) receptor inhibitor, angiotensin 1-7, Mas receptor, age, gender, respiratory diseases, diabetes, and autoimmune diseases. Key publications on the epidemiology and pathogenesis of COVID-19 and AAAs were identified and reviewed. RESULTS: All vascular structural cells, including endothelial and smooth muscle cells, fibroblasts, and pericytes express ACE2. Cigarette smoking, diabetes, chronic obstructive pulmonary disease, lupus, certain types of malignancies, and viral infection promote ACE2 expression and activity, with the magnitude of response varying by sex and age. Genetic deficiency of AT1 receptor, or pharmacologic ACE or AT1 inhibition also increases ACE2 and its catalytic product angiotensin 1-7. Genetic ablation or pharmacologic inhibition of ACE2 or Mas receptor augments, whereas ACE2 activation or angiotensin 1-7 treatment attenuates, progression of experimental AAAs. The potential influences of SARS-CoV-2 on AAA pathogenesis include augmented ACE-angiotensin II-AT1 receptor activity resulting from decreased reciprocal ACE2-angiotensin 1-7-Mas activation; increased production of proaneurysmal mediators stimulated by viral spike proteins in ACE2-negative myeloid cells or by ACE2-expressing vascular structural cells; augmented local or systemic cross-talk between viral targeted nonvascular, nonleukocytic ACE2-expressing cells via ligand recognition of their cognate leukocyte receptors; and hypoxemia and increased systemic inflammatory tone experienced during severe COVID-19 illness. CONCLUSIONS: COVID-19 may theoretically influence AAA disease through multiple SARS-CoV-2-induced mechanisms. Further investigation and clinical follow-up will be necessary to determine whether and to what extent the COVID-19 pandemic will influence the prevalence, progression, and lethality of AAA disease in the coming decade.

Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model.

OBJECTIVE: We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti-VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A-positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti-VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice. CONCLUSIONS: VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.

Variability in hospital costs for carotid artery revascularization.

OBJECTIVE: The objective of this study was to understand drivers of cost for carotid endarterectomy (CEA) and carotid artery stenting (CAS) and to compare variation in cost among cases performed by vascular surgery (VS) with other services (OSs). METHODS: We collected internal hospital claims data for CEA and CAS between September 2013 and August 2015 and performed a financial analysis of all hospital costs including room accommodations, medications, medical and surgical supplies, imaging, and laboratory tests. Cases were stratified by presence of symptoms and procedure type, and costs of procedures performed by VS were compared with those performed by OSs. RESULTS: The cohort comprised 144 patients (78 asymptomatic, 66 symptomatic; 44 CAS, 100 CEA) receiving unilateral revascularization. VS (24 CAS, 70 CEA) and neurosurgery and neurointerventional radiology services (20 CAS, 30 CEA) performed all procedures. Age (71 ± 9 years vs 70 ± 11 years; P = .8) and length of stay (1.7 ± 2.1 days vs 2.2 ± 2.4 days; P = .73) were similar for VS and OSs. Symptoms were present before revascularization for 46% and were more commonly treated by OSs (78% vs 29%; P < .001). Case mix index was similar after stratifying by symptoms (asymptomatic, 1.28 ± 0.35 vs 1.39 ± 0.42 [P = .5]; symptomatic, 1.66 ± 0.73 vs 1.82 ± 0.81 [P = .9]). The largest cost components were operating room (OR)-related costs, beds, and supplies, together accounting for 76% of costs. Asymptomatic patients had 37% lower average hospital costs. For asymptomatic CAS, average index hospitalization cost was 17% less for VS compared with OSs because of 78% lower intensive care unit costs, 44% lower OR-related costs, 40% lower medication costs, and 24% lower cardiac testing costs. VS had 22% higher supply costs. For asymptomatic CEA, average index hospitalization costs were 22% lower for VS, driven by lower OR-related costs (28%), medications (28%), imaging (62%), and neurointerventional monitoring (64%). Costs were 38% higher for CAS vs CEA. For symptomatic CAS, costs were similar for both groups. For symptomatic CEA, total costs were 14% lower for VS compared with OSs, driven by 25% lower OR-related costs, 62% lower neurointerventional monitoring, 20% step-down beds, and 28% lower supply costs (and counterbalanced by 117% higher intensive care unit costs). CONCLUSIONS: VS average hospital costs were lower for asymptomatic CAS and all CEAs compared with OSs. Drivers of higher cost appear to be attributed to variation in physicians' practice as well as patients' complexity, affording an opportunity to reduce cost by establishing standard practices when appropriate.

Benefit of multidisciplinary wound care center on the volume and outcomes of a vascular surgery practice.

OBJECTIVE: Multidisciplinary care is recommended for the treatment of patients with ischemic and diabetic wounds. In addition to integrating care from multiple specialties, outpatient wound care centers provide an opportunity for continuity and organization of care after revascularization or hospitalization. The purpose of this study was to assess changes in the practice patterns and outcomes of patients treated by a tertiary care vascular surgery practice after the introduction of an affiliated outpatient wound care center. METHODS: A prospective institutional database was used to identify patients who underwent lower-extremity revascularization, amputation, or surgical debridement during consecutive 3-year periods before (BWC; n = 735) and after (AWC; n = 1503) the opening of an affiliated wound care center. Patients were included if they underwent intervention for atherosclerotic peripheral arterial disease or diabetic foot ulcers (DFUs). Changes in case volume, surgical indication, and procedural characteristics were assessed. Clinical outcomes included freedom from lower-extremity amputations and mortality. RESULTS: We identified a total of 1751 procedures performed in 1249 limbs that met inclusion criteria. After the opening of the wound clinic, procedures related to limb salvage represented a greater proportion of overall cases performed by the vascular service (19% vs 26%; P < .0001). The volume of lower-extremity interventions increased by 64%, from 662 procedures in the BWC period to 1085 procedures in the AWC period. There was no difference in type of revascularization performed between the two study periods, although surgical debridements (from 8.9% to 13%; P = .01) and infrapopliteal endovascular interventions (from 21% to 28%; P = .04) significantly increased. Compared with BWC patients, AWC patients more frequently presented with DFUs (7.3% vs 13%; P = .002) and chronic wounds (39% vs 45%; P = .05). At 1 year of follow-up, major amputation rates were significantly lower in the AWC group than in the BWC cohort (5.5% vs 8.8%; P = .04). Treatment during the AWC period was associated with a reduced risk of major amputation (adjusted hazard ratio, 0.41; 95% confidence interval, 0.27-0.62; P < .001), but no difference in all-cause mortality. CONCLUSIONS: The opening of an outpatient wound center affiliated with a tertiary vascular surgical practice was associated with a higher volume of limb salvage patients and procedures. The risk of major amputation decreased following the opening of the wound care center. Integrating vascular surgeons into wound centers may result in a synergistic system that promotes more aggressive and effective limb salvage.

Episode-based cost reduction for endovascular aneurysm repair.

OBJECTIVE: Effective strategies to reduce costs associated with endovascular aneurysm repair (EVAR) remain elusive for many medical centers. In this study, targeted interventions to reduce inpatient EVAR costs were identified and implemented. METHODS: From June 2015 to February 2016, we analyzed the EVAR practice at a high-volume academic medical center to identify, to rank, and ultimately to reduce procedure-related costs. In this analysis, per-patient direct costs to the hospital were compared before (September 2013-May 2015) and after (March 2016-January 2017) interventions were implemented. Improvement efforts concentrated on three categories that accounted for a majority of costs: implants, rooming costs, and computed tomography scans performed during the index hospitalization. RESULTS: Costs were compared between 141 EVAR procedures before implementation (PRE period) and 47 EVAR procedures after implementation (POST period). Based on data obtained through the Society for Vascular Surgery EVAR Cost Demonstration Project, it was determined that implantable device costs were higher than those at peer institutions. New purchasing strategies were implemented, resulting in a 30.8% decrease in per-case device costs between the PRE and POST periods. Care pathways were modified to reduce use of and costs for computed tomography scans obtained during the index hospitalization. Compared with baseline, per-case imaging costs decreased by 92.9% (P < .001), including a 99.0% (P = .001) reduction in postprocessing costs. Care pathways were also implemented to reduce preprocedural rooming for patients traveling long distances the day before surgery, resulting in a 50% decrease in utilization rate (35.4% PRE to 17.0% POST; P = .021), without having a significant impact on median postprocedural length of stay (PRE, 2 days [interquartile range, 1-11 days]; POST, 2 days [1-7 days]; P = .185). Medication costs also decreased by 38.2% (P < .001) as a hospital-wide effort. CONCLUSIONS: Excessive costs associated with EVAR threaten the sustainability of these procedures in health care organizations. Targeted cost reduction efforts can effectively reduce expenses without compromising quality or limiting patients' access.

Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population.

BACKGROUND: Identification of a safe and effective medical therapy for abdominal aortic aneurysm (AAA) disease remains a significant unmet medical need. Recent small cohort studies indicate that metformin, the world's most commonly prescribed oral hypoglycemic agent, may limit AAA enlargement. We sought to validate these preliminary observations in a larger cohort. METHODS: All patients with asymptomatic AAA disease managed in the Veterans Affairs Health Care System between 2003 and 2013 were identified by International Classification of Diseases, Ninth Revision codes. Those with a concomitant diagnosis of diabetes mellitus who also received two or more abdominal imaging studies (computed tomography, magnetic resonance imaging, or ultrasound) documenting the presence and size of an AAA, separated by at least 1 year, were included for review. Maximal AAA diameters were determined from radiologic reports. Further data acquisition was censored after surgical AAA repair, when performed. Comorbidities, active smoking status, and outpatient medication records (within 6 months of AAA diagnosis) were also queried. Yearly AAA enlargement rates, as a function of metformin treatment status, were compared using two statistical models expressed in millimeters per year: a multivariate linear regression (model 1) and a multivariate mixed-effects model with random intercept and random slope (model 2). RESULTS: A total of 13,834 patients with 58,833 radiographic records were included in the analysis, with radiology imaging follow-up of 4.2 ± 2.6 years (mean ± standard deviation). The average age of the patients at AAA diagnosis was 69.8 ± 7.8 years, and 39.7% had a metformin prescription within ±6 months of AAA. The mean growth rate for AAAs in the entire cohort was 1.4 ± 2.0 mm/y by model 1 analysis and 1.3 ± 1.6 mm/y by model 2 analysis. The unadjusted mean rate of AAA growth was 1.2 ± 1.9 mm/y for patients prescribed metformin compared with 1.5 ± 2.2 mm/y for those without (P < .001), a 20% decrease. This effect remained significant when adjusted for variables relevant on AAA progression: metformin prescription was associated with a reduction in yearly AAA growth rate of -0.23 mm (95% confidence interval, -0.35 to -0.16; P < .001) by model 1 analysis and 0.20 mm/y (95% confidence interval, -0.26 to -0.14; P < .001) by model 2 analysis. A subset analysis of 7462 patients with baseline AAA size of 35 to 49 mm showed a similar inhibitory effect (1.4 ± 2.0 mm/y to 1.7 ± 2.2 mm/y; P < .001). Patients' factors associated with an increased yearly AAA growth rate were baseline AAA size, metastatic solid tumors, active smoking, chronic obstructive pulmonary disease, and chronic renal disease. Factors associated with decreased yearly AAA growth rates included prescriptions for angiotensin II type 1 receptor blockers or sulfonylureas and the presence of diabetes-related complications. CONCLUSIONS: In a nationwide analysis of diabetic Veterans Affairs patients, prescription for metformin was associated with decreased AAA enlargement. These findings provide further support for the conduct of prospective clinical trials to test the ability of metformin to limit progression of early AAA disease.

Infrarenal endovascular aneurysm repair with large device (34- to 36-mm) diameters is associated with higher risk of proximal fixation failure.

OBJECTIVE: Endovascular aneurysm repair (EVAR) has become the standard of care for infrarenal aneurysms. Endografts are commercially available in proximal diameters up to 36 mm, allowing proximal seal in necks up to 32 mm. We sought to further investigate clinical outcomes after standard EVAR in patients requiring large main body devices. METHODS: We performed a retrospective review of a prospectively maintained database for all patients undergoing elective EVAR for infrarenal abdominal aortic aneurysms at a single institution from 2000 to 2016. Only endografts with the option of a 34- to 36-mm proximal diameter were included. Requisite patient demographics, anatomic and device-related variables, and relevant clinical outcomes and imaging were reviewed. The primary outcome in this study was proximal fixation failure, which was a composite of type IA endoleak and stent graft migration >10 mm after EVAR. Outcomes were stratified by device diameter for the large-diameter device cohort (34-36 mm) and the normal-diameter device cohort (<34 mm). RESULTS: There were 500 patients treated with EVAR who met the inclusion criteria. A total of 108 (21.6%) patients received large-diameter devices. There was no difference between the large-diameter cohort and the normal-diameter cohort in terms of 30-day (0.9% vs 0.95%; P = .960) or 1-year mortality (9.0% vs 6.2%; P = .920). Proximal fixation failure occurred in 24 of 392 (6.1%) patients in the normal-diameter cohort and 26 of 108 (24%) patients in the large-diameter cohort (P < .001). There were 13 (3.3%) type IA endoleaks in the normal-diameter cohort and 16 (14.8%) in the large-diameter cohort (P < .001). Stent graft migration (>10 mm) occurred in 15 (3.8%) in the normal-diameter cohort and 16 (14.8%) in the large-diameter cohort (P < .001). After multivariate analysis, only the use of Talent (Medtronic, Minneapolis, Minn) endografts (odds ratio [OR], 4.50; 95% confidence interval [CI], 1.18-17.21) and neck diameter ≥29 mm (OR, 2.50; 95% CI, 1.12-5.08) remained significant independent risk factors for development of proximal fixation failure (OR, 3.99; 95% CI, 1.75-9.11). CONCLUSIONS: Standard EVAR in patients with large infrarenal necks ≥29 mm requiring a 34- to 36-mm-diameter endograft is independently associated with an increased rate of proximal fixation failure. This group of patients should be considered for more proximal seal strategies with fenestrated or branched devices vs open repair. Also, this group likely needs more stringent radiographic follow-up.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

BACKGROUND: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. RESULTS: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.