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Background: Inflammation is a key element in the initiation and progression of peripheral arterial disease (PAD). Understanding the impact of inflammatory molecules, as cytokines in PAD could help us to improve the prognosis of these patients. The main goal of this study was to compare the serum level of cytokines between patients with claudication to those with chronic limb-threatening ischemia (CLTI). The second objective was to evaluate the relationship between the levels of cytokines and death or amputation rate., Methods: An observational, single-center, and prospective study was conducted from January 2018 to July 2022. The study was approved by the ethical commission of the Local Hospital (75/2017). Patients with PAD, suggested by the clinical history and objective examination and confirmed with ankle-brachial index, attending vascular surgery consultations of the first author were included. The following exclusion criteria were applied: i) bedridden individuals or subjects who refused to participate in the protocol; ii) diseases responsible for body composition changes or proinflammatory state; iii) recent diet change, iv) active malignancy, v) autoimmune disease, vi) active infection, vii) chronic renal failure (glomerular filtration rate <30 mL/min/1.73 m 2 ), or viii) heart failure in the past 3 months. This cohort was observed at admission, 3, 6, and 12 months. A panel of 27 cytokines was determined with ELISA, at baseline., Results: We included 119 subjects (mean age: 67.58 ± 9.60 years old; 79.80% males), 65 patients with claudication and 54 with CLTI. From the 27 cytokines analyzed, patients with CLTI, when compared to those with claudication, had a higher serum level of 11 cytokines: IL1ra, IL-6, IL-8, IL12 p70, G-CSF, IP-10, MCP-1, MIP-1α, PDGF-β, RANTES, and TNF-α. From the group of patients with CLTI those who underwent a major amputation had a higher serum level of FGF-basic [median = 49.04; interquartile range = 37.03-52.49; versus median = 33.04; interquartile range = 28.60-38.98; P = 0.001]., Conclusions: Patients with CLTI have higher serum level of inflammatory cytokines, which may have role in the prognosis of these patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adherence to the Mediterranean diet (MeD) has been associated with a reduced incidence of peripheral arterial disease (PAD)/lower extremity arterial disease (LEAD) in observational trials and in a randomized trial. In secondary prevention, a lower hazard ratio for composite major adverse cardiovascular events has been associated with better adherence to MeD in a relatively small, randomized trial. This has not been confirmed in a sub-analysis of a large interventional trial of dual antithrombotic treatment. The effects of vegetarian, vegan or low carbohydrate/ketogenic diets on the incidence and outcomes of PAD/LEAD are not known. While abdominal obesity is associated with diabetes mellitus and PAD/LEAD, the lowest incidence of PAD/LEAD has been found in subjects with a body mass index 25-29.9 kg/m 2 . Malnutrition is a negative prognostic factor for survival of patients with chronic limb threatening ischemia. Physical activity (PA) is an acute stressor, but habitual recreational PA results in beneficial adaptations and improved health. In observational studies, lower levels of exercise and lower physical fitness have been associated with more prevalent PAD/LEAD. In contrast to coronary artery disease, that shows a reverse J-shaped relationship between long-term endurance exercise and coronary atherosclerosis, such a relationship is not known for PAD/LEAD. A general recommendation for maintaining cardiovascular health is performing regular moderate-intensity exercise with some vigorous-intensity aerobic PA, and resistance exercise at least twice a week. Combinations of healthy behaviors are more effective in preventing PAD/LEAD than a single behavioral component. In treatment of PAD/LEAD causing intermittent claudication, supervised walking training is recommended among measures of first-line treatment, while unsupervised walking training should be considered as an alternative.

Introduction: Dyslipidemia is an established risk factor for cardiovascular diseases. We aimed to review its role in the pathogenesis of lower extremity arterial disease (LEAD), as well as the effect of lipid-lowering treatment on the progression of LEAD., Evidence Acquisition: PubMed/MedLine, EMBASE and Scopus were searched between January 1990 and January 2024 for articles investigating the role of dyslipidemias and hyperlipidemias in the pathogenesis of LEAD. A separate search focused on the effects of lipid-lowering therapy on patients with LEAD., Evidence Synthesis: There is evidence that dyslipidemias play a major role in the development of LEAD. All patients with LEAD should receive intensive lipid-lowering therapy for the reduction not only of claudication symptoms and amputation rates, but also of myocardial infarction and cardiovascular event rates., Conclusions: Vascular specialists should keep in mind the pivotal role of dyslipidemia in the pathogenesis and progression of LEAD.

Diabetes mellitus (DM) is a major risk factor for lower extremity arterial disease (LEAD) and about 20% of symptomatic patients with LEAD have DM. In subjects with DM, LEAD is a cause of morbidity and mortality. DM typically causes complications in the form of macro- and microangiopathy. In these patients, macroangiopathy manifests as atherosclerosis like in non-diabetic patients. However, its course is accelerated due to accompanying risk factors like hyperlipidemia and hypertension, with cumulative effects. Other factors are also relevant such as inflammation, endothelial dysfunction, platelet activation, blood rheological properties, hypercoagulability, and factors stimulating vascular smooth muscle cell proliferation. Additionally, DM is a risk factor for restenosis and amputation. DM is strongly associated with femoral-popliteal and tibial LEAD, which manifests earlier in patients with DM and may progress more rapidly to critical limb ischemia. Diabetic microangiopathy is characterized by arteriolosclerosis and interstitial fibrosis which additionally affects progression and outcomes of angiopathy of lower limbs. Glycemic control particularly decreases microangiopathic complications, while prevention of macrovascular complications requires treatment of accompanying risk factors like hypertension and dyslipidemia.

Background: Peripheral artery disease is characterized by an intense inflammatory process that can be associated with a higher mortality rate, particularly in chronic limb-threatening ischemia (CLTI). This study aims to compare the evolution of inflammatory markers between patients with claudication with those with CLTI at 3, 6, and 12 months., Methods and Results: An observational, single-center, and prospective study was conducted. A total of 119 patients with peripheral artery disease (65 with claudication and 54 with CLTI) were observed and inflammatory markers collected at admission and 3, 6, and 12 months. At admission, patients with CLTI, when compared with patients with claudication, had significantly higher serum levels of C-reactive protein and fibrinogen (positive acute-phase proteins) and lower serum level of albumin, total cholesterol, and high-density lipoprotein (negative acute-phase proteins): C-reactive protein (g/dL), 2.90 (25th-75th percentile, 2.90-4.90) versus 6.80 (25th-75th percentile, 2.90-53.26) ( P =0.000); fibrinogen (mg/dL), 293.00 (25th-75th percentile, 269.25-349.00) versus 415.50 (25th-75th percentile, 312.00-615.75) ( P =0.000); total cholesterol (mg/dL), 161.79±95% [152.74-170.85] versus 146.42%±95% [135.30-157.53] ( P =0.034); high-density lipoprotein (mg/dL), 50.00 (25th-75th percentile, 41.00-60.00) versus 37.00 (25th-75th percentile, 30.00-45.50) ( P =0.000); albumin (g/dL): 4.00 (25th-75th percentile, 3.70-4.20) versus 3.60 (25th-75th percentile, 3.10-4.00) ( P =0.003). The association between CLTI and total cholesterol was lost after adjusting for confounders. Three months after the resolution of the CLTI, there was an increase in the levels of negative acute-phase proteins and a decrease in positive acute-phase proteins. These inflammatory proteins did not register an evolution in patients with claudication. The differences in the inflammatory proteins between groups disappeared at 6 months., Conclusions: CLTI has an inflammatory environment that can be partially reverted after resolution of the ischemic process, emphasizing the importance of timely intervention.

Background: The loss of skeletal muscle is a prognostic factor in several diseases including in patients with chronic limb threatening ischemia (CLTI). Patients with CLTI also have a lower skeletal mass and area when compared to those with claudication. However, there are no currently available data regarding the histological characteristics of core muscles in patients with CLTI. This study aims to determine the differences in core skeletal muscles between patients with claudication and those with CLTI. The second aim is to evaluate the differences in myokines, which are molecules secreted by skeletal muscle, between patients with claudication and those with CLTI., Methods: An observational, prospective study was conducted from January 2018 to July 2022 involving consecutive patients with peripheral arterial disease (PAD). The clinical characteristics were registered. In PAD patients with surgical indication for common femoral artery approach, samples of sartorius skeletal muscle (and not from the limb muscles directly involved in the ischemic process) were collected. The samples were submitted to histological characterization on hematoxylin-eosin and to immunohistochemical analysis to detect CD45+ leukocytes and CD163+ macrophages. The extent of the inflammatory cells (leukocytes and macrophages) was semiquantitatively assessed using a 0-to-4 grade scale as follows: absent (0†), mild (†), moderate (††), severe (†††), and very severe (††††). Serum levels of myokines: irisin, myostatin, IL-8, and lL-6 were determined with multiplex bead-based immunoassay., Results: 119 patients (mean age: 67.58 ± 9.60 years old, 79.80% males) 64 with claudication and 54 with CLTI were enrolled in the study. No differences were registered between patients with claudication and those with CLTI on age, gender, cardiovascular risk factors, and medication, except on smoking habits. There was a significantly higher prevalence of smokers and a higher smoking load in the claudication group. Samples of sartorius skeletal muscle from 40 patients (14 with claudication and 26 with CLTI) were submitted to histological analysis. No differences were found in skeletal muscle fibers preservation, trauma, or hemorrhage (on hematoxylin-eosin staining). However, in the immunohistochemistry study, we found more inflammatory cells CD45+ leukocytes in patients with CLTI when compared to those with claudication [CD45+ ≥ moderate (††): claudication (n = 14): 4; 28.57%; CLTI (n = 25): 16; 64.00%; P = 0.034]. Patients with CLTI also had higher tissue levels of CD163+ macrophages, but this difference was not significant [CD163+ ≥ moderate (††): claudication (n = 13): 7; 53.85%; CLTI (n = 27): 21; 77.78%; P = 0.122]. The serum levels of the myokines, irisin, and myostatin were below the lower limit of detection, in the majority of patients, so no valid results were obtained. However, patients with CLTI had a higher serum level of Interleukin (IL)-6 and IL-8., Conclusions: CLTI patients exhibit increased quantities of leukocytes in their sartorius muscle, as well as elevated serum levels of myokines IL-8 and IL-6. Inflamed skeletal muscle can contribute to the loss of muscle mass and account for the lower density of skeletal muscle observed in CLTI. Additionally, inflamed skeletal muscle may contribute to the development of systemic inflammation through the secretion of pro-inflammatory cytokines into the systemic circulation. Halting the inflammatory process could eventually improve the prognosis of CLTI patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) is defined as coronary heart disease (CHD), cerebrovascular disease, or lower extremity arterial disease (LEAD) also named peripheral arterial disease (PAD). ASCVD is considered to be of atherosclerotic origin and is the leading cause of morbidity and mortality mainly for individuals with diabetes mellitus (DM). In this consensus document of the International Union of Angiology the authors discuss epidemiology, risk factors, primary and secondary prophylaxis, the correlation between diabetes mellitus and LEAD, conservative and surgical treatment.

Background: Lower extremity peripheral arterial disease (PAD) is an atherosclerotic disease of the lower extremities. Atherosclerosis, inflammation, and sarcopenia are independently associated and potentiate each other. Inflammation is deeply involved in the formation and progression of atherosclerosis and is also involved in the pathophysiology of sarcopenia. Sarcopenia is defined as low muscle mass, with low muscle strength. This study aims to determine the differences in skeletal muscle characteristics and in inflammatory parameters between patients with claudication and with chronic limb threatening ischemia (CLTI)., Methods: An observational, prospective study in patients with PAD was conducted from January 2018 to December 2020. The clinical characteristics and the cardiovascular risk factors were prospectively registered. The inflammatory parameters determined were: positive acute phase proteins (C-reactive Protein- CRP- and fibrinogen) and negative acute phase proteins albumin, total cholesterol and high-density lipoprotein (HDL). The skeletal muscle area and density were quantified with a computed topography (CT) scan. The strength was determined with a Jamar® hydraulic hand dynamometer., Results: A total of 116 patients (mean age: 67.65 ± 9.53 years-old) 64% with claudication and 46% with CLTI were enrolled in the study. No differences were registered between patients with claudication and CLTI on age, cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, and smoking habits) and medication. There was a higher prevalence of men in the claudication group (88.89% vs. 71.70%, P = 0.019). Analyzing the inflammatory parameters, we noted that patients with CLTI had increased serum levels of positive acute phase proteins: CRP (37.53 ± 46.61 mg/L vs. 9.18 ± 26.12 mg/L, P = 0.000), and fibrinogen (466.18 ± 208.07 mg/dL vs. 317.37 ± 79.42 mg/dL, P = 0.000). CLTI patients had decreased negative acute phase proteins: albumin (3.53 ± 0.85 g/dL vs. 3.91 ± 0.72 g/dL, P = 0.001), total cholesterol (145.41 ± 38.59 mg/dL vs. 161.84 ± 34.94 mg/dL, P = 0.013) and HDL (38.70 ± 12.19 mg/dL vs. 51.31 ± 15.85 mg/dL, P = 0.000). We noted that patients with CLTI had lower skeletal muscle area and mass (14,349.77 ± 3,036.60 mm 2 vs. 15,690.56 ± 3,183.97 mm 2 P = 0.013; 10.11 ± 17.03HU vs. 18.02 ± 13.63HU P = 0.013). After adjusting for the variable sex, the association between skeletal muscle density and CLTI persisted (r (97) = -0.232, P = 0.021). The groups did not differ in strength (patients with claudication: 25.39 ± 8.23 Kgf vs. CLTI: 25.17 ± 11.95 Kgf P = 0.910)., Conclusions: CLTI patients have decreased skeletal muscle mass and a systemic inflammation status. Recognizing the deleterious triad of atherosclerosis, inflammation and loss of skeletal mass patients with CLTI is an opportunity to improve medical therapy and to perform a timely intervention to stop this vicious cycle., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This position paper, written by members of International Union of Angiology (IUA) Youth Committee and senior experts, shows an overview of therapeutical approaches for patients with chronic limb-threatening ischemia (CLTI) and absence of 'standard' solutions for revascularization. The aim was to demonstrate the accurate management of the 'no-option' CLTI patient including the wound treatment and the rehabilitation, considering always the goal of the increase of quality of life of the patients.

Introduction: Intermittent claudication (IC) stage of peripheral artery disease (PAD) is associated with significant impairment of quality of life. In the subset of patients with disabling IC refractory to best medical treatment (BMT), revascularization procedures may be considered. However, evidence comparing open revascularization surgery, endovascular treatment and BMT focusing on the impact on quality of life is very sparse. We aim to review clinical, anatomical and hemodynamic outcomes after bypass surgery compared to BMT and/or endovascular treatment in IC patients., Evidence Acquisition: We systematically reviewed controlled trials and comparative cohort studies assessing quality of life, walking performance, clinical/ symptomatic improvement, symptom recurrence, patency rates, Ankle-Brachial Index (ABI) improvement and adverse events after bypass surgery versus endovascular treatment/BMT in IC patients., Evidence Synthesis: Eleven studies involving 16,608 patients were included. Compared to BMT, bypass surgery was associated with a significantly greater improvement on Short-Form 36 (SF-36) physical functioning score (mean difference (MD), -14.0; 95% confidence interval [CI], -21.2 to -6.8), Walking Impairment Questionnaire (WIQ) walking distance score (MD, -0.23; 95% CI, -0.29 to -0.16) and SF-36 bodily pain score (MD, -13.0; 95% CI, -20.2 to -5.8). There were no significant differences between bypass and endovascular treatment regarding the three scores. Bypass surgery presented better primary patency rates at 1 (odds ratio [OR], 0.47; 95% CI, 0.29 to 0.76) and 5 years (OR, 0.44; 95% CI, 0.34 to 0.57) and better ABI improvement (MD, -0.07; 95% CI, -0.12 to -0.03) when compared to endovascular treatment. There were no statistically significant differences between bypass and endovascular patients regarding secondary patency rates, 30-day mortality and major amputation., Conclusions: Lower limb revascularization may be beneficial in patients with disabling and refractory IC when the primary goal is to improve quality of life and walking capacity. Bypass surgery is associated to better symptomatic status, long-term primary patency and ABI improvement when compared to endovascular surgery, especially in anatomically extensive disease. Further studies addressing patient-reported outcomes and including a BMT group are paramount for more robust evidence on IC treatment and, consequently, better decision making.

Background: Determine the influence of sarcopenia on the prognosis of peripheral arterial disease (PAD)., Methods: A systematic search of the PubMed and Cochrane Library databases was performed with the keywords and medical subject heading (MesH): "muscle, skeletal", "sarcopenia", "prognosis", "duration of stay", "death", "mortality", "patient readmission", "length of stay", "peripheral arterial disease", "intermittent claudication" and "critical limb ischemia". Papers published from January 2010 to October 2020 in English, French, Spanish and Portuguese were eligible for inclusion. The primary outcome was overall survival. Secondary outcomes included post-operative complications, amputation, length of hospital stay and hospital readmission., Results: Of 1071 papers, 8 articles and 1511 patients were included (68.96% male, mean age 71.83 years). Five papers found an inverse relationship between SM area and mortality. Matsubara (2015) found that the 5-year overall survival rates were lower for patients with sarcopenia (23.5% ± 0.18% vs 77.5% ± 0.09% P = 0.001). Matsubara (2016) registered 3-year cardiovascular event-free survival rates of 43.1% and 91.2% for patients with and without sarcopenia (P < 0.01). Juszczak (2018) found that survival was lower in patients with reduced total psoas area. Taniguchi (2019) found that 3-year overall survival rate was 60% for patients with sarcopenia and 87% for patients without sarcopenia (P < 0.05). Shimazoe (2019) concluded sarcopenia was a significant predictor of overall survival. Distinctly, Nyers (2017) concluded that higher ratio bilateral psoas area to L4 vertebral body was associated with an increased risk of death. Two other studies analyzed other characteristics of the SM (density and strength). McDermott (2012) and found that lower calf muscle density and strength were associated with an increase in mortality. Sugai (2019) concluded that patients with major cardiovascular and limb events had a lower SM density., Conclusions: Lower SM area and mass seem to be associated with a higher mortality in PAD patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Peripheral artery disease (PAD) is one of the most frequent manifestations of atherosclerosis with high rates of morbidity and mortality. Platelets and coagulation are involved in the progression of atherosclerosis and thromboembolic complications. PAD patients have increased prothrombotic potential, which includes platelet hyperaggregability and increased pro-coagulant state. Therefore, antithrombotic treatment is of utmost importance for the prevention of cardiovascular events in this group of patients. Aspirin is the basic antiplatelet drug, but with limited efficacy in PAD. In contrast to coronary artery disease, its effect on the prevention of cardiovascular events in PAD has been limited proven. Particularly in asymptomatic PAD, there is no evidence for risk reduction with aspirin. Clopidogrel and ticagrelor are more effective than aspirin. Clopidogrel is thus an effective alternative to aspirin for prevention of cardiovascular events in symptomatic PAD. In patients who are non-responders to clopidogrel, ticagrelor is indicated. Dual antiplatelet treatment (DAPT) with aspirin and ticagrelor in patients with coronary artery disease and concomitant PAD significantly decreased the rate of major adverse cardiovascular events, including adverse limb events. However, in the CHARISMA Trial, aspirin and clopidogrel were not more effective than aspirin alone and increased bleeding complications. Therefore, DAPT seems effective only in PAD accompanied by coronary artery disease. Anticoagulant treatment for symptomatic PAD with vitamin K antagonists alone or in combination with aspirin is not more effective than single antiplatelet treatment but increases the rate of major bleeding. Low dose rivaroxaban combined with aspirin in PAD patients significantly reduces cardiovascular events, including limb-threatening ischemia and limb amputations. Anticoagulation and antiplatelet treatment after percutaneous or surgical revascularization of PAD improve the patency of treated vessels. Aspirin with or without dipyridamole improved patency of infra-inguinal by-pass grafts at one year. The combination of clopidogrel with aspirin was more effective than aspirin alone in the prevention of prosthetic graft occlusions in patients undergoing below-knee by-pass-grafting. Oral vitamin K antagonists were not more effective than aspirin in the prevention of infra-inguinal by-pass occlusion. The combination of low dose rivaroxaban and aspirin was effective in preventing major adverse cardiovascular events and adverse limb events after infrainguinal endovascular or surgical revascularization in patients with intermittent claudication. However, the data on antithrombotic treatment after revascularization for limb-threatening ischemia is scanty and inconclusive. In conclusion: Antithrombotic treatment of PAD is a cornerstone for the management of these patients. Antiplatelet drugs prevent the initiation and progression of atherosclerosis and are effective also in the prevention of thromboembolic events. Simultaneous use of antiplatelet and anticoagulation drugs is accompanied by an increased risk of bleeding. However, combined treatment with aspirin and low-dose rivaroxaban is more effective than single antithrombotic treatment and safer than full-dose combined treatment.