Markers Of Endothelial Dysfunction Research Articles

Long COVID syndrome: a case-control study

Abstract Background Cardiovascular complications are rapidly emerging as a major threat in COVID-19 infection. Nonetheless, the mechanisms underlying the disproportionate effect of SARS-CoV-2 infection on patients with cardiovascular comorbidities remain incompletely understood. Purpose To assess whether COVID-19 infection has an adverse clinical outcome at medium-term follow-up. Methods A case-control study was performed. Cases were subjects who were diagnosed with COVID-19 infection following nasopharyhngeal swabbing. Controls were age- and gender-matched subjects who were not found to be infected with COVID-19 following swabbing and were negative on testing for COVID-19 IgG antibodies. All participants were submitted a standardised questionnaire regarding past medical history. Baseline blood investigations were taken including N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin levels. High-sensitivity C-reactive protein (hsCRP) was taken as marker of inflammation and von Willebrand factor (vWF) was taken as marker of endothelial dysfunction. Results 270 subjects were recruited, comprising 174 cases and 96 controls. Of the latter, 21 were found to be COVID-19 IgG positive and were excluded from the analysis. Hence, the study cohort comprised 174 cases and 75 controls. The mean age of the participants was 46.1±13.8 years. The median follow-up was of 173.5 days (IQR 129–193.25 days). There was no statistically significant difference in the baseline demographics between cases and controls with regards age, gender as well as cardiovascular risk factors and underlying medical conditions. Regarding symptomatology at follow-up, there was a statistically significant difference between the groups in deterioration in general condition (p<0.001), shortness of breath (SOB) (p=0.008), fatigue (p=0.044), arthralgia (p<0.001), abnormal taste (p<0.001) and anosmia (p<0.001), all being more frequent in subjects with prior COVID-19 infection. At follow-up, the blood investigations showed that only hsCRP was statistically significantly higher in the cases as compared to the controls (p=0.03, Figure 1). Correlation analysis consequently revealed a negative correlation in both troponin (p=0.013, r=−0.19) and vWF levels (p=0.026, r=−0.169) with time. Finally, the association between the cases experiencing dyspnoea and the blood investigations at follow-up was assessed. Multivariate analysis revealed that COVID-19 positive cases experiencing dyspnoea have significantly higher white cell count (WCC) (OR 1.22, 95% CI 1.02–1.46, p=0.029) and troponin levels (OR 1.15, 95% CI 1.02–1.29, p=0.015) and lower haemoglobin levels at follow-up (OR 0.66, 95% CI 0.5–0.86, p<0.002), Figure 2. Conclusion Patients previously infected with COVID-19 have persistent symptomatology at medium-term follow-up. The role of troponin, together with markers of inflammation and endothelial dysfunction at long-term follow-up merit further investigation. Funding Acknowledgement Type of funding sources: None.

Associations of soluble fms-like tyrosine kinase-1 with cardiovascular events and stroke in patients with atrial fibrillation and suspected or known coronary artery disease: the EXCEED-J study

Abstract Background Atrial fibrillation (AF) increases the risk of stroke. Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction, which are associated with both AF and coronary artery disease (CAD). Recently, we demonstrated that sFlt-1 is independently associated with major adverse cardiovascular (CV) events (MACE) in patients with suspected or known CAD. However, the prognostic utility of sFlt-1 in patients with AF remains unknown. Methods Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD, we investigated whether AF modifies the prognostic utility of sFlt-1. Heparin-free serum levels of sFlt-1, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin-I, high-sensitivity C-reactive protein, cystatin C, neutrophil gelatinase-associated lipocalin, VEGF, and placental growth factor were measured in 324 patients with AF and 2931 patients without AF. The primary outcome was MACE defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, stroke, heart failure (HF) hospitalization, and coronary/peripheral artery revascularization. The biomarkers were natural log-transformed for use as continuous variables. Results After adjustment for potential clinical confounders including anticoagulant drug use, sFlt-1 was significantly associated with MACE (hazard ratio for 1 standard deviation increase [HR], 1.55; 95% confidence interval [CI], 1.14–2.08), CV death (HR, 1.68; 95% CI, 1.10–2.48), and stroke (HR, 1.89; 95% CI, 1.16–3.10), but not with all-cause death (HR, 1.32; 95% CI, 0.99–1.73), HF hospitalization (HR, 0.97; 95% CI, 0.73–1.25), or revascularization (HR, 0.99; 95% CI, 0.74–1.28) in patients with AF, whereas sFlt-1 was significantly associated with MACE (HR, 1.19; 95% CI, 1.02–1.37), all-cause death (HR, 1.19; 95% CI, 1.05–1.34), CV death (HR, 1.26; 95% CI, 1.03–1.48), and HF hospitalization (HR, 1.26; 95% CI, 1.11–1.42), but not with stroke (HR, 1.06; 95% CI, 0.81–1.33) or revascularization (HR, 1.01; 95% CI, 0.95–1.07) in patients without AF. Among other biomarkers, only VEGF was significantly associated with MACE (HR, 1.55; 95% CI, 1.02–2.44), and no biomarkers were significantly associated with CV death or stroke in patients with AF. sFlt-1 added incremental prognostic information for MACE (P=0.005 for net reclassification improvement [NRI], P=0.026 for integrated discrimination improvement [IDI]) and stroke (P=0.034 for NRI, P=0.018 for IDI), but not for CV death (P=0.021 for NRI, P=0.134 for IDI), to the model with potential clinical confounders in patients with AF. Conclusions sFlt-1 independently predicted MACE and stroke in patients with AF and suspected or known CAD. sFlt-1 may serve as a novel prognostic biomarker to stratify the risk of MACE and stroke in patients with AF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008)

Enrichment in procoagulant microparticles in calcified human aortic valve – role in valvular endothelium alterations and enhanced thrombogenicity

Abstract Background Aortic stenosis (AS) is characterized by endothelial dysfunction (ED), inflammatory cell infiltration, myofibroblastic and osteoblastic differentiation. Subclinical leaflet thrombosis was recently linked to higher rates of stroke and transient ischemic attack after transcatheter aortic valve implantation (TAVI). Procoagulant microparticles (MPs) are associated with ED, inflammation and clot formation. There is limited evidence regarding intra-valvular MPs content and their potential biological effects. This question is particularly relevant in TAVI in which the residing native valve could constitute a source of thrombotic activity enhancing leaflet thrombosis and valve dysfunction. Purpose Therefore, we hypothesized that MPs trapped within the native aortic valve contribute to valvular dysfunction including enhanced thrombogenicity. Methods Human valves were collected from patients undergoing surgical valve replacement for AS or aortic insufficiency (AI). Pro-thrombotic, pro-inflammatory, and ED markers were identified in the calcified vs non-calcified part of the valves by Western-blot. Calcium content was measured through colorimetric method. MPs were extracted from human pathological valves, and quantified through their prothrombinase activity. Primary cultures of porcine valvular endothelial cells (VEC) were treated with the MPs (10 nmol/L) or thrombin (1U/ml) for 24hrs. Phenotypic change was appreciated through gene expression pattern assessed by RT-qPCR. IL-8 secretion was measured by ELISA. Results The phenotype of the AS valve was characterized through increased expression of thrombogenic (tissue factor, thrombomodulin, PAI-1), adhesive (VCAM-1, ICAM-1) and inflammatory (COX-1, COX-2) molecules in the calcified part of the valve. Moreover, MPs content was increased in the calcified vs non-calcified part of the valve or AI valves. MPs levels was correlated with valvular calcium content (R=0.3862: p<0.001). Tissue factor was increased in MPs extracted from AS vs AI. The biological effect of MPs was tested on VEC in-vitro. Results showed dramatic increase in expression of inflammatory cytokines (CXCL10, CCL11, CXCL8, MCP1) adhesion molecules (VCAM-1, ICAM-1, SELP, SELE) and proangiogenic factors (VEGFR2, ANGPTL4) in VEC exposed to MPs (24h) from AS vs AI. Enhanced secretory phenotype was evidenced through IL-8 determination in the supernatant of VEC stimulated with MPs from AS valve. Conclusion Calcified aortic valve is a potent reservoir of MPs, acting as a pro-thrombogenic source per se and promoting a switch of VEC phenotype toward prothrombotic, proinflammatory and proangiogenic pattern. These data suggest that MPs released from the native valve constitute an important source of mediators involved in enhanced thrombogenicity and valvular remodeling. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): GERCA-Groupe Etudes Reali Commercia Avignon

Quantification of exceedingly high levels of von Willebrand factor in cirrhosis: Next upgrading of the MELD-Na score?

That Von Willebrand factor antigen (VWF Ag) levels predict clinical outcome in patients with cirrhosis and portal hypertension was firstly stated by La Mura et al. [1] who described the relation of this (and other) markers of endothelial dysfunction with systemic and hepatic haemodynamics [1]. They found that VWF levels significantly correlated with the Hepatic Vein Pressure Gradient (HVPG), Child–Pugh score and the model for end-stage liver disease (MELD), but independently predicted clinical outcome.

Biochemical and clinical markers of endothelial dysfunction do not outweigh traditional risk factors for the presence of diabetic retinopathy in patients with type 1 diabetes

BackgroundThis study aimed to evaluate whether soluble vascular cytoadhesive molecule-1 (sVCAM-1), intracellular cytoadhesive molecule-1 (sICAM-1), and endothelial function as assessed by EndoPat outweighed traditional risk factors for the presence of diabetic retinopathy (DR) in patients with type 1 diabetes (T1D).MethodsPatients aged ≥ 12 years completed a clinical–epidemiological questionnaire. Fasting venous blood samples were obtained (lipid profile, glycemic control, and C-reactive protein levels). Vascular reactivity was assessed via peripheral arterial tonometry performed by supplying the reactive hyperemia index (RHI) through the EndoPAT device. sVCAM-1 and sICAM-1 levels were measured using multiplex assays.ResultsData were obtained from 187 patients (51.3% female), aged 32 ± 13 years with a disease duration of 14 (6–15) years and mean hemoglobin A1c (HbA1c) of 9.1% ± 2.1%. After adjustments were made, age, HbA1c, arterial blood pressure, and use of drugs that could interfere with endothelial function were found to be associated with DR. No association was noted with sVCAM-1 and sICAM-1 levels and RHI.ConclusionsIn our sample, sVCAM-1, sICAM and EndoPAT did not outweigh the traditional DR risk factors, such as age, high HbA1c, arterial blood pressure, and use of drugs that could interfere with endothelial function and are significantly associated with DR. Further prospective studies should evaluate if markers of endothelial dysfunction could predict diabetes-related micro and macrovascular complications in T1D.

Прогнозування і профілактика прееклампсії при багатоплідній вагітності після допоміжних репродуктивних технологій

Purpose - to assess the effectiveness of the implemented algorithm of treatment and preventive measures by analyzing the course of pregnancy, childbirth and the condition of newborns in multiple pregnancies after assisted reproductive technologies to assess of changes in biochemical markers of endothelial dysfunction in the detection of pre-clinical manifestations of preeclampsia in pregnant women with multiple pregnancies after the use of assisted reproductive technologies. Materials and methods. A prospective study of pregnant women with dichorionic diamniotic twins after assisted reproductive technologies was conducted: the Group І (main) - 35 pregnant women with twins who were offered a developed monitoring algorithm; the Group ІІ (control) 27 pregnant women who were monitored according to generally accepted methods of managing multiple pregnancies. Statistical processing of the research results was carried out using standard programs “Microsoft Excel 5.0” and “Statistica 6.0”. Results. In the Group І 2 cases of moderate preeclampsia were found in 32 and 33 weeks of pregnancy (PLGF results - 63.2 pg/ml and 58.7 pg/ml, sFlt-1/PLGF ratio - 51.7 and 66.3). In the Group II 4 cases of preeclampsia were identified: 2 cases of moderate preeclampsia (PLGF - 74.1 pg/ml and 69.3 pg/ml, sFlt-1/PLGF ratio - 98.6 and 104.5); 2 cases of severe preeclampsia at 33 and 34 weeks (PLGF data - 44.1 pg/ml and 47.3 pg/ml, sFlt-1/ PLGF ratio 122.4 and 130.1) against the background of signs of gestational hypertension. Fetal growth retardation in the Group І was noted in 3 (8.6%) women (І stage - in 2 (5.7%) cases, II stage - in 1 (2.9%) case, III stage was not diagnosed), in the Group II - in 7 (25.9%) women (I stage - in 2 (7.4%) cases, II stage - in 4 (14.8%) cases, III stage - in 1 (3.7%) case). Fetal distress in the Group І was detected in 4 (11.4%) pregnant women (during pregnancy - in 1 (2.9%) case, during deliveries - in 3 (8.6%) cases); in the Group II - in 7 (25.9%) women (during pregnancy - in 5 (18.5%) cases, during deliveries - in 2 (7.4%) cases). Premature deliveries in the Group I was noted in 5 (14.3%) women (before 34 weeks of gestation - in 2 (5.7%) cases, after 34 weeks of gestation - in 3 (8.6%) cases); in the Group II - in 8 (29.6%) women (before 34 weeks of gestation - in 5 (18.5%) cases, after 34 weeks of gestation - in 3 (11.1%) cases). Premature detachment of a normally located placenta was detected in 2 (7.4%) women in the Group II, and in the Group I such cases were not recorded. Vaginal delivery was observed in 14 (40%) women in the Group I and 7 (25.9%) patients in the Group II; cesarean section - in 21 (60%) and 19 (70.4%) women, respectively. Combined delivery was performed in 1 (3.7%) woman of the Group II, and in the Group I - not recorded. Hypoxic-ischemic lesions were detected in 2 (5.7%) children from women of the Group I and in 4 (14.8%) children from mothers of the Group II. Adaptation disorders were noted in 5 (14.3%) cases in the Group I and in 8 (29.6%) cases in the Group II. Transfer to the second stage of treatment required 3 (8.6%) children from mothers of the Group I and 6 (22.2%) children from mothers of the Group II. Conclusions. The proposed algorithm of modern diagnostic and treatment-prophylactic measures made it possible to reliably reduce the frequency of development of preeclampsia, obstetric and perinatal complications and can be recommended for use in practical health care. The study of the anti-angiogenic factor sFlt-1 and the pro-angiogenic factor PLGF and their ratio is promising in the prediction and early diagnosis of preeclampsia in multiple pregnancies after assisted reproductive technologies. The use of Triage PLGF and sFlt-1/PLGF ratio should be widely implemented in the practice of obstetrician-gynecologists as a prognostic marker for early recognition of preeclampsia in order to reduce perinatal complications, both from the mother and the fetus. Based on monitoring the growth dynamics of the sFlt-1/PLGF ratio, it is possible to predict the early development of preeclampsia even without clinical symptoms, and to make a decision about the possibility of extending the pregnancy or the need for urgent delivery. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the author.

Plasma Endocan as a Biomarker of Thrombotic Events in COVID-19 Patients.

(1) Background: Endocan is a marker of endothelial dysfunction that may be associated with thrombotic events. The aim of the study was to investigate the performance of endocan as a marker of thrombotic events in COVID-19 patients. (2) Methods: We measured endocan in plasma from 79 documented COVID-19 patients classified according to disease severity (from mild to critical). Thrombotic events were recorded. (3) Results: Endocan concentrations at admission were significantly increased according to COVID-19 severity. Levels of endocan were significantly increased in patients experiencing thrombotic events in comparison with those without (16.2 (5.5–26.7) vs. 1.81 (0.71–10.5) ng/mL, p < 0.001). However, endocan concentrations were not different between pulmonary embolism and other thrombotic events. The Receiver Operating Characteristic (ROC) analysis for the identification of thrombotic events showed an area under the ROC curve (AUC) of 0.776 with an optimal threshold at 2.83 ng/mL (93.8% sensitivity and 54.7% specificity). When combining an endocan measurement with D-dimers, the AUC increased to 0.853. When considering both biomarkers, the Kaplan–Meier survival curves showed that the combination of endocan and D-dimers better discriminated patients with thrombotic events than those without. The combination of D-dimers and endocan was independently associated with thrombotic events. (4) Conclusions: Endocan might be a useful and informative biomarker to better identify thrombotic events in COVID-19 patients.

A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study

Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1β and endothelial dysfunction markers was also observed in the albumin group. In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. www. gov NCT03585257. Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Endothelial dysfunction and atherosclerosis related miRNA-expression in patients with haemophilia.

Elevated markers of endothelial dysfunction and inflammation indicate worse endothelial function in the aging haemophilia population. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. Several miRNAs have been shown to be involved in the process of endothelial dysfunction and atherosclerosis. The aim of this study was to determine the underlying molecular pathways of endothelial dysfunction and inflammation in haemophilia patients. A total of 25 patients with severe or moderate haemophilia A (20 patients) or B (5 patients), 14 controls and 18 patients with coronary artery disease (CAD) after myocardial infarction were included in this study. Expression of miRNA-126, -155, -222, -1, -let7a, -21 and -197 were analysed using a real time polymerase chain reaction. Network-based visualisation and analysis of the miRNA-target interactions were performed using the MicroRNA ENrichment TURned NETwork (MIENTURNET). Expression of miRNA-126 (p<.05) and miRNA-let7a (p<.05) were significantly higher in CAD patients compared to haemophilia patients and controls. MiRNA-21 (p<.05) was significantly elevated in CAD patients compared to controls. MiRNA-155 (p<.05), miRNA-1 (p<.05) and miRNA-197 (p<.05) were significantly higher expressed in CAD and haemophilia patients compared to controls and showed a strong correlation with increased levels of interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1). The network analysis revealed interactions in the cytokine signalling, focal adhesion and VEGFA-VEGFR2 pathway (Vascular endothelial growth factor, -receptor). This study characterises miRNA expression in haemophilia patients in comparison to CAD patients and healthy controls. The results imply comparable biological processes in CAD and haemophilia patients.

Fundamentals and Applications of the Receiver Operating Characteristic Curve Analysis in the Research of Endothelial Dysfunction in Chronic Kidney Disease.

Endothelial dysfunction (ED) starts early in chronic kidney disease (CKD) and is the hallmark of atherosclerosis in these patients. During recent years, numerous markers have emerged, aiming to predict the onset of ED in CKD patients. Therefore, there is a need to evaluate and assess the discriminatory ability (or diagnostic accuracy) of such a marker (i.e., the ability to correctly classify individuals as having a given disease or not) and identify the optimal cut-off value. A receiver operating characteristic (ROC) curve analysis has been used in the majority of the research papers evaluating the predictive ability of a marker of ED. It is a graphical plot combining pairs of sensitivity (true positive rate) on the y axis and the complement of specificity (1—specificity, false positive rate) in the x axis, corresponding to several of the cut-off values covering the complete range of possible values that this test/marker might take. Herein, using a series of practical examples derived from clinical studies on ED in the special population of CKD, we address the principles, fundamentals, advantages and limitations regarding the interpretation of the ROC analysis.

Study of Peripheral Microcirculation Assessed by Nailfold Video-Capillaroscopy and Association with Markers of Endothelial Dysfunction and Inflammation in Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease that primarily affects synovial joints and is associated with increased cardiovascular (CV) mortality and morbidity. This association is only partially attributed to the presence of classic CV disease risk factors, and is strongly associated with characteristics of disease itself namely systemic chronic inflammation and autoimmune activation. Growing evidence suggests that microvascular endothelial dysfunction contributes to the initiation and progression of vascular disease. Nailfold capillaroscopy is a non-invasive method that evaluates the morphology and the structure of nailfold capillaries. Extension of this method is the Nailfold Videocapillaroscopy (NVC), which provides the possibility of combining functional and anatomical study of peripheral microcirculation. The present cross-sectional study aims to evaluate using NVC the peripheral microcirculation in adult patients with RA and investigate the associations between structural and functional indices of digital capillaries with markers of atherosclerosis.

RELATIONSHIP BETWEEN VISFATIN AND SOME BIOMARKERS OF BONE TURNOVER IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Chronic kidney disease (CKD) is a progressive disease that might result in an end stage renal disease (ESRD), raising cardiovascular morbidity and mortality. Life expectancy among patients with CKD could significantly be reduced as a result of an advanced atherosclerosis and followed by a premature death from cardiovascular disease (CVD). CVD is a condition of a subclinical systematic inflammation that involves cytokines produced by adipose tissue. Visfatin is an adipocytokine with potentially important effects on glucose metabolism and atherosclerosis. Therefore, it could be treated like a new marker of endothelial dysfunction (ED) in CKD patients. It has been suggested that visfatin levels could increase as CKD progresses, which could be due to either the chronic inflammation associated with CKD and/or the hypoxia resulting from tubular necrosis, anemia and reduced capillary blood flow. As CKD progresses, visfatin levels among these patients most often spell increased mortality caused by cardiovascular events. The current research has been conducted among a total of 80 subjects with CKD who were divided into two groups - pre-dialysis (30) and hemodialysis treatment (50) patients from the Nephrology and Dialysis Clinic at the UMHAT “Sveta Marina” Varna. Demographics indicators and levels of visfatin, iFGF-23 and iPTH were inevstigated.

Markers of endothelial glycocalyx dysfunction in Clarkson disease

BackgroundClarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia.MethodsWe analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining.ResultsSerum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells.ConclusionseGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS.Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.

Polycyclic Aromatic Hydrocarbons (PAHs) Exposure Triggers Inflammation and Endothelial Dysfunction in BALB/c Mice: A Pilot Study.

The particulate matter present in air pollution is a complex mixture of solid and liquid particles that vary in size, origin, and composition, among which are polycyclic aromatic hydrocarbons (PAHs). Although exposure to PAHs has become an important risk factor for cardiovascular disease, the mechanisms by which these compounds contribute to increased cardiovascular risk have not been fully explored. The aim of the present study was to evaluate the effects of PAH exposure on systemic pro-inflammatory cytokines and markers of endothelial dysfunction. An intervention was designed using a murine model composed of twenty BALB/c male mice separated into controls and three groups exposed to a mixture of phenanthrene, fluoranthene, and pyrene using three different concentrations. The serum levels of the inflammatory cytokines and gene expression of adhesion molecules located on endothelial cells along with inflammatory markers related to PAH exposure in aortic tissue were determined. Furthermore, the expression of the ICAM-1 and VCAM-1 proteins was evaluated. The data showed significant differences in IL-6 and IFN-γ in the serum. In the gene expression, significant differences for ICAM-1, VCAM-1, and E-Selectin were observed. The results suggest that phenanthrene, fluoranthene, and pyrene, present in air pollution, stimulate the increase in serum inflammatory cytokines and the expression of markers of endothelial dysfunction in the murine model studied, both relevant characteristics associated with the onset of disease atherosclerosis and cardiovascular disease.

Hyperphosphatemia and its relationship with blood pressure, vasoconstriction, and endothelial cell dysfunction in hypertensive hemodialysis patients

BackgroundHyperphosphatemia occurs frequently in end-stage renal disease patients on hemodialysis and is associated with increased mortality. Hyperphosphatemia contributes to vascular calcification in these patients, but there is emerging evidence that it is also associated with endothelial cell dysfunction.MethodsWe conducted a cross-sectional study in hypertensive hemodialysis patients. We obtained pre-hemodialysis measurements of total peripheral resistance index (TPRI, non-invasive cardiac output monitor) and plasma levels of endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA). We ascertained the routine peridialytic blood pressure (BP) measurements from that treatment and the most recent pre-hemodialysis serum phosphate levels. We used generalized linear regression analyses to determine independent associations between serum phosphate with BP, TPRI, ET-1, and ADMA while controlling for demographic variables, parathyroid hormone (PTH), and interdialytic weight gain.ResultsThere were 54 patients analyzed. Mean pre-HD supine and seated systolic and diastolic BP were 164 (27), 158 (21), 91.5 (17), and 86.1 (16) mmHg. Mean serum phosphate was 5.89 (1.8) mg/dL. There were significant correlations between phosphate with all pre-hemodialysis BP measurements (r = 0.3, p = .04; r = 0.4, p = .002; r = 0.5, p < .0001; and r = 0.5, p = .0003.) The correlations with phosphate and TPRI, ET-1, and ADMA were 0.3 (p = .01), 0.4 (p = .007), and 0.3 (p = .04). In our final linear regression analyses controlling for baseline characteristics, PTH, and interdialytic weight gain, independent associations between phosphate with pre-hemodialysis diastolic BP, TPRI, and ET-1 were retained (β = 4.33, p = .0002; log transformed β = 0.05, p = .005; reciprocal transformed β = -0.03, p = .047).ConclusionsSerum phosphate concentration is independently associated with higher pre-HD BP, vasoconstriction, and markers of endothelial cell dysfunction. These findings demonstrate an additional negative impact of hyperphosphatemia on cardiovascular health beyond vascular calcification.Trial registrationThe study was part of a registered clinical trial, NCT01862497 (May 24, 2013).

Assessment of the Proton Pump Inhibitor, Esomeprazole Magnesium Hydrate and Trihydrate, on Pathophysiological Markers of Preeclampsia in Preclinical Human Models of Disease.

Previously, we demonstrated that the proton pump inhibitor, esomeprazole magnesium hydrate (MH), could have potential as a repurposed treatment against preeclampsia, a serious obstetric condition. In this study we investigate the difference in the preclinical effectiveness between 100 µM of esomeprazole MH and its hydration isomer, esomeprazole magnesium trihydrate (MTH). Here, we found that both treatments reduced secretion of sFLT-1 (anti-angiogenic factor) from primary cytotrophoblast, but only esomeprazole MH reduced sFLT-1 secretion from primary human umbilical vein endothelial cells (assessed via ELISA). Both drugs could mitigate expression of the endothelial dysfunction markers, vascular cell adhesion molecule-1 and endothelin-1 (via qPCR). Neither esomeprazole MH nor MTH quenched cytotrophoblast reactive oxygen species production in response to sodium azide (ROS assay). Finally, using wire myography, we demonstrated that both compounds were able to induce vasodilation of human omental arteries at 100 µM. Esomeprazole is safe to use in pregnancy and a candidate treatment for preeclampsia. Using primary human tissues and cells, we validated that esomeprazole is effective in enhancing vascular relaxation, and can reduce key factors associated with preeclampsia, including sFLT-1 and endothelial dysfunction. However, esomeprazole MH was more efficacious than esomeprazole MTH in our in vitro studies.

Increased Levels of ANGPTL3 and CTRP9 in Patients With Obstructive Sleep Apnea and Their Relation to Insulin Resistance and Lipid Metabolism and Markers of Endothelial Dysfunction.

Obstructive sleep apnea (OSA) has a close relation with obesity and perturbation in adipokines and hepatokines, which are linked to OSA consequences such as insulin resistance, dyslipidemia, and endothelial dysfunction. This study aimed to assess the relation of C1q/TNF-related protein 9 (CTRP9) and angiopoietin-like protein 3 (ANGPTL3) with OSA and biochemical measurements. Serum levels of ANGPTL3, CTRP9, adiponectin, leptin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion protein 1 (VCAM-1) were determined in 74 OSA patients and 27 controls using enzyme-linked immunosorbent assay kits. Levels of ANGPTL3, CTRP9, leptin, ICAM-1, and VCAM-1 were increased in the patients compared to the controls, whereas adiponectin levels decreased. ANGPTL3 had a positive correlation with total cholesterol, triglyceride, low-density lipoprotein cholesterol, ICAM-1, and VCAM-1 and was inversely correlated with leptin. CTRP9 showed a positive correlation with body mass index, insulin resistance, ICAM-1, and VCAM-1. The results indicated the relation of ANGLTP3 and CTRP9 with OSA and its complications, which suggested a possible role for these factors in the consequences of OSA.

Association of Umbilical Cord Serum Oxidative Stress Markers, ADMA and Adiponectin with Adverse Fetal Outcomes in Hypertensive Disorders of Pregnancy

Background: Limited studies are available on fetal oxidative stress and endothelial dysfunction and their association with adverse fetal outcomes in hypertensive disorders of pregnancy (HDP). Method: Umbilical cord blood samples were collected at delivery from 134 pregnant women with HDP and 59 controls. Markers of oxidative stress, endothelial dysfunction and inflammation and adipokines were analyzed. Results were correlated with adverse fetal outcomes. Results: Malondialdehyde, total antioxidant status(TAS), ADMA and hsCRP levels were increased in late and early onset preeclampsia. Adiponectin levels were decreased in early onset preeclampsia. High ADMA levels were positively associated with preterm births and fetal mortality and high TAS, protein carbonyl content(PC), ADMA and low adiponectin levels were positively associated with low birth weight babies. Conclusion: Fetal systemic oxidative stress, endothelial dysfunction and inflammation were altered in early and late onset preeclampsia. High TAS, PC and ADMA levels and low adiponectin levels were positively associated with adverse fetal outcomes in HDP.

Optimization of the prevention of perinatal pathology in women with gestational endotheliopathy

Objectives: to evaluate the clinical effectiveness of the Metida for the prevention of perinatal pathology in pregnant women with gestational endotheliopathy and with the risk of preeclampsia.Materials and methods. 68 pregnant women with verified gestational endotheliopathy and with risk of preeclampsia &gt; 1:150 participated in a prospective clinical comparative study. The patients were divided into subgroups: the first subgroup included 30 women who from 11–13 weeks of pregnancy received acetylsalicylic acid 100 mg/day and vitamin D 2000 IU/day; the II subgroup included 38 pregnant women who from 11–13 weeks of gestation received acetylsalicylic acid 100 mg/day, vitamin D 2000 IU/day and Metida (300 mg of elemental magnesium, 30 mg of vitamin B6). 28 practically healthy pregnant women of the control group received vitamin D 1000 IU/day. The clinical effectiveness of therapy was evaluated by comparing the number of cases of perinatal pathology; cases of intrauterine suffering of the fetus; the dynamics of indicators of laboratory-instrumental research methods (markers of the risk of perinatal pathology) and the pregnancy outcomes.Results. Metida as an additional preventive therapy made it possible to significantly reduce the number of cases of placental dysfunction (р = 0.01) and intrauterine suffering of the fetus (р = 0.02) compared to standard preventive therapy. There was also a 6-fold reduction in the incidence of preeclampsia and premature birth due to magnesium supplementation, compared to pregnant women who received only acetylsalicylic acid and vitamin D. There was a significant decrease in serum indicators of markers of endothelial dysfunction in women with gestational endotheliopathy as a result of taking magnesium: vascular endothelial growth factor (p &lt; 0.00001), endoglin (p &lt; 0.00001) compared to patients who did not receive magnesium, and there was also normalization of the of 25(OH)D level in blood serum compared to the control group (p = 0.33).Conclusions. Additional Mg supplementation during pregnancy may reduce the likelihood of perinatal pathology in high-risk patients and help normalize serum markers of endothelial dysfunction in women with high risk of preeclampsia.

Estimated GFR, Albuminuria, and Physical Function: The Brain in Kidney Disease (BRINK) Cohort Study

Rationale & ObjectiveChronic kidney disease (CKD) is associated with impaired physical performance. However, the association between albuminuria, a marker of vascular endothelial dysfunction, and physical performance has not been fully characterized. We hypothesized that estimated glomerular filtration rate (eGFR) and albuminuria would be independently associated with physical performance.Study DesignCross-sectional analysis.Setting & ParticipantsA total of 571 adults with and without CKD.PredictorsCreatinine-based eGFR (eGFRCr) and cystatin C-based eGFR (eGFRCysC) and urine albumin to creatinine ratio (UACR).OutcomeShort Physical Performance Battery (SPPB).Analytical ApproachUnivariate and multivariable logistic regression models were used to examine associations of eGFR and UACR with impaired physical performance.ResultsOf the 571 participants (mean age, 69.3 years), 157 (27.5%) had eGFRCr (mL/min/1.73m2) <30, 276 (48.3%) had eGFRCr 30-<60, and 138 (24.2%) had eGFRCr ≥60; 303 (55.3%) participants had eGFRcysC <30, 141 (25.7%) had eGFRcysC 30-<60, and 104 (19.0%) had eGFRcysC ≥60. Impaired physical performance was observed in 222 (38.9%) participants. Separate univariate analyses showed that lower eGFRCr, lower eGFRCysC, and higher UACR were associated with higher odds of impaired physical performance. In the adjusted model with eGFRCr or eGFRCysC, UACR, and covariates, UACR retained a statistically significant association with impaired physical performance (adjusted odds ratio [OR], 2.04; 95% confidence interval [CI], 1.21-3.47 for UACR from 30-300 mg/g vs <30 mg/g and adjusted OR, 1.93; 95% CI, 1.01-3.69 for UACR >300 mg/g vs <30 mg/g), but eGFRCr and eGFRCysC did not.LimitationsCross-sectional analysis, estimated rather than measured GFR.ConclusionsOnly UACR was associated with worse physical performance in the fully adjusted model, suggesting that vascular endothelial function and inflammation may be important mechanisms of decreased physical function. Similar results were found using eGFRCr or eGFRCysC, suggesting that confounding based on muscle mass does not explain the lack of an association between eGFRCr and physical performance.