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Background: Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source of these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels., Objective: We describe placental growth factor, soluble Fms-like tyrosine kinase 1, soluble endoglin, and endothelin 1-3 in 5 vessels in healthy pregnancies, early- and late-onset preeclampsia. Specifically, we aimed to (1) compare protein abundance in vessels at the maternal-fetal interface between early- and late-onset preeclampsia, and healthy pregnancies, (2) describe placental uptake and release of proteins, and (3) describe protein abundance in the maternal vs fetal circulations., Study Design: Samples were collected from the maternal radial artery, uterine vein and antecubital vein, and fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 early-onset preeclampsia and 18 late-onset preeclampsia), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray-based SomaScan assay quantified the proteins., Results: The abundance of soluble Fms-like tyrosine kinase 1 and endothelin 1 was higher in the maternal vessels in preeclampsia than in healthy pregnancies, with the highest abundance in early-onset preeclampsia. Placental growth factor was lower in the maternal vessels in early-onset preeclampsia than in both healthy and late-onset preeclampsia. Maternal endothelin 2 was higher in preeclampsia, with late-onset preeclampsia having the highest abundance. Our model confirmed placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 to the maternal circulation in all groups. The placenta released soluble Fms-like tyrosine kinase 1 into the fetal circulation in healthy and late-onset preeclampsia pregnancies. Fetal endothelin 1 and soluble Fms-like tyrosine kinase 1 were higher in early-onset preeclampsia, whereas soluble endoglin and endothelin 3 were lower in both preeclampsia groups than healthy controls. Across groups, abundances of placental growth factor, soluble Fms-like tyrosine kinase 1, and endothelin 3 were higher in the maternal artery than the fetal umbilical vein, whereas endothelin 2 was lower., Conclusion: An increasing abundance of maternal soluble Fms-like tyrosine kinase 1 and endothelin 1 across the groups healthy, late-onset preeclampsia and early-onset combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated endothelin 1 in the fetal circulation in early-onset preeclampsia represents a novel finding. The long-term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins' involvement in the pathophysiology and as treatment targets is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: Idiopathic restrictive cardiomyopathy (RCM) has a low incidence. This study aimed to determine the prognostic value of big endothelin-1 (ET-1) in idiopathic RCM., Materials and Methods: We prospectively enrolled patients with idiopathic RCM from 2009 to 2017 and followed them up. The primary outcome was a composite of all-cause mortality and cardiac transplantation, and the secondary outcome was a composite of cardiac death and cardiac transplantation., Results: Ninety-one patients were divided into the high big ET-1 (>0.85 pmol/L, n = 56) and low big ET-1 (≤0.85 pmol/L, n = 35) groups, and 87 of them completed the follow-up. Big ET-1 concentrations (hazard ratio: 1.756, 95 % confidence interval [CI]: 1.117-2.760) and late gadolinium enhancement (LGE) (hazard ratio: 3.851, 95 % CI: 1.238-11.981) were independent risk factors for the primary outcome. Big ET-1 concentrations (C-statistic estimation: 0.764, 95 % CI: 0.657-0.871) and the combination of LGE and big ET-1 concentrations (C-statistic estimation: 0.870, 95 % CI: 0.769-0.970) could accurately predict the 5-year transplant-free survival rate, and 0.85 pmol/L was a suitable cutoff for big ET-1., Conclusion: Big ET-1 and its combination with LGE may be useful to predict an adverse prognosis in patients with idiopathic RCM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Eugenol has various curative properties. It affects the dilatation of cerebral arteries through voltage-dependent Ca2+ channel inhibition. This study is the first to explore the impact of eugenol on neuroprotection and vasospasm in an experimental subarachnoid hemorrhage (SAH) model., Methods: Twenty-four adult male Sprague-Dawley rats were indiscriminately separated into 3 groups: the control group (n = 8), the SAH group (n = 8), and the eugenol group (n = 8). A double-bleeding method was used. The eugenol group received intracisternal eugenol (Sigma-Aldrich, St. Louis, MO, USA) at 30 μg/20 μl after induction of SAH. On the day 7, all groups were euthanized. Measurements were taken for basilar artery wall thickness, lumen diameter, serum endothelin-1 (ET-1), and caspase-3 levels., Results: The eugenol group exhibited significantly lower wall thickness, ET-1, oxidative stress index, and caspase-3 levels compared to the SAH group. In comparison to the control group, the eugenol group showed a higher oxidative stress index along with higher ET-1 and caspase-3 levels, but these differences were not statistically significant. Wall thickness was significantly higher in the eugenol group than in the control group., Conclusions: This study represents the first literature exploration of intrathecal eugenol's impact on vasospasm induced after experimental SAH. Administration of intrathecal eugenol demonstrates a positive effect on the treatment of experimental vasospasm as well as on the reduction of oxidative stress and apoptosis., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate the possible link between different types of systemic sclerosis-specific antinuclear antibodies, adipokines and endothelial molecules which were recently found to have a pathogenic significance in systemic sclerosis., Materials/methods: Serum concentration of adiponectin, resistin, leptin, endothelin-1, fractalkine and galectin-3 were determined in the sera of patients with systemic sclerosis (n ​= ​100) and healthy controls (n ​= ​20) using ELISA., Results: The following associations between antinuclear antibodies and increased serum concentrations were identified: anticentromere antibodies with endothelin-1 (p ​< ​0.0001; mean level in patients 2.21 vs control group 1.31 ​pg/ml), anti-topoisomerase I antibodies with fractalkine (p ​< ​0.0001; 3.68 vs 1.68 ​ng/ml) and galectin-3 (p ​= ​0.0010, 6.39 vs 3.26 ​ng/ml). Anti-RNA polymerase III antibodies were associated with increased resistin (p ​< ​0.0001; 15.13 vs 8.54 ​ng/ml) and decreased adiponectin (p ​< ​0.0001; 2894 vs 8847 ​ng/ml)., Conclusion: In systemic sclerosis metabolic and vascular factors may serve as mediators between immunological abnormalities and non-immune driven clinical symptoms., Competing Interests: Declarations of competing interest The authors declare no conflict of interests., (Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: The evaluation of the patent ductus arteriosus (PDA) in the very premature neonate is a challenge. Echocardiography provides an interpretation of the hemodynamic condition. It is however, only a snapshot. Biomarkers may represent a physiological response to the hemodynamic alterations brought on by the PDA and may add to the identification of the clinical significant PDA., Aim: To investigate the association between mid regional proadrenomodulin (MR-proADM), N-terminal pro b-type natriuretic peptide (NT-proBNP), mid regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro endothelin-1 (CT-proET1) and copeptin and echocardiographic measures of PDA., Study Design: Cohort study with echocardiography performed on day 3 and 6. Blood samples from day 3., Subject: 139 consecutive neonates born at a gestational age <32 weeks., Outcome Measures: The main outcomes were presence of a PDA day 3 and 6, PDA diameter, left atrium to aorta ratio (LA:Ao-ratio), and descending aorta diastolic flow (DADF)., Results: Adjusted plasma levels of all investigated biomarkers, except CT-proET1, were found to be associated with both PDA diameter and LA:Ao-ratio, and also the presence of a large PDA. CT-proET1 and copeptin was found to be associated with abnormal DADF. Using pre-specified cut-off values NT-proBNP and MR-proANP day 3 seemed to be of value in identifying a large PDA day 3 and 6 in very preterm neonates., Conclusion: Among the investigated biomarkers NT-proBNP and MR-proANP performed best in relation to echocardiographic markers of PDA severity in very preterm neonates., Competing Interests: Declaration of competing interest The authors of this manuscript have none., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Neuromyelitis optica spectrum disorders (NMOSD) are aquaporin-4 antibody-mediated diseases of the central nervous system. Endothelin-1 (ET-1) is an inflammatory cytokine released by vascular endothelial cells and activated astrocytes. Previous studies have reported the aberrant expressions of cytokines/chemokines in patients diagnosed with NMOSD. However, the serum levels of ET-1 in NMOSD patients remain unknown. The purpose of this study was to measure the serum levels of ET-1 and other immune-related cytokines/chemokines in patients with NMOSD, and to investigate the correlation between serum ET-1 levels and clinical characteristics of NMOSD., Methods: Thirty-eight patients with NMOSD and twenty-eight healthy controls (HCs) were recruited in this study. The serum concentrations of ET-1 and other cytokines/chemokines were measured, and their correlations to the clinical features of patients with NMOSD were analyzed., Results: The serum levels of ET-1 in patients with NMOSD were significantly higher than those in HCs (P =  0.0001). The serum concentrations of ET-1 were positively correlated with the Expanded Disability Status Scale score (r = 0.428, P = 0.0183). High-dose intravenous methylprednisolone treatment significantly reduced the levels of ET-1 and interleukin (IL)-6 in blood, but significantly increased the serum concentrations of IL-10 in NMOSD patients. No correlations were found between serum ET-1 levels and the concentrations of other cytokines/chemokines in these patients., Conclusion: ET-1 and IL-6 might exert pro-inflammatory effects in the pathogenesis of NMOSD, whereas IL-10 played an anti-inflammatory role in this process. ET-1 might be a potential biomarker for predicting the severity of NMOSD. However, the serum levels of ET-1 were not correlated with the changes of other cytokines/chemokines in patients with NMOSD. The involvement of ET-1 in the development of NMOSD needs to be further studied., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier GmbH.)

Background: Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured., Methods and Results: ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors., Conclusions: These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3'-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Endothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE)., Methods: Thirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years., Results: Plasma ET-1 levels correlated with IMR (r = 0.57; p < 0.01) and ADM levels correlated with CFR (r = 0.50; p = 0.04) and cFMD (r = 0.62; p = 0.01). After adjustment for age, gender and cardiovascular risk factors, the association between ADM and cFMD (β = 0.79; p < 0.01) and between ET-1 and IMR (β = 5.7; p = 0.01) remained significant. IMR was higher, although not statistically significant, in patients with long-term MACE (17.9 ± 5.3 vs. 13.1 ± 6.0 units; p = 0.14). In patients free of MACE, cFMD (9.3 ± 7.6 vs. 2.8 ± 5.0%; p = 0.01) and plasma ADM levels (7.6 ± 5.3 vs. 4.0 ± 1.9 pmol/L; p = 0.07) were higher., Conclusions: Plasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recently, advanced maternal age (AMA) has been increasing due to late marriage and assisted reproductive technology. AMA is high-risk pregnancy associated with the life-threatening diseases such as hypertensive disorders of pregnancy (HDP). Recently we have reported novel AMA model mice using aged spontaneous pregnant mice, and found that the phenotypes of AMA model mice reflect the same characteristics as human AMA. We have also demonstrated that atypical angiogenic factors profiles including soluble VEGF-R1 (sFlt-1) and placental growth factor in both AMA pregnant women and AMA model mice. VEGF-endothelin-1 system have been also known as one of HDP-associated factors, however, there has been few reports on the relation between VEGF-endothelin-1 system and AMA. In this study, we investigated the profiles of VEGF-endothelin-1 system using our model mice's samples. As a result, VEGF and endothelin-1 levels were not significantly different between AMA and young individuals. Our results indicated that the mechanisms of hypertension in AMA may differ from those in young individuals from the point of VEGF-endothelin-1 system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report results of the studies relating to the fabrication of a surface plasmon resonance (SPR) based label-free immunosensor for real-time monitoring of endothelin-1 (ET-1), a colon cancer biomarker. A gold disk modified with a self-assembled monolayer (SAM) of 11-mercaptoundecanoic acid (11-MUA) was functionalised via covalent immobilization of monoclonal anti-ET-1 antibodies using EDC-NHS (1-(3-(dimethylamine)-propyl)-3-ethylcarbodiimide hydrochloride, N-hydroxy succinimide) chemistry. This immunosensing platform (ethanolamine/anti-ET-1/11-MUA/Au) was characterized via atomic force microscopy (AFM), contact angle (CA) and Fourier transform infrared (FT-IR) spectroscopic techniques. The fabricated SPR electrode was further used to detect ET-1 in the broad concentration range 2-100 pg mL -1 , with a detection limit of 0.30 pg mL -1 and remarkable sensitivity of 2.18 m o pg -1 mL. The adsorption mechanism was studied using monophasic model and the values of association (k a ) and dissociation (k d ) constants for anti-ET-1 and ET-1 binding were calculated to be 4.4 ± 0.4 × 10 5  M -1  s -1 and 2.04 ± 0.0003 × 10 -3 s -1 , respectively. The results obtained via analysis of serum samples of colorectal cancer patients were found to be in good agreement with those obtained from enzyme-linked immunosorbent assay (ELISA) technique. Further, electrochemical studies were performed to prove the efficacy of the fabricated platform as a point of care device for the detection of ET-1., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Obesity and insulin resistance are positively correlated with plasma endothelin-1 (ET-1) levels; however, the mechanisms leading to increased ET-1 are not understood. Similarly, the full physiological complexity of ET-1 has yet to be described, especially in obesity. To date, one of the best treatments available for morbid obesity is bariatric surgery to quickly reduce body fat and the factors associated with obesity-related disease; however, the effects of vertical sleeve gastrectomy (SG) on plasma ET-1 have not been described., Objectives: To determine if SG will reduce plasma ET-1 levels and to determine if plasma ET-1 concentration is associated with weight loss after surgery., Setting: The studies were undertaken at a University Hospital., Methods: This was tested by measuring plasma ET-1 levels from 12 obese patients before and after SG. All data were collected from clinic visits before SG, 6 weeks after SG, and 6 months after surgery., Results: At 6 weeks after SG, plasma ET-1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared with presurgery. Average weight loss in this cohort was 11.3% ± 2.4% body weight after 6 weeks and 21.4% ± 5.7% body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET-1 and percent body weight loss (R 2 = .49, P = .01) and change in body mass index 6 months (R 2 = .45, P = .011) post bariatric surgery., Conclusions: Our results indicate that SG reduces plasma ET-1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET-1 may serve as a predictor of weight loss after bariatric surgery., (Copyright © 2019. Published by Elsevier Inc.)

Angiotensin II type 1 receptor autoantibodies (AT1-AA) cause endothelial-dependent smooth muscle relaxation disorder. It is well understood that impairment of the NO-cGMP signaling pathway is one of the mechanisms of endothelial-dependent smooth muscle relaxation disorder. However, it is still unclear whether AT1-AA induces endothelial-dependent smooth muscle relaxation disorder via the impairment of the NO-cGMP signaling pathway. In addition, adiponectin exerts vascular endothelial protection through the NO-cGMP signaling pathway. Therefore, the purpose of this investigation was to assess the mechanism of vascular endothelial-dependent smooth muscle relaxation disorder induced by AT1-AA and the role of adiponectin in attenuating this dysregulation. Serum endothelin-1 (ET-1), adiponectin and AT1-AA were detected by enzyme-linked immunosorbent assay. In preeclamptic patients, there was an increased level of AT1-AA, which was positively correlated with ET-1 and negatively correlated with adiponectin, as elevated levels of ET-1 suggested endothelial injury. AT1-AA-positive animal models were actively immunized with the second extracellular loop of the angiotensin II type 1 receptor (AT1R-ECII) for eight weeks. In thoracic aortas of AT1-AA positive rats, ET-1 was elevated, endothelium-dependent vasodilation was decreased. Paradoxically, as the upstream element of the NO-cGMP signaling pathway, NO production was not decreased but increased, and the ratio of p-VASP/VASP, an established biochemical endpoint of NO-cGMP signaling pathway, was reduced. Moreover, the levels of nitrotyrosine and gp91phox which indicate the presence of peroxynitrite (ONOO - ) and superoxide anion (O 2 · - ) were increased. Pretreatment with the ONOO - scavenger FeTMPyP or O 2 · - scavenger Tempol normalized vasorelaxation. Key enzymes responsible for NO synthesis were also assessed. iNOS protein expression was increased, but p-eNOS(Ser1177)/eNOS was reduced. Preincubation with the iNOS inhibitor 1400 W or eNOS agonist nebivolol restored vasorelaxation. Further experiments showed levels of p-AMPKα (Thr172)/AMPKα, which controls iNOS expression and eNOS activity, to have been reduced. Furthermore, levels of the upstream component of AMPK, adiponectin, was reduced in sera of AT1-AA positive rats and supplementation of adiponectin significantly decreased ET-1 contents, improved endothelial-dependent vasodilation, reduced NO production, elevated p-VASP/VASP, inhibited protein expression of nitrotyrosine and gp91phox, reduced iNOS overexpression, and increased eNOS phosphorylation at Ser1177 in the thoracic aorta of AT1-AA positive rats. These results established that impairment NO-cGMP pathway may aggravate the endothelial-dependent smooth muscle relaxation disorder in AT1-AA positive rats and adiponectin improved endothelial-dependent smooth muscle relaxation disorder by enhancing NO-cGMP pathway. This discovery may shed a novel light on clinical treatment of vascular diseases associated with AT1-AA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study investigated effects of grape consumption on biomarkers of cardiovascular health in obese participants in both postprandial and chronic settings. Twenty obese adults participated in this randomized, placebo controlled, double-blinded crossover trial. Participants were randomized to consume 60 g freeze-dried polyphenol-rich whole grape powder (GP) or placebo (PBO) followed by high fat high carbohydrate (HFHC) meal challenge. Following acute challenge, participants consumed their respective treatment daily for 4 weeks to determine effects of chronic consumption. Consumption of GP with HFHC meal significantly increased nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression in peripheral blood mononuclear cells (PBMC) at 3 h (p < 0.05) and decreased plasma endothelin-1 (ET-1) concentration at 5 h (p < 0.05) after meal challenge compared with PBO. Following 4 weeks of daily GP consumption, soluble vascular cell adhesion molecule 1 (sVCAM-1) plasma concentration increased compared with PBO (p < 0.05), however baseline values differed between treatments. In conclusion, GP consumption resulted in decreased vasoconstrictor ET-1 concentration and increased gene expression related to oxidative stress defense following HFHC meal. Except for increase in sVCAM-1 concentration, 4 weeks of chronic GP consumption had little effect on cardiovascular biomarkers measured in this study. This trial was registered: clinicaltrials.gov NCT01674231., (Copyright © 2018. Published by Elsevier Inc.)

Background and Aims: The prognostic role of big endothelin-1 (ET-1) in atrial fibrillation (AF) is unclear. We aimed to assess its predictive value in patients with AF., Methods: A total of 716 AF patients were enrolled and divided into two groups based on the optimal cut-off value of big ET-1 in predicting all-cause mortality. The primary outcomes were all-cause mortality and major adverse events (MAEs). Cox regression analysis and net reclassification improvement (NRI) analysis were performed to assess the predictive value of big ET-1 on outcomes., Results: With the optimal cut-off value of 0.55 pmol/L, 326 patients were classified into the high big ET-1 levels group. Cardiac dysfunction and left atrial dilation were factors related to high big ET-1 levels. During a median follow-up of 3 years, patients with big ET-1 ≥ 0.55 pmol/L had notably higher risk of all-cause death (44.8% vs. 11.5%, p < 0.001), MAEs (51.8% vs. 17.4%, p < 0.001), cardiovascular death, major bleeding, and tended to have higher thromboembolic risk. After adjusting for confounding factors, high big ET-1 level was an independent predictor of all-cause mortality (hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.46-3.05; p < 0.001), MAEs (HR 2.05, 95% CI 1.50-2.80; p = 0.001), and cardiovascular death (HR 2.44, 95% CI 1.52-3.93; p < 0.001). NRI analysis showed that big ET-1 allowed a significant improvement of 0.32 in the accuracy of predicting the risk of both all-cause mortality and MAEs., Conclusions: Elevated big ET-1 levels is an independent predictor of long-term all-cause mortality, MAEs, and cardiovascular death in patients with AF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Hemodialysis (HD) patients have altered pulmonary function and this is associated with impaired endothelial function and cardiovascular events. Respiratory muscle training (RMT) has the potential to improve cardiovascular outcomes in patients undergoing maintenance HD. Here, we evaluated the effects of RMT on endothelium/glycocalyx, oxidative stress biomarkers and pulmonary function test in HD patients., Methods: This is a randomized controlled clinical trial including 41 patients undergoing thrice-weekly maintenance HD. Patients were randomly assigned at a 2:1 ratio to receive or not RMT during HD sessions for 8 weeks. Main outcomes were changes in levels of the biomarkers related to endothelium activation (vascular cell adhesion molecule 1, VCAM-1, and intercellular adhesion molecule 1, ICAM-1), glycocalyx derangement (syndecan-1), aberrant angiogenesis (angiopoietin-2) and oxidative stress (malondialdehyde) compared to baseline. Also, maximal inspiratory/expiratory pressure (MIP, MEP), Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were evaluated. Other outcomes included changes in functional capacity and pulmonary function test. We also performed a post-hoc analysis of plasma endothelin-1 levels., Results: Of 56 randomly assigned patients, 41 were included in the primary final analyses. RMT increased all pulmonary function parameters evaluated and significantly reduced plasma syndecan-1 levels at 8 weeks compared to placebo (between-group difference: -84.5; 95% CI, -148.1 to -20.9). Also, there was a reduction in plasma levels of angiopoietin-2 (between-group difference: -0.48; 95% CI, -1.03 to -0.097). Moreover, there was a significant reduction in mean blood pressure at rest (between-group difference: -12.2; 95%CI, -17.8 to -6.6) associated with a reduction in endothelin-1 levels (between-group difference: -0.164; 95% CI, -0.293 to -0.034). There was no difference regarding biomarkers of endothelial activation or oxidative stress., Conclusion: A short-term RMT program ameliorate FVC, FEV1 and reduces syndecan-1 and angiopoietin-2 biomarker levels. Finally, better blood pressure control was attained during training and it was associated with a reduction in endothelin-1 levels., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, or non-hereditary, chronic demyelinating neuropathy. Currently, there is no reliable molecular biomarker that can identify CIDP patients as well as monitor disease severity., Material and Methods: We measured serum levels of endothelin-1 (ET-1), a factors involved in vasoconstrictive, inflammatory and nerve regenerative processes, in 20 CIDP, 21 acute inflammatory demyelinating polyneuropathy (AIDP), 37 multiple sclerosis (MS), and 10 Alzheimer's disease (AD) patients, as well as 26 healthy control (HC) subjects., Results: Patients with CIDP demonstrated higher serum levels of ET-1 (2.07±1.07pg/mL) than those with AIDP (0.75±0.62ng/mL, P<0.001), AD (0.78±0.49pg/mL, P<0.001), as well as HCs (1.16±0.63pg/mL, P=0.002), while levels of ET-1 in patients with MS (2.10±0.81pg/mL) and CIDP were similar. Furthermore, the serum ET-1 levels significantly correlated with Inflammatory Neuropathy Cause And Treatment (INCAT) disability scale in CIDP patients. Receiver operating characteristic (ROC) curve showed good discrimination ability for ET-1 to distinguish CIDP patients from AIDP (AUC=0.883) or HCs (AUC=0.763)., Conclusion: This study discloses the potential of serum ET-1 as a biomarker for CIDP., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Cardiac remodeling is one of major pathological process in hypertrophic cardiomyopathy (HCM). Endothelin-1 has been linked to cardiac remodeling. Big endothelin-1 is the precursor of endothelin-1., Methods: A total of 245 patients with HCM were enrolled from 1999 to 2011 and partitioned to low, middle and high level groups according to their plasma big endothelin-1 levels., Results: At baseline, significant associations were found between high level of big endothelin-1 and left atrium size, heart function and atrial fibrillation. Big endothelin-1 was positively correlated with N-terminal B-type natriuretic peptide (r=0.291, p<0.001) and late gadolinium enhancement (LGE) on magnetic resonance imaging (r=0.222, p=0.016). During a follow-up of 3 (range, 2-5) years, big endothelin-1 level was positively associated with the risks of all-cause mortality, cardiovascular death and progression to NYHA class 3 or 4 (p=0.020, 0.044 and 0.032, respectively). The rate of above events in the highest tertile were 18.1%, 15.7%, 24.2%, respectively. After adjusting for multiple factors related to survival and cardiac function, the significance remained in the association of big endothelin-1 with the risk of all-cause mortality (hazard ratio (HR)=4.94, 95% confidence interval (CI) 1.07-22.88; p=0.041) and progression to NYHA class 3 or 4 (HR=4.10, 95%CI 1.32-12.75, p=0.015)., Conclusion: Our study showed that high level of plasma big endothelin-1 predicted prognosis for patients with HCM and it can be added to the marker panel in stratifying HCM patients for giving treatment priority to those at high risk., (Copyright © 2017. Published by Elsevier B.V.)

Objective: Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI., Methods: In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients., Results: When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint)., Conclusions: Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies., Key Messages: In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Essential thrombocythemia (ET) patients are at risk of developing thrombotic events. Qualitative platelet (PLT) abnormalities and activation of endothelial cells (ECs) and PLTs are thought to be involved. Microparticles (MPs) can originate from PLTs (PMPs), ECs (EMPs), or red cells (RMPs). Previous studies have indicated that MPs contribute to ET pathophysiology. Endothelial modulators (eg, nitric oxide [NO], adrenomedullin [ADM], and endothelin-1 [ET-1]) are also involved in the pathophysiology of this condition. We hypothesized that treatments for reducing PLT count might also indirectly affect MP generation and endothelial activity by altering endothelial modulator production. The rationale of this study was that hydroxyurea (HU), a cytostatic drug largely used in ET, induces the production of a potent vasoactive agent NO in ECs. An observational retrospective study was designed to investigate the relationship between MPs, NO, ADM, and ET-1 in ET patients on treatment with HU, anagrelide (ANA), aspirin (ASA), and a group of patients before treatment. A total of 63 patients with ET diagnosis: 18 on HU + ASA, 15 on ANA + ASA, 19 on ASA only, and 11 untreated patients, and 18 healthy controls were included in this study. Blood samples were analyzed for MP (absolute total values) and functional markers (percentage values) by flow cytometry. PLT-derived MPs were studied using CD61, CD62P, CD36, and CD63, whereas endothelial-derived MPs were studied using CD105, CD62E, and CD144. Endothelial modulator markers (NO, ADM, and ET-1) were measured by ELISA. Total MP count was higher in the group treated with ANA + ASA (P < 0.01). MP markers modified in ET patients returned to levels of healthy controls following treatment, in particular, in patients on ANA treatment. NO and ADM values were higher in the HU group (P < 0.001). HU and ANA treatment also affected MP production in a cell origin-specific manner. HU and ANA, although acting via different pathways, have similar final effects. For instance, HU causes vasodilatation by increasing NO and ADM levels, whereas ANA impairs vasoconstriction by reducing ET-1. In conclusion, therapy with HU cytostatic drugs and ANA can reduce PLT count in ET, and also affect endothelial modulatory agents, with HU sustaining vasodilation and prothrombotic MP concentration, whereas ANA decreases vasoconstriction., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Big endothelin-1 (ET-1) has been proposed as a novel prognostic indicator of acute coronary syndrome, while its predicting role of cardiovascular outcomes in patients with stable coronary artery disease (CAD) is unclear., Methods and Results: A total of 3154 consecutive patients with stable CAD were enrolled and followed up for 24months. The outcomes included all-cause death, non-fatal myocardial infarction, stroke and unplanned revascularization (percutaneous coronary intervention and coronary artery bypass grafting). Baseline big ET-1 was measured using sandwich enzyme immunoassay method. Cox proportional hazard regression analysis and Kaplan-Meier analysis were used to evaluate the prognostic value of big ET-1 on cardiovascular outcomes. One hundred and eighty-nine (5.99%) events occurred during follow-up. Patients were divided into two groups: events group (n=189) and non-events group (n=2965). The results indicated that the events group had higher levels of big ET-1 compared to non-events group. Multivariable Cox proportional hazard regression analysis showed that big ET-1 was positively and statistically correlated with clinical outcomes (Hazard Ratio: 1.656, 95% confidence interval: 1.099-2.496, p=0.016). Additionally, the Kaplan-Meier analysis revealed that patients with higher big ET-1 presented lower event-free survival (p=0.016)., Conclusions: The present study firstly suggests that big ET-1 is an independent risk marker of cardiovascular outcomes in patients with stable CAD. And more studies are needed to confirm our findings., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The morbidity and mortality associated with preeclampsia is staggering. The physiology of the Page kidney, a condition in which increased intrarenal pressure causes hypertension, appears to provide a unifying framework to explain the complex pathophysiology. Page kidney hypertension is renin-mediated acutely and ischemia-mediated chronically. Renal venous outflow obstruction also causes a Page kidney phenomenon, providing a hypothesis for the increased vulnerability of a subset of women who have what we are hypothesizing is a "renal compartment syndrome" due to inadequate ipsilateral collateral renal venous circulation consistent with well-known variation in normal venous anatomy. Dynamic changes in renal venous anatomy and physiology in pregnancy appear to correlate with disease onset, severity, and recurrence. Since maternal recumbent position is well known to affect renal perfusion and since chronic outflow obstruction makes women vulnerable to the ischemic/inflammatory sequelae, heightened awareness of renal compartment syndrome physiology is critical. The anatomic and physiologic insights provide immediate strategies to predict and prevent preeclampsia with straightforward, low-cost interventions that make renewed global advocacy for pregnant women a realistic goal., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: The development of pulmonary hypertension (PH) and its effect on long-term survival in bronchiectasis subjects has not been explored. The present study aims to analyze the factors associated with PH and its effect on long-term survival in bronchiectasis subjects., Methods: We prospectively evaluated 23 bronchiectasis subjects without PH and 16 with PH, as well as 20 healthy volunteers., Results: Bronchiectasis subjects with PH were more hypoxemic and had a greater number of involved lobes in high resolution computed tomography (HRCT) than did the bronchiectasis subjects without PH (P < 0.001 and P < 0.001, respectively). At three years, the survival rate was 95.7% for bronchiectasis subjects without PH and 56.3% for bronchiectasis with PH, and at 5 years, these rates were 95.7% and 62.5%, respectively (P = 0.002). Multivariate Cox regression analysis revealed that only the Medical Research Council (MRC) dyspnea score was independently related to poor survival in all bronchiectasis subjects (hazard ratio: 6.98; 95% CI: 2.41-20.23; P < 0.00001)., Conclusions: Subjects with PH are more hypoxemic and have a greater number of involvements in the lobes of the lungs. Bronchiectasis subjects with PH have worse survival than do bronchiectasis subjects without PH. MRC dyspnea score is an independent predictor of long-term survival., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: The anti-hyperglycemic agent linagliptin, a dipeptidyl peptidase-4 inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral blood flow in diabetic rats through improved insulin-induced cerebrovascular relaxation and reversal of pathological cerebrovascular remodeling that subsequently leads to improvement of cognitive function., Main Methods: Male type-2 diabetic Goto-Kakizaki (GK) and nondiabetic Wistar rats were treated with linagliptin, and ET-1 plasma levels and dose response curves to ET-1 (0.1-100nM) in basilar arteries were assessed. The impact of TLR2 antagonism on ET-1 mediated basilar contraction and endothelium-dependent relaxation to acetylcholine (ACh, 1nM-1M) in diabetic GK rats was examined with antibody directed against the TLR2 receptor (Santa Cruz, 5μg/mL). The expression of TLR2 in middle cerebral arteries (MCAs) from treated rats and in brain microvascular endothelial cells (BMVEC) treated with 100nM linagliptin was assessed., Key Findings: Linagliptin lowered plasma ET-1 levels in diabetes, and reduced ET-1-induced vascular contraction. TLR2 antagonism in diabetic basilar arteries reduced ET-1-mediated cerebrovascular dysfunction and improved endothelium-dependent vasorelaxation. Linagliptin treatment in the BMVEC was able to reduce TLR2 expression in cells from both diabetic and nondiabetic rats., Conclusions: These results suggest that inhibition of DPPIV using linagliptin improves the ET-1-mediated cerebrovascular dysfunction observed in diabetes through a reduction in ET-1 plasma levels and reduced cerebrovascular hyperreactivity. This effect is potentially a result of linagliptin causing a decrease in endothelial TLR2 expression and a subsequent increase in NO bioavailability., Competing Interests: Authors declare no conflict of interest. Conflict of Interest Statement Boehringer Ingelheim Pharmaceuticals, Inc. provided both the linagliptin and financial support for the study., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: This study aims to investigate the association of exposure to ambient air pollution during pregnancy with cord blood concentrations of surrogate markers of endothelial dysfunction., Methods: This population-based cohort was conducted from March 2014 to March 2015 among 250 mother-neonate pairs in urban areas of Isfahan, the second large and air-polluted city in Iran. We analyzed the association between the ambient carbon monoxide (CO), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particular matter 10 (PM10), and air quality index (AQI) with cord blood levels of endothelin-1, vascular adhesion molecule (VCAM), and intercellular adhesion molecule (ICAM). Multiple regression analysis was conducted after adjustment for potential confounding factors and covariates. The regression coefficient (beta), standard error of the estimate (SE), and 95% confidence intervals for each regression coefficient (95% CI) are reported., Results: Data of 233 mother-neonate pairs were complete, and included in the analysis. Multiple regression analyses showed that AQI, CO and O3 had significant correlation with cord blood ICAM-1 [Beta (SE), 95%CI: 2.93 (0.72), 1.33,5.54; 2.28(1.44), 1.56,5.12; and 2.02(0.01), 1.03,2.04, respectively] as well as with VCAM-1 [2.78(0.91), 1.69,4.57; 2.47(1.47), 1.43,5.37; and 2.01(0.01),1.07,2.04, respectively]. AQI, PM10, and SO2 were significantly associated with Endothelin-1 concentrations [Beta (SE), 95%CI: 10.16(5.08),7.61,14.28; 9.70(3.46), 2.88,16.52; and 1.07(0.02), 1.03,2.11, respectively]., Conclusions: The significant associations of air pollutants with markers of endothelial dysfunction during fetal period may provide another evidence on the adverse health effects of air pollutants on early stages of atherosclerosis from fetal period. Our findings underscore the importance of considering environmental factors in primordial prevention of chronic diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Elevated levels of aldosterone are a modifiable contributor to clinical worsening in heart failure with reduced ejection fraction (HFrEF). Endothelin-1 (ET-1), which is increased in HFrEF, induces pulmonary endothelial aldosterone synthesis in vitro. However, whether transpulmonary aldosterone release occurs in humans or aldosterone relates to functional capacity in HFrEF is not known. Therefore, we aimed to characterize ET-1 and transpulmonary aldosterone levels in HFrEF and determine if aldosterone levels relate to peak volume of oxygen uptake (pVO2)., Methods: Data from 42 consecutive HFrEF patients and 18 controls referred for invasive cardiopulmonary exercise testing were analyzed retrospectively., Results: Radial ET-1 levels (median [interquartile range]) were higher in HFrEF patients compared with controls (17.5 [11.5-31.4] vs 11.5 [4.4-19.0] pg/ml, p = 0.04). A significant ET-1 transpulmonary gradient (pulmonary arterial [PA] - radial arterial levels) was present in HFrEF (p < 0.001) but not in controls (p = 0.24). Compared with controls, aldosterone levels (median [interquartile range]) were increased in HFrEF patients in the PA (364 [250-489] vs 581 [400-914] ng/dl, p < 0.01) and radial compartments (366 [273-466] vs 702 [443-1223] ng/dl, p < 0.001). Akin to ET-1, a transpulmonary increase (median [interquartile range]) in aldosterone concentration was also observed between controls and HFrEF patients at rest (7.5 [-54 to 40] vs 61.6 [-13.6 to 165] ng/dl, p = 0.01) and peak exercise (-20.7 [-39.6 to 79.1] vs 25.8 [-29.2 to 109.3] ng/dl, p = 0.02). The adjusted pVO2 correlated inversely with aldosterone levels at peak activity in the PA (r = -0.31, p = 0.01) and radial artery (r = -0.32, p = 0.01)., Conclusions: These data provide preliminary evidence in support of increased transpulmonary aldosterone levels in HFrEF and suggest an inverse relationship between circulating aldosterone and pVO2. Future prospective studies are needed to characterize the functional effects of transpulmonary and circulating aldosterone on cardiac reserve capacity in HFrEF., (Published by Elsevier Inc.)

In newborn babies, endothelin 1 (ET-1), a potent vasoconstrictor, increases during septicemia and severe respiratory syndromes. Because equine neonatal sepsis (ENS) and perinatal asphyxia syndrome (PAS) are major causes of morbidity and mortality in newborn foals and because no information on the concentration of ET-1 in healthy and sick foals has been reported yet, the aims of this study were (1) to define the serum concentration of Big ET-1 in healthy neonatal foals during the first week of age; (2) to preliminarily explore the diagnostic and prognostic role of Big ET-1 during ENS and PAS. Six healthy and 23 sick foals affected by ENS and/or PAS were enrolled in the study. In healthy foals, Big ET-1 concentration increased in the first hours of life until 24 hours after birth, and it remained constant during the first 3 days, then gradually decreased becoming significantly lower from Day 4 onward (P < 0.05). In sick foals, only 26.1% of animals showed higher values of Big ET-1 than controls at admission, and no difference between surviving and nonsurviving foals was found. Because in nonsurviving foals, Big ET-1 remained over the maximum value recorded in clinically healthy horses or, when normal at admission, increased over time; this study suggested that repeated measurement of Big ET-1 during hospitalization may be helpful in monitoring the course of the disease. In conclusion, possible prognostic information may be obtained by repeated analysis of Big ET-1 during hospitalization, but further studies are needed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations., Methods and Results: The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: -0.30 pg/mL, 95%CI: -0.47, -0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD: -0.51 pg/mL, 95%CI: -0.89, -0.14, p < 0.01; >12 week -WMD: -0.19 pg/mL, 95%CI: -0.36, -0.02; p < 0.05) or by dose of statins (<40 mg/day - WMD: -0.27 pg/mL, 95%CI: -0.49, -0.05; p = 0.01; >40 mg/day - WMD: -0.38 pg/mL, 95%CI: -0.68, -0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD: -0.34 pg/mL, 95%CI: -0.55, -0.13; p < 0.01), but not a hydrophilic statin (pravastatin - WMD: -0.18 pg/mL, 95%CI: -0.44 -0.08; p > 0.05) had a significant effect in promoting ET-1 reduction., Conclusions: Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Neprilysin inhibitors prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. Here we studied the effects of a low and a high dose of the neprilysin inhibitor thiorphan on top of AT1 receptor blockade with irbesartan versus vehicle in TGR(mREN2)27 rats with high renin hypertension. Mean arterial blood pressure was unaffected by vehicle or thiorphan alone. Irbesartan lowered blood pressure, but after 7 days pressure started to increase again. Low- but not high-dose thiorphan prevented this rise. Only during exposure to low-dose thiorphan plus irbesartan did heart weight/body weight ratio, cardiac atrial natriuretic peptide expression, and myocyte size decrease significantly. Circulating endothelin-1 was not affected by low-dose thiorphan with or without irbesartan, but increased after treatment with high-dose thiorphan plus irbesartan. This endothelin-1 rise was accompanied by an increase in renal sodium-hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. Consequently, the endothelin type B receptor antagonist BQ788 no longer enhanced endothelin-1-induced vasoconstriction (indicative of endothelin type B receptor-mediated vasodilation), but prevented it. Thus, optimal neprilysin inhibitor dosing reveals additional cardioprotective effects on top of AT1 receptor blockade in renin-dependent hypertension.

Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea)., Objective: We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health., Design: Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function., Results: Epicatechin supplementation did not change flow-mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (Δ insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (Δ homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors., Conclusions: Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at clinicaltrials.gov as NCT01691404., (© 2015 American Society for Nutrition.)

Objectives: Endothelial dysfunction is a major precursor of atherosclerosis. The aim of this study was to assess the interrelationships between plasma endothelin-1 (ET-1) levels and cardiovascular risk among young and healthy individuals., Methods: We performed a population-based study among 2160 healthy adults aged between 25 and 41 years in the Principality of Liechtenstein. Individuals with prevalent cardiovascular disease, diabetes or a body mass index >35 kg/m(2) were excluded. Plasma ET-1 was measured using a novel high-sensitive, single-molecule counting technology. The relationships between plasma levels of ET-1 and various cardiovascular risk factors were assessed by multivariable regression analyses., Results: Median age of our population was 37 years. Median ET-1 levels across ET-1 quartiles were 1.86, 2.33, 2.76 and 3.48 pg/mL. After multivariable adjustment, there were significant correlations of ET-1 with systolic blood pressure (β per 1-unit increase in log transformed ET-1 2.30 (95% confidence interval (CI) 1.03; 3.58, p = 0.0004), C-reactive protein (β 0.19 (95% CI 0.03; 0.34, p = 0.021), glomerular filtration rate (β -1.73 (95% CI -3.17; -0.29, p = 0.019), and current smoking (Odds ratio 1.94 (95% CI 1.39; 2.71, p < 0.0001). We also found a highly significant association between ET-1 levels and overall cardiovascular risk estimated by the "Prospective Cardiovascular Münster" (PROCAM) and the Framingham score (β 0.18 (95% CI 0.06; 0.31, p = 0.004, and β 0.11 (95% CI 0.05; 0.16), p < 0.0001, respectively)., Conclusions: Plasma ET-1 levels are easily measurable in healthy adults and correlate with major cardiovascular risk factors and global cardiovascular risk., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Endothelin-1 (ET-1) is a mediator of various physiological and pathological processes, including vascular inflammation, cell proliferation and vasoconstriction. Attenuation of ET action using ET-1 antagonists reduces pulmonary vascular leakage and inflammation in several models of lung injuries and experimental acute respiratory distress syndrome (ARDS). Based on these earlier reports, the current study investigates the patterns of ET-1 levels in circulation and pulmonary tissues in an experimental model of lavage-induced surfactant-depleted lung injury. Additionally, we also test the effects of open endotracheal suctioning (OES) and hyperinflation (HI) as recruitment maneuver following OES on ET-1 levels., Main Methods: Briefly, 24 Japanese white rabbits were anesthetized and intubated. Normal saline was instilled into the lung and washed mildly. After instillation, rabbits were ventilated at definite settings at a total duration of 3 hours. OES and HI were performed every 15 minutes from the beginning of the protocol., Key Findings: Here, we show that both circulatory and pulmonary ET-1 levels increased in models with lung injury induced by saline lavage compared to healthy control group. No further aggravation in expression of pulmonary ET-1 was seen after OES and HI, although OES and HI worsened arterial hypoxygenation and severity of lung injury. In contrast, circulatory ET-1 levels significantly decreased after OES and HI but were not associated with blood pressure changes., Significance: We conclude that in a saline lavage-induced lung injury model, both circulatory and pulmonary ET-1 levels increased. Further, OES and HI exerted differential effects on ET-1 expression at both circulatory and pulmonary levels., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Many studies of human subjects have demonstrated the utility of assessing serum levels of endothelin-1 (ET-1) and big ET-1 as clinical biomarkers in cardiopulmonary and neoplastic diseases. In this study we explored the feasibility of using serum big ET-1 as a reliable veterinary marker in dogs with various cardiopulmonary and neoplastic diseases., Main Methods: Serum big ET-1 levels were measured by ELISA in dogs with cardiopulmonary (n=21) and neoplastic diseases (n=57). Dogs exhibiting cardiopulmonary disease were divided into two groups based on the velocity of tricuspid valve regurgitation (3.0>m/s) measured by ultrasound: without and with pulmonary hypertension. Big ET-1 levels for the dogs with the diseases were compared with levels in normal healthy dogs (n=17)., Key Findings: Dogs with cardiopulmonary disease (4.6±4.6 pmol/l) showed a significantly (P<0.01) higher level of big ET-1 than healthy control dogs (1.1±0.53 pmol/l). Serum levels in the dogs with pulmonary hypertension (6.2±5.3 pmol/l) were significantly (P<0.01) higher than those without pulmonary hypertension (2.0±0.6 pmol/l). Dogs with hemangiosarcoma (5.6±2.2 pmol/l), adenocarcinoma (2.0±1.8 pmol/l), histiocytic sarcoma (3.3±1.9 pmol/l), chondrosarcoma or osteosarcoma (3.0±1.6 pmol/l) and hepatocellular carcinoma (2.7±1.8 pmol/l) showed significantly (P<0.05) higher levels than healthy control dogs., Significance: These findings point to the potential of serum big ET-1 as a clinical marker for cardiopulmonary and neoplastic diseases in dogs., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Landiolol hydrochloride, an ultra-short-acting highly cardio-selective β-1 blocker, has become useful for various medical problems. Recent studies have demonstrated that co-treatment with landiolol protects against acute lung injury and cardiac dysfunction in rats of lipopolysaccharide (LPS)-induced systemic inflammation, and was also associated with a significant reduction in serum levels of the inflammation mediator HMGB-1 and histological lung damage. Endothelin (ET)-1, a potent vasoconstrictor, has been implicated in pathogenesis of sepsis and sepsis-induced multiple organ dysfunction syndrome. Here, we investigated whether landiolol hydrochloride can play important roles in ameliorating LPS-induced alterations in cardiac ET system of septic rats., Main Methods: Eight-week-old male Wistar rats were administered LPS only for 3 h and the rest were treated with LPS as well as with landiolol non-stop for 3 h., Key Findings: At 3 h after LPS (only) administration, circulatory tumor necrosis factor (TNF)-α level, blood lactate concentration and percentage of fractional shortening of heart were significantly increased. In addition, LPS induced a significant expression of various components of cardiac ET-1 system compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized LPS-induced blood lactate levels and cardiac functional compensatory events, without altering levels of plasma TNF-α and ET-1. Most strikingly, landiolol treatment significantly normalized various components of cardiac ET-1 signaling system in septic rat., Significance: Taken together, these data led us to conclude that landiolol may be cardio-protective in septic rats by normalizing the expression of cardiac vasoactive peptide such as ET, without altering the circulatory levels of inflammatory cytokines., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: To assess the relationship between both photoreceptor function and choroidal thickness and endothelin-1 (ET-1) plasma levels in patients with early stage retinitis pigmentosa (RP)., Main Methods: We compared 24 RP patients (14 males and 10 females), 25 to 42 years of age (mean age: 34±7 years) with 24 healthy controls (12 males and 12 females) aged between 28 and 45 years (mean 36±6.8 years). All patients underwent visual field test, electroretinogram and multifocal-electroretinogram and choroidal thickness measurement by using spectral domain optical coherence tomography., Key Findings: RP patients had a visual acuity of 0.95, a mean defect of the visual field of -7.90±1.75 dB, a pattern standard deviation index of 6.09±4.22 dB and a b-wave ERG amplitude of 45.08±8.24 μV. Notably RP subjects showed significantly increased ET-1 plasma levels and reduced choroidal thickness compared with controls: respectively, 2.143±0.258 pg/ml vs. 1.219±0.236 pg/ml; p<0.002 and 226.75±76.37 μm vs. 303.9±39.87 μm; p<0.03. Spearman's correlation test highlighted that the increase of ET-1 plasma levels was related with the decrease of choroidal thickness (r=-0.702; p<0.023) and the increase of implicit time in both ring 2 (r=-0.669; p<0.034) and ring 3 (r=-0.883; p<0.007) of mfERG., Significance: Increased ET-1 plasma levels may play a key role in the impairment of retinal and choroidal blood flow due to the vasoconstriction induced by ET-1. This could lead to worsening of the abiotrophic process of the macular photoreceptors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it., Main Methods: Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed., Key Findings: Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group., Significance: We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

We hypothesised that consumption of flavanol-containing apple puree would modulate platelet activity and increase nitric oxide metabolite status, and that high flavanol apple puree would exert a greater effect than low flavanol apple puree. 25 subjects consumed 230 g of apple puree containing 25 and 100mg epicatechin (low and high flavanol apple puree, respectively) and aspirin (75 mg) in random order. Measurements were made at baseline, acutely after treatment (2, 6 and 24 h), and after 14 d of treatment. Low flavanol apple puree significantly attenuated ADP and epinephrine-induced integrin-β3 expression 2 h and 6 h after consumption and ADP and epinephrine-induced P-selectin expression within 2h of consumption. High flavanol apple puree attenuated epinephrine and ADP-induced integrin-β3 expression after 2 and 6h. ADP and epinephrine-induced integrin-β3 expression was significantly attenuated 2, 6 and 24 h after consumption of aspirin, whilst 14 d aspirin consumption attenuated collagen-induced P-selectin expression only. The plasma total nitric oxide metabolite conc. was significantly increased 6h after consumption of both low and high flavanol apple purees. In conclusion, consumption of apple purees containing ⩾25 or 100 mg flavanols transiently attenuated ex vivo integrin-β3 and P-selectin expression and increased plasma nitric oxide metabolite conc. in healthy subjects, but the effect was not enhanced for the high flavanol apple puree., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Aims: Increased potassium intake is related to reduced blood pressure (BP) and reduced stroke rate. The effect of increased dietary potassium on endothelial function remains unknown. The aim was to determine the effect of increased dietary potassium from fruit and vegetables on endothelial function., Methods and Results: Thirty five healthy men and women (age 32 ± 12 y) successfully completed a randomised cross-over study of 2 × 6 day diets either high or low in potassium. Flow mediated dilatation (FMD), BP, pulse wave velocity (PWV), augmentation index (AI) and a fasting blood sample for analysis of Intercellular Adhesion Molecule-1 (ICAM-1), E-selectin, asymmetric dimethylarginine (ADMA) and endothelin-1 were taken on completion of each intervention. Dietary change was achieved by including bananas and potatoes in the high potassium and apples and rice/pasta in the low potassium diet. Dietary adherence was assessed using 6 day weighed food diaries and a 24 h urine sample. The difference in potassium excretion between the two diets was 48 ± 32 mmol/d (P = 0.000). Fasting FMD was significantly improved by 0.6% ± 1.5% following the high compared to the low potassium diet (P = 0.03). There were no significant differences in BP, PWV, AI, ICAM-1, ADMA or endothelin-1 between the interventions. There was a significant reduction in E-selectin following the high (Median = 5.96 ng/ml) vs the low potassium diet (Median = 6.24 ng/ml), z = -2.49, P = 0.013., Conclusion: Increased dietary potassium from fruit and vegetables improves FMD within 1 week in healthy men and women but the mechanisms for this effect remain unclear., Clinical Trial Registry: ACTRN12612000822886., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The diagnostic and prognostic appraisal of patent ductus arteriosus (PDA) in preterm infants is still debatable., Aims: To compare plasma cardiovascular biomarkers with echocardiographic indices alongside ductus arteriosus (DA) evolution in very preterm infants within the first week of life., Methods: Mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) levels were prospectively measured on the second and sixth days of life (DOL) in 52 preterm infants born before 32weeks of gestation. Echocardiographic indices to define DA patency and significance were simultaneously obtained. Logistic regression and receiver operating characteristics (ROC) analyses were used to assess and quantify the biomarkers' diagnostic capacities., Results: Thirty infants exhibited PDA on DOL 2; in 21 of these infants, DA was characterized as hemodynamically significant. Treatment failure after a first course of indomethacin was noted in 8 infants (DOL 6), whereas 7 participants underwent later surgical ligation. The diagnostic accuracy of cardiovascular biomarkers was moderate on DOL 2 but high on DOL 6. PDA was the only significant predictor of MR-proANP levels on DOL 6, independent of the effect of clinical confounders (regression coefficient 0.426, R(2) 0.60). Infants with MR-proANP ≥850pmol/l on DOL 2 had 3.9-fold higher risk (95% CI 1.01 to 14.5) of being diagnosed with significant DA, whereas infants with MR-proANP ≥700pmol/l on DOL 6 had 7.1-fold higher risk (1.9 to 27.2) for pharmaceutical treatment failure., Conclusion: The cardiovascular plasma biomarker MR-proANP is a promising candidate for monitoring PDA evolution in very preterm infants., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We hypothesized that chronic specific endothelin-A (ET-A) receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs, and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed tomography. All pigs with renovascular disease were divided such that seven were untreated, seven were treated with ET-A blockers, and five were treated with ET-B blockers. Four weeks later, all pigs were restudied in vivo, and then killed and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. Renal blood flow, glomerular filtration rate, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation, and fibrosis in the stenotic kidney. These effects were functionally consequential as ET-A blockade improved single kidney microvascular endothelial function, renal blood flow, and glomerular filtration rate, and decreased albuminuria.

Objectives: To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM)., Subjects and Methods: In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively., Results: Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure., Conclusions: Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim: It is unclear if a modest reduction in dietary salt intake has beneficial effects on vascular function. The aim was to compare the effects of 9 g salt/day with 6 g salt/day intake on measures of vascular function and explore mechanisms of effect in overweight and obese adults., Methods: Twenty-five overweight/obese subjects (BMI 27-40 kg/m(2)) completed a randomised cross-over study of 6 weeks each on a reduced salt (RS) (6 g/day) and usual salt diet (US) (9 g/day). Flow-mediated-dilatation (FMD), 24 h blood pressure (BP), augmentation index (AIx), pulse wave velocity (PWV), plasma and urinary nitrate/nitrite, asymmetric dimethylarginine (ADMA), renin, aldosterone and endothelin-1 and vascular adhesion molecules were measured after 2 days and 6 weeks. Adherence to the diets was determined from two 24 h urine collections., Results: Urinary sodium excretion was 155 ± 58 mmol/24 h US vs 113 ± 45 mmol/24 h RS (p = 0.002). Following the RS diet there was a significant improvement in FMD from 3.5 ± 2.8% to 5.6 ± 2.8% (P < 0.001) and decrease in serum endothelin-1 from 1.45 ± 0.38 pg/ml to 1.25 ± 0.39 pg/ml (P < 0.05). Endothelium-independent vasodilatation was also significantly different between treatments (P < 0.05). AIx, PWV, serum ADMA and plasma and urinary nitrate/nitrite concentrations were not different between treatments. Change in FMD was related to the urinary sodium: creatinine ratio (r = -0.47, P < 0.05) and was independent of blood pressure. Aldosterone and renin were unchanged., Conclusions: A small reduction in dietary salt intake of 3 g/day improves endothelial function in normotensive overweight and obese subjects. This response may be mediated by serum endothelin-1. This small reduction in salt had no effect on aldosterone and renin concentrations. This trial was registered with the Australian and New Zealand Clinical Trials Registry Unique Identifier: ACTRN12609000321246 http://www.anzctr.org.au/ACTRN12609000321246.aspx., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Endothelial dysfunction plays a major role in cardiovascular diseases, including acute myocardial infarction (AMI). However, its quantification has not been available as a clinical tool., Methods: In a prospective international multicentre study, we analyzed the diagnostic and prognostic utility of endothelial dysfunction as quantified by C-terminal proendothelin-1 (CT-proET-1) in 658 consecutive patients presenting with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long-term for mortality., Results: The adjudicated final diagnosis was AMI in 145 patients (22%). The diagnostic performance of CT-proET-1 for AMI was moderate; its area under the receiver operating characteristic (ROC) curve amounted to 0.66 (95% confidence interval [CI], 0.61-0.72; P < 0.001). There was no significant increase in the AUC when CT-proET-1 was added to either cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT). Seventy four percent of patients who died during the first 24 months (n = 50) were in the fourth quartile of the CT-proET-1 presentation value (>82 pmol/L). The prognostic accuracy of CT-proET-1 regarding mortality was tantamount to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outperformed cTnT and hs-cTnT both in patients with AMI and in patients without acute coronary syndrome. CT-proET-1 at presentation yielded high prognostic accuracy that was similar to that of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score could be significantly improved by adding CT-proET-1 (integrated discriminatory improvement [IDI] of 0.074 P = 0.004)., Conclusions: Use of CT-proET-1 improves risk stratification of unselected patients with suspected AMI. CT-proET-1 did not provide additional diagnostic value., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH., Methods: Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality., Results: Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6)., Conclusions: CT-proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Endothelin-1 (ET-1) and circulating hormones play important roles in maintaining cardiovascular function. Tai Chi Chuan (TCC) is known to be good for health. This study evaluated the effect of 3 months of TCC training on serum ET-1, blood lipids, and other circulating hormones in the elderly. Twenty-two TCC trainees and 20 normal subjects were included in this study. The TCC trainees practiced classical Yang's TCC 40 min per session, 7 times per week, for 3 months. The hemodynamics and serum ET-1 and lipids before and after TCC were compared. The percentage change in serum ET-1 and triglyceride (TG) were decreased significantly after 3 months of TCC, as compared to the control group. In the TCC group, the percentage decrease in serum ET-1 and TG after 3 months of TCC were -36.6 (-63.4 to -14.0)% and -22.5 (-30.7 to 4.9)%, respectively. TCC exercise for 3 months can reduce serum ET-1 and TG in the elderly., (Copyright © 2013 Elsevier Ltd. All rights reserved.)