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Background: Chronic Limb-Threatening Ischemia (CLTI) represents the most advanced stage of Peripheral Artery Disease (PAD) and is associated with dire prognosis, characterized by a substantial risk of limb amputation and diminished life expectancy. Despite significant advancements in therapeutic interventions, the underlying mechanisms precipitating the progression of PAD to CLTI remain elusive. Methods: Considering diabetes is one of the main risk factors contributing to PAD exacerbation into CLTI, we compared hind limb ischemia recovery in HFD STZ vs. non-HFD STZ mice to identify new mechanisms responsible for the exacerbation of PAD. Results: We used three different mouse models of diabetes and found that blood flow recovery in HFD STZ mice is altered only from day 14 post-surgery. Consistent with this kinetics, we found that angiogenesis and myogenesis which typically occur between day five and day 14 post-surgery are not impaired in mice in which diabetes was induced by a high fat diet and streptozotocin injections (HFD STZ mice). On the contrary, we found that capillary functionality e.i. acquisition of functional intercellular junctions and immune quiescence is impaired in HFD + STZ mice. Notably, 28 days after hind limb ischemia surgery, HFD + STZ mice display significantly increased capillary permeability to IgG and significantly increased levels of ICAM1. This was associated with an increased macrophage infiltration and an impaired myocyte differentiation. Importantly, we used ICAM1-blocking antibodies to demonstrate that increased ICAM1 expression in HFD + STZ mice decreases white blood cell circulation velocity within the microcirculation, which impairs its perfusion. Notably anti-ICAM1 therapy did diminish macrophage infiltration and oxidative stress but not myopathy suggesting that myopathy characterized by small myocytes expressing higher level of MYH2 could be responsible for microangiopathy. Conclusion: ICAM1 expression by the microvasculature impairs ischemic muscle reperfusion in HFD + STZ mice. Importantly, the increase in blood flow between day 14 and day 90 post-HLI surgery is not associated with an increased capillary density but with an improved functionality of capillaries. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Vascular complications after venoarterial extracorporeal membrane oxygenation (ECMO) remains poorly studied, although they may highly impact patient management after ECMO removal. Our aim was to assess their frequency, predictors, and management. DESIGN: Retrospective, observational cohort study. SETTING: Two ICUs from a tertiary referral academic hospital. PATIENTS: Adult patients who were successfully weaned from venoarterial ECMO between January 2021 and January 2022. INTERVENTIONS: None. PRIMARY OUTCOME: Vascular complications frequency related to ECMO cannula. MEASUREMENTS AND MAIN RESULTS: A total of 288 patients were implanted with venoarterial ECMO during the inclusion period. One hundred ninety-four patients were successfully weaned, and 109 underwent a CT examination to assess for vascular complications until 4 days after the weaning procedure. The median age of the cohort was 58 years (interquartile range [IQR], 46–64 yr), with a median duration of ECMO support of 7 days (IQR, 5–12 d). Vascular complications were observed in 88 patients (81%). The most frequent complication was thrombosis, either cannula-associated deep vein thrombosis (CaDVT) (n = 63, 58%) or arterial thrombosis (n = 36, 33%). Nonthrombotic arterial complications were observed in 48 patients (44%), with 35 (31%) presenting with bleeding. The most common site of CaDVT was the inferior vena cava, occurring in 33 (50%) of cases, with 20% of patients presenting with pulmonary embolism. There was no association between thrombotic complications and ECMO duration, anticoagulation level, or ECMO rotation flow. CT scans influenced management in 83% of patients. In-hospital mortality was 17% regardless of vascular complications. CONCLUSIONS: Vascular complications related to venoarterial ECMO cannula are common after ECMO implantation. CT allows early detection of complications after weaning and impacts patient management. Patients should be routinely screened for vascular complications by CT after decannulation. [ABSTRACT FROM AUTHOR]

Purpose: Tryptophan (TRP) degradation through the kynurenine pathway is responsible for converting 95% of free TRP into kynurenines, which modulate skeletal muscle bioenergetics, immune and central nervous system activity. Therefore, changes in the kynurenines during exercise have been widely studied but not in the context of the effects of remote ischemic preconditioning (RIPC). In this study, we analyzed the effect of 14-day RIPC training on kynurenines and TRP in runners after running intervals of 20 × 400 m. Methods: In this study, 27 semi-professional long-distance runners were assigned to two groups: a RIPC group performing 14 days of RIPC training (n = 12), and a placebo group, SHAM (n = 15). Blood was collected for analysis before, immediately after, and at 6 h and 24 h after the run. Results: After the 14-day RIPC/SHAM intervention, post hoc analysis showed a significantly lower concentration of XANA and kynurenic acid to kynurenine ratio (KYNA/KYN) in the RIPC group than in the SHAM group immediately after the running test. Conversely, the decrease in serum TRP levels was higher in the RIPC population. Conclusion: RIPC modulates post-exercise changes in XANA and TRP levels, which can affect brain health, yet further research is needed. [ABSTRACT FROM AUTHOR]

Background/Objectives: Chronic Limb-Threatening Ischemia (CLTI) is a chronic limb ischemic disease caused by vascular lesions, characterized by pain, ulcers, and gangrene, which can be life-threatening in severe cases. The objective of this study is to explore whether Berbamine (BBM) can protect against and repair ischemic muscle tissue in the lower limbs; Methods: Using a mouse hindlimb ischemia (HLI) model, 36 C57BL6 mice were divided into sham, HLI, and HLI+BBM treatment groups. Results: Our findings indicate that BBM can restore motor function and muscle tissue pathology in mice, potentially by inhibiting the nuclear translocation of nuclear factor kappa-B (NF-κB), thereby alleviating tissue inflammation caused by chronic ischemia, reducing muscle cell apoptosis, inhibiting M1 macrophage polarization, and promoting angiogenesis. Conclusions: Our research suggests that BBM has the potential to protect against ischemic damage in lower limb muscle tissue, providing a new approach to the treatment of CLTI. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the impact of sex on mid-term outcomes following stenting for aorto-iliac occlusive disease (AIOD). Methods: The Covered versus Balloon Expandable Stent Trial (COBEST) compared the safety and efficacy of the covered stent (CS) with those of the bare metal stent (BMS) in the treatment of hemodynamically significant AIOD. It was identified that CS provided a significant benefit. The primary endpoint of our analysis was the rate of primary patency 5 years following stenting for AIOD (inclusive of both CS and BMS) in both sexes. Results: Of the 168 lesions treated, 103 (61%) were present in men and 65 (39%) were present in women. Of the concomitant comorbidities, diabetes mellitus was significantly more common in women (17.5% vs 41.5%, p =.006). Although chronic limb threatening ischemia (CLTI) at the time of intervention was more common in women, the difference was not significant (16.5% vs 24.6%, p =.395). Sex was not associated with the primary patency rate (male; 0.70, 95% confidence interval [CI]: 0.23–2.19, p =.543). When considering both male sex and the utilization of BMS, no significant impact was found on the primary patency rate (hazard ratio [HR]: 3.43, 95% CI: 0.69–17.10, p =.133). All-cause mortality at 60 months was 22.6% in men compared to 19.4% in women (p =.695). Conclusions: No significant difference was identified in the primary patency rate between the sexes. Further investigation is warranted to ascertain whether sex-specific interventional guidelines are required in this regard. [ABSTRACT FROM AUTHOR]

Photobiomodulation (PBM) has been shown to be promising for the promotion of angiogenesis. The present study investigated the effects of PBM on vascularization in an animal model of peripheral artery disease. Wistar rats were divided into three groups. The control group received no procedures. The ischemia group was submitted to ligation of the femoral artery of the hindleg. The ischemia + PBM group was submitted to ligation of the femoral artery followed by PBM (660 and 808 nm, 100 mW, 4 J) over the site. Animals with ischemia treated with PBM exhibited comparable results to the control group with regards to the diameter of the α‐SMA+ vessels, cross‐sectional area of muscle fibers, percentage of collagen and serum concentration of IL‐17A, as well as similarities in terms of vertical mobility, temperature of the hindleg, number of acts of grooming, and percentage of movement, indicating a condition like that of limbs unaffected by ischemia. [ABSTRACT FROM AUTHOR]

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Background: Popliteal artery is a continuation of femoral artery, which extends obliquely from the osseoaponeurotic opening of adductor magnus to lower border of popliteus muscle, where it terminates by dividing into anterior tibial artery and tibioperoneal trunk, this ranges from 92% to 96%. Knowledge of anatomic variability in this region may have clinical implications and are very essential during vascular grafting, direct surgical repair, transluminal angioplasty, embolectomy, and other arterial injury. Materials and Methods: This study was conducted in anatomy department where 50 lower limbs embalmed with 10% of formalin will be procured from the department. Artery and its branches were exposed. Side determination, branching pattern of terminal branches will be noted, and measurements of the length of tibioperoneal trunk will be taken with the help of digital micrometer. Results: Length of tibioperoneal trunk was taken with the help of digital Vernier caliper. All data obtained will be produced in tabulated form and if any variations was photographed. Conclusions: Proper characterization of the anatomical properties of popliteal artery requires adequate knowledge of its terminal branching variants. Increasing rates of surgical reconstructions and vascular surgical procedures of the lower extremity place more significance on having detailed anatomical information. Endovascular treatment of critical limb ischemia in diabetics with crural and pedal diseases can be an exceedingly challenging and complex problem, in this regard prior awareness of variant branching pattern of terminal end of popliteal artery is important for planning appropriate surgery and to reduce arterial injury.

The OBJECTIVE was to study the short-term results of surgical treatment of patients with brachial artery injury in peacetime upper limb injury.METHODS AND MATERIALS. This study presents the short-term results of surgical treatment of 61 patients with brachial artery injury in peacetime upper limb injury. The study included 33 patients who were admitted to the City Hospital of St. Martyr Elizabeth in St. Petersburg from 2011 to 2022 and 28 patients who were admitted to Hospitals in the Leningrad Region from 2017 to 2022.RESULTS. All 61 patients underwent emergency surgery: autovenous prosthetics of the brachial artery was performed in 46 patients, an end-to-end anastomosis was formed in 10 patients, and a lateral suture was applied to 5 patients. In the early postoperative period, there were 3 thrombosis of the reconstruction zone, 1 amputation of a limb, 1 fatal outcome from severe blood loss.CONCLUSION. Upper limb injury with brachial artery injury without specialized assistance can lead to disability and even death of a patient, therefore requires emergency intervention by a vascular surgeon to stop bleeding, restore the main blood flow and stop limb ischemia.

Introduction: Pediatric acute limb ischemia (PALI) is a consequence of sudden loss of blood flow to an extremity that can progress to irreversible ischemia if not promptly treated. This may unfortunately result in life-changing consequences which include limb loss, limb length discrepancy, emotional trauma, and or financial stress. Due to the rarity of this condition, and the lack of high-quality evidence, treatment strategies have largely been anecdotal or extrapolated from treatment of the adult patient. The article is a guide to improve overall functional outcomes and reduce morbidity of PALI. Methods: The authors retrospectively analysed patient data on the electronic patient record of the hospital between January 2021 and December 2023. The patients with PALI were divided into three broad categories: iatrogenic arterial injury managed with the best medical management, managed surgically; iatrogenic deep vein injury/thrombosis, and trauma. Results: A total of 13 patients were referred during the study period. 9 were male. 8 cases were line related, 2 trauma and 3 acute deep vein thrombosis [DVT]. Two patients succumbed prior to intervention. Eight patients were managed with best medical therapy, two surgically and one by endovascular means. Conclusion: Since experience worldwide is limited with PALI, we decided to share our experience and a propose comprehensive algorithm for the management of PALI emphasizing a multi-disciplinary team approach that we follow at our hospital. Early and decisive involvement of vascular surgeons, hematologists, intervention radiologists, and pediatric intensive care physicians is necessary to achieve the most favorable outcomes.

Background Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease (PAD) and has poor clinical outcomes. Recently, stimulating arteriogenesis has been proposed to improve clinical outcomes. Several studies have shown that miRNAs have beneficial effects on limb ischemia related to arteriogenesis. This study aimed to review the roles of therapeutic miRNAs in the arteriogenesis of limb ischemia. Methods A systematic search was conducted through July 2021 using the PubMed, Scopus, and ScienceDirect databases. Two authors independently assessed studies that investigated the role of miRNAs in the arteriogenesis of limb ischemia, both in vivo and in clinical studies. Results All selected studies were in vivo studies, with a total of 36 articles and 28 types of miRNAs. miRNAs potentially regulate arteriogenesis by targeting different targets. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. MiRNA-126 was the most studied miRNA, and SPRED1 was the most common target of microRNA. However, the included studies showed high heterogeneity in terms of inducing hindlimb ischemia, the timing of administration, and the method used for evaluating arteriogenesis. Moreover, most studies presented unclear or high-risk bias. Conclusion MicroRNA application in a preclinical model of hindlimb ischemia has beneficial effects on arteriogenesis. This result indicates that miRNAs might be potentially beneficial in patients with CLTI. Registration The review protocol was registered with PROSPERO under registration number CRD42024484988.

Acute limb ischemia (ALI) is a sudden lack of blood flow to a limb, primarily caused by arterial embolism and thrombosis. Various experimental animal models, including non-invasive and invasive methods, have been developed and successfully used to induce limb ischemia-reperfusion injuries (L-IRI). However, there is no consensus on the methodologies used in animal models for L-IRI, particularly regarding the assessment of functional recovery. The present study aims to compare different approaches that induce L-IRI and determine the optimal animal model to study functional limb recovery. In this study, we applied a pneumatic cuff as a non-invasive method and ligated the aorta, iliac, or femoral artery as invasive methods to induce L-IRI. We have measured grip strength, motor function, creatine kinase level, inflammatory markers such as nuclear factor NF-κB, interleukin-6 (IL-6), hypoxia markers such as hypoxia-induced factor-1 α (HIF-1 α ), and evaluated the muscle injury with hematoxylin and eosin (H&E) staining in Sprague Dawley rats after inducing L-IRI. The pneumatic pressure cuff method significantly decreased the muscle strength of the rats, causing the loss of ability to hold the grid and inducing significant limb function impairment, while artery ligations did not. We conclude from this study that the tourniquet cuff method could be ideal for studying functional recovery after L-IRI in the rat model. [ABSTRACT FROM AUTHOR]

Persistent sciatic artery (PSA) is a rare congenital vascular anomaly resulting from embryologic axial artery malformation in the lower limb. This case report presents three patients aged 45–60, each with bilateral PSA presenting with symptoms indicative of PSA complications, including aneurysmal degeneration, limb ischemia, thromboembolism, or neuralgia from nerve compression. It highlights the diagnostic process, management strategies, and clinical outcomes observed at a tertiary referral hospital. Treatment involved a collaborative, multidisciplinary approach with vascular surgeons, internists, and radiologists tailoring interventions to individual patient findings and disease progression. This report aims to provide insights into the diverse presentations and management of PSA in a resource limited setting, encouraging further reporting and case studies to enhance understanding of therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Motorcycle accidents can cause complex orthopedic and vascular injuries, posing diagnostic and treatment challenges. We present a case of a 34-year-old Albanian man with a multi-ligament knee injury and arterial thrombosis in his left leg following a motorcycle accident. The patient initially received conservative care but developed severe leg pain, coldness, and numbness, prompting urgent vascular imaging. Imaging confirmed popliteal artery thrombosis, necessitating surgical intervention. This case highlights the severe complications of motorcycle accidents, emphasizing the need for prompt vascular injury detection and a multidisciplinary approach in trauma management. Early recognition and timely intervention are crucial to prevent long-term morbidity and to optimize recovery. Further research is needed to improve diagnostic and treatment strategies for vascular complications in such injuries.

PurposeTryptophan (TRP) degradation through the kynurenine pathway is responsible for converting 95% of free TRP into kynurenines, which modulate skeletal muscle bioenergetics, immune and central nervous system activity. Therefore, changes in the kynurenines during exercise have been widely studied but not in the context of the effects of remote ischemic preconditioning (RIPC). In this study, we analyzed the effect of 14-day RIPC training on kynurenines and TRP in runners after running intervals of 20 × 400 m.MethodsIn this study, 27 semi-professional long-distance runners were assigned to two groups: a RIPC group performing 14 days of RIPC training (n = 12), and a placebo group, SHAM (n = 15). Blood was collected for analysis before, immediately after, and at 6 h and 24 h after the run.ResultsAfter the 14-day RIPC/SHAM intervention, post hoc analysis showed a significantly lower concentration of XANA and kynurenic acid to kynurenine ratio (KYNA/KYN) in the RIPC group than in the SHAM group immediately after the running test. Conversely, the decrease in serum TRP levels was higher in the RIPC population.ConclusionRIPC modulates post-exercise changes in XANA and TRP levels, which can affect brain health, yet further research is needed.

Aim: This study aims to investigate the effects of large extracellular vesicles (EVs) induced by pluripotent stem cell-derived mesenchymal stem cells on lower limb ischemic disease and explore its potential mechanisms. Materials & methods: The pathology of muscles was accessed by H&E staining and immunofluorescence staining. In vitro, we conducted wound-healing assay, tube formation assay, RT qPCR, ELISA, RNA sequencing and proteomic analysis. Results: iMSCs-lEVs alleviated the injury of ischemic lower limb and promoted the recovery of lower limb function. In vitro, iMSCs-lEVs promoted the proliferation, migration, and angiogenesis of HMEC-1 cells by regulating the ERK/MAPK signing pathway. Conclusion: This study demonstrated that iMSCs-lEVs promoted endothelial cell angiogenesis via the ERK/MAPK signaling pathway, thereby improving function after lower limb ischemic injury. Article highlights The therapeutic potential of large extracellular vesicles derived from induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs-lEVs) in promoting recovery after lower limb ischemia has rarely been investigated so far. Improving the functional status of endothelial cells may be effectively alleviate the symptoms of lower limb ischemia. iMSCs-lEVs could restore blood flow perfusion in ischemic tissues of mouse lower limbs and improved their function following ischemia. iMSCs-lEVs promoted endothelial cell proliferation, migration and tube formation by regulating the ERK/MAPK signaling pathway. These findings reveal the molecular mechanisms underlying the application of iMSCs-lEVs on mast cells and provide a novel therapeutic strategy for pain caused by tendinopathy. [ABSTRACT FROM AUTHOR]

A persistent sciatic artery (PSA) is a rare congenital vascular anomaly with an extremely low incidence of about 0.04%–0.06%. It is due to the persistence of the embryological axial limb artery, representing a continuation of the internal iliac artery into the thigh through the greater sciatic foramen below the piriformis muscle and down the thigh alongside the sciatic nerve. In normal embryologic development of the lower limb, the axial artery normally regresses after week 12. Persistent sciatic artery is often asymptomatic until a complication develops, it can be classified into two types, complete and incomplete. PSA can cause serious lower limb complications such as acute or critical limb ischemia. [ABSTRACT FROM AUTHOR]

ObjectiveLifestyle choices such as tobacco and e-cigarette use are a risk factor for peripheral arterial disease (PAD) and may influence therapeutic outcomes. The effect of chronic nicotine exposure on the angiogenic capacity of human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) was assessed in a murine model of PAD.MethodsMice were exposed to nicotine or phosphate-buffered saline (PBS) for 28 days, followed by induction of limb ischemia and iPSC-EC transplantation. Cells were injected into the ischemic limb immediately after induction of hindlimb ischemia and again 7 days later. Limb perfusion was assessed by laser Doppler spectroscopy, and transplant cell survival was monitored for 14 days afterward using bioluminescence imaging, followed by histological analysis of angiogenesis.ResultsTransplant cell retention progressively decreased over time after implantation based on bioluminescence imaging, and there were no significant differences in cell survival between mice with chronic exposure to nicotine or PBS. However, compared with mice without nicotine exposure, mice with prior nicotine exposure had had an impaired therapeutic response to iPSC-EC therapy based on decreased vascular perfusion recovery. Mice with nicotine exposure, followed by cell transplantation, had significantly lower mean perfusion ratio after 14 days (0.47 ± 0.07) compared with mice undergoing cell transplantation without prior nicotine exposure (0.79 ± 0.11). This finding was further supported by histological analysis of capillary density, in which animals with prior nicotine exposure had a lower capillary density (45.9 ± 4.7 per mm2) compared with mice without nicotine exposure (66.5 ± 8.1 per mm2). Importantly, the ischemic limbs mice exposed to nicotine without cell therapy also showed significant impairment in perfusion recovery after 14 days, compared with mice that received PBS + iPSC-EC treatment. This result suggested that mice without chronic nicotine exposure could respond to iPSC-EC implantation into the ischemic limb by inducing perfusion recovery, whereas mice with chronic nicotine exposure did not respond to iPSC-EC therapy.ConclusionsTogether, these findings show that chronic nicotine exposure adversely affects the ability of iPSC-EC therapy to promote vascular perfusion recovery and angiogenesis in a murine PAD model.

OBJECTIVES: Venous thrombosis has been widely described in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, arterial thrombosis has rarely been reported. This study aims to assess the incidence, risk factors, interventions, and outcomes of acute aortoiliac arterial thrombosis in patients with active SARS-CoV-2 infections. METHODS: We present seven SARS-CoV-2-positive patients from our institution who acutely developed thrombi in the aortoiliac arterial system (7/2020-1/2021). A systematic review of the literature on aortoiliac arterial thrombosis in patients with SARS-CoV-2 infections in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was also performed. The available data from all reported cases in the literature and at our institution were analyzed. RESULTS: Thirty published articles and journal correspondences, including 52 patients, were reviewed and analyzed in addition to our institutions 7 cases. In total, 59 SARS-CoV-2-positive patients were found to have acute aortoiliac thrombosis. The abdominal aorta was the most frequent location for the development of a thrombus. Baseline demographics and medical comorbidities were not significantly different between the symptomatic and asymptomatic cohorts. Seventy-one percent of patients were symptomatic (lower limb ischemia: 75.0%, renal infarction: 20.0%, stroke: 12.5%, mesenteric ischemia: 10.0%). All patients with thrombus involving the ascending aorta, aortic bifurcation, or iliac artery developed thromboembolic or ischemic complications. All patients received systemic anticoagulation. Fifty-three percent of all patients were managed medically. Ninety-four percent of the asymptomatic patients were managed medically. One asymptomatic patient underwent endovascular aspiration of a mobile thrombus. Three (23.1%) deaths occurred in the asymptomatic cohort from hypoxic respiratory failure. Fourteen (36.8%) deaths occurred in the symptomatic cohort. The in-hospital mortality rate was 33.3% overall and 43.8% for patients with thrombi involving more than one aortoiliac segment. CONCLUSIONS: The presence of thrombi in the aortoiliac arterial system appears to be a poor prognostic indicator for patients with active SARS-CoV-2 infections. Medical management of patients with asymptomatic aortoiliac thrombi may be considered. The presence of thrombi involving the ascending aorta, aortic bifurcation, or iliac artery may warrant consideration for operative intervention due to the risk for thromboembolic or ischemic complications. Further study is needed to fully delineate the risk factors, optimal treatment, and outcomes of arterial thrombosis in the setting of SARS-CoV-2 infection.

Background Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral artery disease (PAD) and has poor clinical outcomes. Recently, stimulating arteriogenesis has been proposed to improve clinical outcomes. Several studies have shown that miRNAs have beneficial effects on limb ischemia related to arteriogenesis. This study aimed to review the roles of therapeutic miRNAs in the arteriogenesis of limb ischemia. Methods A systematic search was conducted through July 2021 using the PubMed, Scopus, and ScienceDirect databases. Two authors independently assessed studies that investigated the role of miRNAs in the arteriogenesis of limb ischemia, both in vivo and in clinical studies. Results All selected studies were in vivo studies, with a total of 36 articles and 28 types of miRNAs. miRNAs potentially regulate arteriogenesis by targeting different targets. The following miRNAs were upregulated to enhance arteriogenesis: miRNA-126-3p, -93, -675, -143-3p, -130a, -210, -146b, -21, -let-7g, -132/212, -150, and 155. Meanwhile, microRNAs needed to be downregulated, namely: miRNA-939-5p, -503, -199a-5p, -146a, -92a, -14q32 microRNA gene cluster, -15a/16, -100, -133a, -139-5p, -223, -352, -615-5p, -15b/5p, -124-3p, and 29a. MiRNA-126 was the most studied miRNA, and SPRED1 was the most common target of microRNA. However, the included studies showed high heterogeneity in terms of inducing hindlimb ischemia, the timing of administration, and the method used for evaluating arteriogenesis. Moreover, most studies presented unclear or high-risk bias. Conclusion MicroRNA application in a preclinical model of hindlimb ischemia has beneficial effects on arteriogenesis. This result indicates that miRNAs might be potentially beneficial in patients with CLTI. Registration The review protocol was registered with PROSPERO under registration number CRD42024484988.

Endovascular stent placement is commonly used to treat vascular stenosis/occlusions to maintain hemodialysis access patency. These procedures are generally safe and associated with low incidence of serious complications, including stent infection, migration, fracture, and erosion. We present a case of venous stent erosion causing acute limb ischemia in a patient with an arteriovenous fistula for dialysis.

Abstract Objective Thromboangiitis obliterans (TAO) is one of the most common types of peripheral arterial disease (PAD). This study aimed to explore the characteristics of the top 100 most cited articles in the TAO. Methods A bibliometric analysis based on the Web of Science (WOS) database was performed. Literature was retrieved and ranked by the citations. Listed below are the top 100 citations, including original articles, reviews, full-length proceeding papers, and case reports that were included for analysis. The type of literature, research areas, and languages were recorded. The trends of citations including the total citations, an analysis of publication and citation numbers were conducted each year. We analyzed citations from highly cited countries, authors, institutions, and journals. Research hotspots were gathered by a visualized analysis of author keywords. Results Most of the highly cited literature was original articles. A rising trend was observed in the number of citations per year. The peaks in the number of highly cited articles appeared in the year 1998 and 2006. The majority of the articles focused on the cardiovascular system and surgery. Journal of Vascular Surgery published most of the highly cited articles. The USA and Japan contributed nearly half the number of highly cited articles. Mayo Clinic and Nagoya University were highly cited institutions. Shionoya S and Olin JW were both the author with the largest number of citations and the most highly cited author in the reference. Articles that were highly cited most often addressed the following topics: “vasculitis”, “autoimmune disease”, and “critical limb ischemia”. Keywords that were mostly used in recent years were “stem cell therapy”, “progenitor therapy”, and “immunoadsorption”. The detection of bursts of author keywords showed the following: “permeability”, “differentiation”, and “critical limb ischemia” are recent keywords that have burst. Conclusions In this study, the highly cited contributors in the field of TAO research were identified. Most cited articles in the top 100 focused on the cardiovascular system and surgery. Treatment and pathophysiology including stem cell therapy, progenitor therapy, genetics, autoimmunity, and inflammation are the hotspots of TAO.

Acute limb ischemia (ALI) is a sudden lack of blood flow to a limb, primarily caused by arterial embolism and thrombosis. Various experimental animal models, including non-invasive and invasive methods, have been developed and successfully used to induce limb ischemia-reperfusion injuries (L-IRI). However, there is no consensus on the methodologies used in animal models for L-IRI, particularly regarding the assessment of functional recovery. The present study aims to compare different approaches that induce L-IRI and determine the optimal animal model to study functional limb recovery. In this study, we applied a pneumatic cuff as a non-invasive method and ligated the aorta, iliac, or femoral artery as invasive methods to induce L-IRI. We have measured grip strength, motor function, creatine kinase level, inflammatory markers such as nuclear factor NF-κB, interleukin-6 (IL-6), hypoxia markers such as hypoxia-induced factor-1α (HIF-1α), and evaluated the muscle injury with hematoxylin and eosin (H&E) staining in Sprague Dawley rats after inducing L-IRI. The pneumatic pressure cuff method significantly decreased the muscle strength of the rats, causing the loss of ability to hold the grid and inducing significant limb function impairment, while artery ligations did not. We conclude from this study that the tourniquet cuff method could be ideal for studying functional recovery after L-IRI in the rat model.

Objective: Data regarding management of lower-extremity malperfusion in the setting of type A aortic dissection are limited. This study aimed to compare acute type A aortic dissection with lower-extremity malperfusion outcomes in patients undergoing lower-extremity revascularization with no revascularization. Methods: Consecutive patients undergoing acute type A aortic dissection surgery were identified from a prospectively maintained database. Perioperative variables were compared between patients with and without lower-extremity malperfusion. Factors associated with lower-extremity malperfusion, revascularization, and mortality were determined using univariable Cox regression and Firth's penalized likelihood modeling. Results: From January 2007 to December 2021, 601 patients underwent proximal aortic repair for acute type A aortic dissection at a quaternary care center. Of these, 85 of 601 patients (14%) presented with lower-extremity malperfusion and were more often male (P = .02), had concomitant moderate or greater aortic insufficiency (P = .05), had lower ejection fraction (P = .004), had preoperative dialysis dependence (P = .01), and had additional cerebral, visceral, and renal malperfusion syndromes (P

Occlusive lesions of the main arteries of the extremities are a common and severe disease that leads to disability and has a high rate of death [1]. Many different drugs are known for the treatment of this pathology, however, despite the large number of pharmacological drugs and conservative treatment methods, surgical methods of treatment are the most effective in terms of saving the limb [3, 4]. However, methods of conservative therapy continue to be the most important component of the treatment of arterial limb ischemia, which requires the development of more effective methods. As a result of the use of intravenous administration of a 0.01 % solution of nitroglycerin for the treatment of arterial ischemia of the extremities in patients with coronary artery disease, it was possible to obtain good immediate results in an average of 57.3 % of cases.

Limb ischemia is a refractory disease characterized by persistent inflammation, insufficient angiogenesis, and tissue necrosis. Although mesenchymal stem cells (MSCs) have shown potential for treating limb ischemia, their therapeutic effects are limited by low engraftment rates. Therefore, developing an optimal MSC delivery system that enhances cell viability is imperative. Selenium, known for its cytoprotective properties in various cell types, offers a potential strategy to enhance therapeutic effect of MSCs. In this study, we evaluated the cytoprotective effects of selenium on MSCs, and developed an injectable thermosensitive selenium-containing hydrogel based on PLGA-PEG-PLGA triblock copolymer, as a cell carrier to improve MSC viability after engraftment. The biocompatibility, biodegradability, and cytoprotective capabilities of selenium-containing hydrogels were assessed. Furthermore, the therapeutic potential of MSCs encapsulated within a thermosensitive selenium-containing hydrogel in limb ischemia was evaluated using cellular and animal experiments. Selenium protects MSCs from oxidative damage by upregulating GPX4 through a transcriptional mechanism. The injectable thermosensitive selenium-containing hydrogel exhibited favorable biocompatibility, biodegradability, and antioxidant properties. It can be easily injected into the target area in liquid form at room temperature and undergoes gelation at body temperature, thereby preventing the diffusion of selenium and promoting the cytoprotection of MSCs. Furthermore, MSCs encapsulated within the selenium-containing hydrogel effectively inhibited macrophage M1 polarization while promoting macrophage M2 polarization, thus accelerating angiogenesis and restoring blood perfusion in ischemic limbs. This study demonstrated the potential of an injectable thermosensitive selenium-containing hydrogel as a promising method for MSC delivery. By addressing the challenge of low retention rate, which is a major obstacle in MSC application, this strategy effectively improves limb ischemia.

Background Perfusion deficits contribute to symptom severity, morbidity, and death in peripheral artery disease (PAD); however, no standard method for quantifying absolute measures of skeletal muscle perfusion exists. This study sought to preclinically test and clinically translate a positron emission tomography (PET) imaging approach using an atherosclerosis‐targeted radionuclide, fluorine‐18‐sodium fluoride (18F‐NaF), to quantify absolute perfusion in PAD. Methods and Results Eight Yorkshire pigs underwent unilateral femoral artery ligation and dynamic 18F‐NaF PET/computed tomography imaging on the day of and 2 weeks after occlusion. Following 2‐week imaging, calf muscles were harvested to quantify microvascular density. PET methodology was validated with microspheres in 4 additional pig studies and translated to patients with PAD (n=39) to quantify differences in calf perfusion across clinical symptoms/stages and perfusion responses in a case of revascularization. Associations between PET perfusion, ankle‐brachial index, toe‐brachial index, and toe pressure were assessed in relation to symptoms. 18F‐NaF PET/computed tomography quantified significant deficits in calf perfusion in pigs following arterial occlusion and perfusion recovery 2 weeks after occlusion that coincided with increased muscle microvascular density. Additional studies confirmed that PET‐derived perfusion measures agreed with microsphere‐derived perfusion measures. Translation of imaging methods demonstrated significant decreases in calf perfusion with increasing severity of PAD and quantified perfusion responses to revascularization. Perfusion measures were also significantly associated with symptom severity, whereas traditional hemodynamic measures were not. Conclusions 18F‐NaF PET imaging quantifies perfusion deficits that correspond to clinical stages of PAD and represents a novel perfusion imaging strategy that could be partnered with atherosclerosis‐targeted 18F‐NaF PET imaging using a single radioisotope injection. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03622359.

Acute limb ischemia (ALI) due to arterial thromboembolic occlusion is a critical emergency in vascular medicine, requiring attention for rapid diagnosis and intervention, to prevent limb loss and major amputation, which is associated with patient disability in the long term. Traditionally, surgical embolectomy has been used for the treatment of ALI. Endovascular treatment of ALI traditionally involved catheter-directed thrombolysis. This option, however, poses some limitations, including an increased risk for access site and systemic bleeding complications, especially in patients with high bleeding risk. Therefore, in the last decades, several devices have been developed and tested for the mechanical endovascular treatment of ALI. Such devices involve either rotational thrombectomy or continuous thrombus aspiration. While rotational thrombectomy is limited in rather large arteries due to the risk of dissection and perforation in arteries <3 mm, continuous thrombus aspiration can be applied in smaller vessels and tortuous anatomies. In our case series we present a minimal-invasive endovascular approach for the treatment of two patients with ALI due to thrombotic occlusion of tortious and small diameter arteries. Minimal-invasive mechanical thrombectomy using the Penumbra Aspiration System emerged as a successful alternative to surgical embolectomy, enabling prompt treatment and with a short hospital stay for both patients. Our article therefore highlights the use of continuous thrombus aspiration in small diameter vessels and tortuous anatomies, which may represent a contraindication for the use of rotational thrombectomy. In addition, this technique may be applied even in patients with higher bleeding risk since additional lysis is not necessary in patients, where complete thrombus removal can be achieved by this device. [ABSTRACT FROM AUTHOR]

Introduction: Acute limb ischemia occurs when an extremity is deprived of adequate blood flow. Aim: To study the modes of presentation, investigation and treatment modalities in cases of acute limb ischemia to evaluate the outcomes of management. Methods: This prospective study is conducted on 40 patients aged between 12 to 70 years at a tertiary care hospital from june 2018 to January 2021. All patients of acute limb ischemia presenting to a tertiary care hospital for the first time were taken into study. Results: half of the patients in the study group presented in their 5th and 6th decade of life. 32 patients presented with lower limb ischemia compared to 8 patients of upper limb ischemia. Management was planned as per clinical and imaging findings 58% (n=23) patients underwent thromboembolectomy. Conclusion: Acute ischemia often presents in a patient with multiple medical co-morbidities. Therefore, careful clinical assessment of the individual is as important as assessment of the limb. [ABSTRACT FROM AUTHOR]

Ischemic postconditioning (I-PostC) has a protective effect against acute kidney injury (AKI) induced by limb ischemia–reperfusion (LIR); however, the exact mechanism remains to be elucidated. Our study aims to investigate the potential involvement of high-mobility group box 1 protein (HMGB1) and autophagy in renoprotection generated by I-PostC. A rat model of LIR-induced AKI was established and rats were randomly assigned to five groups: (i) sham-operated control, (ii) I/R, (iii) I/R + I-PostC, (iv) I/R + I-PostC + rapamycin (autophagy activator), and (v) I/R + I-PostC + 3-methyladenine (autophagy inhibitor). Morphological changes in the kidneys were assessed by histology, and ultrastructural changes in renal tubular epithelial cells and glomerular podocytes were observed by transmission electron microscopy. The levels of kidney function parameters, serum inflammatory factors, and autophagy markers were detected. The results showed that the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines (TNF-α and IL-6) were significantly higher in the I/R group compared to the sham control in serum and in renal tissues. I-PostC significantly reduced the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines in renal tissues and improved renal function. Renal histopathology and ultrastructural observations indicated that I-PostC alleviated renal tissue injury. In addition, rapamycin (autophagy activator) treatment increased the levels of inflammatory cytokine expression levels and decreased renal function, reversed the protective effect of I-PostC against LIR-induced AKI. In conclusion, I-PostC could play a protective role against AKI by regulating the release of HMGB1 and inhibiting autophagy activation. [ABSTRACT FROM AUTHOR]

Evidence increasingly shows that the risk of thrombotic complications in COVID-19 is associated with a hypercoagulable state. Several organizations have released guidelines for the management of COVID-19-related coagulopathy and prevention of VTE. However, an urgent need exists for practical guidance on the management of arterial thrombosis and thromboembolism in this setting. What is the current available evidence informing the prevention and management of arterial thrombosis and thromboembolism in patients with COVID-19? A group of approved panelists developed key clinical questions by using the Population, Intervention, Comparator, and Outcome (PICO) format that address urgent clinical questions regarding prevention and management of arterial thrombosis and thromboembolism in patients with COVID-19. Using MEDLINE via PubMed, a literature search was conducted and references were screened for inclusion. Data from included studies were summarized and reviewed by the panel. Consensus for the direction and strength of recommendations was achieved using a modified Delphi survey. The review and analysis of the literature based on 11 PICO questions resulted in 11 recommendations. Overall, a low quality of evidence specific to the population with COVID-19 was found. Consequently, many of the recommendations were based on indirect evidence and prior guidelines in similar populations without COVID-19. The existing evidence and panel consensus do not suggest a major departure from the management of arterial thrombosis according to recommendations predating the COVID-19 pandemic. Data on the optimal strategies for prevention and management of arterial thrombosis and thromboembolism in patients with COVID-19 are sparse. More high-quality evidence is needed to inform management strategies in these patients. [ABSTRACT FROM AUTHOR]

The primary purpose of this study was to identify factors associated with the development of arterial line–related limb ischemia in patients on extracorporeal membrane oxygenation (ECMO). The authors also sought to characterize and report the outcomes of patients who developed arterial line–related limb ischemia. Retrospective cohort study. A single academic tertiary referral ECMO center. Consecutive patients who were treated with ECMO over 6 years. Use of arterial line. A total of 278 consecutive ECMO patients were included, with 19 (7%) patients developing arterial line–related limb ischemia during the ECMO run. Postcannulation Sequential Organ Failure Assessment (SOFA) (adjusted odds ratio [aOR] 1.20, 95% CI 1.08-1.32), Acute Physiology and Chronic Health Evaluation–II (aOR 0.84, 95% CI 0.74-0.95), and adjusted Vasopressor Dose Equivalence (aOR 1.03, 95% CI 1.01-1.05) scores were independently associated with the development of arterial line–associated limb ischemia. A SOFA score of ≥17 at the time of ECMO cannulation had an 80% sensitivity and 87% specificity for predicting arterial line–related limb ischemia. Arterial line–related limb ischemia is much more common in ECMO patients than in the typical intensive care unit setting. The SOFA score may be useful in identifying which patients may be at risk for arterial line–related limb ischemia. As this was a single-center retrospective study, these results are inherently exploratory, and prospective multicenter studies are necessary to validate these results. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD), the pathophysiologic narrowing of the arterial blood vessels of the lower limbs due to atherosclerosis, is estimated to affect more than 200 million people worldwide and its prevalence ranges from 0.9 to 31.3% in people aged ≥50 years. It is an established marker of systemic obstructive atherosclerosis, which depicts patients at higher risk of myocardial infarction and stroke, due to the involvement of coronary and cerebral arteries in the atherosclerotic process. Therefore, identifying PAD, particularly in patients with coronary artery disease, is important to assess the cardiovascular risk score and implement specific therapies and prevention strategies. Since PAD emerged as an important clinical cardiovascular predictor, even more than other typical cardiovascular risk factors, an aggressive strategy to identify and treat PAD patients should be pursued by general practitioners, cardiologists, and vascular surgeons; similarly, preventive strategies should be implemented to improve prognosis and outcomes, particularly in patients suffering from both coronary artery disease and PAD. In this review, we describe the pathophysiology, including limb vasoconstriction after coronary angioplasty, the diagnosis of PAD, prognosis according to cardiovascular events, coronary artery disease, and heart failure. Furthermore, a large section of this review is on management, which spans from risk factors' modification to antithrombotic therapy, and revascularization is provided. Finally, considerations about newer therapeutic options for the "desert foot" are discussed, including gene therapy. [ABSTRACT FROM AUTHOR]

Objective: Thromboangiitis obliterans (TAO) is one of the most common types of peripheral arterial disease (PAD). This study aimed to explore the characteristics of the top 100 most cited articles in the TAO. Methods: A bibliometric analysis based on the Web of Science (WOS) database was performed. Literature was retrieved and ranked by the citations. Listed below are the top 100 citations, including original articles, reviews, full-length proceeding papers, and case reports that were included for analysis. The type of literature, research areas, and languages were recorded. The trends of citations including the total citations, an analysis of publication and citation numbers were conducted each year. We analyzed citations from highly cited countries, authors, institutions, and journals. Research hotspots were gathered by a visualized analysis of author keywords. Results: Most of the highly cited literature was original articles. A rising trend was observed in the number of citations per year. The peaks in the number of highly cited articles appeared in the year 1998 and 2006. The majority of the articles focused on the cardiovascular system and surgery. Journal of Vascular Surgery published most of the highly cited articles. The USA and Japan contributed nearly half the number of highly cited articles. Mayo Clinic and Nagoya University were highly cited institutions. Shionoya S and Olin JW were both the author with the largest number of citations and the most highly cited author in the reference. Articles that were highly cited most often addressed the following topics: "vasculitis", "autoimmune disease", and "critical limb ischemia". Keywords that were mostly used in recent years were "stem cell therapy", "progenitor therapy", and "immunoadsorption". The detection of bursts of author keywords showed the following: "permeability", "differentiation", and "critical limb ischemia" are recent keywords that have burst. Conclusions: In this study, the highly cited contributors in the field of TAO research were identified. Most cited articles in the top 100 focused on the cardiovascular system and surgery. Treatment and pathophysiology including stem cell therapy, progenitor therapy, genetics, autoimmunity, and inflammation are the hotspots of TAO. [ABSTRACT FROM AUTHOR]

• VA ECMO is a treatment option for refractory cardiogenic shock and cardiac arrest. • Lower limb ischemia (LLI) could represent a complication of femoral VA ECMO. • Surgical femoral VA ECMO is associated with a low rate of LLI. • LLI does not result into an increased risk of in-hospital mortality. • Female sex is an independent risk factor of LLI. To analyze the incidence, clinical impact on survival, and risk factors of lower limb ischemia (LLI) of surgical peripheral femoral venoarterial extracorporeal membrane oxygenation (VA ECMO) in the current era. A retrospective analysis of the authors' institutional database of VA ECMO was performed. Patients were divided into 2 groups according to the occurrence of LLI. The primary endpoint was survival to hospital discharge. Risk factors of LLI were searched with multivariate analyses. University hospital. Adult patients receiving peripheral VA ECMO for refractory cardiogenic shock and cardiac arrest. None. From January 2018 to December 2021, 188 patients (mean age: 52.0 ± 14.1 years; 63.8% male, 36.2% female) received peripheral VA ECMO. Male sex was more prevalent in the group without LLI (65.9% v 33.3%; p = 0.031). Twelve (6.4%) patients developed LLI during VA ECMO support (n = 6) or after VA ECMO removal (n = 6). Survival to hospital discharge was not statistically different between patients with and without LLI (50.0% v 48.3%; p = 0.571). Female sex patients were at increased risk for LLI (odds ratio 4.38, 95% CI 1.21-15.81; p = 0.024). Peripheral femoral VA ECMO through a surgical approach is associated with a low LLI rate, which does not increase the risk of in-hospital mortality. The female sex is an independent risk factor for LLI. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of lower extremity artery disease (LEAD) continues to increase worldwide. This is expected to translate into logarithmic rise in lower-limb amputations especially in the developing world. Majority of patients suffering from LEAD remain asymptomatic until late and are vulnerable to limb-threatening complications unless actively screened and treated. Methods: This was a prospective, single-center, observational study to determine the prevalence and predictors of LEAD. Patients with known atherosclerotic vascular disease (but not known LEAD) or those at risk were enrolled. All underwent ankle brachial index (ABI) measurement as per the standard protocol. A threshold of ABI ≤0.90 was taken to diagnose LEAD. Results: A total of 1000 patients were enrolled. The mean age of the group was 61.4 ± 10.0 years and the prevalence of LEAD was 10.2%. Amongst those who had LEAD, the majority of patients (69.6%) had no symptoms. The prevalence of LEAD in diabetic population in our study was 13.2% and it was 30.9% in coronary artery disease patients . Factors independently linked to LEAD on regression analysis included advanced age, presence of diabetes, smoking history, lower serum HDL and a lower ejection fraction. Conclusions: The vast majority of patients suffering from LEAD are asymptomatic. Early diagnoses and institution of appropriate medical and physical therapy can prevent excess morbidity and mortality due to LEAD. Factors independently linked to LEAD are advanced age, presence of diabetes, smoking history, lower serum HDL and a lower ejection fraction. The presence of either of these should signal undertaking of appropriate steps to unmask underlying LEAD.

An attempt to preserve the knee joint in a patient on hemodialysis with stage IV lower limb ischemia with a high risk of thrombotic and hemorrhagic complications is presented. Multifocal atherosclerosis and extensive occlusion of the arteries of the lower leg ruled out the technical possibility of revascularization. The patient refused the proposed hip amputation. An attempt was made to perform amputation at the level of the lower leg. Required therapy aimed at the treatment and prevention of thrombotic complications, and optimization of microcirculation in the ischemic limb. For this purpose, a prolonged blockade of the sciatic and femoral nerves, combined anticoagulant therapy, and treatment with alprostadil were performed. Therapy with antithrombotic and vasoactive drugs was not effective and was complicated by the state of persistent hypocoagulation with an episode of bleeding. Amputation of the limb at the level of the thigh was performed according to vital indications after correction of hypocoagulation. The lack of clinical recommendations on anticoagulant therapy for critical lower limb ischemia in patients with stage 5 chronic kidney disease requires an individual approach to the choice of antithrombotic drugs and their doses, monitoring the state of blood coagulation using an integral method for assessing the hemostasis system thromboelastography.

Background: Intraoperative transfusions in vascular patients undergoing major lower limb amputations (LLAs) are associated with worse postoperative outcomes. Methods: We conducted a retrospective study from 2015 to 2020 to identify perioperative factors associated with the need for intraoperative transfusion for patients undergoing below knee or above knee amputations secondary to vascular disease. Results: A total of 65 patients with major LLAs were identified, 39 (60%) with below knee and 26 (40%) with above knee amputations. There were 15 (23%) patients who were transfused intraoperatively and 50 (77%) who were not. Six (15%) of the below knee patients and 9 (34%) of the above knee patients required intraoperative transfusion. Of the variables studied, only preoperative hemoglobin (8.6 ±.4 vs 9.9 ±.2 g/dL, P =.01), change in hemoglobin (−.1 ±.4 vs.8 ±.2 g/dL, P =.01), estimated intraoperative blood loss (416 ± 168 vs 126 ± 14 mL, P =.04), and operative duration (116 ± 19 min. vs 89 ± 6 min, P =.046) were associated with a transfusion requirement with these patients having a longer length of stay (42 [13-76] vs 21 [12-31] days, P =.04) and a higher risk of mortality (33% vs 10%, P =.03). Discussion: The study is limited by a small sample size from a single institution. However, patients who received an intraoperative transfusion had a lower starting hemoglobin, higher estimated blood loss, required longer hospital stays, and were at a higher risk for post-discharge mortality. [ABSTRACT FROM AUTHOR]

Exercise has a profound effect on cardiovascular disease, particularly through vascular remodeling and regeneration. Peripheral artery disease (PAD) is one such cardiovascular condition that benefits from regular exercise or rehabilitative physical therapy in terms of slowing the progression of disease and delaying amputations. Various rodent pre-clinical studies using models of PAD and exercise have shed light on molecular pathways of vascular regeneration. Here, I review key exercise-activated signaling pathways (nuclear receptors, kinases, and hypoxia inducible factors) in the skeletal muscle that drive paracrine regenerative angiogenesis. The rationale for highlighting the skeletal muscle is that it is the largest organ recruited during exercise. During exercise, skeletal muscle releases several myokines, including angiogenic factors and cytokines that drive tissue vascular regeneration via activation of endothelial cells, as well as by recruiting immune and endothelial progenitor cells. Some of these core exercise-activated pathways can be extrapolated to vascular regeneration in other organs. I also highlight future areas of exercise research (including metabolomics, single cell transcriptomics, and extracellular vesicle biology) to advance our understanding of how exercise induces vascular regeneration at the molecular level, and propose the idea of "exercise-mimicking" therapeutics for vascular recovery. [ABSTRACT FROM AUTHOR]

The impairment in microvascular network formation could delay the restoration of blood flow after acute limb ischemia. A high-content screen of a GSK-published kinase inhibitor library identified a set of ROCK inhibitor hits enhancing endothelial network formation. Subsequent kinase activity profiling against a panel of 224 protein kinases showed that two indazole-based ROCK inhibitor hits exhibited high selectivity for ROCK1 and ROCK2 isoforms compared to other ROCK inhibitors. One of the chemical entities, GSK429286, was selected for follow-up studies. We found that GSK429286 was ten times more potent in enhancing endothelial tube formation than Fasudil, a classic ROCK inhibitor. ROCK1 inhibition by RNAi phenocopied the angiogenic phenotype of the GSK429286 compound. Using an organotypic angiogenesis co-culture assay, we showed that GSK429286 formed a dense vascular network with thicker endothelial tubes. Next, mice received either vehicle or GSK429286 (10 mg/kg i.p.) for seven days after hindlimb ischemia induction. As assessed by laser speckle contrast imaging, GSK429286 potentiated blood flow recovery after ischemia induction. At the histological level, we found that GSK429286 significantly increased the size of new microvessels in the regenerating areas of ischemic muscles compared with vehicle-treated ones. Our findings reveal that selective ROCK inhibitors have in vitro pro-angiogenic properties and therapeutic potential to restore blood flow in limb ischemia. [ABSTRACT FROM AUTHOR]

Background: Peripheral arterial disease (PAD) affects a substantial proportion of the global population, particularly older individuals, affecting around 200 million people worldwide highlighting its significant impact on human health. Critical limb ischemia (CLI) is the most severe clinical presentation of PAD characterized by ischemic rest pain tissue ulceration or gangrene. The objective of the study is to assess the efficacy of infra popliteal angioplasty (in terms of wound healing and limb salvage) in patients with below-the-knee total chronic occlusion (TCO). Methods: In this cross-sectional study, all consecutive patients in one year with TCO and fulfilling the inclusion criteria were included. Results: A total of 64 limbs underwent angioplasty. The mean age was 55.38 ± 13.12 (Range 22-88) years and there were 73% (n=47) males. Diabetes mellitus was the most prevalent risk factor in 59.4% (n=38) of patients. 48.4 % (n=31) of patients had belowknee TCO in all three arteries. Technical Success was achieved in 95.3% (n=61/64). All 3 patients who had technical failure ended up with below-the-knee amputation. Furthermore, 2 more patients who had technical success also ended up with below-the-knee amputation. The difference between these two rates was significant (100% vs 3.3%; p-value =0.004). In terms of wound healing, statistically significant improvement was noted within the first 6 months (p-value = 0.05). The limb salvage rate was 90.6% (n=59/64). The primary patency rate was 81.3% (n=52) and 76.6% (n=49) at 6 and 12 months respectively. Conclusion: Angioplasty results in statistically significant wound healing leading to a higher limb salvage rate, in patients with TCO of infrapopliteal arteries. [ABSTRACT FROM AUTHOR]

End-stage renal disease patients with arteriovenous fistula (AVF) encounter many vascular risks related to reduced or increased arteriovenous fistula flow. Dialysis access-associated steal syndrome is one of the devastating complications that may lead to limb loss. Multiple vascular techniques (surgical and endovascular) can be used to correct this complication. In this article, we present two endovascular approaches. One approach uses a stent graft covering two thirds of anastomosis for arteriovenous fistulas to generate artificial stenosis and divert more flow to the hand. The other approach applies Supera® stent jailing to the arteriovenous fistula to divert more flow to the hand. Over 12 months of follow up, there was no clinical manifestation of dialysis access-associated steal syndrome and the AV fistula continued to function. [ABSTRACT FROM AUTHOR]

Objective: Here, we report a new method to increase the therapeutic potential of mesenchymal stem/stromal cells (MSCs) for ischemic wound healing. We tested biological effects of MSCs modified with E-selectin, a cell adhesion molecule capable of inducing postnatal neovascularization, on a translational murine model. Background: Tissue loss significantly worsens the risk of extremity amputation for patients with chronic limb-threatening ischemia. MSC-based therapeutics hold major promise for wound healing and therapeutic angiogenesis, but unmodified MSCs demonstrate only modest benefits. Methods: Bone marrow cells harvested from FVB/ROSA26SormTmG donor mice were transduced with E-selectin-green fluorescent protein (GFP)/AAV-DJ or GFP/AAV-DJ (control). Ischemic wounds were created via a 4 mm punch biopsy in the ipsilateral limb after femoral artery ligation in recipient FVB mice and subsequently injected with phosphate-buffered saline or 1×106 donor MSCGFP or MSCE-selectin-GFP. Wound closure was monitored daily for 7 postoperative days, and tissues were harvested for molecular and histologic analysis and immunofluorescence. Whole-body DiI perfusion and confocal microscopy were utilized to evaluate wound angiogenesis. Results: Unmodified MSCs do not express E-selectin, and MSCE-selectin-GFP gain stronger MSC phenotype yet maintain trilineage differentiation and colony-forming capability. MSCE-selectin-GFP therapy accelerates wound healing compared with MSCGFP and phosphate-buffered saline treatment. Engrafted MSCE-selectin-GFP manifest stronger survival and viability in wounds at postoperative day 7. Ischemic wounds treated with MSCE-selectin-GFP exhibit more abundant collagen deposition and enhanced angiogenic response. Conclusions: We establish a novel method to potentiate regenerative and proangiogenic capability of MSCs by modification with E-selectin/adeno-associated virus. This innovative therapy carries the potential as a platform worthy of future clinical studies. [ABSTRACT FROM AUTHOR]

Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and "outside-in" integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell-material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in "no-option" patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI).

Objective(s): Acute hindlimb ischemia is a peripheral arterial disease that severely affects the patient’s health. Injection of stem cells-derived exosomes that promote angiogenesis is a promising therapeutic strategy to increase perfusion and repair ischemic tissues. This study aimed to evaluate the efficacy of adipose stem cell-derived exosomes injection (ADSC-Exos) in treating acute mouse hindlimb ischemia.Materials and Methods: ADSC-Exos were collected via ultracentrifugation. Exosome-specific markers were analyzed via flow cytometry. The morphology of exosomes was detected by TEM. A dose of 100 ug exosomes/100 ul PBS was locally injected into acute mice ischemic hindlimb. The treatment efficacy was evaluated based on the oxygen saturation level, limb function, new blood vessel formation, muscle structure recovery, and limb necrosis grade. Results: ADSC-exosomes expressed high positivity for markers CD9 (76.0%), CD63 (91.2%), and CD81 (99.6%), and have a cup shape. After being injected into the muscle, in the treatment group, many small and short blood vessels formed around the first ligation and grew down toward the second ligation. The SpO2 level, reperfusion, and recovery of the limb function are more positively improved in the treatment group. On day 28, the muscle’s histological structure in the treatment group is similar to normal tissue. Approximately 33.33% of the mice had grade I and II lesions and there were no grade III and IV observed in the treatment group. Meanwhile, in the placebo group, 60% had grade I to IV lesions. Conclusion: ADSC-Exos showed the ability to stimulate angiogenesis and significantly reduce the rate of limb necrosis.

Abstract Background Acute tumour embolism to the popliteal artery resulting in limb-threatening ischemia is a rare complication of neoplastic disease. Generally, tumors embolize to the pulmonary circulation via the venous system. In this case, the originating tumor was a lung cancer of a large size and advanced stage that had invaded the left atrium of the heart and disseminated in the systemic circulation. The tumor likely fragmented, resulting in showering to the right popliteal artery, superior mesenteric artery, and left renal artery, which is a unique presentation of tumor embolism. Case report We present a case of a 62-year-old Caucasian gentleman with a large left lower lobe squamous cell lung cancer that had invaded into the left atrium via the pulmonary veins. He presented with acute limb threatening ischemia. A computed tomographic angiogram revealed an occlusion of the left popliteal artery as well as embolization to the superior mesenteric artery and the right renal artery. He was started on intravenous heparin and underwent an emergency popliteal embolectomy and calf fasciotomies, which was limb saving. His fasciotomy wounds were closed after 1 week and he was discharged on anticoagulation. Conclusion This is a rare case of tumor embolism resulting in both an embolectomy and calf fasciotomies. In the light of such cases, we suggest that tumors invading the bloodstream should be considered high risk for embolization and hypothesize that prophylactic antithrombotic therapy may avoid major morbidity.

Background: Coronavirus disease 2019 (COVID-19) is a pandemic that has affected many patients worldwide. Infection with this virus appears to be associated with a high risk of macrovascular complications. Methods: In this descriptive study, we examined the clinical and demographic information of 67 patients in whom COVID-19 was confirmed in terms of vascular complications. Results: The results of this study showed that 65.6% of COVID-19 patients had venous complications and 34.4% had arterial complications. In the patients who had more severe symptoms caused by COVID-19 such as fever, cough, sore throat, nausea and vomiting, diarrhea, anorexia, shortness of breath, joint pain, and fatigue, they had more severe venous complications. Conclusions: Better and more accurate understanding of the pathophysiological mechanisms causing severe disease of COVID-19, as well as identifying the prevalence of macrovascular complications and possible disorders resulting from them in patients with COVID-19 in different ethnicities and populations to develop new treatment, is needed.