Markers Of Endothelial Damage Research Articles

Enumeration of circulating endothelial cell frequency as a diagnostic marker in aortic valve surgery - a flow cytometric approach

BackgroundThe frequency of circulating endothelial cells (CEC) in patients’ peripheral blood can be assessed as a direct marker of endothelial damage. However, conventional enumeration methods are extremely challenging. We developed a novel, automated approach to determine CEC frequencies and tested this method on two groups of patients undergoing conventional (CAVR) versus trans-catheter aortic valve implantation (TAVI).MethodsCEC frequencies were assessed by a flow cytometric approach, including automated pre-enrichment of CD34 positive blood cell subpopulation and isotype controls. The efficacy and reproducibility of the CEC enumeration method was validated by spiking blood samples of healthy control donors with defined numbers of endothelial cells.ResultsCEC frequencies were significantly higher in the TAVI group before (9.8 ± 4.1 vs. 5.5 ± 2.2, p = 0.019) and 1 h after surgery (13.4 ± 5.1 vs. 8.2 ± 4.1, p = 0.030) corresponding to higher Euroscore, STS score in higher risk patients from the TAVI group. Five days after surgery, CEC frequencies became significantly higher in the more invasive CAVR group (39.0 ± 13.0 vs. 14.3 ± 4.4, p < 0.001) compared to minimally invasive TAVI approach.ConclusionsThe new flow cytometric approach might be a robust and reliable method for CEC enumeration. Initial results show that CEC frequency is a valid clinical marker for the assessment of pre-operative risk, invasiveness of surgical procedure and clinical outcome. Further studies are necessary to validate the practical clinical usefulness and the potential superiority compared to conventional markers.

The effect of pre-operative methylprednisolone on early endothelial damage after total knee arthroplasty: a randomised, double-blind, placebo-controlled trial.

We wished to evaluate whether inhibition of the systemic inflammatory response by a single pre-operative dose of methylprednisolone reduced markers of early endothelial damage after fast-track total knee arthroplasty. We randomly allocated 70 patients undergoing elective unilateral total knee arthroplasty (1:1) to receive either pre-operative intravenous methylprednisolone 125 mg (methylprednisolone group) or isotonic saline (control group). All procedures were performed under spinal anaesthesia without a tourniquet, using a standardised multimodal analgesic regime. The outcomes included changes in Syndecan-1 concentrations, a marker of glycocalyx degradation, markers of endothelial cell damage and activation (plasma soluble thrombomodulin and sE-Selectin), and permeability by vascular endothelial growth factor, as well as C-reactive protein concentrations. Blood samples were collected at baseline and 2 h, 6 h and 24 h after surgery, with complete sampling from 63 patients for analyses. Methylprednisolone significantly reduced markers of endothelial damage at 24 h following surgery compared with saline (methylprednisolone group vs. control group, adjusted means (SEM)) expressed by circulating Syndecan-1: 11.6 (1.0) ng.ml-1 vs. 13.4 (1.1) ng.ml-1 p = 0.046; soluble thrombomodulin: 5.1 (0.1) ng.ml-1 vs. 5.7 (0.2) ng.ml-1 , p = 0.009; sE-Selectin: 64.8 (1.8) ng.ml-1 vs. 75.7 (1.9) ng.ml-1 , p = 0.001, and vascular endothelial growth factor: 35.3 (2.7) ng.ml-1 vs. 58.5 (2.8) ng.ml-1 , p < 0.001. The effect of the intervention increased with time for soluble thrombomodulin, sE-Selectin and vascular endothelial growth factor, and was more pronounced in patients with high baseline values. Finally, methylprednisolone reduced the C-reactive protein response 24 h postoperatively; 31.1 (1.1) mg.l-1 vs. 68.4 (1.1) mg.l-1 , p < 0.001. Pre-operative administration of methylprednisolone 125 mg reduced circulating markers of endothelial activation and damage, as well as the systemic inflammatory response (C-reactive protein) early after fast-track total knee arthroplasty. These findings may have a positive effect on surgical outcome, but require studies in major surgery.

P 35 First trimester maternal serum neutrophil gelatinase-associated lipocalin (NGAL) in prediction of preeclampsia in nulliparous women

Introduction Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDA glycoprotein and a marker of endothelial damage. Pregnancies complicated by preeclampsia (PE) are characterized by placental insufficiency and endothelial dysfunction. Its speculated that NGAL is elevated in pregnancies with PE. Objectives To establish first trimester maternal serum NGAL concentration in normal pregnancies and in pregnancies complicated by PE. Furthermore, to evaluate the screening performance for PE. Material and methods Case-cohort study based on a cohort of nulliparous women consecutively enrolled into the first trimester combined screening programme for trisomy 21. The NGAL concentration was measured in cases with late-onset (GA ⩾ 37 weeks + 0 days) PE (n = 213), early-onset (GA Results Serum samples were drawn at a median gestational age of 11 weeks + 0 days (range 8 weeks + 1 day – 13 weeks + 5 days). The NGAL concentration was not correlated with gestational age (r = 0.07, p = 0.14), but correlated very weakly with maternal weight (r = 0.12, p = 0.01). The median NGAL concentration in controls was 68.0 ng/mL (IQR 38.5 ng/mL). The NGAL concentration was significantly elevated in cases with early-onset PE (median 78.0 ng/mL, IQR 50 ng/mL, p = 0.04). In contrast, no significant change was found in cases with late-onset PE (median 69.0 ng/mL, IQR 49.5 ng/mL, p = 0.07). The detection rate was 15% for a 10% false positive rate in screening for early-onset PE. The area under the ROC curve was 0.59. Conclusion First trimester maternal serum NGAL is not correlated with gestational age. NGAL is significantly elevated in pregnancies that develop early-onset PE. In contrast, NGAL is unchanged in cases with late-onset PE. Screening performance for early-onset PE is poor.

Detection of early endothelial damage in patients with Raynaud's phenomenon

ObjectivesRaynaud's phenomenon (RP) can be the first manifestation of systemic sclerosis (SSc) or other connective tissue diseases (CTDs), often preceding an overt disease by years. It is not known if markers of endothelial damage are detectable in those RP patients who subsequently develop a CTD. MethodsWe studied 82 RP patients at their first evaluation to correlate the levels of endothelial markers with the subsequent development of an overt disease 36months later. We measured plasma levels of tissue-type plasminogen activator (t-PA) and von Willebrand factor (vWF), two markers of endothelial damage, and interleukin-6 (IL-6), a pro-inflammatory cytokine. Thirty sex- and age-matched healthy subjects (HS) served as controls. ResultsAt baseline, 67 patients showed capillaroscopic normal pattern (CNP) and 15 patients, of which 11 were very early SSc, had capillaroscopic scleroderma pattern (CSP). Plasma levels of t-PA, vWF and IL-6 were higher in patients with CNP (p=0.0001) than in HS and even much higher in patients with CSP (p=0.0001). In patients with CNP and RP of recent onset (<18months), vWF plasma levels were higher when autoantibodies were present (p=0.020). After 36months, among 48 RP patients with CNP who remained in follow-up, 24 were diagnosed as primary and 24 as secondary RP. In secondary RP, basal levels of t-PA, IL-6 and particularly vWF were higher than in primary RP (p=0.005, p=0.004, p=0.0001 respectively) and HS (p=0.0001 for all). ConclusionsOur findings indicate that markers of endothelial damage are elevated in RP patients who subsequently develop SSc or other CTDs, even in the absence of capillaroscopic abnormalities.

Association between arsenic exposure and soluble thrombomodulin: A cross sectional study in Bangladesh.

Chronic exposure to arsenic is associated with increased morbidity and mortality from cardiovascular disease (CVD); however, plausible biomarker for early prediction and the underlying mechanism of arsenic-related CVD have not yet been clearly understood. Endothelial dysfunction plays a central role in the development of CVD. We hypothesized that endothelial damage or dysfunction is an important aspect and may be an early event of arsenic-related CVD. Soluble thrombomodulin (sTM) in serum is thought to be a specific and stable marker for endothelial damage or dysfunction. This study was designed to evaluate the association between chronic exposure to arsenic and sTM among human subjects in arsenic-endemic and non-endemic rural areas in Bangladesh. A total of 321 study subjects (217 from arsenic-endemic areas and 104 from a non-endemic area) were recruited. Subjects’ arsenic exposure levels (i.e., drinking water, hair and nail arsenic concentrations) were measured by Inductively Coupled Plasma Mass Spectroscopy. The subjects’ serum sTM levels were quantified by immunoassay kit. The average sTM levels of the subjects in arsenic-endemic and non-endemic areas were 4.58 ± 2.20 and 2.84 ± 1.29 (ng mL-1) respectively, and the difference was significant (p<0.001). Arsenic exposure levels showed a significant (water arsenic: rs = 0.339, p<0.001, hair arsenic: rs = 0.352, p<0.001 and nail arsenic: rs = 0.308, p<0.001) positive associations with sTM levels. Soluble TM levels were higher in the higher exposure gradients if we stratified the subjects into tertile groups (low, medium and high) based on the arsenic concentrations of the subjects’ drinking water, hair and nails. Finally, increased levels of sTM were negatively correlated with high density lipoprotein cholesterol (HDL-C), and positively correlated with intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Results of this study show that chronic exposure to arsenic has mild to moderate association with sTM levels.

Effect of delayed onset prostacyclin on markers of endothelial function and damage after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a neurological emergency. Delayed ischemic neurological deficit is one of the main causes of poor outcome after SAH and is probably caused, at least in part, by cerebral vasospasm. The pathophysiology of this is multifaceted, but endothelial damage and activation as well as glycocalyx damage have been implicated. Prostacyclin has been shown to protect damaged and activated endothelium and to facilitate glycocalyx repair. We investigated biomarkers of endothelial activation and damage in patients with SAH randomized to 5days prostacyclin infusion or placebo. Patients with aneurysmal SAH managed by coiling or surgery, and a World Federation of Neurological Surgeons score between 1 and 4, and Fisher grade 3 or 4, were treated with a continuous low-dose intravenous prostacyclin infusion or placebo initiated on day 5 and discontinued on day 10 after SAH. Blood samples were drawn from the patients before, during and after prostacyclin/placebo infusion. Soluble biomarkers of endothelial cell activation (sE-selectin, sVE-cadherin) and damage (sTM), glycocalyx damage (syndecan-1) and sympathoadrenal activation (adrenaline, noradrenaline), were measured by ELISA. Ninety patients were randomized. Prostacyclin infusion influenced neither biomarkers of sympathoadrenal activation, endothelial activation and damage nor biomarkers of endothelial glycocalyx breakdown. We did not find any effects on markers of sympathoadrenal activation, endothelial damage and activation, or glycocalyx degradation of delayed onset prostacyclin infusion compared to placebo. Further trials investigating early onset endothelial repair using prostacyclin are warranted.

Markers of endothelial dysfunction

Endothelial dysfunction is considered as a universal non-specific link in the pathogenesis of many diseases, primarily the cardiovascular system. This review is devoted to the discussion of the main functions of the endothelium and mechanisms for their implementation. One of the most striking features of endothelial cells is their morphological heterogeneity, which allows us to identify several typical forms of endothelial dysfunction (vasomotor, hemostatic, adhesion and angiogenous). Also, the review presents the most promising predictors of cardiovascular diseases and their complications among endothelial damage markers.

Evaluation of the Effects of Mesoglycan on Some Markers of Endothelial Damage and Walking Distance in Diabetic Patients with Peripheral Arterial Disease

The aim of this study was to evaluate the variation of some parameters involved in peripheral artery disease progression in diabetic patients with peripheral artery disease after six months of mesoglycan. We enrolled 64 Caucasian, type 2 diabetic patients, with stage IIa peripheral artery disease. They were randomized to mesoglycan (Prisma®), 50 mg twice a day, or placebo, for six months. We evaluated: glycemic control, metalloproteinase-2, and -9 (MMP-2, and -9), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion protein-1 (sVCAM-1), interleukin-6 (IL-6), soluble E-selectin (sE-selectin), high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1). We recorded a decrease of MMP-2, MMP-9, sE-selectin, TNF-α, sVCAM-1, and IL-6 compared to baseline, and to placebo in the group treated with mesoglycan. Regarding sICAM-1, and hs-CRP, instead, we recorded a decrease with mesoglycan only compared to baseline. Preliminary results seem to suggest an improvement of pain free walking distance with mesoglycan in 18 patients both compared to baseline and to placebo, even if data should be taken cautiously. Our study showed that supplementation with mesoglycan improved endothelial dysfunction in type 2 diabetic patients with peripheral artery disease. Regarding the preliminary data suggesting also a slight improvement of clinical parameters such as pain free walking distance, more data and a bigger sample of patients are necessary to better verify this aspect.

Abstract S5-07: Aromatase inhibitors and endothelial function: Is there an association with early cardiovascular disease?

Abstract Background: As more women are cured from their breast cancer, survivors with early stage breast cancer are at greater risk of dying from cardiovascular disease than their breast cancer. Aromatase inhibitors (AI) have been shown to reduce breast cancer-related mortality in women with estrogen receptor (ER)-positive disease which makes up 75% of all breast cancer cases. The use of AIs has been associated with higher rates of hypertension, hypercholesterolemia, angina pectoris and ischemic cardiovascular disease. In the aging population taking AIs, little is known about the direct impact of AIs on endothelial function, a predictor of cardiovascular disease. Endothelial dysfunction identified by reactive hyperemia using Endo-PAT has been associated with an increased risk of cardiac adverse events, independent of Framingham risk score. Methods: At the University of Minnesota in 2014-2015, 25 healthy postmenopausal women and 36 postmenopausal women with locally advanced breast cancer and prescribed an aromatase inhibitor were identified. Subjects with a history of hypertension or hyperlipidemia were excluded. Consented subjects underwent biomarker analysis and pulse wave analysis using the HDI/Pulse Wave CR-2000 Cardiovascular Profiling System and pulse contour analysis using the Endo-PAT2000 system. Biomarkers and functional test markers were compared between cases and controls using T-tests and Wilcoxon Rank-Sum tests. Results: Mean age (61.7 vs 58.8 years), body mass index (27.4 vs 26.2 kg/m2), race (93% vs 92% Caucasian), and tobacco use (100% nonsmokers) were similar between cases and controls, respectively. Mean systolic blood pressure (BP) was elevated in cases (128.3 mmHg vs 114.5 mmHg, p=0.0006). There were no differences in lipid profiles. Median ultrasensitive estradiol levels were reduced in cases (2 vs 15 pg/mL, p&amp;lt;0.0001). Median high sensitive C-reactive protein was significantly elevated in cases (4146 vs 1406 ng/L, p=0.05). There were no differences seen in markers of hemostasis or endothelial damage, including circulating endothelial cells, vascular cell adhesion molecule, P-selectin. Median large artery elasticity (12.5 vs 15.1 ml/mmHg, p=0.02), small artery elasticity (5.2 vs 6.7 ml/mmHg, p=0.04), and endoPAT ratio (0.8 vs 2.6, p&amp;lt;0.0001) were significantly reduced in breast cancer survivors on AIs as compared to controls. There was no correlation between use of chemotherapy, radiation therapy, type of AI, or duration of AI use and endothelial function among the cases. When adjusting for differences in BP, endoPAT ratio continued to remain significantly decreased in breast cancer survivors (0.8 vs 2.6, p&amp;lt;0.0001). Conclusion: Postmenopausal women with breast cancer on AIs have reductions in endothelial function, a predictor of adverse cardiovascular disease (acute coronary syndrome, chest pain, myocardial infarction, cardiac death). With the growing trend that longer duration of endocrine therapy is needed, further work is needed to confirm these findings. Citation Format: Blaes AH, Beckwith H, Hebbel R, Solovey A, Potter D, Yee D, Vogel R, Luepker R, Duprez D. Aromatase inhibitors and endothelial function: Is there an association with early cardiovascular disease? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S5-07.

Apolipoprotein B vs non–high-density lipoprotein cholesterol: Association with endothelial hemostatic markers and carotid intima-media thickness

Both apolipoprotein B (apoB) and non-high-density lipoprotein cholesterol (non-HDL-C) are accepted as alternative risk factors or targets for lipid-lowering therapy, which correlate more strongly with cardiovascular events than low-density lipoprotein cholesterol. The aim of this cross-sectional study was to evaluate the differences in plasma levels of plasminogen activator inhibitor-1 (PAI-1) and of von Willebrand factor (vWF) as endothelial hemostatic markers and carotid intima-media thickness (C-IMT) as a morphologic marker for atherosclerotic vascular disease among dyslipidemic individuals with apoB levels higher, estimated or lower based on regression equation of apoB vs non-HDL-C. A total of 594 dyslipidemic subjects without atherosclerotic manifestation were divided into 3 groups (according to tertiles of apoB levels above, within, and below the line of identity): H-apoB (n=200), E-apoB (n=194), and L-apoB (n=200). PAI-1, vWF, C-IMT and lipids, anthropometric parameters, markers of insulin resistance, and inflammation were measured. Differences in variables between groups were analyzed using analysis of variance. There was a strong association between apoB and non-HDL-C. The correlations of apoB and of non-HDL-C with markers of endothelial damage and C-IMT were very similar. Despite these facts, individuals with higher apoB levels had significantly higher levels of PAI-1 compared with individuals with estimated (P<.05) or lower apoB (P<.001). There were no significant differences in vWF, C-IMT, markers of insulin resistance, obesity, and inflammation. Individuals with apoB higher than predicted by non-HDL-C had significantly higher levels of PAI-1, which may contribute to the increased risk of future atherothrombotic events.

Markers of endothelial damage in patients with chronic kidney disease on hemodialysis.

Patients with Stage 5 chronic kidney disease who are on hemodialysis (HD) remain in a chronic inflammatory state, characterized by the accumulation of uremic toxins that induce endothelial damage and cardiovascular disease (CVD). Our aim was to examine microvesicles (MVs), monocyte subpopulations, and angiopoietins (Ang) to identify prognostic markers in HD patients with or without diabetes mellitus (DM). A total of 160 prevalent HD patients from 10 centers across Spain were obtained from the Biobank of the Nephrology Renal Network (Madrid, Spain): 80 patients with DM and 80 patients without DM who were matched for clinical and demographic criteria. MVs from plasma and several monocyte subpopulations (CD142+/CD16+, CD14+/CD162+) were analyzed by flow cytometry, and the plasma concentrations of Ang1 and Ang2 were quantified by ELISA. Data on CVD were gathered over the 5.5 yr after these samples were obtained. MV level, monocyte subpopulations (CD14+/CD162+ and CD142+/CD16+), and Ang2-to-Ang1 ratios increased in HD patients with DM compared with non-DM patients. Moreover, MV level above the median (264 MVs/µl) was associated independently with greater mortality. MVs, monocyte subpopulations, and Ang2-to-Ang1 ratio can be used as predictors for CVD. In addition, MV level has a potential predictive value in the prevention of CVD in HD patients. These parameters undergo more extensive changes in patients with DM.

CELLULAR BIOMARKERS OF ENDOTHELIAL DAMAGE ASSOCIATED WITH ADVERSE PROGNOSIS IN ACUTE CORONARY EVENTS

This literature review considers the cellular markers of endothelial damage as a new diagnostic and prognostic marker of cardiovascular risk the emphasis is on endothelial dysfunction as a key element in the development of systemic inflammatory response and activation of coagulation in patients after acute cardiovascular events.

Assessment of subclinical cardiac damage in chronic plaque psoriasis patients: a case control study

IntroductionEpidemiological studies have suggested that patients with psoriasis are at an increased risk of developing cardiovascular diseases. Chronic inflammation may play a role in the pathogenesis of atherosclerosis in psoriasis patients. Recent studies have evaluated the expression of plasma endocan and homocysteine levels. Endocan is a marker of vascular endothelial damage, and homocysteine plays a role in the development of atherosclerosis. Plasma endocan and homocysteine levels, as well as echocardiographic parameters, were evaluated in patients with psoriasis to assess cardiovascular disease risk.Material and methodsThis was a prospective cohort analysis of 40 patients who were diagnosed with psoriasis and 40 healthy controls matched to the patient group according to demographic and biochemical parameters.ResultsSerum endocan and homocysteine concentrations were significantly higher in the psoriasis group than the control group (p < 0.001). Serum endocan concentrations correlated positively with disease duration (p < 0.001; r = 0.725). The Tei index (myocardial performance) was elevated in psoriasis patients (p < 0.001). Additionally, the E/A (mitral valve early diastolic peak flow velocity/mitral valve late diastolic peak flow velocity) and E/Em (early diastolic myocardial velocity) ratios were reduced in psoriasis patients (p < 0.001). Parameters indicative of left ventricular asynchrony were elevated significantly in the psoriasis group versus the control group (p < 0.001).ConclusionsWe observed a substantial increase in serum endocan and homocysteine concentrations, and significant differences in key parameters of cardiac function, in psoriasis patients relative to controls. These results are consistent with the hypothesis that subclinical cardiac damage is increased in patients with psoriasis and that psoriasis itself may be a cardiovascular risk factor.

The Complex Inter-Relationship Between Diabetes and Schizophrenia.

Schizophrenia is a chronic and debilitating brain disorder. It is associated with increased mortality, primarily due to elevated cardio-metabolic risk. Affected patients have higher rates of obesity, metabolic syndrome and diabetes [1]. Intrinsic factors contributing to this increased risk include a shared underlying pathophysiology between schizophrenia and diabetes mellitus involving stress, inflammation and genetics. Extrinsic contributing factors include diet, lifestyle, health care access, low socioeconomic status and overburden of traditional diabetes risk factors. Antipsychotics are associated with an increased risk of obesity, metabolic syndrome and diabetes mellitus [1]. Appetite-regulating hormones, pharmacodynamics and alterations in glucose metabolism may underlie the negative effect of these medications. Reduction in diabetes risk is achieved by mitigating traditional risk factors. Non-pharmacologic and pharmacologic approaches to cardio-metabolic risk reduction may be helpful in these patients.

Variable ventilation improves pulmonary function and reduces lung damage without increasing bacterial translocation in a rat model of experimental pneumonia.

BackgroundVariable ventilation has been shown to improve pulmonary function and reduce lung damage in different models of acute respiratory distress syndrome. Nevertheless, variable ventilation has not been tested during pneumonia. Theoretically, periodic increases in tidal volume (VT) and airway pressures might worsen the impairment of alveolar barrier function usually seen in pneumonia and could increase bacterial translocation into the bloodstream. We investigated the impact of variable ventilation on lung function and histologic damage, as well as markers of lung inflammation, epithelial and endothelial cell damage, and alveolar stress, and bacterial translocation in experimental pneumonia.MethodsThirty-two Wistar rats were randomly assigned to receive intratracheal of Pseudomonas aeruginosa (PA) or saline (SAL) (n = 16/group). After 24-h, animals were anesthetized and ventilated for 2 h with either conventional volume-controlled (VCV) or variable volume-controlled ventilation (VV), with mean VT = 6 mL/kg, PEEP = 5cmH2O, and FiO2 = 0.4. During VV, tidal volume varied randomly with a coefficient of variation of 30% and a Gaussian distribution. Additional animals assigned to receive either PA or SAL (n = 8/group) were not ventilated (NV) to serve as controls.ResultsIn both SAL and PA, VV improved oxygenation and lung elastance compared to VCV. In SAL, VV decreased interleukin (IL)-6 expression compared to VCV (median [interquartile range]: 1.3 [0.3–2.3] vs. 5.3 [3.6–7.0]; p = 0.02) and increased surfactant protein-D expression compared to NV (2.5 [1.9–3.5] vs. 1.2 [0.8–1.2]; p = 0.0005). In PA, compared to VCV, VV reduced perivascular edema (2.5 [2.0–3.75] vs. 6.0 [4.5–6.0]; p < 0.0001), septum neutrophils (2.0 [1.0–4.0] vs. 5.0 [3.3–6.0]; p = 0.0008), necrotizing vasculitis (3.0 [2.0–5.5] vs. 6.0 [6.0–6.0]; p = 0.0003), and ultrastructural lung damage scores (16 [14–17] vs. 24 [14–27], p < 0.0001). Blood colony-forming-unit (CFU) counts were comparable (7 [0–28] vs. 6 [0–26], p = 0.77). Compared to NV, VCV, but not VV, increased expression amphiregulin, IL-6, and cytokine-induced neutrophil chemoattractant (CINC)-1 (2.1 [1.6–2.5] vs. 0.9 [0.7–1.2], p = 0.025; 12.3 [7.9–22.0] vs. 0.8 [0.6–1.9], p = 0.006; and 4.4 [2.9–5.6] vs. 0.9 [0.8–1.4], p = 0.003, respectively). Angiopoietin-2 expression was lower in VV compared to NV animals (0.5 [0.3–0.8] vs. 1.3 [1.0–1.5], p = 0.01).ConclusionIn this rat model of pneumonia, VV improved pulmonary function and reduced lung damage as compared to VCV, without increasing bacterial translocation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0476-7) contains supplementary material, which is available to authorized users.

Maternal endothelial damage as a disorder shared by early preeclampsia, late preeclampsia and intrauterine growth restriction.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are separate disease entities that have frequently been reported as sharing the same pathogenesis. In both of them, angiogenesis disorders and generalized endothelial damage with an accompanying inflammation are the dominant symptoms. In this study, we attempted to prove that both these processes demonstrate the same profile in early PE, late PE and IUGR patients, while the only difference is in the degree of exacerbation of the lesions. In 167 patients divided into four groups, three of those with early PE, late PE and IUGR and one control group, fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), high sensitive c-reactive protein (hsCRP) and fibronectin were determined. The behavior of these parameters in each of the groups was studied, and correlations between them were sought for. Higher concentrations of sFlt-1, hsCRP and fibronectin and a lower concentration of PlGF were found in the study groups compared to the control group. Significant correlations were observed between the factors concerned. The higher values of disordered angiogenesis markers, endothelial damage markers and inflammatory markers both in the PE and the intrauterine growth restriction (IUGR) groups suggest the existence of shared disorders in the development of these pathologies. The correlations between disordered angiogenesis markers and endothelial damage markers argue in favor of a mutual relationship between these two processes in the development of pathologies evolving as secondary to placental ischemia. The results obtained confirm that the lesion profiles are the same in both PE and IUGR patients, which can be utilized in developing common diagnostic criteria.

Hemoglobin as a response marker of endothelial cell damage in elderly nonoverweight non-anemic subjects.

Title Hemoglobin as a response marker of endothelial cell damage in elderly nonoverweight non-anemic subjects. Author(s) Kadota, Koichiro; Shimizu, Yuji; Nakazato, Mio; Noguchi, Yuko; Koyamatsu, Jun; Yamanashi, Hirotomo; Nagayoshi, Mako; Murase, Kunihiko; Arima, Kazuhiko; Maeda, Takahiro Citation Acta medica Nagasakiensia, 60(3), pp.103-108; 2016 Issue Date 2016-04 URL http://hdl.handle.net/10069/36572 Right NAOSITE: Nagasaki University's Academic Output SITE

Preoperative values of inflammatory markers predict clinical outcomes in patients after CABG, regardless of the use of cardiopulmonary bypass

ObjectiveThe impact of systemic inflammation on clinical outcomes after CABG surgery is still controversial. In this study, we evaluated the impact of the markers of inflammation, endothelial damage and platelet activation on clinical outcomes after on- and off-pump CABG. MethodsA group of 191 consecutive on- and off-pump CABG patients were prospectively studied. Blood samples were drawn before surgery, 18–36h after the procedure and 5–7 days postoperatively and analyzed for 8-iso-prostaglandin F2α (8-iso-PGF2α), asymmetric dimethylarginine (ADMA) and β-thromboglobulin (β-TG). White blood count and C-reactive protein were measured twice, first before and then during the first 18–36h after CABG. The primary clinical end-points were: low cardiac output syndrome (LCOS), postoperative myocardial infarction (PMI) and in-hospital cardiovascular death. ResultsElevation of 8-iso-PGF2α, ADMA and β-TG before surgery was associated with an increased risk of morbidity and mortality after CABG. There were no differences in analyzed markers and clinical outcomes between the on- and off-pump groups. Even during the uncomplicated postoperative course the inflammatory response was enhanced and still remained higher than baseline 5–7 days after surgery. ConclusionLinks between preoperative 8-iso-PGF2α, ADMA and β-TG and unfavorable early post-CABG outcomes suggest that these markers could be useful in identifying patients with increased risk of LCOS, PMI and in-hospital cardiovascular death following elective CABG.

Highly sensitive turn-on fluorescence detection of thrombomodulin based on fluorescence resonance energy transfer

As an integral glycoprotein on the surface of endothelial cells, thrombomodulin (TM) has very high affinity for thrombin. TM has been regarded to be a marker of endothelial damage since it can be released during endothelial cell injury. In this work, a highly sensitive fluorescence method for the quantitative detection of TM was developed. TM antibody (Ab) and bovine serum albumin (BSA) were bound on gold nanoparticles (AuNPs) to construct BSA-AuNPs-Ab nanocomposites and they were characterized by transmission electron microscope and UV–vis spectrophotometry. The fluorescence of acridine orange (AO) was quenched by the prepared gold nanocomposites based on fluorescence resonance energy transfer (FRET). In the presence of TM, the fluorescence was turned on due to the effective separation of AO from the surface of gold nanocomposites. Under optimum conditions, the enhanced fluorescence intensity displayed a linear relationship with the logarithm of the TM concentration from 0.1pgmL−1 to 5ngmL−1 with a low detection limit of 12fgmL−1. The release of soluble thrombomodulin (sTM) by the injured HUVEC-C cells in the presence of H2O2 was investigated using the proposed method. The released sTM content in the growth medium was found to be increased with the enhancement of contact time of the cells with H2O2.

Coagulopathy in patients with acute pulmonary embolism: a pilot study of whole blood coagulation and markers of endothelial damage

Whole blood coagulation and markers of endothelial damage were studied in patients with acute pulmonary embolism (PE), and evaluated in relation to PE severity. Twenty-five patients were enrolled prospectively each having viscoelastical analysis of whole blood done using thrombelastography (TEG) and Multiplate aggregometry. Fourteen of these patients were investigated for endothelial damage by ELISA measurements of Syndecan-1 (endothelial glycocalyx degradation), soluble endothelial Selectin (endothelial cell activation), soluble Thrombomodulin (endothelial cell injury) and Histone Complexed DNA fragments (endothelial cytotoxic histones). The mean values of TEG and Multiplate parameters were all within the reference levels, but a significant difference between patients with high and intermediate risk PE was observed for Ly30 (lytic activity) 1.5% [0–10] vs. 0.2% [0–2.2] p = .04, and ADP (platelet reactivity) 92 U [20–145] vs. 59 U [20–111] p = .03. A similar difference was indicated for functional fibrinogen 21 mm [17–29] vs. 18 mm [3–23] p = .05. Analysis of endothelial markers identified a significant difference in circulating levels between high and intermediate risk PE patients for Syndecan-1 118.6 ng/mL [76–133] vs. 36.3 ng/mL [11.8–102.9] p = .008. In conclusion, patients with acute PE had normal whole blood coagulation, but high risk PE patients had signs of increased activity of the haemostatic system and significantly increased level of endothelial glycocalyx degradation.