Stage Of Peripheral Arterial Disease Research Articles

Three-Year Safety and Efficacy of Endovascular Treatment of Common Femoral Artery in 150 PAD Patients.

Background: The gold standard treatment for peripheral arterial disease (PAD) of the common femoral artery (CFA) is open common femoral endarterectomy (CFAE). Interest in the less invasive endovascular treatment (EVT) is growing due to PAD patients' frequent co-morbidities. Aims: We aimed to evaluate three-year EVT outcomes in multimorbid PAD patients with severe calcified CFA lesions. Methods: Using the prospectively maintained "all-comers" Duesseldorf PTA Registry, we analysed the three-year outcomes of 150 patients with EVT of the CFA. Between January 2017 and October 2023, 66 patients received a rotational excisional atherectomy (REA) followed by a drug-coated balloon angioplasty (DCB), and 84 patients received a DCB alone. Results: All procedures involved the CFA, 49% additionally involved the proximal superficial femoral artery (SFA), and 10% of the lesions involved the profunda femoris artery (PFA). The procedural success rate was 97% and independent of PAD stage, with a higher level of stent implantation in the DCB group (58% vs. 39%, p < 0.05). The primary patency rate at one year was 83% for REA + DCB and 87% for DCB (p = 0.576), while secondary patency after three years was 97%. The MALE rate at three years was mainly driven by cdTLR (REA + DCB: (20%) vs. DCB: (14%), p = 0.377), while major amputations were low in both groups (REA + DCB: 3% vs. DCB: 1%). Overall, the major adverse cardiovascular events (MACEs) rate at three years was low (REA + DCB: (5%) vs. DCB: (11%), p = 0.170). Conclusions: The EVT of severely calcified CFA lesions is safe and effective, with high three-year patency rates and low rates of major adverse limb events (MALEs) and MACEs. This registry demonstrates that vessel preparation with REA minimizes the need for stenting.

Temporal Trends and Outcomes of Peripheral Artery Disease and Critical Limb Ischemia in the United States.

Peripheral arterial disease (PAD) is a progressive, systemic atherosclerotic disease that is associated with an increased risk of coronary artery disease (CAD), cerebrovascular disease (CVD), and critical limb ischemia (CLI). CLI represents the most severe stage of PAD, characterized by progressive endothelial dysfunction and arterial narrowing. We hypothesized that the incidence of CLI and PAD would increase over the study period and that the rates of in-hospital mortality and major amputations among patients admitted with CLI would rise correspondingly. We utilized the National Inpatient Sample (NIS) database from year 2016 to 2021 using the ICD-10-CM codes. Patients with a primary or secondary diagnoses of PAD were initially selected and subsequently hospitalization with CLI were appropriately identified. Cochran Armitage test was used to describe the trend of outcomes across the years. All statistical analyses were conducted using the software Stata version 17.0. From 2016-2021, there were 2,930,639 admissions for critical limb ischemia. 65% of these patients were over the age of 60 and 35.8% of these patients were women. Most of these individuals were white (64.7%), followed by African Americans (15.8%) and Hispanics (12.6%). In-hospital mortality rates varied by revascularization method, with hybrid revascularization showing the highest rate at 2.6%, followed by endovascular revascularization at 1.8%, and surgical revascularization at 1.6%. Additionally, hospitalization costs were highest for patients undergoing hybrid revascularization ($46,257 ± $36,417), compared to endovascular ($36,924 ± $27,945) and surgical revascularization ($35,672 ± $27,127). Endovascular revascularization rates seemed to increase while surgical revascularization rates decreased during this time period. PAD is a progressive, systemic atherosclerotic disease that is associated with an increased risk of CAD, CVD, and CLI. Our data showed that the rates of PAD and CLI hospitalizations has remained relatively stable from 2016-2021, but there seems to be a trend towards doing more revascularization via an endovascular approach as compared to a surgical approach.

The application of cell products for the treatment of critical limb ischemia in patients with diabetes mellitus: a review of the literature

The number of patients with diabetes mellitus (DM) has been progressively increasing worldwide over the past decades, and many international organizations consider DM as a public health emergency of the 21st century.Critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease (PAD) in DM and is characterized by a high risk of limb loss without revascularization. Traditional treatment tactics include open and endovascular revascularization surgical techniques. However, in patients not eligible for revascularization and in cases where performed surgical treatment performed has been ineffective, there are almost no therapeutic alternatives, often leading to amputations and death. As of today, one of the newest non-surgical treatment options is cell therapy. Among different cells, mesenchymal stromal cells (MSCs) are potentially one of the most prospective for use in this patient population.This article provides an overview of clinical trials using cell therapy in patients with CLI.To analyze publications, electronic databases PubMed, SCOPUS, ClinicalTrials, and ScienceDirect were searched to identify published data from clinical trials, research studies, and review articles on cell therapy for critical lower extremity ischemia. After the search, 489 results were received.As a result of systematic selection, 22 clinical trials were analyzed.According to the analyzed literature data, the use of cell products in this category of patients is effective and safe. Cell therapy can stimulate the formation of new vessels and enhances collateral circulation; it is also reported improved distal perfusion, increased pain-free walking distance, decreased amputation rates, and increased survival rates.Nevertheless, further study of the potential use of this category of drugs is needed.

MiRNA in the Diagnosis and Treatment of Critical Limb Ischemia.

Chronic threatening limb ischemia of the inferior limbs (CLTI) is the final stage of peripheral arterial disease (PAD) and is one of the most feared atherosclerotic manifestations because if left untreated, in time, it can lead to amputation. Although there are currently numerous treatment techniques, both open and endovascular, it is a pathology that has no underlying treatment. Therefore, current studies are very much focused on new therapeutic possibilities that can be applied in the early stages of the atherosclerotic process. In numerous studies in the literature, miRNAs have been identified as important markers of atherosclerosis. The present study aims to identify the expression of three miRNAs-miR-199a, miR-20a, and miR-30c-in patients with chronic limb-threatening ischemia in the pre- and post-revascularization periods. The aim of the study is to identify whether these three markers play a role in critical ischemia and whether they have the potential for future use in new treatments of this pathology.

Current Applications and Future Perspectives of Artificial and Biomimetic Intelligence in Vascular Surgery and Peripheral Artery Disease.

Artificial Intelligence (AI) made its first appearance in 1956, and since then it has progressively introduced itself in healthcare systems and patients' information and care. AI functions can be grouped under the following headings: Machine Learning (ML), Deep Learning (DL), Artificial Neural Network (ANN), Convolutional Neural Network (CNN), Computer Vision (CV). Biomimetic intelligence (BI) applies the principles of systems of nature to create biological algorithms, such as genetic and neural network, to be used in different scenarios. Chronic limb-threatening ischemia (CLTI) represents the last stage of peripheral artery disease (PAD) and has increased over recent years, together with the rise in prevalence of diabetes and population ageing. Nowadays, AI and BI grant the possibility of developing new diagnostic and treatment solutions in the vascular field, given the possibility of accessing clinical, biological, and imaging data. By assessing the vascular anatomy in every patient, as well as the burden of atherosclerosis, and classifying the level and degree of disease, sizing and planning the best endovascular treatment, defining the perioperative complications risk, integrating experiences and resources between different specialties, identifying latent PAD, thus offering evidence-based solutions and guiding surgeons in the choice of the best surgical technique, AI and BI challenge the role of the physician's experience in PAD treatment.

Effects of Rheopheresis in dialysis patients with peripheral artery disease and diabetic foot ulcers: A multicentric Italian study.

Peripheral artery disease (PAD) in hemodialysis (HD) patients has a significant social impact due to its prevalence, poor response to standard therapy and dismal prognosis. Rheopheresis is indicated by guidelines for PAD treatment. Twenty-five HD patients affected by PAD stage IV Lerichè-Fontaine and ischemic ulcer 1C or 2C according to the University of Texas Wound Classification System (UTWCS), without amelioration after traditional medical therapy and/or revascularization, were selected and underwent 12 Rheopheresis sessions in 10 weeks. Improvements in pain symptoms using Numerical Rating Scale (NRS), healing ulcers and laboratory hemorheological parameters have been evaluated. A clinically and statistically significant mean value reduction and of relative percentage differences between estimated marginal means (Δ), calculated at each visits, of NRS was observed, with a maximum value (-48.5%) between the first and last visit. At the end of the treatment period 14.3% of ulcers were completely healed, 46.4% downgraded, 53.6% were stable. Overall, no ulcers upgraded. A statistically significant reduction of the Δ, between the first and last visit, for fibrinogen (-16%) was also observed. Rheopheresis reduced overall painful symptoms; data suggest that it could heal or improve ulcers and hemorheological laboratory parameters in HD patients with PAD and ischemic ulcers resistant to standard therapies.

Clinical evolution of patients with lower extremity peripheral artery disease during the COVID-19 pandemic (the COVID-PAD study).

Background: The COVID-19 pandemic has led to significant disruptions in chronic disease care and forced people to stay at home. The effects of such issues on outpatients with lower extremity peripheral artery disease (PAD) remain unknown. Patients and methods: Single-centre, retrospective-prospective study conducted in a Swiss University Hospital. Patients with PAD were included between May 1 and July 31, 2020, with a follow-up visit at 12 months. Upon both visits, the Leriche-Fontaine PAD stage was recorded, and study participants underwent ankle-brachial index (ABI) calculation to assess limb perfusion. Functional capacities were assessed through the 6-minute walking and treadmill tests. Major adverse cardiovascular (MACE) and limb events (MALE) were recorded. Data collected during the pandemic were compared with the pre-pandemic period (January 1, 2019-April 30, 2020). Results: Overall, 259 patients were included. Mean age was 69 years and male sex was prevalent (69.1%). Odds of experiencing a degradation in PAD stage were lower during the pandemic than before (odds ratio [OR]: 0.43; 95% confidence interval [CI]: 0.21-0.87; p = 0.018). No significant difference was found between periods in terms of ABI trends. Both pain-free walking time at treadmill test (p = 0.003) and maximal pain intensity at 6-minute walking test (p = 0.001) significantly improved during the pandemic. Compared with the pre-pandemic period, during the pandemic patients were hospitalized less frequently (p = 0.028) and were less likely to undergo elective limb revascularization (p<0.001). No significant difference was found between periods in terms of MALE (p = 0.311), whereas non-fatal strokes were less frequently reported during the pandemic (p = 0.043). Conclusion: In a cohort of outpatients with PAD, we found no evidence of clinical deterioration during the pandemic compared with the pre-pandemic period, though rates of adverse events were nonnegligible in both periods. In case of future pandemics, patients with PAD should be encouraged to maintain an active lifestyle while being closely monitored to avoid clinical worsening.

Current Opinion on Diagnosis of Peripheral Artery Disease in Diabetic Patients.

Peripheral arterial disease (PAD) prevalence and diabetes mellitus (DM) prevalence are continuously increasing worldwide. The strong relationship between DM and PAD is highlighted by recent evidence. PAD diagnosis in diabetic patients is very important, particularly in patients with diabetic foot disease (DFD); however, it is often made difficult by the characteristics of such diseases. Diagnosing PAD makes it possible to identify patients at a very high cardiovascular risk who require intensive treatment in terms of risk factor modification and medical therapy. The purpose of this review is to discuss the diagnostic methods that allow for a diagnosis of PAD in diabetic patients. Non-invasive tests that address PAD diagnosis will be discussed, such as the ankle-brachial index (ABI), toe pressure (TP), and transcutaneous oxygen pressure (TcPO2). Furthermore, imaging methods, such as duplex ultrasound (DUS), computed tomography angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA), are described because they allow for diagnosing the anatomical localization and severity of artery stenosis or occlusion in PAD. Non-invasive tests will also be discussed in terms of their ability to assess foot perfusion. Foot perfusion assessment is crucial in the diagnosis of critical limb ischemia (CLI), the most advanced PAD stage, particularly in DFD patients. The impacts of PAD diagnosis and CLI identification in diabetic patients are clinically relevant to prevent amputation and mortality.

Long-Term Outcome of Lower Extremity Bypass Surgery in Patients with Chronic Kidney Disease and Critical Limb Ischemia in Germany

The aim of this study is to present short- and long-term outcomes after lower extremity bypass (LEB) surgery in patients with chronic limb-threatening ischemia (CLTI) and chronic kidney disease (CKD), differentiated by peripheral artery disease (PAD) Fontaine stage III and IV. Methods: Retrospective analysis of anonymized data from a nationwide German health insurance company (AOK). Data from 22,633 patients (14,523 men) who underwent LEB from 2010 to 2015, were analyzed, presenting 18,271 with CKD stage 1/2, 2,483 patients with CKD stage 3 and 1,879 with CKD stage 4/5. Results: Perioperative mortality (60-day mortality) was 7.2% for CKD stage 1/2, 12.4% for CKD stage 3, and 18.0% for CKD stage 4/5. Patients with PAD stage IV had a significantly higher perioperative mortality (43.2%) than patients with PAD stage III (22.7%). The perioperative major amputation rate depended significantly on PAD stage IV (Odds Ratio (OR): 2.57 CI: 2.16 – 3.05, p < .001), the LEB level below the knee and crural/pedal (OR: 2.49 CI: 2.14 – 2.90, p < .001), CKD stage 4/5 (OR: 1.28, CI: 1.06 – 1.54, p = .009), and the presence of diabetes mellitus type 2 (OR: 1.19, CI: 1.05 – 1.36, p = .007). Kaplan-Meier estimated long-term survival of up to 9 years after surgery was 31.7% for patients with CKD stage 1 and 2, 14.3% for CKD stage 3, and only 10.1% for CKD stage 4 and 5 (p < .001). PAD Fontaine stage IV vs. III (Hazard Ratio (HR): 1.64, CI: 1.56 – 1.71, p < .001), but not bypass level had an independent adverse influence on long-term survival. Conclusion: CKD and PAD stage were equally significant independent predictors of patient survival and MACE with higher PAD and CKD stages associated with less favorable long-term outcomes.

Mortality in Amputees with Peripheral Artery Disease during the Post-COVID Era: A Three-Year Analysis.

Patients with peripheral artery disease (PAD) have 40-70% higher three-year mortality after lower limb amputation compared to non-amputees. In this study, we examined the consequences of delayed treatment for patients with PAD during the coronavirus disease 2019 (COVID-19) pandemic. This study employed a retrospective single-centre cohort design at a large tertiary care hospital. We compared amputees with PAD during the initial COVID-19 outbreak period in 2020 with a control group of amputees from 2019 after a three-year follow-up. In total, 134 amputees with PAD were included due to unsuccessful revascularization (n = 84 in 2020 vs. n = 50 in 2019). Patients in 2020 were significantly younger than those in 2019 (p = 0.01) and mostly admitted with advanced stages of PAD (p < 0.03). The proportion of major limb amputations increased significantly in 2020 (p = 0.03). Non-COVID-19-related deaths among patients in 2020 were more than twice as many as those in 2019, and long-term mortality in 2020 was 49% compared to 39% in 2019 (p = 0.04). Diabetes and renal insufficiency had a significantly negative impact on the survival of amputees with PAD (p < 0.01). Delayed treatment in patients with PAD leads to high long-term mortality risk after amputation, especially in PAD patients with diabetes and renal insufficiency. Therefore, in future pandemics, continuously monitoring patients with PAD will be crucial to prevent delayed treatment and severe short-term and long-term consequences.

Loss of c-Kit in Endothelial Cells Protects against Hindlimb Ischemia.

Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic benefits of c-Kit have been reported in the ischemia scenario; however, the present study demonstrates the effects of specific endothelial c-Kit signaling in arteriogenesis during hindlimb ischemia. We created conditional knockout mouse models that decrease c-Kit (c-Kit VE-Cadherin CreERT2-c-Kit) or its ligand (SCF VE-Cadherin CreERT2-SCF) specifically in endothelial cells (ECs) after tamoxifen treatment. These mice and a control group (wild-type VE-Cadherin CreERT2-WT) were subjected to hindlimb ischemia or aortic crush to evaluate perfusion/arteriogenesis and endothelial barrier permeability, respectively. Our data confirmed the lower gene expression of c-Kit and SCF in the ECs of c-Kit and SCF mice, respectively. In addition, we confirmed the lower percentage of ECs positive for c-Kit in c-Kit mice. Further, we found that c-Kit and SCF mice had better limb perfusion and arteriogenesis compared to WT mice. We also demonstrated that c-Kit and SCF mice had a preserved endothelial barrier after aortic crush compared to WT. Our data demonstrate the deleterious effects of endothelial SCF/c-Kit signaling on arteriogenesis and endothelial barrier integrity.

New Horizons in Peripheral Artery Disease.

Peripheral artery disease (PAD) is the lower limb manifestation of systemic atherosclerotic disease. PAD may initially present with symptoms of intermittent claudication, whilst chronic limb-threatening ischaemia (CLTI), the end stage of PAD, presents with rest pain and/or tissue loss. PAD is an age-related condition present in over 10% of those aged ≥65 in high-income countries. Guidelines regarding definition, diagnosis and staging of PAD and CLTI have been updated to reflect the changing patterns and presentations of disease given the increasing prevalence of diabetes. Recent research has changed guidelines on optimal medical therapy, with low-dose anticoagulant plus aspirin recommended in some patients. Recently published randomised trials highlight where bypass-first or endovascular-first approaches may be optimal in infra-inguinal disease. New techniques in endovascular surgery have increased minimally invasive options for ever more complex disease. Increasing recognition has been given to the complexity of patients with CLTI where a high prevalence of both frailty and cognitive impairment are present and a significant burden of multi-morbidity and polypharmacy. Despite advances in minimally invasive revascularisation techniques and reduction in amputation incidence, survival remains poor for many with CLTI. Shared decision-making is essential, and conservative management is often appropriate for older patients. There is emerging evidence of the benefit of specialist geriatric team input in the perioperative management of older patients undergoing surgery for CLTI. Recent UK guidelines now recommend screening for frailty, cognitive impairment and delirium in older vascular surgery patients as well as recommending all vascular surgery services have support and input from specialist geriatrics teams.

Efficacy of retrograde revascularization in diabetic patients with chronic limb-threatening ischemia after a failed antegrade approach.

Chronic limb-threatening ischemia is the end stage of peripheral arterial disease. The revascularization of patients suffering from diabetes mellitus who present chronic total occlusions of below-the-knee vessels can be technically very difficult and sometimes impossible to achieve by performing only an antegrade approach. As regards retrograde recanalization, several studies have investigated the efficacy and safety of this technique in the femoropopliteal axis or in the infrageniculate arterial vessels in patients with advanced atherosclerotic disease. Currently in the literature there are still few studies analyzing the effectiveness of the retrograde approach in the treatment of occlusions of below-the-knee vessels in patients suffering from diabetes mellitus. The purpose of the study was to retrospectively evaluate safety, technical success, and clinical outcome of retrograde transpedal/transtibial recanalization in patients suffering from diabetes mellitus. This is a retrospective observational monocentric study. We retrospectively analyzed data over a three-year period (August 2019-September 2022) of patients that underwent revascularization of one or more below-the-knee vessels for chronic limb-threatening ischemia and had a retrograde transpedal/transtibial approach after a failed antegrade transfemoral revascularization. We identified and included in the study 28 out of 352 patients. We evaluated clinical comorbidities, Rutherford-Becker classification, Texas classification, and the occluded vessels (only below-the-knee or multi-level occlusions); we then analyzed technical, procedural and clinical success, survival rate, and procedural complications. All patients included in the study underwent a 6 months follow-up. Patients belonged to Rutherford-Becker stage V (18) or VI (10), Texas wound classification IIC: 7 IID: 8 IIIC: 4 IIID: 9, all suffering from diabetes, and five were on dialysis. Treatment of a femoropopliteal lesion was performed during the same procedure in 6 of 28 patients (28.6%). Technical success was obtained in 25 out of 28 patients (89.3%), and procedural success was achieved in 23 of 28 patients (82.1%). No complications occurred at the pedal/tibial access. One minor complication at the femoral access was observed. The cure rate 6 months after the procedure was 57.1% (16/28 patients), and the 6-month survival rate was 96.4%. Three major amputations (10.7%) and four minor amputations (14.2%) were performed after revascularization procedures. Two patients were readmitted for vascular causes (7.1%). Retrograde approach for revascularization of below-the-knee vessels in diabetic patients is safe and effective with high procedural and clinical success rates in the absence of significant complications. It should be considered when revascularization cannot be achieved with an antegrade transfemoral approach.

Pedal Acceleration Time An Alternative Tool To Ankle-Brachial Index In Peripheral Arterial Disease.

Ankle-Brachial Index (ABI) is a well-established diagnostic tool for evaluating peripheral arterial disease (PAD). Limitations in its application led to the development of alternative diagnostic methods, including Toe-Brachial Index (TBI) and Transcutaneous Pressure of Oxygen (TcPO2), yet these are not as widely available as ABI. Recently, Pedal Acceleration Time (PAT), has gained popularity as a new tool to assess PAD, requiring only an ultrasound. This study seeks to further establish the correlation between ABI and PAT, determining whether PAT can be a reliable alternative for diagnosing and assessing the severity of PAD. ABI and PAT were measured in patients attending our consult with no history of vascular or endovascular surgery. Limbs with unmeasurable ABI were excluded. Patients were categorized into groups based on their PAD stage according to the Fontaine classification. Patient demographics, comorbidities and respective ABI and PAT were analysed. Sixty-nine patients (114 limbs) were included in the study. Mean age 68 ± 11.7 years, 78.3% male and 33.3% diabetic patients. Fifty-three claudicant limbs (46.5%) and 26 limbs (22.8%) with chronic limb threatening ischemia. Pearson correlation coefficient between ABI and PAT, showed a strong negative correlation (r= -0.78; p<0.01). Mean ABI and PAT for limbs in Fontaine stage I were 0.94 ± 0.17 and 82.0 ± 27.4 ms; Fontaine stage IIa 0.69 ± 0.21 and 141.3 ± 57.8 ms; Fontaine stage IIb 0.54 ± 0.14 and 173.4 ± 65.1 ms; Fontaine stage III 0.43 ± 0.15 and 216 ± 33.2 ms; Fontaine stage IV 0.49 ± 0.17 and 206.7 ± 78.1 ms, respectively. Our study suggests an inverse correlation between ABI and PAT, in accordance with the findings published in the literature, thus supporting the use of PAT as an easily reproducible and efficient alternative to ABI for evaluating the severity of PAD.

The role of therapeutic MicroRNA in arteriogenesis process in limb ischemia: A systematic review

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.

Narrative Review of Biological Markers in Chronic Limb-Threatening Ischemia.

Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral arterial disease, is diagnosed in the presence of ischemic rest pain, non-healing ulcers, or gangrene. Several studies have demonstrated that inflammation and endothelial dysfunction are some of the main substrates of CLTI. A narrative review was conducted and reported according to PRISMA guidelines. Three databases were searched-Web of Science, Medline, and EMBASE-for the studies assessing CLTI and the biological markers related to it. We included 22 studies, and all the markers identified (C-reactive protein, D-dimers, fibrinogen, cytokines, IL-6, TNF-α, ICAM-1 (Intracellular Adhesion Molecule-1), VCAM-1 (Vascular Cell Adhesion Molecule-1), neutrophile-to-lymphocytes ratio (NLR), IL-8, Pentraxin-3, neutrophil gelatinase-associated lipocalin (NGAL), calprotectin, E-selectin, P-selectin, neopterin, High-Mobility Group Box-1 protein (HGMB-1), Osteoprotegerin (OPG) and Sortilin) were positively associated with advanced CLTI, with major limb or major cardiovascular events in these patients. All the studied markers had increased values in patients with CLTI, especially when associated with diabetes mellitus, proving a very important association between diabetes and major limb or cardiovascular events in these patients. There is a need for more studies to validate these markers in terms of diagnosis or prognosis in CLTI patients and in trying to find new medical strategies that target inflammation or endothelial dysfunction in these patients.

Mitochondrial respiration in peripheral arterial disease depends on stage severity.

Peripheral arterial disease (PAD) is an increasing cause of morbidity and its severity is graded based on clinical manifestation. To investigate the influence of the different stages on myopathy of ischemic muscle we analysed severity-dependent effects of mitochondrial respiration in PAD. Eighteen patients with severe PAD, defined as chronic limb-threatening ischemia, 47 patients with intermittent claudication (IC) and 22 non-ischemic controls were analysed. High-resolution respirometry (HRR) was performed on muscle biopsies of gastrocnemius and vastus lateralis muscle of patients in different PAD stages to investigate different respiratory states. Results from HRR are given as median and interquartile range and were normalized to citrate synthase activity (CSA), a marker for mitochondrial content. In order to account for inter-individual differences between patients and controls, we calculated the ratio of O₂-flux in gastrocnemius muscle over vastus muscle ('GV ratio'). CSA of the gastrocnemius muscle as a proxy for mitochondrial content was significantly lower in critical ischemia compared to controls. Mitochondrial respiration normalized to CSA was higher in IC compared to controls. Likewise, the GV ratio was significantly higher in IC compared to control. Mitochondrial respiration and CSA of PAD patients showed stage-dependent modifications with greater changes in the mild PAD stage group (IC).

The Clinical Utility of Lower Extremity Dual-Energy CT Angiography in the Detection of Bone Marrow Edema in Diabetic Patients with Peripheral Artery Disease.

(1) Background: Type 2 diabetes is a major cause of incidences and the progression of peripheral artery disease (PAD). Bone marrow edema (BME) is an important finding suggestive of underlying bone inflammation in non-traumatic diabetic patients with PAD. Our aim was to evaluate the presence, severity, and clinical implications of BME detected by virtual non-calcium application (VNCa) of dual-energy CT angiography (DE-CTA). (2) Methods: A consecutive series of 76 diabetic patients (55 men; mean age 71.6 ± 11.2 yrs) submitted to lower limb DE-CTA for PAD evaluation and revascularization planning, which were retrospectively analyzed. VNCa images were independently and blindly revised for the presence, location, and severity of BME by two radiologists with 10 years of experience. BME and non-BME groups were evaluated in terms of PAD clinical severity and 6-month secondary major amputation rate. (3) Results: BME was present in 17 (22%) cases, while 59 (78%) patients were non-BME. The BME group showed a significantly higher incidence of major amputation (p < 0.001) and a significantly higher number of patients with advanced clinical stages of PAD compared to the non-BME group (p = 0.024). (4) Conclusions: Lower limb DE-CTA with VNCa application is a useful tool in the detection of BME in diabetic patients with PAD, simultaneously enabling the evaluation of the severity and location of the arterial disease for revascularization planning. BME presence could be a marker of clinically severe PAD and a possible risk factor for revascularization failure.

Establishing a Critical Limb Ischemia Outpatient Center: Separating Facts from Myth

Critical Limb Ischemia or chronic limb-threatening ischemia represents the end stage of peripheral artery disease where arterial flow is compromised to the lower extremities and risk of limb loss may become imminent. Revascularization of lower extremities is one of the cornerstones of limb salvage and amputation prevention. Establishing centers of high quality CLI therapy requires creating different foundational pillars in order to be successful. This article discusses critical limb ischemia center creation from the perspective of critical limb ischemia therapists working in an outpatient setting.

The prevalent causes of death in patients with peripheral artery disease undergoing revascularisation or amputation.

Preventing untimely death in patients with peripheral artery disease (PAD) requires a detailed understanding of the predominant causes of death (COD). This literature review aims to describe how short- and long-term COD are reported in patients who had surgery for PAD. A literature review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for articles reporting specific causes of mortality in patients who had surgery for all stages of PAD. Articles were included if they reported COD after open surgical or endovascular revascularisation, or major or minor amputation for PAD. Critical appraisals were conducted according to included study types, using the Joanna Briggs Institute tools. Cause of death was reported in 21 publications. Twenty were observational and one was a randomised control trial. Study size ranged from 25 to 10,505 patients. Cardiovascular disease was the most prevalent COD in perioperative periods (42.5% from 13 studies). Long-term follow-up ranged from 1month and 7years with 15 studies reporting cardiac related mortality as the most frequent cause of death. However, mortality from neoplasia, respiratory disease (including pneumonia and pulmonary emboli), stroke and sepsis were prevalent. Many studies were low-average quality, with few population-based observational studies. Whilst cardiovascular COD are the most prevalent reasons for mortality in patients with PAD, the proportion of patients dying from neoplasia and respiratory disease is high. Improved reporting standards for COD in studies examining PAD are needed.