Form Of Peripheral Arterial Disease Research Articles

Quality improvement efforts to address racial and ethnic disparities in patients with peripheral vascular disease and chronic limb-threatening ischemia

IntroductionRacial and ethnic disparities in care have been documented among patients who present with chronic limb-threatening ischemia (CLTI), the most severe form of peripheral artery disease (PAD). This scoping review was designed to explore the different types of quality improvement (QI) initiatives that have been set up to address disparities in access to care and treatment outcomes for this vulnerable patient population. MethodsA systematic search of the MEDLINE, Embase, and CINAHL databases was performed to identify articles that evaluated QI programs, care processes, or outcomes established to address disparities in access and treatment among non-White and ethnic minority patients with PAD and/or CLTI. This search was limited to studies published in the English language after 1990, and abstracts were screened and abstracted by the authors. The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines for scoping reviews. ResultsOur search yielded six articles published between 1990 and 2023 that reported on QI initiatives designed to address some aspect of differential care among non-White patients with different types of PAD including CLTI. QI protocols were primarily focused on addressing disparities in the care of non-White patients with diabetic foot infections and/or adherence to guidelines for patients with CLTI. Findings from these studies identified potential for improvement through multidisciplinary care teams and algorithm-based treatment protocols that emphasize the importance of medication compliance, timely revascularization, and frequent follow-up. Nevertheless, data between studies were heterogeneous, and there were limited protocols that specifically focused on measures to mitigate differential access for non-White patients with PAD or CLTI. ConclusionsThere has been a paucity of QI initiatives and processes established to address disparities in access to care and treatment outcomes for non-White and ethnic minority patients with PAD and/or CLTI. More hospital and community-based programs are needed to improve access to vascular surgery care for this vulnerable patient population.

Management of peripheral arterial disease in the context of a multidisciplinary limb program.

Peripheral artery disease (PAD) continues to increase in prevalence worldwide due to risk factors such as advanced age, diabetes mellitus, and obesity. Critical limb ischemia (CLTI) is the advanced form of PAD that can result in a lack of healing and limb loss as the most devastating consequence. Patients with PAD, especially CLTI, benefit from multidisciplinary care to optimize outcomes by reducing cardiovascular morbidity and mortality and preventing lower extremity amputation. Collaboration between various specialties allows a focus on problems involved in treating the patient with PAD including prevention, screening, medical care, wound care, infection, and revascularization when needed. Although there is no clear definition or consensus on the structure of the PAD team, certain guidelines are applicable to most clinical scenarios emphasizing "provider champions" in leading a clinical program. A vascular specialist (vascular surgery, interventional radiology, interventional cardiology) and a soft tissue specialist (podiatry, plastic surgery) are the typical "champions," often involving orthopedics, general surgery, vascular medicine, diabetology/endocrinology, infectious disease, nephrology, and rehabilitation medicine. The team should also include wound nurses, nutritionists, occupational therapists, orthotists, pharmacists, physical therapists, prosthetists, and social workers. This paper presents a brief overview of the structure of the multidisciplinary team with key components and functions of such a team to optimize treatment outcomes for PAD and CLTI.

Validation of the global limb anatomical staging system in Vietnamese patients treated for chronic limb-threatening ischemia

BackgroundChronic limb-threatening ischemia (CLTI) is the most severe clinical form of peripheral artery disease (PAD), accounting for approximately 11%, and is strongly associated with the incidence of amputation, cardiovascular events, and mortality. The Global Vascular Guideline (GVG) proposed a new Global Anatomic Staging System (GLASS) for evaluating the anatomic complexity of arterial lesions. However, more research is required to evaluate outcomes after endovascular intervention in CLTI patients using the GLASS.ObjectiveOur study aimed to describe clinical characteristics, arterial lesions, and endovascular interventions according to three grades of GLASS in the Vietnamese population. We evaluated the technical success, mortality rate, and probability to preserve the limb according to the GLASS.MethodsAll patients were diagnosed with CLTI and underwent infrainguinal endovascular intervention at the Department of Thoracic and Vascular Surgery, University Medical Center, Ho Chi Minh City from June 2020 to June 2022. All patients were evaluated before intervention and follow-up at 6 and 12 months after intervention. Patients were divided into three groups according to the GLASS, thereby comparing the technical success, mortality, and amputation rates. This retrospective study describes a series of cases.ResultsThe study sample evaluated 82 lower limbs of 82 patients, in which GLASS class I, II, and III lesions accounted for 36.6%, 43.9%, and 19.5% of the patients, respectively. The rates of technical success in the groups gradually decreased according to the complexity of the lesions (90%, 86.11%, and 56.25% for GLASS I, II, and III, respectively; p = 0.012). Notably, limb-based patency (LBP) at 12 months was significantly lower in the GLASS III group than in the GLASS I and II groups (22.22% vs 88.89% and 67.74%, respectively; p = 0.001). The amputation rates at 12 months in GLASS groups I, II, and III were 13.3%, 22.2%, and 50%, respectively (p = 0.021), while the mortality rates at 12 months were 0%, 8.33%, and 25%, respectively (p = 0.015).ConclusionIn patients with CLTI of higher GLASS stages, the rates of technical success were lower and the amputation and mortality rates were higher.

Femoro-popliteal Artery Bypass and Transmetatarsal Amputation Followed by Delayed Forefoot Flap

Critical limb ischemia (CLI) is a severe blockage in the arteries of the lower extremities, which markedly reduces blood-flow. It is a serious form of peripheral arterial disease, or PAD, but less common than claudication. PAD is caused by atherosclerosis, the hardening and narrowing of the arteries over time due to the buildup of fatty deposits called plaque. CLI is a chronic condition that results in severe pain in the feet or toes, even while resting. Complications of poor circulation can include sores and wounds that won't heal in the legs and feet. Left untreated, the complications of CLI will result in amputation of the affected limb. The authors present a patient with CLI, and a left forefoot gangrene treated with multi-stage operations (femoro-popliteal arterial bypass, transmetatarsal amputation and delayed forefoot free-flap) with good results.

Anatomical Distribution Patterns of Peripheral Arterial Disease in the Upper Extremities According to Patient Characteristics: A Retrospective Cohort Study.

Peripheral arterial disease (PAD) greatly affects the patients' quality of life. We aimed to investigate the affected anatomical sites and distribution patterns in upper extremity PAD using computed tomography angiography (CTA). Furthermore, we sought to identify the correlations between patient characteristics and the identified patterns. This was a retrospective chart review of upper limb CTA findings from patients with symptomatic PAD aged >18 years. Significant variables from univariate logistic regression analysis were further tested using multivariate logistic regression analysis. Statistical significance was set at p < 0.05, with confidence intervals of 95%. The mean age of the 102 included patients with upper extremity PAD was 55.45 years. Laterality analysis revealed that the upper left limb segments were more affected than the upper right limb segments (42 vs 63; left-to-right ratio, 3:2). The forearm was the segment most affected by stenotic PAD (62 segments, 3.37%). The arm was the segment most affected by occlusive PAD (14 segments, 0.76%). Diabetes mellitus (DM) and hypertension (HTN) were significant predictors of PAD (p = 0.046). In patients with DM, the occlusive form of PAD was dominant in the arm (18.18%); however, the stenotic form prevailed in the forearm (72.72%). In patients with HTN, the occlusive form of PAD was predominant in the arm (45.45%); however, the stenotic form tended to occur in the arm and forearm (90.90%). The distribution patterns of upper extremity PAD are linked to its underlying pathophysiology. HTN and DM are the most frequent comorbidities in patients with upper extremity PAD. Angiographically, PAD in these patients is likely to present as stenosis rather than as occlusion. This is vital for interventionists who deviate from radial arterial access in patients with PAD. Therefore, targeted screening standards are required, and further studies on PAD are warranted.

Role of Hemodynamic Assessment and Limitations in Ankle-Brachial Pressure Index, Toe- Brachial Pressure Index to Predict Wound Healing After Revascularization.

Chronic limb-threatening ischemia (CLTI) represents one of the most severe forms of peripheral arterial disease implying impaired wound healing and tissue loss at the same time posing a significant impact on the quality of life of patients and a serious economic burden on healthcare systems around the world. A major challenge in the management of patients with CLTI is the validity and role of non-invasive hemodynamic parameters in assessing their clinical status before and after revascularization. Traditionally, the diagnosis of CLTI is routinely based on clinical symptoms and confirmed by measurements of non-invasive limb hemodynamics including ankle-brachial pressure index (ABPI) and toe-brachial pressure index (TBPI). However, whether these indices alone can provide definitive treatment or be used as adjunctive tool along with the implementation of novel techniques to help guide revascularization for CLI patients still remains unclear.

Chronic Limb-Threatening Ischemia Is Associated With Higher Mortality and Limb Revascularization After Transcatheter Aortic Valve Replacement

Peripheral arterial disease (PAD) is common in patients with symptomatic aortic stenosis. PAD exists as a spectrum, and patients with chronic limb-threatening ischemia (CLTI), the most severe form of PAD, are at high risk for limb loss and death. We seek to determine patient characteristics and clinical outcomes among patients who underwent TAVR with or without CLTI. We identified all hospitalizations for TAVR from October 2015 to December 2018 using the National Inpatient Sample database. Patients with any diagnosis of CLTI were identified using the International Classification of Diseases 10th Revision codes. The primary outcome was in-hospital mortality, and secondary outcomes were major complications, open revascularization, and endovascular revascularization after TAVR. During the study period, a total of 31,335 hospitalizations for TAVR procedures were included, including 7,048 (22.5%) in patients with CLTI. CLTI was associated with higher in-hospital mortality (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.13 to 1.74, p=0.002) and major complications (OR 1.2, 95% CI 1.09 to 1.25, p <0.001). CLTI was also associated with a significantly higher rate of open limb revascularization (OR 5.1, 95% CI 3.94 to 6.48, p <0.001) and endovascular revascularization (OR 4.0, 95% CI 3.54 to 4.59, p <0.001). CLTI among patients who underwent TAVR is associated with higher in-hospital mortality, major complications, and longer lengths of stay compared with patients without CLTI. However, the overall rates of adverse events remain low. Further studies are needed to optimize the multidisciplinary care of these patients before TAVR with a focus on shared decision-making.

Limb Salvage and Survival in Chronic Limb-Threatening Ischemia: The Need for a Fast-Track Team-Based Approach.

Chronic limb-threatening ischemia (CLTI) represents the end-stage form of peripheral arterial disease (PAD) and is associated with a very poor prognosis and high risk of limb loss and mortality. It can be considered very similar to a terminal cancer disease, reflecting a large impact on quality of life and healthcare costs. The aim of this study is to offer an overview of the relationship between CLTI, limb salvage, and mortality, with a focus on the need of a fast-track team-based management that is a driver to achieve better survival results. This review can be useful to improve management of this growing impact disease, and to promote the standardisation of care and communication between specialist and non-specialist healthcare professionals.

Current status of low-density lipoprotein apheresis treatment for patients with peripheral artery disease and chronic kidney disease in Japanese clinical database.

Patients with peripheral arterial disease (PAD) have a poorer prognosis than those without PAD. PAD complications worsen the prognosis of patients with chronic kidney disease (CKD), especially those on maintenance dialysis. Although low-density lipoprotein apheresis (LDL-A) is expected to be effective in treating severe PAD, there are no large-scale reports on the prognosis of patients undergoing LDL-A. We obtained a clinical database from April 2008 to August 2021 and selected 924 238 patients with CKD. We selected patients with disease codes of lower limb arteriosclerosis obliterans, arteriosclerosis obliterans, and critical limb ischemia or foot ulcer. Patients who were prescribed antithrombotic medications were included. Patients who used steroids were excluded. Among these patients, those undergoing blood purification considered LDL-A were selected, and their current status was investigated. We included 147 patients (113 males and 34 females). The mean patient age was 70 ± 10 years. Diabetes mellitus was present in 86%, ischemic heart disease in 34%, and stroke in 48%. Maintenance dialysis patients accounted for 86% of the patients. Statins were administered to 40% of the patients, and bypass surgery was performed in 2.7%. The median observation period was 812 days, and the mortality rate was 41%. LDL-A was performed in a small population of patients with CKD with the most severe form of PAD. The prognosis for these patients is extremely poor. Therefore, strategies to improve prognosis are important.

Revascularisation Options for Chronic Limb Threatening Ischaemia in Diabetes: Implications From Two Recent Trials.

Chronic limb-threatening ischaemia (CLTI) is a severe form of peripheral arterial disease (PAD) and is associated with an increased risk of amputation, mortality, and significantly impaired quality of life. International guidelines recommend considering timely revascularisation and optimal medical therapy to improve limb perfusion in individuals with CLTI. The 2 primary revascularization approaches for CLTI are open bypass surgery (BS) and endovascular therapy (EV), however, there is currently no consensus on the best initial treatment strategy for CLTI, leading to uncertainty among clinicians. To shed light on this issue, 2 recent trials, namely best endovascular versus best surgical therapy in patients with CLI (BEST-CLI) and bypass versus angioplasty for severe ischaemia of the leg (BASIL-2), have tried to provide valuable insights. While a definitive conclusion on the optimal revascularisation approach is still pending, these trials offer immediate and clinically relevant information to the diabetic foot multidisciplinary team. The trials encompassed a distinct range of patient cohorts and included participants with varying degrees of medical and physical frailty. Taken together, their findings, highlight the need for an individualised revascularisation strategy which accounts for underlying comorbidities, risk factors, disease severity, availability of suitable bypass conduits, surgical risks, and timely access to procedures. Regardless of the chosen strategy, early referral of patients with diabetes and CLTI to a specialist team within a multidisciplinary environment is crucial. Comprehensive care should encompass essential elements such as adequate debridement, infection control, offloading, glycaemic control, smoking cessation, and patient education. By addressing these aspects, healthcare providers can optimise the management and outcomes for individuals with CLTI and diabetes.

Modalities to Deliver Cell Therapy for Treatment of Chronic Limb Threatening Ischemia.

Significance: Chronic limb threatening ischemia (CLTI) is a severe form of peripheral arterial disease (PAD) that is associated with high rates of morbidity and mortality, and especially limb loss. In patients with no options for revascularization, stem cell therapy is a promising treatment option. Recent Advances: Cell therapy directly delivered to the affected ischemic limb has been shown to be a safe, effective, and feasible therapeutic alternative for patients with severe PAD. Multiple methods for cell delivery, including local, regional, and combination approaches, have been examined in both pre-clinical studies and clinical trials. This review focuses on delivery modalities used in clinical trials that deliver cell therapy to patients with severe PAD. Critical Issues: Patients with CLTI are at high risk for complications of the disease, such as amputations, leading to a poor quality of life. Many of these patients do not have viable options for revascularization using traditional interventional or surgical methods. Clinical trials have shown therapeutic benefit for cell therapy in these patients, but methods of cell treatment are not standardized, including the method of cell delivery to the ischemic limb. Future Directions: The ideal delivery approach for stem cell therapy in PAD patients remains unclear. Further studies are needed to determine the best modality of cell delivery to maximize clinical benefits.

A phantom study: Evaluation of a novel three-lumen balloon catheter for potential treatment of intractable limb ischemia.

Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease (PAD) which induces extremity rest pain, extremity gangrene or ulcers that mostly might lead to limb loss. One of the most common criteria of CLI is 50 mmHg or less systolic ankle arterial pressure. In this study, a custom made three-lumen catheter (9 Fr) including a distal inflatable balloon in between the inflow and outflow lumen holes was designed and fabricated based on the patented design of Hyper Perfusion Catheter. The proposed catheter design aims to increase ankle systolic pressure to 60 mmHg or more to promote healing and/or alleviating severe pain due to intractable ischemia for patients with CLI. To simulate the blood circulation of related anatomy, in vitro CLI model phantom was designed and constructed by using a modified hemodialysis circuit, a hemodialysis pump and a tube set for cardio-pulmonary bypass surgery. A blood mimicking fluid (BMF) with dynamic viscosity of 4.1 mPa.s was used at 22 ºC to prime the phantom. The data was collected by a custom-made circuit design in real time and all measurements were verified with commercial certificated medical devices. The results of in vitro CLI model phantom experiments have shown that it is feasible to elevate the pressure distal to the occlusion (representing ankle pressure) above 80 mmHg without affecting the systemic pressure.

Management of Critical Limb Ischemia Prognostic Factors

Introduction: Critical limb ischemia (CLI) represents the most severe form of Peripheral artery disease (PAD). Its prevalence is estimated to be between 0.5% and 2.3% of the population over 40 years old. Despite its importance, epidemiological studies on CLI remain patchy. In Morocco, few studies have been carried out on this subject, and we have no epidemiological data on the morbimortality of chronic critical ischemia of the lower limbs on a national scale. Objective: The objective of our study was to evaluate the results of surgical treatment of critical limb ischemia and to identify the factors associated with the medium-term evolution. Methods: We conducted a retrospective cohort study of all patients admitted to the vascular surgery department of the Hassan II University Hospital for the management of critical ischemia of the lower limbs, who underwent revascularization surgery between 01/01/2013 and 31/12/2019. Patients who underwent a major amputation of the affected limb and those for whom the revascularization procedure was a revision were subsequently excluded. The follow-up period was 2 years and the events of major interest were the occurrence of a major limb amputation and 30-day mortality. Results: The cohort included 232 patients with critical ischemia. The mean age was 62 years with a clear male predominance of 84.5%. The most common comorbidities were diabetes (65.8%), active smoking (42.5%), and hypertension (31.2%). The majority of patients (62%) benefited from endovascular procedures. The primary technical success was 94.1%, the major amputation rate was 19.7%, and the 30-day mortality was 4.3%. In multivariate analysis, factors independently associated with a high postoperative complication rate were preoperative hyperglycemia, concomitant ischemic heart disease, female sex, young age, and intensive care unit stay. Conclusion: Our study highlights several risk factors for the occurrence of postoperative complications of CLI. These results .....

Association of Sarcopenia With Mortality in Patients With Chronic Limb-Threatening Ischemia Undergoing Endovascular Revascularization

IntroductionChronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease and leads high mortality. Sarcopenia, characterized by the loss of muscle mass or poor muscle quality, is associated with adverse clinical outcomes. This study aimed to investigate the association between sarcopenia and the long-term outcomes in patients with CLTI after endovascular revascularization. MethodsWe retrospectively reviewed the medical records of all patients with CLTI who underwent endovascular revascularization between January 2015, and December 2021. The skeletal muscle area was calculated at the third lumbar vertebra from computed tomography images using the manual trace method and normalized to patient height. Sarcopenia was defined as a third lumbar skeletal muscle index of <40.8 cm2/m2 in males and <34.9 cm2/m2 in females. The Kaplan–Meier and Cox proportional hazards regression analyses were used for survival analysis and to evaluate the association between sarcopenia and mortality. ResultsA total of 137 patients (90 men; mean age 71.7 ± 9.6 y) were enrolled for the study, of whom 56 (40.8%) had sarcopenia. The 3-year overall survival rate in patients with CLTI who underwent endovascular revascularization was 71.2%. The sarcopenic group had a significantly worse 3-year overall survival rate than the nonsarcopenic group (55.3% versus 78.6%, P = 0.001). Multivariate Cox proportional hazard regression analyses revealed that sarcopenia (hazard ratio, 2.262; 95% confidence interval, 1.132-4.518; P = 0.021) and dialysis (hazard ratio, 3.021; 95% confidence interval, 1.337-6.823; P = 0.008) were independently associated with increased risk of all-cause mortality, whereas technical success had significantly opposing correlation with mortality. (hazard ratio, 0.400, 95% confidence interval, 0.194-0.826, P = 0.013). ConclusionsSarcopenia can be highly prevalent in patients with CLTI who undergo endovascular revascularization, and is independently associated with long-term mortality. These results may help risk stratification to assist in personalized assessment and clinical decision-making.

Chronic Limb Ischemia: Awareness and Treatment in Primary Care

Chronic limb ischemia (CLI) is a type of peripheral arterial disease (PAD) that is still underdiagnosed and undertreated despite the increasing incidence, thus becoming a global health burden. The prevalence of PAD is quite high, approximately around 200 million globally in the adult population and increased drastically in older age population. It might be difficult to diagnose at an early stage because around 20-50% patients may be asymptomatic. More than 70% of primary physicians also did not notice that the diagnosis was already established during screening of the PAD patients. All these problems could increase the incidence of PAD in the following year. The untreated conditions will develop into a more severe form of PAD known as chronic limb-threatening ischemia (or critical limb ischemia), and patients are at a higher risk of having limb loss, and also increased morbidity and mortality. The primary physicians in the primary health facilities hold an important role in the early diagnosis and management of patients with CLI symptoms or with risk factors of CLI. Due to the limitation of diagnostic testing modality at primary health facilities, the physician can assess the ankle-brachial index (ABI) to determine the presence of CLI. Management of the disease is different for every patient and is customized based on the other comorbidities. Risk factors should be controlled in order to achieve a better outcome. A good management strategy will improve the condition. This review aims to describe how to give an early diagnosis and management for CLI patients in primary health care.

Nanoceria-GO-intercalated multicellular spheroids revascularize and salvage critical ischemic limbs through anti-apoptotic and pro-angiogenic functions

Critical limb ischemia (CLI) is a serious form of peripheral arterial disease that involves severe blockage of blood flow in lower extremities, often leading to foot necrosis and limb loss. Lack of blood flow and high pro-inflammation with overproduced reactive oxygen species (ROS) in CLI aggravate the degenerative events. Among other therapies, cell delivery is considered potential for restoring regenerative capacity, and preservation of cell survival under high oxidative stress has been challenging and prerequisite to harness cellular functions. Here, we introduce a multicellular delivery system that is intercalated with nanoceria-decorated graphene oxide (CeGO), which is considered to have high ROS scavenging ability while providing cell-matrix interaction signals. The CeGO nano-microsheets (8-nm-nanoceria/0.9-μm-GO) incorporated in HUVEC/MSC (7/3) could form cell-material hybrid spheroids mediated by cellular contraction. Under in vitro oxidative-stress-challenge with H2O2, the CeGO-intercalation enhanced the survival and anti-apoptotic capacity of cellular spheroids. Pro-angiogenic events of cellular spheroids, including cell sprouting and expression of angiogenic markers (HIF1α, VEGF, FGF2, eNOS) were significantly enhanced by the CeGO-intercalation. Proteomics analysis also confirmed substantial up-regulation of a series of angiogenesis-related secretome molecules. Such pro-angiogenic events with CeGO-intercalation were proven to be mediated by the APE/Ref-1 signaling pathway. When delivered to ischemic hindlimb in mice, the CeGO-cell spheroids could inhibit the accumulation of in vivo ROS rapidly, preserving high cell survival rate (cells were more proliferative and less apoptotic vs. those in cell-only spheroids), and up-regulated angiogenic molecular expressions. Monitoring over 28 days revealed significantly enhanced blood reperfusion and tissue recovery, and an ultimate limb salvage with the CeGO-cell delivery (∼60% salvaged vs. ∼29% in cell-only delivery vs. 0% in ischemia control). Together, the CeGO intercalated in HUVEC/MSC delivery is considered a potential nano-microplatform for CLI treatment, by scavenging excessive ROS and enhancing transplanted cell survival, while stimulating angiogenic events, which collectively help revascularization and tissue recovery, salvaging critical ischemic limbs.

Temporal analysis of skeletal muscle remodeling post hindlimb ischemia reveals intricate autophagy regulation.

Hind limb ischemia (HLI) is the most severe form of peripheral arterial disease, associated with a substantial reduction of limb blood flow that impairs skeletal muscle homeostasis to promote functional disability. The molecular regulators of HLI-induced muscle perturbations remain poorly defined. This study investigated whether changes in the molecular catabolic-autophagy signaling network were linked to temporal remodeling of skeletal muscle in HLI. HLI was induced in mice via hindlimb ischemia (femoral artery ligation) and confirmed by Doppler echocardiography. Experiments were terminated at time points defined as early- (7 days; n = 5) or late- (28 days; n = 5) stage HLI. Ischemic and nonischemic (contralateral) limb muscles were compared. Ischemic versus nonischemic muscles demonstrated overt remodeling at early-HLI but normalized at late-HLI. Early-onset fiber atrophy was associated with excessive autophagy signaling in ischemic muscle; protein expression increased for Beclin-1, LC3, and p62 (P < 0.05) but proteasome-dependent markers were reduced (P < 0.05). Mitophagy signaling increased in early-stage HLI that aligned with an early and sustained loss of mitochondrial content (P < 0.05). Upstream autophagy regulators, Sestrins, showed divergent responses during early-stage HLI (Sestrin2 increased while Sestrin1 decreased; P < 0.05) in parallel to increased AMP-activated protein kinase (AMPK) phosphorylation (P < 0.05) and lower antioxidant enzyme expression. No changes were found in markers for mechanistic target of rapamycin complex 1 signaling. These data indicate that early activation of the sestrin-AMPK signaling axis may regulate autophagy to stimulate rapid and overt muscle atrophy in HLI, which is normalized within weeks and accompanied by recovery of muscle mass. A complex interplay between Sestrins to regulate autophagy signaling during early-to-late muscle remodeling in HLI is likely.

MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia.

Peripheral artery disease (PAD) is an occlusive disease of limb arteries. Critical limb ischemia (CLI) is an advanced form of PAD that is prognostically worse in subjects with diabetes and can result in limb loss, gangrene, and death, although the underlying signaling mechanisms that contribute to its development remain poorly understood. By comparing plasma samples from diabetic humans with PAD and mouse models of PAD, we identified miR-375 to be significantly downregulated in humans and mice during progression to CLI. Overexpression of miR-375 was pro-angiogenic in endothelial cells in vitro and induced endothelial migration, proliferation, sprouting, and vascular network formation, whereas miR-375 inhibition conferred anti-angiogenic effects. Intramuscular delivery of miR-375 improved blood flow recovery to diabetic mouse hindlimbs following femoral artery ligation (FAL) and improved neovessel growth and arteriogenesis in muscle tissues. Using RNA-sequencing and prediction algorithms, Kruppel-like factor 5 (KLF5) was identified as a direct target of miR-375 and siRNA knockdown of KLF5 phenocopied the effects of miR-375 overexpression in vitro and in vivo through regulatory changes in NF-kB signaling. Together, a miR-375-KLF5-NF-kB signaling axis figures prominently as a potential therapeutic pathway in the development CLI in diabetes.

The relationship between sarcopenia and one-year mortality in patients with critical limb ischemia undergoing endovascular therapy below the knee.

Critical limb ischemia (CLI) is a progressive form of peripheral artery disease (PAD). Patients with CLI have poor long-term prognosis. The aim of this study was to investigate the value of sarcopenia in terms of 1-year mortality in patients with below-the-knee lesions who underwent endovascular treatment for CLI. A total of 190 patients with critical limb ischemia who underwent endovascular treatment (EVT) for below-the-knee (BTK) lesions were enrolled in this study. Sarcopenia was defined using the psoas muscle index (PMI). PMI was obtained by calculating the average psoas muscle area (APMA) of the left and right psoas muscles at the third lumbar vertebra level and dividing by the square of the height (cm2/m2). The primary endpoint of the study was 1-year mortality and the secondary endpoint was 1-year amputation. Patients were divided into 2 groups according to presence of sarcopenia. We detected sarcopenia in 64 patients. The mean age, height, and EF were higher in sarcopenia group. The psoas muscle area, weight, psoas muscle index, body-mass index, albumin level, and GFR were lower in sarcopenia group. The incidence of amputation (11.9% vs 29.7%, p = 0.003) and mortality (15.1% vs 35.9%, p = 0.001) were higher in patients with sarcopenia. Univariate and multivariate logistic regression analyses were used to determine the independent predictors of amputation and mortality. The survival curve for 1-year using the sarcopenia was analyzed using the Kaplan-Meier method, and statistical analysis was performed with the log-rank test. The presence of sarcopenia, glomerular filtration rate level, and low ejection fraction were found to be independent predictors of mortality. Sarcopenia was associated with 1-year mortality in patients with CLI undergoing EVT for BTK lesions. Also, patients with sacropenia had higher 1-year amputation rates. Sarcopenia may be a simple method to help patient selection, assessment, and intervention strategy for EVT and may improve patient outcomes.

Sourcing of human peripheral blood-derived myeloid angiogenic cells under xeno-free conditions for the treatment of critical limb ischemia

BackgroundCritical limb ischemia (CLI) is the most severe form of peripheral artery disease and exhibits a high risk of lower extremity amputations. As even the most promising experimental approaches based on mesenchymal stem cells (MSCs) demonstrated only moderate therapeutic effects, we hypothesized that other cell types with intrinsic roles in angiogenesis may exhibit a stronger therapeutic potential. We have previously established a protocol to source human peripheral blood-derived angiogenic cells (BDACs). These cells promoted revascularization and took perivascular location at sites of angiogenesis, thus resembling hematopoietic pericytes, which were only described in vivo so far. We thus hypothesized that BDACs might have a superior ability to promote revascularization and rescue the affected limb in CLI.MethodsAs standard BDAC sourcing techniques involve the use of animal-derived serum, we sought to establish a xeno- and/or serum-free protocol. Next, BDACs or MSCs were injected intramuscularly following the ligation of the iliac artery in a murine model. Their ability to enhance revascularization, impair necrosis and modulate inflammatory processes in the affected limb was investigated. Lastly, the secretomes of both cell types were compared to find potential indications for the observed differences in angiogenic potential.ResultsFrom the various commercial media tested, one xeno-free medium enabled the derivation of cells that resembled functional BDACs in comparable numbers. When applied to a murine model of CLI, both cell types enhanced limb reperfusion and reduced necrosis, with BDACs being twice as effective as MSCs. This was also reflected in histological evaluation, where BDAC-treated animals exhibited the least muscle tissue degeneration. The BDAC secretome was enriched in a larger number of proteins with pro-angiogenic and anti-inflammatory properties, suggesting that the combination of those factors may be responsible for the superior therapeutic effect.ConclusionsFunctional BDACs can be sourced under xeno-free conditions paving the way for their safe clinical application. Since BDACs are derived from an easily accessible and renewable tissue, can be sourced in clinically relevant numbers and time frame and exceeded traditional MSCs in their therapeutic potential, they may represent an advantageous cell type for the treatment of CLI and other ischemic diseases.