2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Factors associated with 90-day reintervention following lower extremity revascularization.

OBJECTIVE: Peripheral artery disease (PAD) represents a high-volume, high-cost burden on the health care system. The Centers for Medicare and Medicaid Services has developed the Bundled Payments for Care Improvement-Advanced program, in which a single payment is provided for all services administered in a postsurgical 90-day episode of care. Factors associated with 30- and 90-day reinterventions after PAD interventions would represent useful data for both payors and stake holders. METHODS: We conducted a national cohort study of adults 65 years and older in the Vascular Quality Initiative and Centers for Medicare and Medicaid Services-linked dataset who underwent an open, endovascular, or hybrid revascularization procedure for PAD between January 1, 2010, and December 31, 2018. Procedures for acute limb ischemia and aneurysms were excluded. The primary outcome was 90-day reintervention. Reintervention at 30 days was a secondary outcome. Covariates of interest included demographics, comorbidities, and patient- and facility-level characteristics. Multivariable Cox regression was used to determine the association between patient- and facility-level characteristics and the risk of 30- and 90-day reinterventions. RESULTS: Among 42,429 patients (71.3% endovascular, 23.3% open, and 5.4% hybrid), median age was 74 years (interquartile range, 69-80 years), 57.9% were male, and 84.3% were White. Chronic limb-threatening ischemia was the operative indication in 40.4% of the procedures. Overall, 42.8% were completed in the outpatient setting (40.3% outpatient, 2.5% office-based lab). Over 70% of procedures for chronic limb-threatening ischemia were completed as inpatient, whereas 60% of the claudication interventions were done as outpatient. The 90-day reintervention rate was 14.5%, and the 30-day reintervention rate was 5.5%. Compared with inpatient procedures, PAD interventions completed in the outpatient or office-based lab setting had significantly higher 90- and 30-day reintervention rates (reference, inpatient; outpatient 90-day reintervention: hazard ratio [HR], 1.41; 95% confidence interval [CI] 1.25-1.60; outpatient 30-day reintervention: HR, 1.90; 95% CI, 1.62-2.24; office-based lab 90-day reintervention: HR, 2.09; 95% CI, 1.82-2.41; office-based lab 30-day reintervention: HR, 3.54; 95% CI, 3.17-3.94). Open and hybrid approaches demonstrated lower risk of reintervention compared with endovascular procedures at 30 and 90 days and, compared with aortoiliac disease, all other anatomic segments of disease were associated with higher 90-day reintervention, but no difference was noted at 30 days. CONCLUSIONS: Although outpatient PAD interventions may be convenient for patients and providers, the outpatient setting is associated with a significant risk of subsequent reintervention. Additional work is needed to understand how to improve the longevity of outpatient PAD interventions.

Prosthetic fitting and mortality after major lower extremity amputation.

BACKGROUND: Studies suggest that ambulation after major lower extremity amputation (LEA) is low and mortality after LEA is high. Successful prosthetic fitting after LEA has a significant quality of life benefit; however, it is unclear if there are benefits in post-LEA mortality. Our objective was to examine a contemporary cohort of patients who underwent LEA and determine if there is an association between fitting for a prosthetic and mortality. METHODS: We reviewed all patients who underwent LEA between 2015 and 2022 at two academic health care systems in a large metropolitan city. The exposure of interest was prosthetic fitting after LEA. The primary outcomes were mortality within 1 and 3 years of follow-up. Ambulation after LEA was defined as being ambulatory with or without an assistive device. Patients with prior LEA were excluded. Extended Cox models with time-dependent exposure were used to evaluate the association between prosthetic fitting and mortality at 1 and 3 years of follow-up. RESULTS: Among 702 patients who underwent LEA, the mean (SD) age was 64.3 (12.6) years and 329 (46.6%) were fitted for prosthetic. The study population was mostly male (n = 488, 69.5%), predominantly non-Hispanic Black (n = 410, 58.4%), and nearly one-fifth were non-ambulatory before LEA (n = 139 [19.8%]). Of note, 14.3% of all subjects who were nonambulatory at some point after LEA, and 28.5% of patients not ambulatory preoperatively were eventually ambulatory after LEA. The rate of death among those fitted for a prosthetic was 12.0/100 person-years at 1 year and 5.8/100 person-years at 3 years of follow-up; among those not fitted for a prosthetic, the rate of death was 55.7/100 person-years and 50.7/100 person-years at 1 and 3 years of follow-up, respectively. After adjusting for several sociodemographic data points, comorbidities, pre- or post- coronavirus disease 2019 pandemic timeframe, and procedural factors, prosthetic fitting is associated with decreased likelihood of mortality within 1 year of follow-up (adjusted hazard ratio, 0.24; 95% confidence interval, 0.14-0.40) as well as within 3 years (adjusted hazard ratio, 0.40; 95% confidence interval, 0.29-0.55). CONCLUSIONS: Prosthetic fitting is associated with improved survival, and preoperative functional status does not always predict postoperative functional status. Characterizing patient, surgical, and rehabilitation factors associated with receipt of prosthetic after LEA may improve long-term survival in these patients. Process measures employed by the Department of Veterans Affairs, such as prosthetic department evaluation of all amputees, may represent a best practice.

Search Engines to Capture Missing Deaths From Institutional Data Warehouse.

INTRODUCTION: Clinical publications use mortality as a hard end point. It is unknown how many patient deaths are under-reported in institutional databases. The objective of this study was to query mortality in our patient cohort from our data warehouse and compare these deaths to those identified in different databases. METHODS: We passed the first/last name and date of birth of 134 patients through online mortality search engines (Find a Grave Index, US Cemetery and Funeral Home Collection, etc.) to assess their ability to capture patient deaths and compared that to deaths recorded from our institutional data warehouse. RESULTS: Our institutional data warehouse found approximately one-third of the total patient mortalities. After the Social Security Death Index, we found that the Find a Grave Index captured the most mortalities missed by the institutional data warehouse. These results highlight the advantages of incorporating readily available search engines into institutional data warehouses for the accurate collection of patient mortalities, particularly those that occur outside of index operative admission. CONCLUSIONS: The incorporation of the mortality search engines significantly augmented the capture of patient deaths. Our approach may be useful for tailored patient outreach and reporting mortalities with institutional data.

Association between readmission care fragmentation and outcomes after interventions for peripheral arterial disease.

OBJECTIVE: Lower extremity revascularization (LER) for peripheral artery disease is complicated by the frequent need for readmission. However, it is unclear if readmission to a nonindex LER facility (ie, a facility different from the one where the LER was performed) compared with the index LER facility is associated with worse outcomes. METHODS: This was a national cohort study of older adults who underwent open, endovascular, or hybrid LER for peripheral artery disease (January 1, 2010, to December 31, 2018) in the Vascular Quality Initiative who were readmitted within 90 days of their vascular procedure. This dataset was linked to Medicare claims and the American Hospital Association Annual Survey. The primary outcome was 90-day mortality and the secondary outcome was major amputation at 90 days after LER. The primary exposure was the location of the first readmission after LER (categorized as occurring at the index LER facility vs a nonindex LER facility). Generalized estimating equations logistic regression models were used to assess the association between readmission location and 90-day mortality and amputation. RESULTS: Among 42,429 patients who underwent LER, 33.0% were readmitted within 90 days. Of those who were readmitted, 27.3% were readmitted to a nonindex LER facility, and 42.2% of all readmissions were associated with procedure-related complications. Compared with patients readmitted to the index LER facility, those readmitted to a nonindex facility had a lower proportion of procedure-related reasons for readmission (21.5% vs 50.1%; P < .001). Most of the patients readmitted to a nonindex LER facility lived further than 31 miles from the index LER facility (39.2% vs 19.6%; P < .001) and were readmitted to a facility with a total bed size of <250 (60.1% vs 11.9%; P < .001). Readmission to a nonindex LER facility was not associated with 90-day mortality or 90-day amputation. However, readmission for a procedure-related complication was associated with major amputation (90-day amputation: adjusted odds ratio, 3.33; 95% confidence interval, 2.89-3.82). CONCLUSIONS: Readmission after LER for a procedure-related complication is associated with subsequent amputation. This finding suggests that quality improvement efforts should focus on understanding various types of procedure-related failure after LER and its role in limb salvage.

Evaluation of Lower Extremity Calcium Score as a Measure of Peripheral Arterial Disease Burden and Amputation Risk.

BACKGROUND: The ankle-brachial pressure index (ABI) and toe-brachial pressure index (TBI) are commonly used diagnostic tools for peripheral artery disease (PAD) that are unreliable in the presence of calcified vessels. In this study, we aimed to demonstrate the utility of the lower extremity calcium score (LECS) in addition to ABI and TBI in measuring disease burden and predicting the risk of amputation in patients with PAD. METHODS: Patients who were evaluated in the vascular surgery clinic at Emory University for PAD and who underwent noncontrast computed tomography of the aorta and lower extremities were included in the study. Aortoiliac, femoral-popliteal, and tibial calcium scores were measured using the Agatston method. ABI and TBI that were obtained within 6 months of the computed tomography scan were noted and divided into categories of PAD severity. Associations between ABI, TBI, and LECS of each anatomic segment were evaluated. Univariate and multivariate ordinal regression analyses were performed to predict the outcome of amputation. Receiver operating characteristic analysis was performed to compare LECS with other variables in its ability to predict amputation. RESULTS: Fifty patients included in the study cohort were divided into LECS quartiles, with 12-13 patients in each quartile. The highest quartile tended to be older (P = 0.016), had a higher percentage of diabetics (P = 0.034), and had a higher frequency of major amputations (P = 0.004) compared to the other quartiles. Patients in the highest quartile of tibial calcium score were more likely to have stage 3 chronic kidney disease (CKD) or greater (P = 0.011) and also had a higher frequency of amputation (P < 0.005) and mortality (P = 0.041). We found no significant association between each anatomic LECS and ABI/TBI categories. On univariate analysis, CKD (Odds Ratio [OR] 12.92 (95% CI 2.01 to 82.83), P = 0.007), diabetes mellitus (OR 5.47 (95% CI 1.27 to 23.64), P = 0.023), tibial calcium score (OR 6.62 (95% CI 1.79 to 24.54), P = 0.005), and total bilateral calcium score (OR 6.32 (95% CI 1.18 to 33.78), P = 0.031) were associated with increased risk of amputation. On multivariate stepwise ordinal regression, TBI and tibial calcium score were identified as important predictors of amputation, with hyperlipidemia and CKD increasing the overall prediction of the model. On Receiver operating characteristic analysis, the addition of the tibial calcium score (area under the curve 0.94, standard error 0.048) significantly improved the prediction of amputation compared to hyperlipidemia, CKD, and TBI alone (area under the curve 0.82, standard error 0.071, P = 0.022). CONCLUSIONS: The addition of tibial calcium score to other known PAD risk factors may improve the prediction of amputation in patients with PAD.

A 22-year analysis of the Society for Vascular Surgery Foundation Mentored Research Career Development Award in fostering vascular surgeon-scientists.

OBJECTIVE: Vascular surgeon-scientists shape the future of our specialty through rigorous scientific investigation and innovation in clinical care and by training the next generation of surgeon-scientists. The Society for Vascular Surgery Foundation (SVSF) supports the development of surgeon-scientists through the Mentored Research Career Development Award (SVSF-CDA) program, providing supplemental funds to recipients of National Institutes of Health (NIH) K08/K23 grants. We evaluated the ongoing success of this mission. METHODS: The curriculum vitae of the 41 recipients of the SVSF supplemental funding from 1999 to 2021 were collected and reviewed to evaluate the academic achievements, define the programmatic accomplishments and return on investment, and identify areas for strategic improvement. RESULTS: For nearly 22 years, the SVSF has awarded supplemental funds for 31 K08 and 10 K23 grants to SVS members from 32 institutions. Of the 41 awardees, 34 have completed their K-funding and 7 are still being supported. Eleven awardees (27%) were women, including six of the current awardees (75%). However, only slight ethnic/racial diversity was found in the program. The awardees had obtained K-funding ∼4 years after becoming faculty. Eleven awardees (27%) were supported by Howard Hughes, NIH F32, or NIH T32 grants during training. To date, the SVSF has committed $12 million to the SVSF-CDA program. Among the 34 who have completed their K-funding, 21 (62%) successfully obtained NIH R01, Veterans Affairs, or Department of Defense funding. The awardees have secured >$114 million in federal funding, representing a 9.5-fold financial return on investment for the SVSF. In addition to research endeavors, 11 awardees (27%) hold endowed professorships and 19 (46%) have secured tenure at their institution. Many of the awardees hold or have held leadership positions, including 18 division chiefs (44%), 11 program directors (27%), 5 chairs of departments of surgery (12%), and 1 dean (2%). Eleven (27%) have served as president of a regional or national society, and 24 (59%) participate in NIH study sections. Of the 34 who have completed their K-funding, 15 (44%) have continued to maintain active independent research funding. CONCLUSIONS: The SVSF-CDA program is highly effective in the development of vascular surgeon-scientists who contribute to the leadership and growth of academic vascular surgery with a 9.5-fold return on investment. The number of female awardees has increased in recent years but ethnic/racial diversity has remained poor. Although 62% successfully transitioned to federal funding, fewer than one half have remained funded over time. Retention in research and increasing diversity for the awardees are major concerns and important areas of strategic focus for the SVSF.

Updated research priorities of the Society for Vascular Surgery.

In 2011, the Society for Vascular Surgery (SVS) prepared a set of clinical research priorities through a survey of its membership. These priorities were developed with the goal of enhancing clinical research to improve care for vascular patients. In the subsequent decade, several of these priorities served as the focus of clinical trials and significant research efforts. It was understood from the outset that this list of priorities represented a starting point with the intention that they be reevaluated at suitable intervals. In 2021, the SVS Research Council set out to update the research priorities by surveying the SVS membership and engaged a panel of subject matter experts. This process resulted in an updated set of vascular research priorities that more clearly align with current areas of emphasis. Our priorities remain focused on basic areas including aortic disease, carotid disease, lower extremity arterial disease, venous disease, dialysis access, and medical management of vascular disease, along with the topic of health care disparities. The 10 updated priorities reported herein reflect our increasing awareness of the need to understand vascular disease pathogenesis and prevention in the context of a diverse patient population. Importantly, patient-centered outcomes and personalized vascular care are at the core of these updated priorities. Similar to the aims of the original 2011 clinical research priorities, our hope is that this updated list will help to drive large-scale investigations that will improve how we care for our vascular patients.

Perfusion Assessment in Critical Limb Ischemia: Principles for Understanding and the Development of Evidence and Evaluation of Devices: A Scientific Statement From the American Heart Association.

There are >12 million patients with peripheral artery disease in the United States. The most severe form of peripheral artery disease is critical limb ischemia (CLI). The diagnosis and management of CLI is often challenging. Ethnic differences in comorbidities and presentation of CLI exist. Compared with white patients, black and Hispanic patients have higher prevalence rates of diabetes mellitus and chronic renal disease and are more likely to present with gangrene, whereas white patients are more likely to present with ulcers and rest pain. A thorough evaluation of limb perfusion is important in the diagnosis of CLI because it can not only enable timely diagnosis but also reduce unnecessary invasive procedures in patients with adequate blood flow or among those with other causes for ulcers, including venous, neuropathic, or pressure changes. This scientific statement discusses the current tests and technologies for noninvasive assessment of limb perfusion, including the ankle-brachial index, toe-brachial index, and other perfusion technologies. In addition, limitations of the current technologies along with opportunities for improvement, research, and reducing disparities in health care for patients with CLI are discussed.

Association of Statin Dose With Amputation and Survival in Patients With Peripheral Artery Disease.

BACKGROUND: Statin dose guidelines for patients with peripheral artery disease (PAD) are largely based on coronary artery disease and stroke data. The aim of this study is to determine the effect of statin intensity on PAD outcomes of amputation and mortality. METHODS: Using an observational cohort study design and a validated algorithm, we identified patients with incident PAD (2003-2014) in the national Veterans Affairs data. Highest statin intensity exposure (high-intensity versus low-to-moderate-intensity versus antiplatelet therapy but no statin use) was determined within 1 year of diagnosis of PAD. Outcomes of interest were lower extremity amputations and death. The association of statin intensity with incident amputation and mortality was assessed with Kaplan-Meier plots, Cox proportional hazards modeling, propensity score-matched analysis, and sensitivity and subgroup analyses, as well, to reduce confounding. RESULTS: In 155 647 patients with incident PAD, more than a quarter (28%) were not on statins. Use of high-intensity statins was lowest in patients with PAD only (6.4%) in comparison with comorbid coronary/carotid disease (18.4%). Incident amputation and mortality risk declined significantly with any statin use in comparison with the antiplatelet therapy-only group. In adjusted Cox models, the high-intensity statin users were associated with lower amputation risk and mortality in comparison with antiplatelet therapy-only users (hazard ratio, 0.67; 95% confidence interval, 0.61-0.74 and hazard ratio, 0.74; 95% confidence interval, 0.70-0.77, respectively). Low-to-moderate-intensity statins also had significant reductions in the risk of amputation and mortality (hazard ratio amputation, 0.81; 95% confidence interval, 0.75- 0.86; hazard ratio death, 0.83; 95% confidence interval, 0.81-0.86) in comparison with no statins (antiplatelet therapy only), but effect size was significantly weaker than the high-intensity statins (P<0.001). The association of high-intensity statins with lower amputation and death risk remained significant and robust in propensity score-matched, sensitivity, and subgroup analyses. CONCLUSIONS: Statins, especially high-intensity formulations, are underused in patients with PAD. This is the first population-based study to show that high-intensity statin use at the time of PAD diagnosis is associated with a significant reduction in limb loss and mortality in comparison with low-to-moderate-intensity statin users, and patients treated only with antiplatelet medications but not with statins, as well.

Poor glycemic control is a strong predictor of postoperative morbidity and mortality in patients undergoing vascular surgery.

OBJECTIVE: Hyperglycemia is a common occurrence in patients undergoing cardiovascular surgery. It has been identified in several surgical cohorts that improved perioperative glycemic control reduced postoperative morbidity and mortality. A significant portion of the population with peripheral arterial disease suffers from the sequelae of diabetes or metabolic syndrome. A paucity of data exists regarding the relationship between perioperative glycemic control and postoperative outcomes in vascular surgery patients. The objective of this study was to better understand this relationship and to determine which negative perioperative outcomes could be abated with improved glycemic control. METHODS: This is a retrospective review of a vascular patient database at a large academic center from 2009 to 2013. Eligible procedures included carotid endarterectomy and stenting, endovascular and open aortic aneurysm repair, and all open bypass revascularization procedures. Data collected included standard demographics, outcome parameters, and glucose levels in the perioperative period. Perioperative hyperglycemia was defined as at least one glucose value >180 mg/dL within 72 hours of surgery. The primary outcome was 30-day mortality, with secondary outcomes of complications, need to return to the operating room, and readmission. RESULTS: Of the total 1051 patients reviewed, 366 (34.8%) were found to have perioperative hyperglycemia. Hyperglycemic patients had a higher 30-day mortality (5.7% vs 0.7%; P < .01) and increased rates of acute renal failure (4.9% vs 0.9%; P < .01), postoperative stroke (3.0% vs 0.7%; P < .01), and surgical site infections (5.7% vs 2.6%; P = .01). In addition, these patients were also more likely to undergo readmission (12.3% vs 7.9%; P = .02) and reoperation (6.3% vs 1.8%; P < .01). Furthermore, multivariable logistic regression demonstrated that perioperative hyperglycemia had a strong association with increased 30-day mortality and multiple negative postoperative outcomes, including myocardial infarction, stroke, renal failure, and wound complications. CONCLUSIONS: This study demonstrates a strong association between perioperative glucose control and 30-day mortality in addition to multiple other postoperative outcomes after vascular surgery.

Image-Guided Transarterial Directed Delivery of Human Mesenchymal Stem Cells for Targeted Gastrointestinal Therapies in a Swine Model.

PURPOSE: To evaluate the feasibility of catheter-directed intra-arterial stem cell delivery of human mesenchymal stem cells (MSCs) to the small bowel in a porcine model. MATERIALS AND METHODS: The cranial mesenteric artery of 6 Yucatan minipigs was selectively catheterized under fluoroscopic guidance following cut-down and carotid artery access. A proximal jejunal branch artery was selectively catheterized for directed delivery of embolic microspheres (100-300 µm) or MSCs (0.1-10 million cells). The pigs were euthanized after 4 hours and specimens collected from the proximal duodenum and the targeted segment of the jejunum. The Chiu/Park system for scoring intestinal ischemia was used to compare hematoxylin and eosin-stained sections of jejunum and duodenum. RESULTS: Successful delivery of microspheres or MSCs in a proximal jejunal branch artery of the cranial mesenteric artery was achieved in all subjects. Radiopaque microspheres and post-delivery angiographic evidence of stasis in the targeted vessels were observed on fluoroscopy after delivery of embolics. Preserved blood flow was observed after MSC delivery in the targeted vessel. The Chiu/Park score for intestinal ischemia in the targeted proximal jejunal segments were similar for microspheres (4, 4; n = 2) and MSCs (4, 4, 4, 3; n = 4), indicating moderate ischemic effects that were greater than for control duodenal tissue (3, 1; 0, 0, 3, 3). CONCLUSIONS: Selective arteriographic deployment of MSCs in swine is feasible for study of directed intestinal stem cell delivery. In this study, directed therapy resulted in intestinal ischemia.

Outcomes and Durability of Endovascular Aneurysm Repair in Octogenarians.

BACKGROUND: Endovascular aneurysm repair (EVAR) accounts for the majority of all abdominal aortic aneurysm (AAA) repairs in the United States. EVAR utilization in the aging population is increasing due to the minimally invasive nature of the procedure, the low associated perioperative morbidity, and early survival benefit over open repair. The objective of this study is to compare the outcomes of octogenarians after elective EVAR to their younger counterparts, a question that can be answered by a long-term, institutional data set. METHODS: This was a retrospective series of 255 patients, who underwent elective EVAR within our institution from 2008 to 2015. A comparative analysis of patients aged 80 years and older and less than 80 years was performed. Outcomes measured included perioperative death and myocardial infarction (MI), length of stay, and readmission within 30 days. Aneurysm reintervention, long-term surveillance imaging, and aneurysm-related deaths were also evaluated. In addition, subset analyses of octogenarians were compared for survival at 24 months. RESULTS: Overall, 255 patients were included in our analysis. Fifty-nine patients were octogenarians, and 196 patients were nonoctogenarians. The mean age difference between the two groups was significant (84.5 years [SD, ±3.44] vs. 69.6 years [SD, ±6.13] in the ≥80 and <80 groups, respectively; P < 0.0001). There was no significant difference in the mean aneurysm size (6.03 cm [SD, ±1.12] vs. 5.535 cm [SD, ±0.9]; P < 0.06) between the ≥80 and < 80 groups. Octogenarians had higher rates of perioperative MI (5% vs. 1%, P < 0.04), thirty-day mortality (7% vs. 0%, P < 0.003), a higher number of perioperative complications (0.64 incidence per patient [SD, ±1.11] vs. 0.31 [SD, ±0.69], P < 0.005), and a longer mean hospital stay (5.34 [SD, ±5.75] days vs. 3.16 [SD, ±3.23] days, P < 0.0003), and they were also less likely to be discharged home after surgery (75% vs. 91%, P < 0.002). In the evaluated long-term outcomes, the two groups were similar with regard to aneurysm reintervention (10% vs. 9%, P < 0.06) and the stability of aneurysm sac size on imaging at last follow-up (71% vs. 80%, P < 0.27). The overall aortic related cause of death was different between the groups (8% vs. 1%, P < 0.003); however, the long-term aortic related mortality was not different between the two groups (2% vs. 1%, P < 0.4). Finally, a subset analysis of the octogenarian group was performed comparing patients based on survival status at 24 months. Higher preoperative creatinine (1.73 mg/dL [SD, ±1.54] vs. 1.15 mg/dL [SD, ±0.46]) and lower preoperative hematocrit (33.9% [SD, ±3.43] vs. 37.2% [SD, ±4.9]) along with number of perioperative complications (1.2 incidence per patient [SD, ±1.74] vs. 0.45 [SD, ±0.73]) were associated with death at 24 months after the index operation. CONCLUSIONS: Elective endovascular repair of AAA in octogenarians carries a higher risk of perioperative mortality but acceptable long-term outcomes. Appropriateness of elective EVAR in octogenarians should be answered based on this potential short-lived survival benefit, taking into account that advanced age should not be the sole basis of exclusion for otherwise suitable candidates for elective EVAR.

Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1.

BACKGROUND: Arterial stiffness and wall shear stress are powerful determinants of cardiovascular health, and arterial stiffness is associated with increased cardiovascular mortality. Low and oscillatory wall shear stress, termed disturbed flow (d-flow), promotes atherosclerotic arterial remodeling, but the relationship between d-flow and arterial stiffness is not well understood. The objective of this study was to define the role of d-flow on arterial stiffening and discover the relevant signaling pathways by which d-flow stiffens arteries. METHODS: D-flow was induced in the carotid arteries of young and old mice of both sexes. Arterial stiffness was quantified ex vivo with cylindrical biaxial mechanical testing and in vivo from duplex ultrasound and compared with unmanipulated carotid arteries from 80-week-old mice. Gene expression and pathway analysis was performed on endothelial cell-enriched RNA and validated by immunohistochemistry. In vitro testing of signaling pathways was performed under oscillatory and laminar wall shear stress conditions. Human arteries from regions of d-flow and stable flow were tested ex vivo to validate critical results from the animal model. RESULTS: D-flow induced arterial stiffening through collagen deposition after partial carotid ligation, and the degree of stiffening was similar to that of unmanipulated carotid arteries from 80-week-old mice. Intimal gene pathway analyses identified transforming growth factor-ß pathways as having a prominent role in this stiffened arterial response, but this was attributable to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to transforming growth factor-ß. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of transforming growth factor-ß in the upregulation of these genes. TSP-1 knockout animals had significantly less arterial stiffening in response to d-flow than wild-type carotid arteries. Human arteries exposed to d-flow had similar increases TSP-1 and collagen gene expression as seen in our model. CONCLUSIONS: TSP-1 has a critical role in shear-mediated arterial stiffening that is mediated in part through TSP-1's activation of the profibrotic signaling pathways of transforming growth factor-ß. Molecular targets in this pathway may lead to novel therapies to limit arterial stiffening and the progression of disease in arteries exposed to d-flow.

Reversible secretome and signaling defects in diabetic mesenchymal stem cells from peripheral arterial disease patients.

OBJECTIVE: Regenerative medicine seeks to stall or to reverse the pathologic consequences of chronic diseases. Many people with diabetes have peripheral arterial disease (PAD), which increases their already high risk of major amputation. Cellular therapies are a promising regenerative medicine approach to PAD that can be used to focally inject regenerative cells to endangered tissue beds. Mesenchymal stem cells (MSCs) are known to promote tissue regeneration through stromal support and paracrine stimulation of new blood vessels (angiogenesis). Whereas little is known about human diabetic MSCs (dMSCs), particularly those from patients with PAD, dMSCs have a limited expansion capacity but can be improved with human platelet lysate (PL) supplementation. PL is rich in many growth factors, including epidermal growth factor (EGF), which is known to be important to cell proliferation and survival signaling pathways. We hypothesize that dMSCs have a reversible defect in EGF receptor pathways. The objective of this work was to test this hypothesis using dMSCs from PAD patients. METHODS: The secretome expression of EGF and prominent angiogens was characterized from bone marrow (BM)-derived and adipose tissue-derived (ATD) dMSCs from five patients (six limbs) undergoing major amputation. Western blot was used to characterize the AKT and extracellular signal-regulated protein kinases 1 and 2 expression in dMSCs under standard culture (5% fetal bovine serum plus fibroblast growth factor 2 [FGF2]), 5% human PL, or 5% fetal bovine serum plus EGF. Healthy donor MSCs were control cells. The angiogenic activity of BM- and ATD-dMSCs was tested on human umbilical vein endothelial cells (ECs). Paired t-test, analysis of variance, and Kruskal-Wallis tests were used as appropriate. RESULTS: Both BM- and ATD-dMSCs had typical MSC surface marker expression and similar expansion profiles, and they did not express EGF in their secretome. PL supplementation of dMSCs improved AKT signaling, but they were resistant to FGF2 activation of extracellular signal-regulated protein kinases 1 and 2. EGF supplementation led to similar AKT expression as with PL, but PL had greater phosphorylation of AKT at 30 and 60 minutes. The conditioned media from both BM- and ATD-dMSCs had robust levels of prominent angiogens (vascular endothelial growth factor, monocyte chemoattractant protein 1, hepatocyte growth factor), which stimulated EC proliferation and migration, and the co-culture of dMSCs with ECs led to significantly longer EC sprouts in three-dimensional gel than EC-alone pellets. CONCLUSIONS: PL and EGF supplementation improves AKT expression in dMSCs over that of FGF2, but PL improved pAKT over that of EGF. Thus, PL supplementation strategies may improve AKT signaling, which could be important to MSC survival in cellular therapies. Furthermore, BM- and ATD-dMSCs have similar secretomes and robust in vitro angiogenic activity, which supports pursuing dMSCs from both reservoirs in regenerative medicine strategies.

High hemoglobin A1c associated with increased adverse limb events in peripheral arterial disease patients undergoing revascularization.

OBJECTIVE: Diabetes and peripheral arterial disease (PAD) are independently associated with increased risk of amputation. However, the effect of poor glycemic control on adverse limb events has not been studied. We examined the effects of poor glycemic control (high hemoglobin A1c level) on the risk of amputation and modified major adverse limb events (mMALEs) after lower extremity revascularization. METHODS: Patients undergoing PAD revascularization who had hemoglobin A1c (HbA1c) levels available within 6 months were identified in the Veterans Affairs database of 2003 to 2014 (N = 26,799). The diagnosis of preoperative diabetes mellitus (PreopDM) was defined using diabetes diagnosis codes and evidence of treatment. Amputation and mMALE risk was compared for HbA1c levels using Kaplan-Meier analysis. Cox proportional hazards models were created to assess the effect of high HbA1c levels on amputation and mMALE (adjusted for age, gender, race, socioeconomic status, comorbidities, cholesterol levels, creatinine concentration, suprainguinal or infrainguinal procedure, open or endovascular procedure, severity of PAD, year of cohort entry, and medications) for all patients and stratified by PreopDM. RESULTS: High HbA1c levels were present in 33.2% of the cohort, whereas 59.9% had PreopDM. Amputations occurred in 4359 (16.3%) patients, and 10,580 (39.5%) had mMALE. Kaplan-Meier curves showed the worst outcomes in patient with PreopDM and high HbA1c levels. In the Cox model, incremental HbA1c levels of 6.1% to 7.0%, 7.1% to 8.0%, and >8% were associated with 26% (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.15-1.39), 53% (HR, 1.53; 95% CI, 1.37-1.7), and 105% (HR, 2.05; 95% CI, 1.87-2.26) higher risk of amputation, respectively. Similarly, the risk of mMALE also increased by 5% (HR, 1.05; 95% CI, 0.99-1.11), 21% (HR, 1.21; 95% CI, 1.13-1.29), and 33% (HR, 1.33, 95% CI, 1.25-1.42) with worsening HbA1c levels of 6.1% to 7.0%, 7.1% to 8.0%, and >8%, respectively (vs HbA1c ≤6.0%). In stratified analysis by established PreopDM, the relative risk of amputation or mMALE was much higher with poor glycemic control (HbA1c >7.0%) in patients without PreopDM. CONCLUSIONS: PAD patients with worse perioperative glycemic control have a significantly higher risk of amputation and mMALE. Incremental increases in HbA1c levels are associated with higher hazards of adverse limb outcomes independent of PreopDM status. Poor glycemic control (HbA1c >7.0%) in patients without a PreopDM diagnosis carries twice the relative risk of amputation and mMALE than in those with good glycemic control. These results suggest that screening of diabetic status and better management of glycemic control could be a target for improvement of perioperative and long-term outcomes in PAD patients.

Expansion and angiogenic potential of mesenchymal stem cells from patients with critical limb ischemia.

BACKGROUND: Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1% to 10% of the population with peripheral arterial disease. Traditional revascularization options are not possible for up to 50% of CLI patients, in which case, the use of cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs), hold great promise as an alternative revascularization therapy. However, no randomized, controlled phase 3 trials to date have demonstrated an improvement in limb salvage with cellular therapies. This may be due to poor cell quality (ie, inability to generate a sufficient number of angiogenic MSCs) or to the inadequate retention and viability of MSCs after delivery, or both. Because concerns remain about the expansion and angiogenic potential of autologous MSCs in the CLI population, the objective of this study was to examine the effect of our novel culture media supplement, pooled human platelet lysate (PL), in lieu of the standard fetal bovine serum (FBS), to improve the expansion potential of MSCs from CLI patients. We also characterized the in vitro angiogenic activity of MSCs from the tibia of amputated CLI limbs compared with MSCs from healthy donors. METHODS: MSCs were obtained from the tibia of four CLI patients (ISC) and four ISC patients with diabetes mellitus (ISC+DM) undergoing major amputation. Healthy MSCs were aspirated from the iliac crest of four young and healthy donors. MSCs were isolated and expanded in culture with PL or FBS. MSCs from passage 3 to 6 were used for phenotypic marker expression and for adipogenic and osteogenic differentiation and were tested for their in vitro angiogenic activity on human microdermal endothelial cells. In parallel MSCs were cultured to passage 11 for population-doubling calculations. RESULTS: MSCs from ISC and ISC+DM patients and from healthy patients exhibited appropriate expression of cell surface markers and differentiation capacity. Population doublings were significantly greater for PL-stimulated compared with FBS-stimulated MSCs in all groups. Biologically active amounts of angiogens were identified in the secretome of all MSCs without consistent trends among groups. PL expansion did not adversely affect the angiogenic activity of MSCs compared with FBS. The ISC and ISC+DM MSCs demonstrated angiogenic effects on endothelial cells similar to those of healthy and ISC MSCs. CONCLUSIONS: PL promotes the rapid expansion of MSCs from CLI and healthy persons. Importantly, MSCs expanded from CLI patients demonstrate the desired angiogenic activity compared with their healthy counterparts. We conclude that autologous MSCs from CLI patients can be sufficiently expanded with PL and be expected to deliver requisite angiogenic effects in vivo. We expect the improved expansion of ISC and ISC+DM with PL to be helpful in improving the successful delivery of autologous MSCs to patients with CLI.

An endovascular model of ischemic myopathy from peripheral arterial disease.

OBJECTIVE: Peripheral arterial disease (PAD) is a significant age-related medical condition with limited pharmacologic options. Severe PAD, termed critical limb ischemia, can lead to amputation. Skeletal muscle is the end organ most affected by PAD, leading to ischemic myopathy and debility of the patient. Currently, there are not any therapeutics to treat ischemic myopathy, and proposed biologic agents have not been optimized owing to a lack of preclinical models of PAD. Because a large animal model of ischemic myopathy may be useful in defining the optimal dosing and delivery regimens, the objective was to create and to characterize a swine model of ischemic myopathy that mimics patients with severe PAD. METHODS: Yorkshire swine (N = 8) underwent acute right hindlimb ischemia by endovascular occlusion of the external iliac artery. The effect of ischemia on limb function, perfusion, and degree of ischemic myopathy was quantified by weekly gait analysis, arteriography, hindlimb blood pressures, femoral artery duplex ultrasound scans, and histologic examination. Animals were terminated at 5 (n = 5) and 6 (n = 3) weeks postoperatively. Ossabaw swine (N = 8) fed a high-fat diet were used as a model of metabolic syndrome for comparison of arteriogenic recovery and validation of ischemic myopathy. RESULTS: There was persistent ischemia in the right hindlimb, and occlusion pressures were significantly depressed compared with the untreated left hindlimb out to 6 weeks (systolic blood pressure, 31 ± 21 vs 83 ± 15 mm Hg, respectively; P = .0007). The blood pressure reduction resulted in a significant increase of ischemic myopathy in the gastrocnemius muscle in the treated limb. Gait analysis revealed a functional deficit of the right hindlimb immediately after occlusion that improved rapidly during the first 2 weeks. Peak systolic velocity values in the right common femoral artery were severely diminished throughout the entire study (P < .001), and the hemodynamic environment after occlusion was characterized by low and oscillatory wall shear stress. Finally, the internal iliac artery on the side of the ischemic limb underwent significant arteriogenic remodeling (1.8× baseline) in the Yorkshire but not in the Ossabaw swine model. CONCLUSIONS: This model uses endovascular technology to produce the first durable large animal model of ischemic myopathy. Acutely (first 2 weeks), this model is associated with impaired gait but no tissue loss. Chronically (2-6 weeks), this model delivers persistent ischemia, resulting in ischemic myopathy similar to that seen in PAD patients. This model may be of use for testing novel therapeutics including biologic therapies for promoting neovascularization and arteriogenesis.

Percutaneous Image-Guided Cryoablation for the Treatment of Phantom Limb Pain in Amputees: A Pilot Study.

PURPOSE: To prospectively evaluate percutaneous image-guided nerve cryoablation for treatment of refractory phantom limb pain (PLP) in a pilot cohort for purposes of deriving parameters to design a larger, randomized, parallel-armed, controlled trial. MATERIALS AND METHODS: From January 2015 to January 2016, 21 patients with refractory PLP underwent image-guided percutaneous cryoneurolysis procedures. Visual analog scale scores were documented at baseline and 7, 45, and 180 days after the procedure. Responses to a modified Roland Morris Disability Questionnaire were documented at baseline and 7 and 45 days after the procedure. RESULTS: Technical success rate of the procedures was 100%. There were 6 (29%) minor procedure-related complications. Disability scores decreased from a baseline mean of 11.3 to 3.3 at 45-day follow-up (95% confidence interval 5.8, 10.3; P < .0001). Pain intensity scores decreased from a baseline mean of 6.2 to 2.0 at long-term follow-up (95% confidence interval 2.8, 5.6; P < .0001). CONCLUSIONS: Image-guided percutaneous nerve cryoablation is feasible and safe and may represent a new efficacious therapeutic option for patients with phantom pains related to limb loss.