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A bidirectional approach is necessary for treating critical limb ischemia with complex, multiple lesions. We report an ultrasound-guided bidirectional puncture through an occluded vessel to treat an obstruction extending from the anterior tibial artery to the dorsal foot artery in a patient with toe gangrene and rest pain. This technique effectively restored arterial patency and is a promising approach for managing challenging critical limb ischemia occlusions.

Current assessment standards for peripheral arterial disease (PAD), such as the ankle brachial index, are limited in their utility and portability. Near-infrared spectroscopy (NIRS) has shown some promise in diagnosing PAD when used in conjunction with a provocative maneuver. The purpose of this study was to assess the viability of NIRS in conjunction with a transient leg elevation provocative maneuver for detecting severe PAD. This retrospective observational cross-sectional study assessed 57 limbs in 34 patients receiving routine vascular screening for PAD at Madigan Army Medical Center. The patient limbs were stratified into normal (n = 17), mild (n = 9), moderate (n = 16), and severe (n = 15) PAD groups based on the clinician assessments. Additionally, the patients were assessed with NIRS measurements taken with the patient in the supine position at rest and using a provocative leg raise maneuver of transient leg elevation of 45° for 60 seconds. The resting tissue oxygen saturation (StO2) and the change in StO2 (ΔStO2) from rest to elevation were recorded and compared between the PAD severity groups via independent measures analysis of variance with the Tukey honest significant difference post hoc test. The supine resting StO2 was not different between the normal (77.5% ± 7.7%), mild (72.5% ± 7.4%), moderate (72.0% ± 10.3%), and severe (74.2% ± 5.4%) PAD groups (P = .23). However, the ΔStO2 with transient leg elevation was significantly greater in the severe PAD group (−17.2% ± 6.0%) compared with the normal (−3.9% ± 4.8%), mild (−6.9% ± 4.7%), and moderate (−9.7% ± 5.2%) PAD groups (P < .002 for all). Similar results were observed in the changes in oxyhemoglobin and deoxyhemoglobin. The leg elevation protocol was also used for two patients before and after lower limb revascularization, which demonstrated that the ΔStO2 corresponded with the clinical assessment of PAD severity. Resting supine NIRS images were unable to detect any differences among normal and limbs with different PAD severity. However, NIRS imaging with 45° leg elevation for 60 seconds showed a significant difference between severe PAD compared healthy patients and those with mild to moderate PAD in a fast, precise, and accurate manner. These preliminary data support the use of NIRS and transient leg elevation as a tool to diagnose severe PAD but do not support the use of NIRS alone as a screening test for PAD. NIRS measurements with leg elevation might be a viable noninvasive, noncontact, and portable method of assessing severe PAD for home monitoring, in rural communities, and/or in standard clinical practice.

Objective: Patients with peripheral arterial disease (PAD) have a significant risk of myocardial infarction and death secondary to concomitant coronary artery disease (CAD). This is particularly true in patients with critical limb-threatening ischemia (CLTI) who exceed a 20% mortality rate at 6 months despite standard treatment with risk factor modification. Although systematic preoperative coronary testing is not recommended for patients with PAD without cardiac symptoms, the clinical manifestations of CAD are often muted in patients with CLTI due to poor mobility and activity intolerance. Thus, the true incidence and impact of “silent” CAD in a CLTI cohort is unknown. This study aims to determine the prevalence of ischemia-producing coronary artery stenosis in a CLTI cohort using coronary computed tomography angiography (cCTA) and computed tomography (CT)-derived fractional flow reserve (FFRCT), a noninvasive imaging modality that has shown significant correlation to cardiac catheterization in the detection of clinically relevant coronary ischemia. Methods: Patients presenting with newly diagnosed CLTI at our institution from May 2020 to April 2021 were screened for underlying CAD. Included subjects had no known history of CAD, no cardiac symptoms, and no anginal equivalent complaints at presentation. Patients underwent cCTA and FFRCT evaluation and were classified by the anatomic location and severity of CAD. Significant coronary ischemia was defined as FFRCT ≤0.80 distal to a >30% coronary stenosis, and severe coronary ischemia was documented at FFRCT ≤0.75, consistent with established guidelines. Results: A total of 170 patients with CLTI were screened; 65 patients (38.2%) had no coronary symptoms and met all inclusion/exclusion criteria. Twenty-four patients (31.2%) completed cCTA and FFRCT evaluation. Forty-one patients have yet to complete testing secondary to socioeconomic factors (insurance denial, transportation inaccessibility, testing availability, etc). The mean age of included subjects was 65.4 ± 7.0 years, and 15 (62.5%) were male. Patients presented with ischemic rest pain (n = 7; 29.1%), minor tissue loss (n = 14; 58.3%) or major tissue loss (n = 3; 12.5%). Significant (≥50%) coronary artery stenosis was noted on cCTA in 19 of 24 patients (79%). Significant left main coronary artery stenosis was identified in two patients (10%). When analyzed with FFRCT, 17 patients (71%) had hemodynamically significant coronary ischemia (FFRCT ≤0.8), and 54% (n = 13) had lesion-specific severe coronary ischemia (FFRCT ≤0.75). The mean FFRCT in patients with coronary ischemia was 0.70 ± 0.07. Multi-vessel disease pattern was present in 53% (n = 9) of patients with significant coronary stenosis. Conclusions: The use of cCTA-derived fractional flow reserve demonstrates a significant percentage of patients with CLTI have silent (asymptomatic) coronary ischemia. More than one-half of these patients have lesion-specific severe ischemia, which may be associated with increased mortality when treated solely with risk factor modification. cCTA and FFRCT diagnosis of significant coronary ischemia has the potential to improve cardiac care, perioperative morbidity, and long-term survival curves of patients with CLTI. Systemic improvements in access to care will be needed to allow for broad application of these imaging assessments should they prove universally valuable. Additional study is required to determine the benefit of selective coronary revascularization in patients with CLTI.

We describe the case of a 62-year-old man presenting 2 months after a reversed great saphenous vein femoropopliteal bypass performed for critical limb ischemia. He was found to have early, high-grade bypass graft stenosis on duplex ultrasound. Subsequent angiography demonstrated flow limitations secondary to two areas of retained venous valves in the proximal and mid-portions of the vein graft. The culprit valve lesions were successfully lysed endovascularly with a HawkOne (Medtronic) directional atherectomy device. This case demonstrates a safe, novel use of a directional atherectomy device for treatment of remnant valves causing hemodynamically significant flow problems in peripheral vein grafts.

Critical limb ischemia (CLI) remains a significant clinical challenge with high morbidity and mortality. Considering the critical role of hypoxia-inducible factor 1α (HIF-1α) in hypoxic site to induce angiogenesis by regulating the expression of growth factors, we prepared a cooperative composite (P-F-HKUST-1) by mixing thermo-responsive hydrogel (PPCN) with folic acid modified copper-based MOFs (F-HKUST-1) for the hindlimb ischemia therapy. The gelation of P-F-HKUST-1 in hindlimb muscle generated a more serious ischemia environment and subsequently induced the expression of HIF-1α, while the slowly released Cu2+ from P-F-HKUST-1 increased HIF-1α stability by inactivating the factor-inhibiting hypoxia-inducible factor 1 (FIH-1), which synergistically induced the productions of downstream growth factors and finally restored the blood perfusion rapidly. In addition, P-F-HKUST-1 hydrogel exhibited a long in vivo retention time, which endowed the sustaining action on HIF-1α to reduce the frequency of administration. The rapid blood flow recovery, together with the good biocompatibility suggested that P-F-HKUST-1 could be a potential novel combined therapy (HIF-1α stimulation and stabilization) for critical limb ischemia.

α-Gal syndrome (AGS) is an allergy to meat and other products derived from non-primate mammals resulting from development of IgE antibodies against the oligosaccharide galactose-α,1,3-galactose (α-Gal). Sensitivity to α-Gal is linked to tick bites, particularly bites from Amblyomma americanum (lone star tick). Recent studies demonstrate early failure of bioprosthetic valves in the setting of chronic inflammation following exposure to animal-derived surgical implants. We report a case of AGS associated with restenosis of prior bovine pericardium used for a common femoral patch angioplasty requiring reoperation.

Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disorder that can result in significant morbidity and mortality. This report details an iatrogenic aortic rupture during an endovascular approach in the management of critical limb ischemia in a 27-year-old woman who presented with acute onset of severe sensory deficit of the left leg. Conversion to open repair with a midline laparotomy and an aortic-left popliteal bypass was performed. In the endovascular era, we highlight that even minimally invasive therapeutic interventions can have devastating adverse events in patients with vascular Ehlers-Danlos syndrome.

Chronic limb-threatening ischemia in the pediatric population is a rare phenomenon. When open repair is necessitated, an autogenous conduit is preferred. However, venous grafts are prone to their own long-term complications. We have presented the case of a 10-year-old boy with chronic limb-threatening ischemia due to popliteal artery thrombosis that was treated with an ipsilateral great saphenous vein bypass. Seven years after the initial procedure, the venous graft had developed aneurysmal degeneration with acute thrombosis, necessitating bypass revision. Through the present case, we have discussed the surgical approach and highlighted the importance of long-term postoperative surveillance after open repair in the pediatric population.

Background and aims: The increasing prevalence of diabetes mellitus is causing a massive growth of peripheral artery disease incidences, a disabling complication of diabetic atherosclerosis, which leads often to the amputation of the affected limb. Critical limb ischemia is the terminal disease stage, which requires a prompt intervention to relieve pain and save limbs. However, patients undergoing revascularization often suffer from cardiovascular, cerebrovascular and major adverse limb events with poor outcomes. Furthermore, the same procedure performed in apparently similar patients has various outcomes and lack of an outcome predictive support causes a high lower limb arterial revascularization rate with disastrous effects for patients. We collected the main risk factors of major adverse limb events in a more readable and immediate format of the topic, to propose an overview of parameters to manage effectively peripheral artery disease patients and to propose basics of a new predictive tool to prevent from disabling vascular complications of the disease. Methods: Most recent and updated literature about the prevalence of major adverse limb events in peripheral artery disease was reviewed to identify possible main predictors. Results: In this article, we summarized major risk factors of limb revascularization failure and disabling vascular complications collecting those parameters principally responsible for major adverse limb events, which provides physio-pathological explanation of their role in peripheral artery disease. Conclusion: We evaluated and listed a panel of possible predictors of MALE (Major Adverse Limb Event) in order to contribute to the development of a predictive score, based on a summary of the main risk factors reported in scientific articles, which could improve the management of peripheral artery disease by preventing vascular accidents.

Introduction: The treatment of intractable toe ulcer with critical limb ischemia (CLI) is a challenge because of its poor blood flow and the wound. Here, a novel fixation technique for artificial dermis with negative pressure wound therapy (NPWT) was reported. Method: After the amputation of toe, artificial dermis made of collagen-gelatin sponge (CGS) was grafted onto the wound where human recombinant basic fibroblast growth factor (bFGF) was sprayed. The foot was put on adhesive iodine-impregnated drape, the artificial-dermis area was covered with a sponge dressing of which another end reached to the drape, and the vacuum port was applied on the dressing sponge sandwiched with two drapes and connected to an NPWT system. Since the shape of sponge-dressing was similar to that of elephant-trunk, the technique in this study was named an “Elephant-trunk” technique. Result: During NPWT period, no complications such as air leakage, skin erosion, ischemic around tissue were confirmed. The artificial dermis was engrafted completely at one week after surgery, and the wound was confirmed to close completely. Conclusion: This NPWT technique with bFGF and CGS accelerated the healing of wound treated conservatively with artificial dermis in CLI patients.

Downstream paclitaxel particle embolization for nonhealing ischemic ulcers and systemic adverse effects caused by a paclitaxel drug-coated balloon are of concern, and safety measures to prevent these adverse risks are needed. To reduce distal particle embolization and movement of the paclitaxel particles to systemic blood flow during drug-coated balloon inflation, proximal balloon occlusion using a sheathless temporary occlusion balloon-guiding catheter and extraction by manual aspiration of the paclitaxel-containing blood through the catheter are good treatment options to overcome these risks. Here, we introduce this method with tips and tricks, and demonstrate initial experience of this technique.

Objective: Prior studies have described risk factors associated with amputation in patients with concomitant diabetes and peripheral arterial disease (DM/PAD). However, the association between the severity and extent of tissue loss type and amputation risk remains less well-described. We aimed to quantify the role of different tissue loss types in amputation risk among patients with DM/PAD, in the context of demographic, preventive, and socioeconomic factors., Methods: Applying International Classification of Diseases (ICD)-9 and ICD-10 codes to Medicare claims data (2007-2019), we identified all patients with continuous fee-for-service Medicare coverage diagnosed with DM/PAD. Eight tissue loss categories were established using ICD-9 and ICD-10 diagnosis codes, ranging from lymphadenitis (least severe) to gangrene (most severe). We created a Cox proportional hazards model to quantify associations between tissue loss type and 1- and 5-year amputation risk, adjusting for age, race/ethnicity, sex, rurality, income, comorbidities, and preventive factors. Regional variation in DM/PAD rates and risk-adjusted amputation rates was examined at the hospital referral region level., Results: We identified 12,257,174 patients with DM/PAD (48% male, 76% White, 10% prior myocardial infarction, 30% chronic kidney disease). Although 2.2 million patients (18%) had some form of tissue loss, 10.0 million patients (82%) did not. The 1-year crude amputation rate (major and minor) was 6.4% in patients with tissue loss, and 0.4% in patients without tissue loss. Among patients with tissue loss, the 1-year any amputation rate varied from 0.89% for patients with lymphadenitis to 26% for patients with gangrene. The 1-year amputation risk varied from two-fold for patients with lymphadenitis (adjusted hazard ratio, 1.96; 95% confidence interval, 1.43-2.69) to 29-fold for patients with gangrene (adjusted hazard ratio, 28.7; 95% confidence interval, 28.1-29.3), compared with patients without tissue loss. No other demographic variable including age, sex, race, or region incurred a hazard ratio for 1- or 5-year amputation risk higher than the least severe tissue loss category. Results were similar across minor and major amputation, and 1- and 5-year amputation outcomes. At a regional level, higher DM/PAD rates were inversely correlated with risk-adjusted 5-year amputation rates (R 2  = 0.43)., Conclusions: Among 12 million patients with DM/PAD, the most significant predictor of amputation was the presence and extent of tissue loss, with an association greater in effect size than any other factor studied. Tissue loss could be used in awareness campaigns as a simple marker of high-risk patients. Patients with any type of tissue loss require expedited wound care, revascularization as appropriate, and infection management to avoid amputation. Establishing systems of care to provide these interventions in regions with high amputation rates may prove beneficial for these populations., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The comorbidity-polypharmacy score (CPPS) was created to evaluate the clinical burden of comorbidities in geriatric patients. It represents an objective tool to stratify patients' risk in different settings. The study aimed to evaluate CPPS in predicting mortality and amputation in patients undergoing elective revascularization procedures in CLTI patients., Methods: This is 2 years retrospective single-centre study. We included all patients undergoing elective lower-limb revascularization procedures admitted with CLTI diagnosis. Four CPPS groups were defined: mild, moderate, severe and morbid. The primary early and long-term outcomes were 30-day overall mortality, 30-day amputation rate and overall survival and limb salvage respectively., Results: A total of 442 patients were enrolled in the study. Mean age was 76.5±9.9 years and 61.5% (272/442) were male. CPPS was calculated: 22.6% (100/442) have mild CPPS, 54.3% (240/442) moderate, 21.9% (97/442) severe and 1.2% (5/442) morbid. Kaplan-Meier curves for overall survival stratified for CPPS grade highlighted a strong statistically significant difference (p<0.0001) among the four CPPS classes. Mild CPPS has significantly higher limb salvage rate among moderate, severe and morbid CPPS groups (p<0.0001). Limb salvage for mild and severe CPPS, at 36 months was 95% vs. 85.1% respectively. Stepwise multivariable Cox-analysis revealed that mortality was independently associated with dialysis, Rutherford Classification V, age and CPPS. Male sex, multilevel arterial disease, and hybrid surgical repair were independently associated with amputations., Conclusion: CPPS is a straightforward tool to evaluate the patient's complexity and could be used as an adjuvant tool to stratify early- and long-term outcomes in CLTI patients undergoing elective revascularization procedures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Chronic limb-threatening ischemia (CLTI) due to isolated tibial occlusive disease is treated by either popliteal distal bypass or tibial angioplasty, although there is limited data directly comparing efficacy and outcomes between these two treatment modalities. This study compares 30-day mortality and major adverse limb events following infrapopliteal bypass and tibial angioplasty in patients with CLTI., Methods: Patients who underwent popliteal distal bypass for CLTI were extracted from American College of Surgeons National Surgical Quality Improvement Program targeted lower extremity open database, whereas patient with CLTI who underwent isolated tibial angioplasty were identified in the targeted lower extremity endovascular database. Any case with more proximal angioplasty such as femoral/pop/iliac was excluded. The time interval was 2011-2022. The two groups were comparable in demographics and pre-operative comorbidities were obtained using propensity matching. Mortality, systemic complications, and major adverse limb events were measured. Multivariable logistic regression was used for data analysis. To obtain granular data on the angiographic characteristics of patients undergoing popliteal-distal bypass or tibial angioplasty, The George Washington University institutional data from 2014 to 2019 was used as supplement to the database., Results: There were 1,947 and 3,423 cases identified in the bypass and endovascular groups, respectively. After propensity matching for all preoperative variables, 1,747 cases remained in each group. Although bypass was associated with higher major adverse cardiovascular events, pulmonary, renal, and wound complications, bypass had significantly better 30-day limb salvage when compared to tibial angioplasty (major amputation rate 3.32% vs. 6.12%; p<0.01). Institutional data identified 69 patients with CLTI due to isolated tibial occlusive disease; 25 (36.2%) underwent popliteal-distal bypass and 44 (63.8%) underwent tibial angioplasty. Reviewing of angiographic details revealed patients who underwent popliteal-distal bypass had better pedal targets (inframalleolar/pedal score of P0 [24.0% vs 15.9%] or P1 [68.0% vs 61.3%]) than tibial angioplasty patients (inframalleolar/pedal score of P2 [22.7% vs 8.0%])., Conclusion: Popliteal-distal bypass was associated with higher morbidity but better limb salvage than endovascular interventions. However, this could be explained by the association with better pedal targets in patients who underwent popliteal-tibial bypass. Prospective studies should be done comparing popliteal distal bypasses and tibial angioplasty in cases with similar pedal targets., (Copyright © 2024. Published by Elsevier Inc.)

Background/objectives: Recent trends indicate a rise in the incidence of critical limb ischemia (CLI) among younger adults. This study examines trends in CLI hospitalization and outcomes among young adults with peripheral arterial disease (PAD) in the United States., Methods: Adult hospitalizations (18-40 years) for PAD/CLI were analyzed from the 2016-2020 nationwide inpatient sample database using ICD-10 codes. Rates were reported per 1000 PAD or 100,000 cardiovascular disease admissions. Outcomes included trends in mortality, major amputations, revascularization, length of hospital stay (LOS), and hospital costs (THC). We used the Jonckheere-Terpstra tests for trend analysis and adjusted costs to the 2020 dollar using the consumer price index., Results: Approximately 63,045 PAD and 20,455 CLI admissions were analyzed. The mean age of the CLI cohort was 32.7 ± 3 years. The majority (12,907; 63.1 %) were female and white (11,843; 57.9 %). Annual CLI rates showed an uptrend with 3265 hospitalizations (227 per 1000 PAD hospitalizations, 22.7 %) in 2016 to 4474 (252 per 1000 PAD hospitalizations, 25.2 %) in 2020 (Ptrend<0.001), along with an increase in PAD admissions from 14,405 (188 per 100,000, 0.19 %) in 2016 to 17,745 (232 per 100,000, 0.23 %%) in 2020 (Ptrend<0.0001). Annual in-hospital mortality increased from 570 (2.8 %) in 2016 to 803 (3.9 %) in 2020 (Ptrend = 0.001) while amputations increased from 1084 (33.2 %) in 2016 to 1995 (44.6 %) in 2020 (Ptrend<0.001). Mean LOS increased from 5.1 (SD 2.7) days in 2016 to 6.5 (SD 0.9) days in 2020 (Ptrend = 0.002). The mean THC for CLI increased from $50,873 to $69,262 in 2020 (Ptrend<0.001). The endovascular revascularization rates decreased from 11.5 % (525 cases) in 2016 to 10.7 % (635 cases) in 2020 (Ptrend = 0.025). Surgical revascularization rates also increased from 4.9 % (225 cases) in 2016 to 10.4 % (600 cases) in 2020 (Ptrend = 0.041)., Conclusion: Hospitalization and outcomes for CLI worsened among young adults during the study period. There is an urgent need to enhance surveillance for risk factors of PAD in this age group., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Peripheral artery disease (PAD) is an ischemic disease with a rising incidence worldwide. The lncRNA H19 (H19) is enriched in endothelial progenitor cells (EPCs), and transplantation of pyroptosis-resistant H19-overexpressed EPCs (oe-H19-EPCs) may promote vasculogenesis and blood flow recovery in PAD, especially with critical limb ischemia (CLI)., Methods: EPCs isolated from human peripheral blood was characterized using immunofluorescence and flow cytometry. Cell proliferation was determined with CCK8 and EdU assays. Cell migration was assessed by Transwell and wound healing assays. The angiogenic potential was evaluated using tube formation assay. The pyroptosis pathway-related protein in EPCs was detected by western blot. The binding sites of H19 and FADD on miR-107 were analyzed using Luciferase assays. In vivo, oe-H19-EPCs were transplanted into a mouse ischemic limb model, and blood flow was detected by laser Doppler imaging. The transcriptional landscape behind the therapeutic effects of oe-H19-EPCs on ischemic limbs were examined with whole transcriptome sequencing., Results: Overexpression of H19 in EPCs led to an increase in proliferation, migration, and tube formation abilities. These effects were mediated through pyroptosis pathway, which is regulated by the H19/miR-107/FADD axis. Transplantation of oe-H19-EPCs in a mouse ischemic limb model promoted vasculogenesis and blood flow recovery. Whole transcriptome sequencing indicated significant activation of vasculogenesis pathway in the ischemic limbs following treatment with oe-H19-EPCs., Conclusions: Overexpression of H19 increases FADD level by competitively binding to miR-107, leading to enhanced proliferation, migration, vasculogenesis, and inhibition of pyroptosis in EPCs. These effects ultimately promote the recovery of blood flow in CLI., Competing Interests: Declaration of competing interest The authors affirm that there are no commercial or financial relationships that could be interpreted as a possible conflict of interest during the course of the research., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Critical limb ischemia is an important clinical entity due to its association with increased morbidity and mortality. The mortality and amputation-free survival remains poor especially in those where revascularization is not an option. Recently, the role of cellular therapy has emerged as a promising therapeutic measure that may aid in wound healing and revascularization and improve functional outcomes., Competing Interests: Disclosure Dr J.W. Harmon is a founding member of MedRegen Baltimore, Maryland, which was established to develop a therapeutic to mobilize endogenous stem cells for wound healing., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Novel therapeutic angiogenic concepts for critical limb ischemia are still needed for limb salvage. E-selectin, a cell-adhesion molecule, is vital for recruitment of the stem/progenitor cells necessary for neovascularization in ischemic tissues. We hypothesized that priming ischemic limb tissue with E-selectin/adeno-associated virus (AAV) gene therapy, in a murine hindlimb ischemia and gangrene model, would increase therapeutic angiogenesis and improve gangrene. Methods: FVB/NJ mice were given intramuscular hindlimb injections of either E-selectin/AAV or LacZ/AAV and then underwent induction of gangrene via femoral artery ligation and concomitant systemic injections of the nitric oxide synthesis inhibitor L-NAME (L-NG-Nitro arginine methyl ester; 40 mg/kg). Gangrene was evaluated via the Faber hindlimb appearance score. The rate of ischemic limb reperfusion and ischemic tissue angiogenesis were evaluated using laser Doppler perfusion imaging and DiI perfusion with confocal laser scanning microscopy of the ischemic footpads, respectively. The treadmill exhaustion test was performed on postoperative day (POD) 8 to determine hindlimb functionality. Results: The E-selectin/AAV–treated mice (n = 10) had decreased Faber ischemia scores compared with those of the LacZ/AAV–treated mice (n = 7) at both PODs 7 and 14 (P < .05 and P < .01, respectively), improved laser Doppler perfusion imaging reperfusion indexes by POD 14 (P < .01), and greater gangrene footpad capillary density (P < .001). E-selectin/AAV–treated mice also had improved exercise tolerance (P < .05) and lower relative muscular atrophy (P < .01). Conclusion: We surmised that E-selectin/AAV gene therapy would significantly promote hindlimb angiogenesis, reperfusion, and limb functionality in mice with hindlimb ischemia and gangrene. Our findings highlight the reported novel gene therapy approach to critical limb ischemia as a potential therapeutic option for future clinical studies. : Clinical Relevance: In the United States, >150,000 limb amputations are performed annually for critical limb ischemia (CLI) despite the use of medical and surgical therapy. Thus, novel therapeutic angiogenic concepts for CLI are still needed for limb salvage. We used a novel gene therapy approach in a mouse model of gangrene, the most severe form of CLI, to demonstrate the efficacy of our gene therapy with E-selectin. Preclinical studies such as ours are a vital step in the development of new therapies for CLI patients with threatened limbs and no further medical or surgical options.

Background: Critical limb ischemia (CLI), the most severe form of peripheral artery disease, is associated with pain, poor wound healing, high rates of amputation, and mortality (>20% at 1 year). Little is known about the processes of care, patients’ preferences, or outcomes, as seen from patients’ perspectives. The SCOPE-CLI study was co-designed with patients to holistically document patient characteristics, treatment preferences, patterns of care, and patient-centered outcomes for CLI. Methods: This 11-center prospective observational registry will enroll and interview 816 patients from multispecialty, interdisciplinary vascular centers in the United States and Australia. Patients will be followed up at 1, 2, 6, and 12 months regarding their psychosocial factors and health status. Hospitalizations, interventions, and outcomes will be captured for 12 months with vital status extending to 5 years. Pilot data were collected between January and July of 2021 from 3 centers. Results: A total of 70 patients have been enrolled. The mean age was 68.4 ± 11.3 years, 31.4% were female, and 20.0% were African American. Conclusions: SCOPE-CLI is uniquely co-designed with patients who have CLI to capture the care experiences, treatment preferences, and health status outcomes of this vulnerable population and will provide much needed information to understand and address gaps in the quality of CLI care and outcomes.ClinicalTrials.gov identifier (NCT Number): NCT04710563 https://clinicaltrials.gov/ct2/show/NCT04710563.

Background: Balloon angioplasty is the standard endovascular treatment for symptomatic infrapopliteal peripheral artery disease (PAD). However, recent trials have studied the effectiveness of drug-eluting stents (DES) for infrapopliteal PAD. Objective: This study investigated the use of DES compared with standard endovascular techniques for treatment of infrapopliteal artery disease. Methods: This is a comprehensive systematic review and meta-analysis of 9 recent randomized controlled trials. The primary clinical outcome assessed was primary patency. The secondary outcomes were target lesion revascularization (TLR), major limb amputation, and all-cause mortality. Results: A total of 945 patients met the inclusion criteria. Patients treated with DES were found to have increased primary patency than control at maximum follow-up (hazard ratio [HR] 2.17, 95% confidence interval [CI] 1.58-2.97, P < .0001, I2 = 62%). A similar result was seen in the subgroup of patients with critical limb ischemia (HR 2.58, 95% CI 1.49-4.49, P = .0008, I2 = 75%). DES were associated with significantly lower rates of TLR than control at maximum follow-up (HR 0.48, 95% CI 0.33-0.68, P < .0001; I2 = 11%). There was no statistical difference between DES versus control in rates of major limb amputation and mortality. Conclusions: DES have superior primary patency and TLR rates with no difference in amputation and all-cause mortality rates compared with conventional endovascular therapies in patients with infrapopliteal PAD.

Gene or cell therapy is currently not fully efficacious for arteriosclerosis obliterans (ASO). In this study, we determined whether YS-1402, a slow-release synthetic prostacyclin agonist, promoted neovascularization and skeletal muscle regeneration in a mouse model of critical limb ischemia (CLI). We ligated the femoral artery and its branches to obtain the CLI mouse model, administered saline (S group) or YS-1402 (YS group) to the thigh adductor 1 week after femoral artery occlusion, and evaluated tissue blood flow after surgery. After treatment, the leg muscle was obtained for histological, gene expression, and protein analyses to assess angiogenesis and skeletal muscle regeneration. Tissue blood flow improved in the YS group compared with that in the S group, and the number of CD31+/α-smooth muscle actin (αSMA)+ arterioles increased in the YS group. Prostacyclin receptor (IPR), stromal cell-derived factor-1, hepatocyte growth factor, and neural cell adhesion molecule expression levels were higher in the YS than in the S group. Skeletal muscle regeneration was detected based on PAX7- and Ki-67-positive satellite cells in the YS group. Myogenin and MyoD expression was higher in the YS than in the S group. Therefore, YS-1402 promoted functional angiogenesis and skeletal muscle regeneration in the CLI mouse model, suggesting a new therapy for ASO.

A 77-year-old woman with critical limb ischemia, venous insufficiency, and progressive pulmonary hypertension presented for evaluation. Lower extremity angiography showed a common iliac arteriovenous fistula. Closure was achieved with a covered stent placed in the artery. (Level of Difficulty: Intermediate.)

Impaired wound healing in critical limb ischemia (CLI) results from multiple factors that affect many cell types and their behavior. Epidermal keratinocytes and dermal fibroblasts play crucial roles in wound healing. However, it remains unclear whether these cell types irreversibly convert into a non-proliferative phenotype and are involved in impaired wound healing in CLI. Here, we demonstrate that skin keratinocytes and fibroblasts isolated from CLI patients maintain their proliferative potentials. Epidermal keratinocytes and dermal fibroblasts were isolated from the surrounding skin of foot wounds in CLI patients with diabetic nephropathy on hemodialysis, and their growth potentials were evaluated. It was found that keratinocytes from lower limbs and trunk of patients can give rise to proliferative growing colonies and can be serially passaged. Fibroblasts can also form colonies with a proliferative phenotype. These results indicate that skin keratinocytes and fibroblasts maintain their proliferative capacity even in diabetic and ischemic microenvironments and can be reactivated under appropriate conditions. This study provides strong evidence that the improvement of the cellular microenvironments is a promising therapeutic approach for CLI and these cells can also be used for potential sources of skin reconstruction.

A bidirectional approach is necessary for treating critical limb ischemia with complex, multiple lesions. We report an ultrasound-guided bidirectional puncture through an occluded vessel to treat an obstruction extending from the anterior tibial artery to the dorsal foot artery in a patient with toe gangrene and rest pain. This technique effectively restored arterial patency and is a promising approach for managing challenging critical limb ischemia occlusions., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Background: The risk of coronary artery disease in peripheral arterial disease (PAD) is high, life prognosis is poor, and lipid-lowering treatment with statins has been reported to improve prognosis. In clinical practice, however, hypolipidemia is more common in patients with severe PAD and statin prescription rates appear to be low, but specific data are scarce in Japan. Therefore, we conducted this cross-sectional study in collaboration with other centers of vascular surgery to determine the rate of statin prescriptions for PAD patients in real-world practice, the rate of achievement of low-density lipoprotein (LDL) cholesterol control targets, and whether statin non-use is a determinant factor of critical limb ischemia (CLI)., Methods: A total of 246 PAD patients (97 with CLI) from 5 sites were included in this study. Medical history and blood test data were obtained from medical records and interviews with patients, and were compared between CLI and non-CLI patients., Results: Statin prescription rate was only 34 %. The overall LDL cholesterol control target rate was 46 % of CLI cases and 51 % of non-CLI cases, according to the lipid management criteria of the Japanese Society for Atherosclerosis 2022 guidelines. Patients in the CLI group had a lower mean body mass index and lower LDL cholesterol levels than those in the non-CLI group, suggesting that these factors were responsible for the lower statin prescription rate. However, multivariate analysis revealed that statin non-use was one of the determinants of CLI., Conclusions: Statin prescription rates for PAD patients were low in real-world practice settings in the field of vascular surgery. Since statin non-use is a determinant of CLI, there is a need to educate physicians engaged in treatment regarding lipid-lowering treatment with statins., Competing Interests: Declaration of competing interest Masatsune Ogura has received lecture fees from Kowa and Amgen. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) randomized trial comparing initial open bypass (OPEN) and endovascular (ENDO) treatment strategies, with a focus on reintervention-related study endpoints., Methods: In a planned secondary analysis, we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation, or death by intention-to-treat assignment in both trial cohorts (cohort 1 with suitable single-segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and all index limb reinterventions over time. Comparisons between treatment arms within each cohort were made using univariable and multivariable Cox regression models., Results: In cohort 1, assignment to OPEN was associated with a significantly reduced hazard of a major limb reintervention (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.28-0.49; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or any reintervention, amputation, or death (HR, 0.68; 95% CI, 0.60-0.78; P < .001). Findings were similar in cohort 2 for major reintervention (HR, 0.53; 95% CI, 0.33-0.84; P = .007) or any reintervention (HR, 0.71; 95% CI, 0.52-0.98; P = .04). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to ENDO as compared with OPEN (14.7% vs 4.5% of cohort 1 subjects; 16.6% vs 5.6% of cohort 2 subjects). The mean number of major (mean events per subject ratio [MR], 0.45; 95% CI, 0.34-0.58; P < .001) or any target limb reinterventions (MR, 0.67; 95% CI, 0.57-0.80; P < .001) per year was significantly less in the OPEN arm of cohort 1. The mean number of reinterventions per limb salvaged per year was lower in the OPEN arm of cohort 1 (MR, 0.45; 95% CI, 0.35-0.57; P < .001 and MR, 0.66; 95% CI, 0.55-0.79; P < .001 for major and all, respectively). The majority of index limb reinterventions occurred during the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial., Conclusions: Reintervention is common following revascularization for chronic limb-threatening ischemia. Among patients deemed suitable for either approach, initial treatment with open bypass, particularly in patients with available SSGSV conduit, is associated with a significantly lower number of major and minor target limb reinterventions., Competing Interests: Disclosures M.C. is on the DSMB for Abbott Vascular. M.M. is an advisor for Janssen. K.R. receives income as a consultant or member of a scientific advisory board for Abbott Vascular, Althea Medical, Angiodynamics, Auxetics, BectonDickinson, Boston Scientific, Contego, Crossliner, Innova Vascular, Inspire MD, Janssen/Johnson and Johnson, Magneto, Mayo Clinic, MedAlliance, Medtronic, Neptune Medical, Penumbra, Philips, Surmodics, Terumo, Thrombolex, Truvic, Vasorum, and Vumedi; owns equity or stock options in the following entities: Access Vascular, Aerami, Althea Medical, Auxetics, Contego, Crossliner, Cruzar Systems, Endospan, Imperative Care/Truvic, Innova Vascular, InspireMD, JanaCare, Magneto, MedAlliance, Neptune Medical, Orchestra, Prosomnus, Shockwave, Skydance, Summa Therapeutics, Thrombolex, Vasorum, and Vumedi; serves as a member of the board of directors of the following organization: The National PERT ConsortiumTMA; and K.R. or his institution (on his behalf) receive research grants from the following entities: NIH, Abiomed, Boston Scientific, Novo Nordisk Foundation, Penumbra, and Gettinge-Atrium. A.F. received a grant from Novo Nordisk Foundation; is a consultant with Sanifit, LeMaitre, and BioGenCell; and is on the advisory board for Dialysis-X and iThera Medical. E.A. is a consultant with Philips and is participating in clinical trials with Inari Medical. C.M. is a consultant with Cook, Abbott, Penumra, and Optum Labs; and received a research grant from Shockwave and Philips., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Peripheral arterial disease (PAD) is a major health care problem. There have been limited advances in medical therapies, and a huge burden of symptomatic patients with intermittent claudication and critical limb ischemia who have limited treatment options. Angiogenesis is the growth and proliferation of blood vessels from existing vasculature. For approximately 2 decades, “therapeutic angiogenesis” has been studied as an investigational approach to treat patients with symptomatic PAD. Despite literally hundreds of positive preclinical studies, results from human clinical studies thus far have been disappointing. Here we present an overview of where the field of therapeutic angiogenesis stands today and examine lessons learned from previously conducted clinical trials. The objective is not to second-guess past efforts but to place the lessons in perspective to allow for trial success in the future to improve agent development, trial design, and ultimately, clinical outcomes for new therapeutics for PAD.

Objective: Endovascular therapy of lower extremity peripheral artery disease (PAD) is associated with higher complication rates and worse outcomes in women vs men. Although intravascular lithotripsy (IVL) has shown similarly favorable outcomes in men and women in calcified coronary arteries, there is no published safety and effectiveness data of peripheral IVL differentiated by sex. This study aims to evaluate sex-specific acute procedural safety and effectiveness following IVL treatment of calcified PAD., Methods: We performed a secondary analysis of the multicenter Disrupt PAD III Observational Study, which assessed short-term procedural outcomes of patients undergoing treatment of symptomatic calcified lower extremity PAD with the Shockwave peripheral IVL system. Adjudicated acute safety and efficacy outcomes were compared by sex using univariate analysis performed with the χ 2 test or Fisher exact test, as appropriate., Results: A total of 1262 patients (29.9% women) were included, with >85% having moderate to severe lesion calcification. Women were older (74 vs 71 years; P < .001), had lower ankle-brachial index (0.7 vs 0.8; P = .003), smaller reference vessel size (5.3 vs 5.6 mm; P = .009), and more severe stenosis at baseline vs men (82.3% vs 79.8%; P = .012). Rates of diabetes, renal insufficiency, chronic limb-threatening ischemia, lesion length, and atherectomy use were similar in both groups. Residual stenosis after IVL alone was significantly reduced in both groups. Final residual stenosis was 21.9% in women and 24.7% in men (P = .001). Serious angiographic complications were infrequent and similar in both groups (1.4% vs 0.6%; P = .21), with no abrupt vessel closure, distal embolization, or thrombotic events during any procedure., Conclusions: The use of IVL to treat calcified PAD in this observational registry demonstrated favorable acute safety and effectiveness in both women and men., Competing Interests: Disclosures S.N. reports consultant for Cardinal Health, Haemonetics, and Veryan Medical. K.M. reports speaker fees from Shockwave Medical and Penumbra Inc. S.S.M. reports speaker fees from Shockwave Medical. G.A. reports consultant for education and research for Shockwave Medical. N.W.S. reports research and educational grants from Bard, AngioDynamics, and Boston Scientific; consultant for Abbott, Shockwave Medical, and VentureMed Group; and speaker bureau for Janssen, Boehringer Ingelheim, Merck, Amgen, and Bayer. A.M. reports speaker fees from Shockwave Medical; and speaker and training fees from Abbott. P.S. reports institutional grant support from W.L. Gore, Boston Scientific, Contego Medical, Endologix, InspireMD, MicroMedical Solutions, Philips, and Shockwave Medical. B.B. reports speaker fees from Shockwave Medical. A.J.L. reports speaker fees from Shockwave Medical., (Copyright © 2023. Published by Elsevier Inc.)

Background: Advancement in endovascular techniques has led to rapid growth in endovascular revascularization, and it has emerged as a treatment for critical limb ischemia (CLI). Clinical effectiveness of revascularization has been frequently judged by vessel patency and limb salvage, but there is paucity of reports on outcomes of the wound. We present a retrospective analysis of immediate angiographic and 3-month clinical outcome of patients who underwent endovascular reconstruction of popliteal and infrapopliteal arteries for CLI. Methods: All patients who underwent endovascular reconstruction of popliteal and/or infrapopliteal arteries for CLI and >70% stenosis on digital subtraction angiography between March 2010 and November 2014 and had a clinical follow-up of at least 3 months were selected for analysis. Results: 34 patients underwent endovascular reconstruction. 9 patients (26%) underwent only POBA and remaining 25 (74%) underwent additional stenting. 13 patients (38%) had multiple segmental revascularization. 24 patients (71%) had successful vessel recanalization. Linear flow to foot in at least one artery could be achieved in 20 patients (59%) post revascularization. Successful wound healing occurred in 11 (35%) patients with an additional 7 (21%) patients showing clinical improvement in their wounds. Limb salvage was achieved in 33 patients (97%) at 3-month follow-up. Conclusion: Endovascular revascularization of popliteal and infrapopliteal arteries is a feasible, safe, and effective procedure for the treatment of CLI. Normal inflow and outflow with at least one of the three infrapopliteal vessels being patent is essential for adequate healing of chronic ulcers and prevention of major amputation.

Although surgical and endovascular revascularization can be performed in peripheral arterial disease (PAD), 40% of patients with critical limb ischemia do not have a revascularization option. This study examines the efficacy and mechanisms of action of acellular extracellular matrix-based hydrogels as a potential novel therapy for treating PAD. We tested the efficacy of using a tissue-specific injectable hydrogel derived from decellularized porcine skeletal muscle (SKM) and compared this to a new human umbilical cord-derived matrix (hUC) hydrogel, which could have greater potential for tissue regeneration because of the younger age of the tissue source. In a rodent hindlimb ischemia model, both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis to 35 days post-injection. There were significant improvements in hindlimb tissue perfusion and perfusion kinetics with both biomaterials. Histologic analysis indicated that the injected hydrogels were biocompatible, and resulted in arteriogenesis, rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue-specific SKM hydrogel more closely matched healthy tissue morphology. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development. These results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment.

Acute onset of a cold, painful leg, also known as acute limb ischemia, describes the sudden loss of perfusion to the lower extremity and carries significant risk of morbidity and mortality. Acute limb ischemia requires rapid identification and the management of suspected vascular compromise and is inherently driven by clinical considerations. The objectives of initial imaging include confirmation of diagnosis, identifying the location and extent of vascular occlusion, and preprocedural/presurgical planning. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Objective: Both bypass surgery and endovascular treatment are well-recognized interventions for the treatment of peripheral artery disease; however, the effect of failed endovascular treatment on subsequent surgeries remains controversial. A systematic review was conducted to compare the outcomes of primary bypass and bypass surgery after endovascular treatment., Methods: Three academic databases (Embase, PubMed, and Scopus) were searched from their inception to August 2022. Two independent investigators searched for studies that reported the outcomes of primary bypass surgery and bypass surgery after endovascular treatment in patients with peripheral artery disease. Abstracts and full-text studies were screened independently using duplicate data abstraction. Dichotomous outcome measures were reported using a random-effects model to generate a summary odds ratio (OR) and 95% confidence interval (CI). The risk of bias was assessed using the Newcastle-Ottawa Scale., Results: Seventeen retrospective observational studies were selected from 3911 articles and included 8064 patients, 6252 of whom underwent primary bypass surgery and 1812 underwent bypass surgery after endovascular treatment. The mean age was 69.0 years and 61.2% (n = 4938) were male. For perioperative outcomes, the 30-day results showed no difference in mortality (OR, 0.76; 95% CI, 0.53-1.10), or amputation (OR, 0.89; 95% CI, 0.67-1.20). For short- to mid-term outcomes, primary patency did not differ at 6 months (OR, 0.98; 95% CI, 0.81-1.19), 1 year (OR, 1.12; 95% CI, 0.97-1.30), or 2 years (OR, 1.17; 95% CI, 0.85-1.61) follow-up. Amputation-free survival did not differ at 6 months (OR, 1.03; 95% CI, 0.82-1.30), 1 year (OR, 1.09; 95% CI, 0.89-1.32), 2 years (OR, 1.18; 95% CI, 0.93-1.50), or 3 years (OR, 1.09; 95% CI, 0.84-1.40) of follow-up. No significant difference was found in overall survival or second patency., Conclusions: This meta-analysis of retrospective, nonrandomized, observational studies suggests that prior endovascular treatment of lower extremity arterial disease does not result in worse perioperative, short-term, or mid-term clinical outcomes of subsequent infrainguinal bypass surgery compared with patients without prior endovascular treatment., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Iloprost has been proposed as an alternative to amputation in Critical Limb Ischemia (CLI) patients when revascularization was unsuccessful or not possible. Nonetheless, there is limited evidence of its benefit. The main objective was to evaluate the effectiveness of iloprost and the secondary objective was to evaluate its safety., Methods: In this cohort study including CLI patients from the COPART registry from 2006/10 to 2021/01, patients exposed to iloprost were matched with up to three unexposed patients according to age, sex, and Propensity Score (PS) for exposure to iloprost. The main outcome combined the occurrence of all-cause death and major amputations; survival was assessed over one-year using Kaplan-Meier estimates and Cox model analyses. Major Adverse Cardiovascular Events (MACE) were chosen as the safety outcome; the association with iloprost was estimated using a logistic regression model., Results: Among 1850 CLI patients, 201 were exposed to iloprost (71.6% men; median age: 72 years vs. 72.1%; 75 years for unexposed). In 134 exposed patients matched to 375 unexposed patients, 14 major amputations and 24 deaths occurred in exposed patients (28.4%) vs. 33 and 46 respectively in the unexposed patients (20.9%). The hazard ratio (HR) was of 1.49 (95% Confidence Interval: 1.01-2.20). The association remained in the subgroup of "no option" patients (HR: 1.74; [1.01-2.20]). Regarding safety, 21/201 (10.7%) exposed patients experienced MACE vs. 146/1649 (9.41%) unexposed patients (unadjusted Odds Ratio [OR]: 1.17 [0.72-1.90]; adjusted OR: 1.23 [0.72-2.11])., Conclusion: The study did not find any benefit of iloprost in CLI patients and even suggested a deleterious effect., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Persons with chronic kidney disease (CKD) are at a higher risk of developing peripheral artery disease (PAD) and its adverse health outcomes than individuals with normal renal function. Among patients with CKD, PAD is predominantly characterized by the calcification of the medial layer of arterial vessels in addition to intimal atherosclerosis and calcification. Vascular calcification (VC) is initiated by CKD-associated hyperphosphatemia, hypercalcemia, high concentrations of parathyroid hormone (PTH) as well as inflammation and oxidative stress. VC is widely prevalent in this cohort (>80% dialysis and 50% patients with CKD) and contributes to reduced arterial compliance and symptomatic peripheral arterial disease (PAD). The most severe form of PAD is critical limb ischemia (CLI) which has a substantial risk for increased morbidity and mortality. Percutaneous endovascular interventions with transluminal angioplasty, atherectomy, and intravascular lithotripsy are the current nonsurgical treatments for severe calcific plaque. Unfortunately, there are no randomized controlled trials that address the optimal approach to PAD and CLI revascularization in patients with CKD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Severe obesity could be an independent risk factor for peripheral artery disease (PAD) and critical limb ischemia (CLI). Bariatric surgery reduces cardiac risk factors, decreasing cardiovascular morbidity and mortality in subjects with severe obesity., Objectives: We aimed to describe the impact of bariatric surgery on risk of hospitalization due to PAD and CLI., Setting: Academic hospital., Methods: The National Inpatient Sample data collected from 2010 to 2015 were examined. Patients were classified as treatment and control groups. Treatment was defined as patients with a previous history of bariatric surgery, and control was defined as patients with a body mass index ≥35 without a history of bariatric surgery. The primary outcome was hospitalization due to PAD; secondary outcomes were CLI, revascularization, major amputation, length of hospital stay (LOS), and total cost of hospitalization. Univariate and multivariate analyses were performed to assess the differences between groups., Results: There were a total of 2,300,845 subjects: 2,004,804 controls and 296,041 treatment patients. Hospitalization rate for PAD was significantly lower compared to the control group (.10% versus .21%, P < .0001), which was confirmed after adjusting for covariables (control versus treatment: odds ratio= 1.20, confidence interval: 1.15-1.47). Subgroup analysis showed patients without a history of bariatric surgery had a higher prevalence of CLI (59.3% versus 52.4%, P < .0219) and a higher mean LOS (6.7 versus 5.7 days, P = .0023) and cost of hospitalization (78.756 versus 72.621$, P = .0089), with no significant differences in other outcomes. After multivariate analysis, only LOS and total costs were significantly different., Conclusions: Bariatric surgery may decrease the risk of hospitalization due to PAD, similarly to the LOS and total cost of hospitalization. Prospective studies should be performed to describe this relationship., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Patients with Critical Limb Ischemia (CLI) present a high risk of cardiovascular events and death. Revascularization is the cornerstone of therapy to relieve ischemic pain and prevent limb loss. Literature data suggest that women tend to present with worse outcomes after revascularization. The aim of the present study is to determine amputation-free survival in a long-term follow-up in women and men following endovascular revascularization procedure for CLI., Methods: From November 2013 to December 2020, 357 consecutive patients were retrospectively included. Clinical and biological parameters were recorded at baseline before endovascular revascularization. During follow-up until February 2023, overall survival and amputation-free survival (freedom from major amputation) were analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed to study the parameters associated with amputation-free survival. A P<0.05 was considered as statistically significant., Results: A total of 357 consecutive patients were included, 189 men and 168 women with CLI, with a mean age of 78.6±12 years. Treated hypertension (79%), diabetes mellitus (48%), coronary artery disease (39%) and protein malnutrition (61%) were the most prevalent comorbidities. Women were older than men with a mean age of 82.4±11.4 years (versus 75.4±11 years in men) and presented more frequently with protein malnutrition (70% of women). Prevalence of diabetes, tobacco use and history of coronary heart disease were significantly higher in men. During the 10-year follow-up period, 241 patients had died (68%) and 38 (11%) underwent major amputation, of whom 22 patients were still alive on February 2023. Median survival was 35.5 months [IQR: 29.5; 43] in the overall population, 38.5 [32; 50.4] months in women and 33.5 months [24.7; 43.5] in men. No gender-related differences were noted according to peri-procedural complications, survival probability and amputation-free survival. In multivariate analysis for amputation-free survival, age, previous coronary heart disease, C-reactive protein level, left ventricular ejection fraction (LVEF)<60% and albumin level<35g/L were correlated with poor outcome. In particular, protein malnutrition, as a treatable risk factor, appears significantly correlated with poor outcome in both men and women (HR=2.50 [1.16;5.38], P=0.0196 in men; HR=1.77 [1.00;3.13], P=0.049 in women)., Conclusion: The present results highlight that mortality in patients after endovascular revascularization remains high with a mortality rate of 28% at 1 year, 40% at 2 years and 51% at 3 years. Women represented a distinct population, almost 10-year older than their male counterparts, with more prevalent protein malnutrition. However, no gender-related difference was noted according to amputation-free survival on the long-term follow-up. Associated risk factors are mainly age, a history of coronary heart disease, pre-procedural inflammatory syndrome and protein malnutrition. Correction of malnutrition could have the potential to improve functional and general long-term prognosis in patients with CLI together with optimal medical and interventional management., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The senior author (ABB) has a US patent on the technology in this manuscript., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial., Methods: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT., Results: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT., Conclusions: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Midterm outcomes of endovascular intervention (EVI) for critical limb ischemia (CLI) have not been previously reported in Taiwan. This study assessed the safety, feasibility, and patient-oriented outcomes for CLI patients after EVI. Methods: From June 2005 to December 2011, 270 patients underwent EVI for CLI of 333 limbs. Primary patency (PP), assisted primary patency (AP), limb salvage, sustained clinical success (SCS), secondary SCS (SSCS), and survival were assessed using Kaplan-Meier analysis. Results: The procedural success rate was 89%, and the periprocedural mortality and major complication rates within 30 days were 0.6% and 6.9%, respectively. During the mean follow-up time of 27 ± 20 months (1–77), 64 patients died and 25 legs required major amputation. Eighty-one percent of the patients with tissue loss had wound healing at 6 months and 75% of the patients were ambulatory, with or without assisting devices, at 1 year. The overall survival and limb salvage rates at 3 years were 70% and 90%, respectively. The PP and AP at 1 and 3 years were 58% and 37% and 79% and 61%, respectively. The SCS and SSCS were 65% and 46% and 80% and 64% at 1 and 3 years, respectively. Conclusion: In Taiwan, EVI was a safe and feasible procedure for CLI patients, with a high procedural success rate and lower complication rate. Sustained limb salvage and clinical success can be afforded with an active surveillance program and prompt intervention during midterm follow-up.

Stem cell therapy has emerged as a promising regenerative medicine strategy but is limited by poor cell survival, leading to low therapeutic outcomes. We developed cell spheroid therapeutics to overcome this limitation. We utilized solid-phase FGF2 to form functionally enhanced cell spheroid-adipose derived (FECS-Ad), a type of cell spheroid that preconditions cells with intrinsic hypoxia to increase the survival of transplanted cells. We demonstrated an increase in hypoxia-inducible factor 1-alpha (HIF-1α) levels in FECS-Ad, which led to the upregulation of tissue inhibitor of metalloproteinase 1 (TIMP1). TIMP1 enhanced the survival of FECS-Ad, presumably through the CD63/FAK/Akt/Bcl2 anti-apoptotic signaling pathway. Cell viability of transplanted FECS-Ad was reduced by TIMP1 knockdown in an in vitro collagen gel block and a mouse model of critical limb ischemia (CLI). TIMP1 knockdown in FECS-Ad inhibited angiogenesis and muscle regeneration induced by FECS-Ad transplanted into ischemic mouse tissue. Genetic overexpression of TIMP1 in FECS-Ad further promoted the survival and therapeutic efficacy of transplanted FECS-Ad. Collectively, we suggest that TIMP1 acts as a key survival factor to improve the survival of transplanted stem cell spheroids, which provides scientific evidence for enhanced therapeutic efficacy of stem cell spheroids, and FECS-Ad as a potential therapeutic agent to treat CLI. STATEMENT OF SIGNIFICANCE: We used FGF2-tethered substrate platform to form adipose-derived stem cell spheroids, as we named as functionally enhanced cell spheroid-adipose derived (FECS-Ad). In this paper, we showed that intrinsic hypoxia of spheroids upregulated expression of HIF-1α, which in turn upregulated expression of TIMP1. Our paper highlights TIMP1 as a key survival factor to improve survival of transplanted stem cell spheroids. We believe that our study has a very strong scientific impact as extending transplantation efficiency is essential for successful stem cell therapy., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Peripheral artery disease is a worldwide epidemic that affects millions of patients, especially the elderly. It has a prevalence of 20% in individuals >80 years old. Although peripheral artery disease affects >20% of octogenarians, information about limb salvage rates in this patient population is limited. Therefore, this study aims to understand the impact of bypass surgery on limb salvage in patients aged >80 years with critical limb ischemia., Methods: We conducted a retrospective analysis by querying the electronic medical records at a single institution from 2016 through 2022 to identify the population of interest and analyzed their outcomes after lower extremity bypass. The primary outcomes were limb salvage and primary patency, with hospital length of stay and 1-year mortality as secondary outcomes., Results: We identified 137 patients who met the inclusion criteria. The lower extremity bypass population was divided into two cohorts: <80 years old (n = 111) with a mean age of 66 or ≥80 years old (n = 26) with a mean age of 84 years. The gender distribution was similar (P = .163). No significant difference was found in the two cohorts when it came to coronary artery disease, chronic kidney disease, or diabetes mellitus. However, when current and former smokers were grouped together, they were significantly more common in the younger cohort when compared with nonsmokers (P = .028). The primary end point of limb salvage was not significantly different between the two cohorts. Hospital length of stay was not significantly different between the two cohorts with 4.13 days vs 4.17 days in the younger vs octogenarian cohorts, respectively (P = .95). The 30-day all-cause readmissions were also not found to be significantly different between the two groups. The primary patency at 1 year was 75% and 77% (P = .16) for the <80-year-old and ≥80-year-old cohorts, respectively. Mortality was low in both cohorts, with two and three for the younger and octogenarian populations, respectively; thus, no analysis was performed., Conclusions: Our study shows that octogenarians who undergo the same preoperative risk assessment as younger populations have similar outcomes when it comes to primary patency, hospital length of stay, and limb salvage when comorbidities were considered. Further studies need to be done to determine the statistical impact on mortality in this population with a larger cohort., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background and purpose: The most proximal ostial site of the chronic occlusive superficial femoral artery is not suitable for ballooning or stenting because the deep femoral artery may be occluded by these procedures. Thus, the feasibility of performing an open endarterectomy for the occluded ostium of the superficial femoral arteries combined with an endovascular therapy for the remaining distal site was evaluated. Methods: Eleven critically ischemic limbs in 10 elderly patients with poor general health were enrolled. They had full-length occlusion of the superficial femoral artery involving its ostium. The ostial site was managed with an open endarterectomy followed by endovascular therapy for the remaining distal site. Results: All procedures were successfully performed. All patients experienced pain relief, and the wounds healed. During the follow-up observation period (average: 23.9 ± 14.7 months), nine patients died. None of the patients, including those who had lost patency of the superficial femoral artery, received major amputation. Conclusion: Elderly patients, including those who were in terminal stage, were able to withstand the operation, and their postoperative quality of life was not compromised. Although the patency following the surgery was limited, sparing the deep femoral artery could either prevent or delay the recurrence of critical limb ischemia.