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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

ABSTRACT: The endothelial function plays key roles in both promoting and protecting against atherosclerotic disease. Several methods, including peripheral arterial tonometry (PAT), have been reported to be useful for investigating endothelial dysfunction. Furthermore, the level of thrombomodulin (TM) is assumed to reflect the endothelial dysfunction. In the present study, we investigated endothelial dysfunction in patients with peripheral arterial disease (PAD) by measuring their TM levels, and evaluated the correlation between TM and various parameters.We measured the TM levels and performed PAT in 17 patients with PAD. We also recorded the patients' demographic information, including comorbidities, and investigated their hemodynamic status by measuring the ankle brachial pressure index (ABI). The PAT results were used to calculate the reactive hyperemia index (RHI), which reflected the patients' level of endothelial dysfunction.The RHI and ABI values and the serum level of creatinine were found to be significantly correlated with the TM level (P = 0.040, 0.041 and 0.005, respectively). After setting an RHI value of 1.67 as the cut-off, the patients with RHI values of <1.67 were found to have significantly higher TM levels (median, 20.3 U/mL) than the patients with RHI values of ?1.67 (median, 13.7 U/mL) (P = 0.023).The degree of endothelial dysfunction, as calculated by the TM level, might influence the prognostic value of the RHI, which is determined by PAT. The measurement of the TM level and PAT might both be useful methods of measuring endothelial dysfunction in patients with PAD.

SUBMITTER: Igari K

PROVIDER: S-EPMC5115826 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

Igari Kimihiro K Kudo Toshifumi T Toyofuku Takahiro T Inoue Yoshinori Y

PloS one 20161118 11

<h4>Introduction</h4>The endothelial function plays key roles in both promoting and protecting against atherosclerotic disease. Several methods, including peripheral arterial tonometry (PAT), have been reported to be useful for investigating endothelial dysfunction. Furthermore, the level of thrombomodulin (TM) is assumed to reflect the endothelial dysfunction. In the present study, we investigated endothelial dysfunction in patients with peripheral arterial disease (PAD) by measuring their TM l ...[more]

PMID: 27861629

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Project description:ObjectiveWe have previously shown that peripheral artery disease (PAD) is associated with marked impairment of endothelial function (EF). Given that poor EF is associated with functional status of PAD patients as well as with increased morbidity and mortality in patients undergoing vascular procedures, determination of factors associated with poor EF in a PAD cohort is important. We hypothesized that decreased kidney function is associated with impaired EF in patients with PAD.MethodsThis was a cross-sectional study of PAD patients presenting to a vascular surgery outpatient clinic at the San Francisco Veterans Affairs Medical Center including patients enrolled in the OMEGA-PAD I trial (NCT01310270) and the OMEGA-PAD Cohort. Brachial artery flow-mediated vasodilation was performed to assess EF. Kidney function was characterized by estimated glomerular filtration rate with the abbreviated Modification of Diet in Renal Disease formula. Linear regression was performed to assess the relationship between EF and kidney function in claudicants.ResultsNinety-seven patients with intermittent claudication participated in this study. Mean age was 69 ± 8 years, 97% were male, and 79% were white. Comorbidities included hypertension (91%), dyslipidemia (87%), coronary artery disease (42%), and diabetes mellitus (38%). Mean ankle-brachial index was 0.73 ± 0.14 and mean flow-mediated vasodilation was 7.0% ± 3.8%, indicating impaired EF. Linear regression showed an association between kidney function and EF (by 10 mL/min/1.73 m(2); β, 0.12; confidence interval, 0.05-0.20; P = .001). After multivariable regression adjusting for age, race, log tumor necrosis factor α, hypertension, dyslipidemia, and diabetes, estimated glomerular filtration rate remained significantly associated with EF (P = .033).ConclusionsIn patients with PAD, decreased kidney function is associated with endothelial dysfunction. Further longitudinal studies are needed to better understand the impact of kidney function on PAD progression and the role of endothelial dysfunction in this process.

Project description:BACKGROUND:Peripheral arterial disease (PAD) involves arterial blockages in the body, except those serving the heart and brain. We explore the relationship of functional limitation and PAD symptoms obtained from a quality-of-life questionnaire about the severity of the disease. We used a supervised artificial intelligence-based method of data analyses known as machine learning (ML) to demonstrate a nonlinear relationship between symptoms and functional limitation amongst patients with and without PAD. OBJECTIVES:This paper will demonstrate the use of machine learning to explore the relationship between functional limitation and symptom severity to PAD severity. METHODS:We performed supervised machine learning and graphical analysis, analyzing 703 patients from an administrative database with data comprising the toe-brachial index (TBI), baseline demographics and symptom score(s) derived from a modified vascular quality-of-life questionnaire, calf circumference in centimeters and a six-minute walk (distance in meters). RESULTS:Graphical analysis upon categorizing patients into critical limb ischemia (CLI), severe PAD, moderate PAD and no PAD demonstrated a decrease in walking distance as symptoms worsened and the relationship appeared nonlinear. A supervised ML ensemble (random forest, neural network, generalized linear model) found symptom score, calf circumference (cm), age in years, and six-minute walk (distance in meters) to be important variables to predict PAD. Graphical analysis of a six-minute walk distance against each of the other variables categorized by PAD status showed nonlinear relationships. For low symptom scores, a six-minute walk test (6MWT) demonstrated high specificity for PAD. CONCLUSIONS:PAD patients with the greatest functional limitation may sometimes be asymptomatic. Patients without PAD show no relationship between functional limitation and symptoms. Machine learning allows exploration of nonlinear relationships. A simple linear model alone would have overlooked or considered such a nonlinear relationship unimportant.

Project description:BackgroundMitochondria play a central role in the regulation of energy metabolism, and the biogenesis of mitochondria is enhanced by the action of nitric oxide (NO), which is the key signaling molecule in the regulation of vascular homeostasis. A disturbance in the regulation of energy metabolism can be a key reason for the formation of insulin resistance and type 2 diabetes mellitus. Moreover, mitochondrial dysfunction leads to oxidative stress, which increases the production of proinflammatory cytokines. In this regard, the aim of this study was to identify the relationship of the copy number of mtDNA in adipose tissue from different locations (subcutaneous adipose tissue (SAT), mesentery (Mes), greater omentum (GO)), liver biopsy samples and mononuclear blood cells (MNCs) with endothelial dysfunction markers (eNOS, ET-1, iCAM-1, vCAM-1, VEGF) and inflammatory mediators (TNF-α, IL-6, IL-8, CRP, leptin) in obese patients (body mass index (BMI) > 35 kg/m2) with and without type 2 diabetes.MethodsThe study included 88 obese patients (BMI > 35 kg/m2) treated at the Kaliningrad Region Hospital. The control group consisted of 20 healthy donors. To measure mtDNA copy number we used droplet digital PCR. The concentrations of molecules (TNF-α, IL-6, IL-8, VEGF, eNOS, ET-1, iCAM-1, vCAM-1, VEGF) were measured in plasma using the following sandwich enzyme-linked immunosorbent assays (ELISAs). Quantitative determination of leptin was evaluated by flow-fluorimetry on a «Bio-Plex Protein Assay System». Statistical analysis and graphs were obtained in R Statistical Software (version 3.3.1).ResultsThe systemic character of chronic subclinical inflammation in obesity is established, and an increase in the level of endothelial dysfunction molecules was observed in the blood plasma. The levels of TNF-a, IL-6, and IL-8 were positively correlated with increases in BMI, serum glucose and cholesterol levels.ConclusionsThe copy number of mtDNA in various fat stores was higher in obese patients with type 2 diabetes than in obese patients without diabetes or in the control subjects and was related to the levels of leptin and proinflammatory cytokines.

Project description:AimsElevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology.Methods and resultsTo test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment.ConclusionVascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.

Project description:BackgroundReactive hyperemia-peripheral arterial tonometry (RH-PAT) is a noninvasive and simple test for evaluating the endothelial function. There has been sparse evidence on the usefulness of the RH-PAT index (RHI) in predicting future cardiovascular diseases among diabetic patients.MethodsAsymptomatic diabetic patients with albuminuria were selected; their medical history and laboratory findings were evaluated every 3 to 4 months, respectively. The primary outcome was a composite of three-point major adverse cardiovascular events (3-point MACE): death from cardiovascular causes, acute coronary events, or nonfatal stroke. On the contrary, secondary outcomes included a composite of 3-point MACE, hospitalization for heart failure, or chronic kidney disease (CKD) progression. RHI was measured using the Endo-PAT2000 at the baseline. RHI < 1.67 was considered to indicate peripheral endothelial dysfunction (PED).ResultsIn total, 149 subjects were included (mean age, 61.8 ± 9.2 years; duration of diabetes was 12 years). During the follow-up period (median, 49.7 months), of the 149 subjects, primary outcomes were detected in 12 (1 [2.3%] and 11 [10.5%] of those without and with PED, respectively). The presence of PED in baseline measurements significantly increased both primary and secondary outcomes, following adjustment for age, sex, hypertension, glycated hemoglobin, low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, baseline estimated glomerular filtration rate, overt proteinuria, duration of diabetes, premedical history of ischemic events, anti-platelet agents, and smoking history (hazard ratio [HR]: 10.95; 95% confidence interval CI 1.00-119.91 for the primary outcome; HR, 4.12; 95% CI 1.37-12.41 for secondary outcome). In addition, PED could predict secondary outcomes independent of the risk score according to the American College of Cardiology/American Heart Association (HR: 3.24; 95% CI 1.14-9.17).ConclusionsPED can independently predict future cardiovascular events among diabetic patients with albuminuria.

Project description:Fewer than half of individuals with peripheral artery disease (PAD) experience classic claudication, and the relationships between PAD typical or atypical symptom intensity, location, and description (classic or atypical) with ischemic changes have not previously been reported.The primary purpose of this study was to evaluate the relationship between self-reported PAD symptom intensity and calf tissue ischemia measured using the tissue saturation index (TSI) during treadmill exercise. The location and descriptors of atypical PAD symptoms in the presence of calf tissue ischemia were also identified.Adults with PAD with exercise-limiting ischemic symptoms were asked to (a) rate symptom intensity using a numerical rating scale (NRS) from 0 to 5 (0 = no pain, 1 = onset of pain, 5 = maximal pain), (b) provide symptom locations and descriptors, and (c) wear a near-infrared spectroscopy device to obtain calf TSI values during treadmill exercise. Multilevel models with TSI as the outcome variable were estimated during exercise and recovery. Covariates included were exercise time, recovery time, baseline TSI, exercise rating, recovery rating, ankle-brachial index (ABI), age, race, gender, body mass index, diabetes, neuropathy, and smoking.During three successive bouts of treadmill exercise for 40 participants (80% Caucasian men; average age = 68 years, SD = 9.2), the most rapid decline in TSI occurred between the start of exercise and symptom onset (when NRS = 1). The TSI nadir was often reached prior to report of maximum discomfort (when NRS = 5), and changes in TSI were related to exercise time (p < .001), baseline TSI (p < .001), exercise ratings (p < .001), and ABI (p < .05). During recovery, TSI increased steadily for most participants as pain eased. In the recovery model, changes in TSI were associated with recovery ratings (p < .001) and ABI (p < .03). Of 120 treadmill exercise tests, 69.2% were stopped due to discomfort in the calf with classic descriptors reported only half the time (55.4%).Exploratory analyses revealed ischemic symptoms extended beyond classic claudication locations and descriptors. Future research should evaluate changes in TSI relative to atypical locations and descriptors to improve understanding of the full range of ischemic symptoms experienced by individuals with PAD.

Dataset Information

The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

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The Relationship between Endothelial Dysfunction and Endothelial Cell Markers in Peripheral Arterial Disease.

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