Novel Marker Of Endothelial Dysfunction Research Articles

Serum Endocan Levels in Postmenopausal Women with Metabolic Syndrome.

Aim: Studies that explored endocan (as a novel marker of endothelial dysfunction) in relation to metabolic syndrome (MetS) are scarce and show discordant results. Importantly, no study has yet examined serum endocan levels in exclusively postmenopausal women with MetS and free of diabetes. Oxidative stress and inflammation are the key features of MetS and consequently cardiovascular diseases. Hence, we aimed to explore the potential relationship between endocan, oxidative stress [i.e., determined by total antioxidant status, total oxidant status, and pro-oxidant/antioxidant balance (PAB)], inflammation, and MetS in a cohort of postmenopausal women. Methods: A total of 126 postmenopausal women were included consecutively. MetS was diagnosed following the International Diabetes Federation criteria. Results: Higher serum endocan levels were found in MetS group as compared with MetS-free counterparts [6.03 (3.47-10.37) pg/mL vs. 2.27 (1.49-3.50) pg/mL, P < 0.001]. Endocan showed good discriminatory ability toward MetS [area under the curve (AUC) = 0.809]. Besides age, the inclusion of oxidative stress and inflammation biomarkers, such as PAB and high-sensitivity C-reactive protein (hsCRP), the AUC for discrimination postmenopausal women with MetS from MetS-free women was 0.845. Conclusion: Postmenopausal women with MetS exhibited almost 2.7 times higher serum endocan level as compared with MetS-free middle-aged women. Endocan showed good discriminatory ability toward MetS and could be a diagnostic marker in MetS. Similar results were confirmed when added an age, oxidative stress, and inflammation biomarkers (i.e., PAB and hsCRP) were included for the discrimination of postmenopausal with MetS from MetS-free women.

Patients with autoimmune chronic inflammatory diseases present increased biomarkers of thromboinflammation and endothelial dysfunction in the absence of flares and cardiovascular comorbidities.

Cardiovascular risk is increased in patients with autoimmune rheumatic diseases. Endothelial, erythrocyte and platelet microvesicles (MVs) are elevated in patients with cardiovascular diseases and represent novel markers of endothelial dysfunction and thromboinflammation. We tested whether their levels are increased in patients with autoimmune rheumatic diseases (ARDs) in the absence of disease flare and cardiovascular comorbidities. Well-controlled patients with rheumatoid arthritis or systemic lupus erythematosus were studied, provided they were free from cardiovascular comorbidities and established cardiovascular disease. We additionally studied (a) a control group consisting of healthy volunteers and (b) a reference group including patients with stable coronary artery disease (CAD). MVs were measured using a standardized flow cytometry protocol. In a population of 74 participants, patients with ARDs (n = 17) presented increased levels of both endothelial (283.3 ± 195.0/μL vs 168.5 ± 54.8/μL, p = 0.029) and platelet MVs (374.0 ± 275.3/μL vs 225.7 ± 101.1/μL, p = 0.046) compared to controls (n = 34), whereas erythrocyte MVs did not significantly differ. In addition, patients with ARDs showed similar levels of endothelial MVs compared to CAD patients (n = 23) (283.3 ± 195.0/μL vs 297.0 ± 211.8/μL, p = 0.846). Platelet MVs were significantly associated with disease duration, and erythrocyte MVs with patients' perceived disease activity. In conclusion, increased levels of endothelial and platelet MVs may be evident in patients with ARDs, even in the absence of disease flares and before the establishment of cardiovascular complications. Levels of endothelial MVs resemble those of patients with profound atherothrombotic profile. The prognostic potential of MVs in terms of cardiovascular disease prevention warrants further investigation in patients with ARDs.

Endocan as a potential biomarker of disease severity and exacerbations in COPD.

Endocan is a proteoglycan that is regarded as a novel marker of endothelial dysfunction. Endothelial dysfunction in pulmonary vascular bed is known to play an important role for the pathogenesis of COPD. This study aimed to determine serum endocan levels in patients with stable COPD and acute exacerbation of COPD (AECOPD) and to test the relationship between serum endocan levels and exacerbations. This study enrolled a total of 55 COPD patients, 24 of which had AECOPD and 31 had stable COPD. All patients' basic demographic and clinical data were recorded and blood samples were collected. Serum endocan levels were significantly higher in the AECOPD group compared to the stable COPD and control groups (for both p<0.001) and stable COPD group had higher levels than the control group (p<0.005). Additionally, serum endocan levels were negatively correlated with FVC, FEV1, partial oxygen pressure and oxygen saturation (r=-0.30, p=0.03; r=-0.34, p=0.01; r=-0.34, p=0.01 and r=-0.36, p=0.007 respectively), and positively correlated with disease duration and systolic pulmonary artery pressure (r=0.47, p<0.001; r=0.31, p=0.02 respectively). A cut-off value of 434.29pg/ml for endocan predicted exacerbation with a sensitivity of 79% and a specificity of 84% (AUC: 0.778, 95% Cl 0.648-0.909; p<0.001). Logistic regression analysis revealed that increased endocan levels was independent predictor of COPD exacerbation (OR=9.32, 95%CI, 1.64-52.95; p=0.01). Endocan may be a novel biomarker for detection of endothelial dysfunction and prediction of exacerbations in patients with COPD.

Novel markers of endothelial dysfunction in hepatitis C virus-related cirrhosis: More than a mere prediction of esophageal varices.

BACKGROUNDHepatitis C virus (HCV) infection may affect lipid metabolism by enhancing the circulating levels of inflammatory cytokines, together with its impact on endothelial function. AIMTo evaluate the potential correlation of changes in lipid profile, carotid intima-media thickness (CIMT), and ankle-brachial index with the severity of fibrosis, grades of esophageal varices (EVs), and fibrosis indices.METHODSThe study included 240 subjects who were divided into 3 groups; group 1 (n = 90, HCV-related cirrhotic patients with EVs), group 2 (n = 90, HCV-related cirrhotic patients without EVs), and group 3 (n = 60, served as the healthy control group). All patients underwent routine laboratory tests, including a lipid profile assay. Low-density lipoproteins (LDL)/platelet count and platelet/splenic diameter ratios were calculated. Abdominal ultrasonography, CIMT by carotid Doppler, bedside ankle-brachial index (ABI), liver stiffness measurement, and upper gastrointestinal endoscopy were performed.RESULTSMultivariate logistic regression revealed that very-low-density lipoprotein (VLDL) (β = 0.988, odds ratio 2.5, P = 0.001), LDL/platelet count ratio (β = 1.178, odds ratio 3.24, P = 0.001), CIMT (β = 1.37, odds ratio 3.9, P = 0.001), and ABI (β = 2.3, odds ratio 5.9, P = 0.001) were the key variables associated with significant fibrosis, EVs and endothelial dysfunction. CIMT and LDL/platelet count ratio were predictive of advanced fibrosis and EVs at cutoff values of 1.1 mm and 1 mm, respectively, with an area under the curve (AUC) of 0.966 and 0.960 (P = 0.001), while VLDL and ABI at a cutoff of 16.5 mg/dL and 0.94 were predictive of advanced fibrosis and EVs with an AUC of 0.891 and 0.823, respectively (P = 0.001).CONCLUSIONCIMT, ABI, VLDL, LDL/platelet count ratio are good non-invasive predictors of advanced fibrosis, presence of EVs, and endothelial dysfunction in liver cirrhosis.

Maternal plasma endocan levels in intrauterine growth restriction

Objectives Intrauterine growth restriction (IUGR) is diagnosed when the estimated fetal weight remains below the 10th percentile of gestational age based on pathological restriction of growth and/or accompanying Doppler abnormalities. Endothelial dysfunction is a common pathogenetic pathway underlying IUGR etiology. Endocan (ESM-1) is a novel marker of endothelial dysfunction and inflammation found in the maternal circulation. This study was designed to compare plasma endocan levels between pregnancies complicated with IUGR and a control group. Study design Forty-four pregnancies complicated with IUGR and 47 healthy pregnancies were included. Maternal plasma endocan levels were detected by ELISA. Parametric data was studied by Student’s t-test. Mann–Whitney U-test was used in analyzing non-parametric data. Categorical variables underwent chi-square test. ROC analysis was performed to define the cutoff value of endocan in detecting IUGR. Spearman correlation test was performed. Results Maternal plasma endocan level varied significantly between IUGR and healthy pregnancies and was 1.8 fold higher in the IUGR group (793.0 (IQR:544.4–1896.0) ng/L vs. 441.8 (IQR: 408.3–512.4) ng/L, p < .001). There was a weak negative correlation between endocan level and 5th and 10th minute APGAR Scores (r = −0.256; p = .015 and r = −0.215; p = .042, respectively), a weak positive correlation with umbilical artery pulsatility index, and a moderate negative correlation with cerebroplacental ratio (r = 0.394; p < .001 and r = −0.459; p < .001, respectively). Conclusions There was a significant difference between endocan levels of IUGR and healthy pregnancies. Further studies might be designed to investigate the performance of endocan in predicting neonatal outcomes for pregnancies complicated with IUGR.

Endocan and Erectile Dysfunction.

Endothelial dysfunction (ED) occurs early in the development of atherosclerosis. Predictors of vascular risk including obesity, hyperlipidemia, metabolic syndrome, diabetes mellitus, and hypertension are associated with both vascular endothelial and ED. Endocan is a novel marker of endothelial dysfunction, inflammation, and atherosclerosis. Raised endocan levels (usually measured by ELISA assays) were reported in some cardiovascular diseases and related conditions. Increased endocan levels may represent the endothelial and inflammatory components of the pathogenesis of ED and may, therefore, prove useful in clinical practice.

The role of endocan and selected pro-inflammatory cytokines in systemic lupus erythematosus.

IntroductionSystemic lupus erythematosus (SLE) is a multisystem inflammatory autoimmune disease with a wide spectrum of clinical manifestations. Cytokines such as interleukin-1 (IL-1) and tumour necrosis factor α (TNF-α) are involved in its pathogenesis. Endocan is a novel marker of endothelial dysfunction and is likely to be engaged in proinflammatory processes in SLE.AimTo determine whether endocan serum concentration in SLE patients vary from healthy controls.Material and methodsThe study included 36 patients with SLE. SLEDAI-2K score was used to assess disease activity. The control group comprised 23 healthy volunteers. ELISA kits were used to assess serum concentrations of endocan, IL-1β, TNF-α, vascular endothelial growth factor (VEGF) and high-sensitivity C reactive protein (hs-CRP).ResultsThe serum concentration of endocan was significantly higher (p < 0.001) in the SLE group than in healthy individuals. A positive correlation was found between serum levels of endocan and IL-1β (r = 0.47, p < 0.05). Active SLE patients (SLEDAI-2K score above 6 points) with an elevated total cholesterol level (above 5.17 mmol/l) were found to have VEGF concentration higher than those with a normal cholesterol level (p < 0.03). No other relevant relationships were found between the serum concentration of endocan, other laboratory parameters, anthropometric features, activity and duration of SLE.ConclusionsA higher serum level of endocan in SLE patients indicates its possible role in the pathogenesis of the disease and reflects endothelial dysfunction. Our findings indicate that endocan could serve as a potential marker of endothelial dysfunction in SLE.

PF545 EASIX FOR PREDICTION OF SURVIVAL IN LOWER RISK MYELODYSPLASTIC SYNDROMES

Background:Patients with myelodysplastic syndromes (MDS) are at risk of early death from cardiovascular complications due to the link between clonal hematopoiesis and endothelial dysfunction. EASIX (Endothelial Activation and Stress Index) is a novel marker of endothelial dysfunction that is calculated from serum creatinine, lactate dehydrogenase levels, and thrombocyte counts. EASIX has been established to predict endothelial complications after allogeneic transplantation.Aims:To analyze the impact of EASIX on the survival of patients with lower risk MDS and correlation with markers of endothelial activation.Methods:We investigated the impact of EASIX measured at first diagnosis on survival of lower risk MDS patients who received supportive treatment in two independent institutions: n = 100 (cohort I) and n = 338 (cohort II). Serum Angiopoietin‐2, suppressor of tumorigenicity (ST)‐2, soluble thrombomodulin (sCD141), interleukin (IL)‐18, IL37, S100A9, and HMGB1 were measured as markers of endothelial cell distress and inflammasomal activity and correlated to EASIX.Results:Univariate analysis showed that high EASIX was associated with shorter survival in both cohorts (Cohort I: hazard ratio (HR) per log2 increase: 1.50; 95% confidence interval (CI) 1.27–1.79; p‐value &lt; 0.001 / Cohort II: HR 1.31 [1.20–1.42]; p‐value &lt; 0.001). We visualized this continuous effect of EASIX by grouping patients into quartiles according to EASIX (Figure 1 A and B). Multivariate Cox regression analysis confirmed that EASIX remains a significant predictor of survival even after adjustment for age, sex, cytogenetic abnormalities and bone marrow blast counts (Cohort I: HR 1.35 [1.12–1.63]; p‐value = 0.002 / Cohort II HR 1.18 [1.08–1.29]; p‐value &lt;0.001]. Models including EASIX showed lower prediction errors over time. Serum levels of Angiopoietin‐2 correlated significantly with EASIX (Spearman's rank correlation = 0.455, 95%CI 0.264–0.616, n = 74). Due to the lack of correlation between EASIX and S100A9 or IL‐1b, we performed a pathway analysis including serum HMGB1 and IL37. We observed a strong intra‐pathway correlation of S100A9 with IL1b, IL18, IL37, and HMGB1, arguing for the validity of our serum analysesSummary/Conclusion:We introduce EASIX as an easily accessible predictor for survival in patients with low‐risk MDS in best supportive care.image

The endothelial status reflected by circulating endothelial cells, circulating endothelial progenitor cells and soluble thrombomodulin in patients with mild and resistant hypertension

BackgroundThe aim of the present study was to evaluate endothelial status by measuring the concentration of novel markers of endothelial dysfunction (ED): a number of circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPCs) and their ratio (CEPCs/CECs) as well as a traditional parameter - soluble thrombomodulin (sTM) in patients with resistant (RH) and mild hypertension (MH). Materials and methodsThirty patients with MH and thirty subjects with RH were involved in the study. The control group included thirty-three age and sex-matched normotensive volunteers. We used multicolor flow cytometry for CECs and CEPCs analysis and the commercial human sTM ELISA kit to measure plasma sTM concentration. ResultsAn elevated CECs number and a decreased CEPCs/CECs ratio was found in MH as well as in RH patients in comparison with normotensive volunteers. CECs correlated positively with an increased triglycerides in MH patients and an elevated LDL-cholesterol and hsCRP in RH group. Positive correlation between CEPCs and LDL-cholesterol level was observed in both types of hypertension. ConclusionsThe results of the present study suggest that an endothelial alteration accompanies hypertension. The number of CECs reflecting the extent of endothelial damage does not appear to be related to the severity of disease. The drastically decreased ratio between CEPCs and CECs observed in both groups of patients suggests an inadequate process of endothelial regeneration. Among analyzed factors inflammation and lipid abnormalities may have significant contribution in endothelial pathology in hypertension.

Serum Visfatin as a Novel Marker of Endothelial Dysfunction in Patients with Type 2 Diabetes

Serum Visfatin as a Novel Marker of Endothelial Dysfunction in Patients with Type 2 Diabetes

Is endocan a biochemical marker for asymptomatic target organ damage in hypertensive patients?

Objective:Identification of the asymptomatic target organ damage (AOD) helps to stratify the overall risk of cardiovascular (CV) diseases and guides a treatment decision in hypertensive patients without a symptomatic CV or renal disease. The endothelial-cell-specific molecule 1 (endocan) is regarded as a novel marker of endothelial dysfunction. Its release is increased in hypertensive patients, especially those with symptomatic CV and renal disease. In the present study, we aimed to evaluate the endocan levels in asymptomatic hypertensive patients with or without AOD.Methods:The study included 132 asymptomatic hypertensive patients, and 101 of who had at least one AOD.Results:Serum endocan levels did not differ between patients with and without AOD (3.81±0.78 vs. 3.83±0.63 ng/mL, p=0.88). An analysis according to the presence of any specific AOD did not show any difference between groups. No significant correlation was found between serum endocan levels and any of the continuous variables related to AOD, such as the pulse pressure, carotid intimae-media thickness, cardio-ankle vascular index, ankle-brachial index, left ventricular mass index, Sokolow–Lyon index, Cornell voltage-duration product, and estimated glomerular filtration rate.Conclusion:Endocan may not serve as a useful biomarker at asymptomatic vascular stages of hypertension, despite its role in indicating disease severity and inflammatory activation in advanced symptomatic CV and renal disease.

Asymmetric Dimethylarginine (Adma): A Novel Marker of Endothelial Dysfunction in Hyperthyroidism

Asymmetric Dimethylarginine (Adma): A Novel Marker of Endothelial Dysfunction in Hyperthyroidism

Increase of endothelial progenitor cells in acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia

IntroductionCirculating endothelial progenitor cells (EPCs; CD31+ CD34brightCD133+ CD45dim cells) are novel markers of endothelial dysfunction and related to inflammatory processes such as acute graft-versus-host disease (aGvHD). Patients and methods47 patients with acute myeloid leukaemia (AML) who were in complete remission as they underwent allogeneic hematopoietic stem cell transplantation with myeloablative conditioning with PBSC as stem cell source were enrolled in the study. Blood samples for the quantitative analysis of circulating EPC levels were drawn at different time points in patients with and without aGvHD. CD34+ VEGFR2/KDR+ CD133+ triple-positive cells identified among CD34+ cells by FACS. EPC were quantified and data are presented as cells/ml whole blood. ResultsCirculating EPC levels were not significantly different in patients with and without aGvHD prior to conditioning (baseline) and at the time of engraftment. However, at diagnosis of aGvHD≥grade 2, EPC levels increased whereas in patients without aGvHD the EPC levels remained significantly lower (3021±278 versus 2322±195 cells/ml; p<0.001). Patients with steroid-refractory aGvHD had high levels of EPC throughout. EPC levels fell in responding patients. ConclusionOur results demonstrate that the number of circulating EPCs is increased in patients with aGvHD compared to patients without aGvHD.

Reduced endothelial progenitor cells in extracranial arterial stenosis but not intracranial arterial stenosis

Endothelial progenitor cells (EPCs) are novel markers of endothelial dysfunction and are related to cardiovascular disease. However, their relationship with cerebral atherosclerosis (CA) has not been investigated extensively. We aim to study the relationship between CA severity and EPC subpopulations levels. We enrolled 197 patients in this study. EPCs were measured by flow cytometry. Digital subtraction angiography was used to assess CA. Arterial lesion severity was evaluated among cerebral arteries which showed steno-occlusion change and the extent of that condition. There was a significant inverse correlation between EPCs level and CA prevalence after adjusting for confounders (CD45(-/dim)CD34(+)CD309(+) cells: odds ratio [OR], 0.110; 95% confidence interval [CI], 0.026-0.475; P = .00; CD45(-/dim)CD133(+)CD309(+) cells: OR, 0.134; 95% CI, 0.030-0.599; P = .01; CD45(-/dim) CD34(+)CD133(+)CD309(+) cells: OR, 0.010; 95% CI, 0.001-0 .541, P = .02). Multivariate logistic regression analysis showed that only the EPCs level was significantly inversely associated with extracranial atherosclerosis rather than intracranial atherosclerosis (P > .05). Our data indicated that EPCs subpopulations were independent predictors for CA severity, even after controlling for traditional risk factors.

Novel markers of endothelial dysfunction and inflammation in Behçet's disease patients with ocular involvement: epicardial fat thickness, carotid intima media thickness, serum ADMA level, and neutrophil-to-lymphocyte ratio.

The etiology of Behçet's disease (BD) has not been fully elucidated. However, immunological and environmental factors, endothelial dysfunction (ED), and genetic susceptibility have been proposed to play a role. In this study, we aimed to evaluate epicardial fat thickness (EFT) together with serum asymmetric dimethylarginine (ADMA), carotid intima media thickness (CIMT), and neutrophil-to-lymphocyte ratio (NLR) in BD patients with ocular involvement. Thirty-six ocular BD patients (17 active and 19 inactive ocular involvement), and 35 age and sex-matched healthy controls were enrolled to this cross-sectional study. All patients underwent examinations with transthoracic echocardiography and carotid Doppler ultrasound. Serum ADMA levels, CIMT, EFT, and NLR were compared between groups, and their association with disease activity was evaluated. Behçet's disease patients had higher WBC counts, neutrophil counts, NLR, CIMT, EFT values, and serum ADMA levels than do healthy controls. The other biochemical, hematological, and echocardiographic parameters were comparable between the two groups. Behçet's disease duration was positively correlated with EFT and CIMT. Multivariate logistic regression analysis revealed that increased serum ADMA concentration and CIMT are independently associated with BD. Neutrophil counts, NLR, and serum ADMA level were higher, and lymphocyte count was lower in patients with active ocular BD compared to those of inactive ocular BD group. Carotid intima media thickness, serum ADMA level, EFT, and NLR were increased in ocular BD patients compared to healthy subjects. In addition, both serum ADMA level and NLR were associated with disease activity of ocular involvement. Increase in disease duration was associated with increase in CIMT and EFT which suggests that anatomical changes occur in time during the disease course. Increased CIMT, serum ADMA level, EFT, and NLR may provide new clues about the role of ED and inflammation in the etiopathogenesis of BD.

Endocan, a novel marker of endothelial dysfunction in patients with essential hypertension: Comparative effects of amlodipine and valsartan

Vascular inflammation plays an important role in the pathophysiology of hypertension and high levels of endocan may reflect ongoing vascular inflammation in hypertensive patients. In the present hypothesis-generating study, we aimed at investigating the comparative effects of amlodipine and valsartan on endocan levels in newly diagnosed hypertensive patients. The study population consisted of 37 untreated hypertensive patients who were randomized to the two treatment arms. After baseline assessment, each patient was randomly allocated to either 10 mg daily of amlodipine (n = 18, 7 males) or 160 mg daily of valsartan (n = 19, 3 males) and treated for a 3-month period. Sphygmomanometric blood pressure (BP) and serum endocan were measured before and every 2 weeks during drug treatment. There was no statistically significant difference between the two treatment arms as far as baseline socio-demographic and clinical characteristics are concerned. After a 3-month treatment period, systolic and diastolic BP values significantly reduced by antihypertensive treatment (p < 0.001). Furthermore, endocan levels were significantly decreased in both treatment arms (p < 0.05). However, amlodipine caused a greater percent decrease in circulating endocan levels compared with valsartan at the end of the treatment period. Both drugs reduced high sensitivity C-reactive protein values. However, the statistical significant difference vs baseline was achieved only in the group treated with amlodipine. No correlation was found between endocan plasma levels and BP reduction. The results of this hypothesis-generating study suggest that amlodipine and valsartan decrease endocan levels in newly diagnosed hypertensive patients. The effects, which are more evident with amlodipine, may contribute to the anti-inflammatory effects exerted by the two drugs on the vascular target.

Serum adiponectin and markers of endothelial dysfunction in stable angina pectoris patients undergoing coronary artery bypass grafting (CABG)

PurposeIt has been established that endothelial dysfunction (ED) occurs after coronary artery bypass grafting (CABG). The aim of the study was to assess whether adiponectin may act as a novel marker of ED and its potential relations with new markers of ED: novel cell adhesion molecule CD146, a natural anti-thrombin glycoprotein – thrombomodulin (TM) and the well-established ED marker – Von Willebrand factor (VWF) in coronary artery disease (CAD) patients undergoing CABG. Material/methods45 CAD patients undergoing elective CABG were included in the study. ResultsIn the study group the concentration of adiponectin and CD146 before the surgery were significantly lower than in the control group – 6.06μg/ml±3.06 vs. 19.0μg/ml±6.4 and 303.2ng/ml±28.7 vs. 328.1ng/ml±22.6 (p<0.05). Significant increase of adiponectin and CD146 concentration 3 months after CABG vs. before the surgery was found. Adiponectin concentration 3 months after CABG correlated with VWF, TM, CD146, and a number of grafts. CD146 before and 3 months after CABG correlated significantly with adiponectin, VWF activity as well as the statins therapy after the surgery. ConclusionsIn CAD patients undergoing CABG new markers of endothelial cell dysfunction as adiponectin and CD146 are significantly lower compared to healthy volunteers. Significant increase in adiponectin and CD146 concentration 3 months after CABG vs. before the surgery was found. However adiponectin concentrations 3 months after CABG were still significantly lower compared to healthy individuals, whereas CD146 concentration returned to the values comparable to the control.

Abstract 3: HDL-MicroRNA-92a and Interleukin-33 Axis Underlies Endothelial Dysfunction Associated With Atherosclerosis and Chronic Kidney Disease

Chronic kidney disease (CKD) is associated with endothelial dysfunction and atherosclerosis. High-density lipoproteins (HDL) serve as a general cargo carrier for a wide-variety of proteins, nucleic acids, and small molecules which likely confer many of HDL’s alternative functions. Human coronary artery endothelial cells (HCAEC) treated with native HDL were found to have increased intracellular levels of miR-92a, a miRNA recently found to protect against endothelial dysfunction and atherosclerosis. Moreover, HDL delivery of miR-92a was inhibited using SR-BI blocking antibodies in endothelial cells. Likewise, aortic endothelial miR-92a levels were found to be significantly decreased (50%) in Apoe-/- mice compared to wild-type controls, which may be a function of the absence of HDL in these mice. Using photoactivatable-ribonucleoside-crosslinked-immunoprecipitation-high-throughput-sequencing, we found that HDL transfer multiple miR-92a isomiR variants from macrophages to HCAECs, which were found in association with Argonaute2 RNA-induced silencing complexes. Using whole-genome arrays, we found that HDL alters the expression of many genes in HCAECs, including the significant down-regulation of 18 putative miR-92a targets. Strikingly, miR-92a was found to be significantly increased 8.5-fold on HDL from CKD subjects. Interleukin-33 (IL-33) is a cytokine and nuclear transcription factor largely expressed in endothelial cells. HDL from both normal and CKD subjects significantly decreased IL-33 expression in HCAECs, as determined by real-time PCR and microarrays. In a mouse model of CKD (Apoe-/-; 5/6 nephrectomy), IL-33 expression was increased in aortic endothelial cells; however, a single HDL injection (4mg) reduced IL-33 mRNA back to sham levels at 7d post-injection. Most interestingly, HDL loaded with locked-nucleic acid miR-92a inhibitors blocked HDL’s ability to suppress CKD induced IL-33 expression in the aortic endothelium. IL-33 may represent a novel marker of endothelial dysfunction, as IL-33 mRNA levels were also found to be increased in HCAECs under disturbed flow conditions. Results from this study suggest that HDL suppression of IL-33 in CKD requires miR-92a, which is also transferred to endothelial cells by HDL.

Cardiovascular Risk and Psoriasis

Psoriasis is a chronic inflammatory disease. Classic manifestations are erythematous patches of skin with periods of exacerbation and remission. The inflammatory process is evidenced by the increase in several markers such as cell adhesion molecules, cytokines, chemokines, and other molecules of the acute phase such as fibrinogen, C-reactive protein (CRP), and serum amyloid A protein. C-reactive protein levels correlate with an increase in potential cardiovascular (CV) risk predictors based on evidence obtained in experimental animals, which have demonstrated a role of toll-like receptor (TLR) type 2 and 4 in the development and progression of atherosclerosis. C-reactive protein promotes endothelial dysfunction by reducing endothelial nitric oxide synthetase expression and activity, reducing prostacyclin release from endothelial cells, increasing plasminogen activator inhibitor 1 expression and activity, endothelin 1 and interleukin 1 release, and by promoting cellular adhesion between endothelial cells and monocytes with increase in the size of atherosclerotic plaques; moreover a novel marker of endothelial dysfunction, endocan, was recently proposed to stratify CV risk in patients with psoriasis, since serum endocan levels correlated with the Psoriasis Area and Severity Index (PASI), CRP, and carotid intima–media thickness. It follows that psoriasis alone, or in combination with other risk factors, may play a role in the development and progression of CV disease but its exact contribution is not clear. Therefore, we performed a search of the literature, selecting the publications that we thought to be of interest. We carried out a systematic search in PubMed and Embase using the keywords ‘‘psoriasis,’’ ‘‘autoimmune disease,’’ ‘‘cardiovascular disease,’’ ‘‘diabetes,’’ ‘‘hypertension,’’ ‘‘high blood pressure,’’ ‘‘dyslipidaemia,’’ ‘‘metabolic syndrome,’’ and ‘‘obesity.’’ We found 231 articles of interest but we selected only 19 as the most representative. Several authors have highlighted the association between coronary heart disease (CHD) and psoriasis. However, there is no single definition of the parameters of severity of the psoriasis or a homogeneity of patient selection in different studies. In 1978, McDonald and Calabresi studied 323 hospitalized patients with psoriasis and showed an association with arterial and venous vascular diseases. Further studies have revealed a correlation between this disease and atherosclerosis, focusing on CHD. The main limitation of these studies was that they could not conclusively define a significant correlation between the 2 conditions mainly because they did not sufficiently take into account the presence of confounding factors, such as the presence of CV risk factors. This correlation, however, was established by Gelfand et al in 2006. Their objective was to ‘‘determine within a population-based cohort if psoriasis is an independent risk factor for acute myocardial infarction (AMI).’’ They studied 130 976 patients with psoriasis of whom 3827 had a severe form (ie, on systemic therapy). Patients were matched with 556 995 controls and followed for a mean of 5.4 years. There was an increased risk of AMI in patients with moderate and severe psoriasis. The authors concluded that psoriasis may be considered as an independent risk factor for AMI. A subsequent study in 2008 examined 2 large US databases and showed an increase in CV risk in patients with mild psoriasis. In 2009, Prodanovich et al in an observational study of 3236 patients with psoriasis reported a higher prevalence of traditional CV risk factors (diabetes mellitus, hypertension, dyslipidemia, and smoking) compared with controls. This association was known from previous studies but the new element was the association of psoriasis with an increased prevalence not only of myocardial ischemia but also of cerebrovascular and peripheral arterial disease. The conclusion was that psoriasis is associated with atherosclerosis. A study published in 2012 compared the severity of psoriasis (PASI score) with coronary flow reserve (CFR). In patients with reduced CFR (<2.5) psoriasis was more severe (higher PASI score). According to the authors in young

Von Willebrand Factor: A Novel Marker of Endothelial Dysfunction in Clinical Hyperthyroidism Patients

Hyperthyroidism is associated with altered endothelial dysfunction and increased risk of arterial thromboembolism and cardiovascular disease. Von Willebrand factor (vWF) is a marker of endothelial dysfunction. There is controversy in reports that have been published concerning the concentrations of vWF in hyperthyroidism. The aim of this study was to investigate the plasma vWF levels in clinical hyperthyroid patients, as well as its relationship to thyroid hormones fT3, fT4 and TSH compared to control subjects. In this study forty recently diagnosed, non-treated clinical hyperthyroid patients (f=37, m=3) and twenty normal volunteers control (f=18, m=2) were included, and subjected to determination of plasma vWF by ELISA technique and serum fT3, fT4 and TSH by Elecsys cobas e 601 analyzer. The data was statistically analysed by SPSS-10 and p values less than 0.05 were considered significant. Our results showed that there were a significant increase of vWF, fT4 and fT3 levels by 100%, 285% and 100%, respectively, and a significant decrease of TSH levels by 12.9-folds in hyperthyroid patients than in control group. For vWF (mean ± SD, 252.2 ± 66.4 vs 126.4 ± 29.9%, repectively; p=0.001). vWF was significantly positively correlated with fT4 and negatively correlated with TSH. In conclusion, we confirmed that hyperthyroidism was associated with increased vWF levels, a novel marker of endothelial dysfunction, FT4 levels being a predictive of vWF levels. Endothelial dysfunction could contribute to higher risk for thromboembolic and cardiovascular disease.