endothelin-1 and Peripheral-Arterial-Disease

The evidence for the role of endothelin-1 (ET-1) in endothelial dysfunction and atherosclerosis has been growing since its discovery. However most studies have focussed on cardiac disease and its role in peripheral arterial disease (PAD) is less clear. In addition to its role in the development and progression of atherosclerotic lesions in lower limb arteries, there is evidence that ET-1 adversely affects microvessels within the muscle and the viability of the ischemic muscle itself. This review summarises some of these findings which underscore the potential use of ET antagonists as an adjunct in the treatment of PAD.

Topics: Arteries; Endothelin-1; Humans; Microvessels; Muscle Fibers, Skeletal; Peripheral Arterial Disease

Lower-extremity peripheral artery disease (PAD) is associated with increased risk of cardiovascular events and impaired exercise tolerance. We have previously reported that leg heat therapy (HT) applied using liquid-circulating trousers perfused with warm water increases leg blood flow and reduces blood pressure (BP) and the circulating levels of endothelin-1 (ET-1) in patients with symptomatic PAD. In this sham-controlled, randomized, crossover study, sixteen patients with symptomatic PAD (age 65 ± 5.7 years and ankle-brachial index: 0.69 ± 0.1) underwent a single 90-min session of HT or a sham treatment prior to a symptom-limited, graded cardiopulmonary exercise test on the treadmill. The primary outcome was the peak walking time (PWT) during the exercise test. Secondary outcomes included the claudication onset time (COT), resting and exercise BP, calf muscle oxygenation, pulmonary oxygen uptake (V̇O

Topics: Aged; Blood Pressure; Endothelin-1; Female; Humans; Hyperthermia, Induced; Interleukin-6; Male; Middle Aged; Oxygen Consumption; Peripheral Arterial Disease; Tumor Necrosis Factor-alpha; Walking

Acute aerobic exercise prevents sitting-induced impairment of flow-mediated dilation (FMD). Further, evidence suggests that sitting-induced impairment of FMD occurs via an oxidative stress-dependent mechanism that disrupts endothelial function.. We hypothesized that acute aerobic exercise would prevent impairment of femoral artery FMD by limiting oxidative stress responses that increase endothelin-1 (ET-1) levels and disrupt nitric oxide (NO) status.. In a randomized, cross-over study, healthy men (n = 11; 21.2 ± 1.9 years) completed two 3 h sitting trials that were preceded by 45 min of either quiet rest (REST) or a single bout of continuous treadmill exercise (65% maximal oxygen consumption) (EX). Superficial femoral artery FMD, plasma glucose, malondialdehyde (MDA), ET-1, arginine (ARG) and its related metabolites [homoarginine (HA), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)] were assessed at baseline, 1 h following EX (or REST) (0 h), and at 1 h intervals during 3 h of uninterrupted sitting. Data were analyzed using repeated measures ANOVA.. During REST, femoral artery FMD declined from baseline (2.6 ± 1.8%) at 1, 2, and 3 h of sitting and resting shear rate decreased at 3 h. In contrast, when sitting was preceded by EX, femoral artery FMD (2.7 ± 2.0%) and resting shear rate responses were unaffected. No between trial differences were detected for plasma glucose, MDA, ET-1, ARG, HA, ADMA, or SDMA.. Prior aerobic exercise prevented the decline in femoral artery FMD that is otherwise induced by prolonged sitting independent of changes in oxidative stress, ET-1, and NO status.

Topics: Arginine; Blood Glucose; Endothelin-1; Endothelium, Vascular; Exercise; Exercise Therapy; Femoral Artery; Humans; Immobilization; Male; Malondialdehyde; Nitric Oxide; Peripheral Arterial Disease; Posture; Regional Blood Flow; Vasodilation; Young Adult

Leg thermotherapy (TT) application reduces blood pressure (BP) and increases both limb blood flow and circulating levels of anti-inflammatory mediators in healthy, young humans and animals. The purpose of the present study was to determine the impact of TT application using a water-circulating garment on leg and systemic hemodynamics and on the concentrations of circulating cytokines and vasoactive mediators in patients with symptomatic peripheral artery disease (PAD). Sixteen patients with PAD and intermittent claudication (age: 63 ± 9 yr) completed three experimental sessions in a randomized order: TT, control intervention, and one exercise testing session. The garment was perfused with 48°C water for 90 min in the TT session and with 33°C water in the control intervention. A subset of 10 patients also underwent a protocol for the measurement of blood flow in the popliteal artery during 90 min of TT using phase-contrast MRI. Compared with the control intervention, TT promoted a significant reduction in systolic (∼11 mmHg) and diastolic (∼6 mmHg) BP (P < 0.05) that persisted for nearly 2 h after the end of the treatment. The serum concentration of endothelin-1 (ET-1) was significantly lower 30 min after exposure to TT (Control: 2.3 ± 0.1 vs. TT: 1.9 ± 0.09 pg/ml, P = 0.026). In addition, TT induced a marked increase in peak blood flow velocity (∼68%), average velocity (∼76%), and average blood flow (∼102%) in the popliteal artery (P < 0.01). These findings indicate that TT is a practical and effective strategy to reduce BP and circulating ET-1 concentration and enhance leg blood flow in patients with PAD.

Topics: Blood Flow Velocity; Blood Pressure; Endothelin-1; Female; Humans; Hypertension; Hyperthermia, Induced; Inflammation Mediators; Leg; Male; Middle Aged; Peripheral Arterial Disease; Treatment Outcome

We evaluated if plasma biomarkers can predict incident peripheral arterial disease (PAD) and mortality in a longitudinal cohort study. Men (n = 3618) and women (n = 1542) were included in the Malmö Preventive Project and underwent analysis of: C-terminal endothelin-1 (CT-proET-1), N-Terminal prosomatostatin (NT-proSST), midregional proatrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and copeptin. Participants were followed up for incident PAD and mortality until December 31, 2016. Median follow-up was 11.2 years (interquartile range 9.4-12.2). Cumulative incidence of PAD was 4.3% (221/5160), 4.5% in men (164/3618) and 3.7% in women (57/1542;

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Female; Glycopeptides; Humans; Incidence; Longitudinal Studies; Male; Peptide Fragments; Peripheral Arterial Disease; Predictive Value of Tests; Procalcitonin; Prognosis; Protein Precursors; Retrospective Studies; Risk Assessment; Risk Factors; Somatostatin; Sweden; Time Factors; Up-Regulation

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

Topics: Aged; Aged, 80 and over; Animals; Aorta; Blotting, Western; Cardiovascular Diseases; Carotid Arteries; Case-Control Studies; Coronary Vessels; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Type 2; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Gastric Inhibitory Polypeptide; Humans; Immunohistochemistry; Male; Mice; Mice, Knockout; Microscopy, Confocal; Microvessels; Middle Aged; Myocytes, Smooth Muscle; Osteopontin; Peripheral Arterial Disease; Plaque, Atherosclerotic; Polymorphism, Single Nucleotide; Rats; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Receptors, Gastrointestinal Hormone; RNA, Messenger; Stroke; Sus scrofa; Swine

To investigate the specific features of arterial wall endothelial dysfunction and stiffness in patients with hypertension concurrent with gout.. A total of 54 patients were examined and divided into 2 groups. A study group consisted of 33 hypertensive patients with gout and a comparison group included 21 hypertensive patients without hyperuricemia. The patients did not differ in blood pressure (BP) readings. Uric acid was determined by the reaction with tungstophosphoric solution AT (Reagent, Dnepropetrovsk, Ukraine). The validity of results was checked using the control sera (Biocont C, Russia). Enzyme immunoassays and Doppler studies were used to investigate peripheral vasoregulation. Body mass index, intima-media thickness (IMT), pulse wave velocity (PWV), cardio-ankle vascular index (CAVI), endothelin-1 (ET-1), and endothelium-dependent vasodilation (EDVD) were determined.. All the studied indicators have directly or indirectly a negative impact, by deteriorating the function of the vessel wall. The found arterial structural changes suggest that there is an early atheromatous process in the arterial wall of hypertensive patients with gout. Addition of gout promotes endothelial dysfunction and worsens the course of hypertension. An elevation of indicators, such as PWV, CAVI, and ET-1 levels, has the poorest prognosis for the course of hypertension.. The determination of CAVI, PWV, ET-1 levels, arterial stiffness index along with additional criteria, such as EDVD and IMT, may be used as criteria for a cardiovascular risk in hypertensive patients.. Цель исследования. Изучение особенностей дисфункции эндотелия и жесткости артериальной стенки у больных артериальной гипертонией (АГ) в сочетании с подагрой. Материалы и методы. Обследовали 54 больных, которых разделили на 2 группы. Основную группу составили 33 пациента с АГ и подагрой, группу сравнения - 21 пациент с АГ без гиперурикемии. По уровням артериального давления (АД) больные не различались. Мочевую кислоту определяли в реакции с фосфорновольфрамовым раствором АТ 'РЕАГЕНТ' (Днепропетровск, Украина). Достоверность результатов проверяли на контрольных сыворотках фирмы 'Биоконт С' (Россия). Использованы иммуноферментные и допплерометрические методы исследования вазорегуляции периферических сосудов. Определяли индекс массы тела, толщину комплекса интима-медиа (ТИМ), скорость распространения пульсовой волны (СРПВ), сердечно-лодыжечный сосудистый индекс (СЛСИ), эндотелин-1 (ЭТ-1), зависимую от эндотелия вазодилатацию (ЗЭВД). Результаты. Все исследуемые показатели, прямо или опосредованно, оказывают неблагоприятное воздействие, ухудшая функцию сосудистой стенки. Выявленные структурные изменения в артериях свидетельствуют о наличии раннего атероматозного процесса в артериальной стенке у больных АГ с подагрой. Присоединение подагры способствует дисфункции эндотелия и ухудшают течение АГ. Неблагоприятный прогноз для течения АГ с подагрой имеет повышение таких показателей, как СРПВ, СЛСИ и уровень ЭТ-1. Заключение. Определение СЛСИ, СРПВ, уровня ЭТ-1, индекса жесткости артерий наряду с такими дополнительными критериями, как ЗЭВД и ТИМ, можно использовать в качестве критериев риска развития сердечно-сосудистых осложнений у больных АГ.

Topics: Adult; Comorbidity; Endothelin-1; Endothelium, Vascular; Female; Gout; Humans; Hypertension; Male; Middle Aged; Peripheral Arterial Disease; Pulsatile Flow; Pulse Wave Analysis; Ultrasonography; Vascular Stiffness

We aimed to study the relationship of peripheral arteries' atherosclerosis with serum and tissue endothelin-1 in chronic kidney disease patients.. Ninety patients were enrolled, including 35 patients with chronic kidney disease (case group), 31 patients with coronary artery diseases who were candidates for coronary artery bypass grafting (positive control group), and 24 living kidney donors (negative control group). Intima-media thickness of the common carotid and femoral arteries was determined by ultrasonography. Serum and tissue endothelin-1 were measured by ELISA method.. The mean serum and tissue endothelin-1 levels in the donor group were significantly lower than other groups (p < 0.001 for both). The coronary artery bypass grafting group had higher carotid and femoral intima-media thickness than other groups (p < 0.001), and the chronic kidney disease group had higher carotid and femoral intima-media thickness than the donor group (p < 0.001). Regression analysis in all groups did not reveal any correlation between the carotid intima-media thickness/femoral intima-media thickness and the serum/tissue endothelin-1. There was a direct linear correlation between the carotid and femoral intima-media thickness (p < 0.001) in all groups.. Endothelin-1 level and intima-media thickness were higher in the chronic kidney disease patients and coronary artery bypass grafting candidates, without any correlation between endothelin-1 and peripheral arteries' intima-media thickness of both groups. Perhaps endothelin-1 rises and remains high upon endothelial damage and initiation of atherosclerosis.

Topics: Adult; Aged; Biomarkers; Carotid Artery, Common; Carotid Intima-Media Thickness; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Femoral Artery; Humans; Iran; Male; Middle Aged; Peripheral Arterial Disease; Predictive Value of Tests; Prognosis; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Ultrasonography, Doppler; Up-Regulation; Young Adult

Presented herein are the findings of examination of 176 people. Of these, 128 were found to suffer lower limb atherosclerosis (LLA) and 48 were apparently healthy people constituting a control group. Amongst the 128 patients, 74 (58%) had atherosclerotic lesions of the iliac arteries, 54 (42%) subjects had lesions of the femoral and popliteal arteries. The average age of the patients amounted to 62.4±4.3 years. There were ten (8%) women and 118 (92%) men. The control group consisted of 42 (89%) men and six (11%) women. The mean age of the control group patients was 58.9±3.2 years. All underwent functional and laboratory examinations including angiography, duplex scanning and dopplerography of lower limb arteries, as well as determining blood serum markers of inflammation (hs-CRP and IL-6), as well as endothelial lesion markers (ET-1 and VWF). The comparative analysis revealed that patients with LLA had signs of chronic vascular inflammation accompanied in the majority of cases by hyperhomocysteinemia with endothelial dysfunction, as well as direct association between the degree of the vascular inflammatory reaction and severity of clinical manifestations of lower limb ischaemia.

Topics: Aged; Angiography; Biomarkers; C-Reactive Protein; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Homocysteine; Humans; Inflammation; Interleukin-6; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Popliteal Artery; Severity of Illness Index; Statistics as Topic; Ultrasonography, Doppler, Duplex; von Willebrand Factor

Patients with chronic kidney disease (CKD) have increased risk of cardiovascular disease to which co-morbidity and associated conventional risk factors contribute. We hypothesised that arterial stiffness (AS) and endothelial dysfunction (ED), as surrogates of cardiovascular risk, would worsen as renal function declined even in patients without co-morbidity and that this would relate to emerging cardiovascular risk factors.. Carotid-femoral pulse wave velocity (PWV), as a measure of AS, and flow-mediated dilatation (FMD) of the brachial artery, as a measure of ED, were assessed in CKD patients without established cardiovascular disease or diabetes mellitus.. PWV increased linearly as renal function declined (r(2) = 0.08, p < 0.01) whereas FMD was reduced only in patients with advanced kidney disease. In multivariable analysis, blood pressure was the major determinant of PWV and FMD. High-sensitivity C-reactive protein and asymmetric dimethylarginine, and isoprostanes and endothelin-1, were independent predictors of PWV and FMD, respectively. However, renal function did not independently predict either AS or ED.. These findings suggest that declining renal function, in the absence of significant co-morbidity, is associated with progressive arterial stiffness, but only patients close to dialysis exhibit endothelial dysfunction. Whilst blood pressure remains the major determinant of PWV and FMD, inflammation, oxidative stress and endothelin-nitric oxide balance contribute to cardiovascular risk, in this non-comorbid cohort.

Topics: Adult; Analysis of Variance; Arginine; Biomarkers; Blood Pressure; Brachial Artery; C-Reactive Protein; Carotid Arteries; Case-Control Studies; Chronic Disease; Comorbidity; Compliance; Cross-Sectional Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Femoral Artery; Glomerular Filtration Rate; Humans; Isoprostanes; Kidney; Kidney Diseases; Linear Models; Male; Middle Aged; Peripheral Arterial Disease; Prospective Studies; Pulsatile Flow; Risk Assessment; Risk Factors; Scotland; Uremia; Vasodilation