endothelin-1 and HELLP-Syndrome

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational

Topics: Animals; Antibodies, Neutralizing; Disease Models, Animal; Endothelin-1; Fas Ligand Protein; Female; HELLP Syndrome; Immunoglobulin G; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1

To evaluate the performance of a combination of angiogenic and vasoactive biomarkers to predict the development of severe pre-eclampsia (PE)/HELLP syndrome in the third trimester.. Included were 215 women referred in the third trimester to an obstetric outpatient clinic with suspected PE (mean gestational age, 35 + 4 weeks), and 94 with normal pregnancy attending a midwife clinic. Cases were categorized as having subclinical PE, essential hypertension, gestational hypertension, moderate PE, and severe PE/HELLP syndrome. Blood samples were analyzed by immunoassay and groups were compared with respect to potential clinical and biochemical biomarkers, with the primary outcome being development of severe PE/HELLP syndrome within 1 week and within 2 weeks of analysis. The most promising markers were also assessed in combination.. In the patients presenting with mild to moderate symptoms of PE, the individual markers which performed best for the prediction of progression to severe PE/HELLP syndrome within 1 week and within 2 weeks of biomarker evaluation were C-terminal pro-endothelin-1 (CT-pro-ET-1) (area under the receiver-operating characteristics curve (AUC), 0.82 and 0.78, respectively), soluble fms-like tyrosine kinase-1 (sFlt-1) (AUC, 0.81 and 0.76), systolic blood pressure (AUC, 0.80 and 0.68) and midregional pro-atrial natriuretic peptide (AUC, 0.79 and 0.77). The combination of biomarkers with the best performance was CT-pro-ET-1, sFlt-1 and systolic blood pressure, achieving an AUC of 0.94 for prediction of development of severe PE/HELLP syndrome within 1 week and an AUC of 0.83 for prediction of their development within 2 weeks of biomarker evaluation.. The performance of CT-pro-ET-1 for prediction of the development of PE/HELLP syndrome in the third trimester was promising, especially in combination with sFlt-1 and systolic blood pressure. This was an exploratory study and our findings should be confirmed in further studies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Topics: Adult; Biomarkers; Blood Pressure; Endothelin-1; False Negative Reactions; Female; HELLP Syndrome; Humans; Peptide Fragments; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, Third; Prenatal Diagnosis; ROC Curve; Vascular Endothelial Growth Factor Receptor-1

HELLP syndrome remains a leading cause of maternal and neonatal mortality and morbidity worldwide, which symptoms include hemolysis, elevated liver enzymes and low platelet count. The objective of this study was to determine whether HELLP is associated with AT1-AA. The positive rate and titer of AT1-AA in plasma from pregnant women were determined, and the correlation of AT1-AA titer with the grade of HELLP was analyzed. A HELLP rat model established by intravenous injection of AT1-AA. Our experimental results show the AT1-AA titer and positive rate were significantly higher in HELLP group, and AT1-AA titer were positively correlated with the level of TNF-α and ET-1 in plasma and the grade of HELLP syndrome. The results of animal experiments showed that the typical features of HELLP in the pregnant rats after AT1-AA injection. The levels of TNF-α and ET-1 in plasma and liver tissue were significantly increased in AT1-AA-treated rats compared with control rats. The HELLP syndrome induced by AT1-AA was attenuated markedly after administration of losartan. These data support the hypothesis that one the potential pathway that AT1-AA induce damage to capillary endothelial cells and liver during pregnancy is through activation of TNF-α and ET-1.

Topics: Adult; Animals; Autoantibodies; Biomarkers; Case-Control Studies; Disease Models, Animal; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; HELLP Syndrome; Hepatocytes; Humans; Liver; Membrane Potential, Mitochondrial; Middle Aged; Pregnancy; Rats; Receptor, Angiotensin, Type 1; Tumor Necrosis Factor-alpha; Young Adult

Women with hypertensive forms of pregnancy such as hemolysis-elevated liver enzymes-low platelet syndrome have increased circulating endothelin 1; however, the relationship between hypertension and endothelin 1 has not been studied. Using an animal model, we sought to determine whether there was an increased activation/dysfunction of endothelin 1, the effect of endothelin 1 receptor-A blockade on hypertension and other manifestations of hemolysis, elevated liver enzymes, and low platelets syndrome. On gestational day 12, timed-pregnant rats were infused with soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEndoglin; 4.7 and 7 µg/kg) via mini-osmotic pumps for 8 days. A subset of rats were treated with receptor-A antagonist (ABT-627, 5mg/kg) for 8 days. Rats with hemolysis-elevated liver enzymes-low platelet syndrome had significantly increased hypertension (P = .0001), circulating endothelin 1 (P = .03), and a significant 3.3- and 7.2-fold increase in preproendothelin messenger RNA (mRNA) expression in the placenta and liver (P = .01 and .04). Urinary protein:creatinine ratio was significantly increased in these animals (P = .0007), and circulating factors from these rats stimulated a significant increase in endothelial cell secretion of endothelin 1 (P = .001) in an in vitro assay. Blockade of the endothelin 1 receptor A significantly decreased hypertension (P = .001), circulating endothelin 1, and interleukin 17 (P = .004 and .003), placental preproendothelin mRNA expression (P = .016), and urinary protein:creatinine ratio (P = .007) in rats with hemolysis-elevated liver enzymes-low platelet syndrome. Blockade of the endothelin 1 receptor A significantly decreased hemolysis (P = .009), liver enzymes (P = .011), and significantly increased platelet levels (P = .03) and decreased circulating CD4+ and CD8+ T lymphocytes (P = .0004 and .0001) in rats infused with sFlt-1 and sEndoglin. These data support the hypothesis that endothelin 1 activation has a critical role in pathophysiology of as hemolysis-elevated liver enzymes-low platelet syndrome.

Topics: Animals; Atrasentan; Disease Models, Animal; Endoglin; Endothelin-1; Female; HELLP Syndrome; Hypertension; Placenta; Pregnancy; Pyrrolidines; Rats; Vascular Endothelial Growth Factor Receptor-1

We aimed to compare the serum levels of ET-1, M30, and Angs-1 and -2 in patients with preeclampsia or HELLP syndrome, and normal controls.. In this cross-sectional study of 74 pregnant women, serum levels of ET-1, M30, and Angs-1 and -2 were measured in preeclamptic patients with or without HELLP syndrome. 74 pregnant women; 37 had healthy pregnancies, 25 had preeclampsia (PE), and 12 had HELLP syndrome.. The age, body mass index, gravidity, and parity of patients with normal pregnancy, PE, and HELLP syndrome were comparable (p > 0.05). In HELLP syndrome, compared to healthy or preeclamptic pregnancies, platelet count was lower (p < 0.05) and the values of hepatic function tests were higher (p < 0.05). In HELLP syndrome, ET-1, M30, and Ang-2 were higher compared to healthy or preeclamptic pregnancies (p < 0.05); however, they increased in preeclamptic pregnancies compared to healthy pregnancies though not significant (p > 0.05). In PE or HELLP syndrome, Ang-1 was higher compared to a healthy pregnancy (p < 0.05); however, in HELLP syndrome, it was also higher than in PE though not significant (p > 0.05). We found no significant correlation among these biomarkers and hematological and biochemical parameters (p > 0.05).. For the diagnosis of HELLP syndrome, increased levels of ET-1, M30, and Angs-1 and -2 appear as promising biomarkers after determination of their standardized threshold levels after further studies. As an apoptosis-related biomarker, serum M30 level has a merit to be the most promising test for prediction or differential diagnosis of HELLP syndrome in PE patients.

Topics: Adult; Angiopoietin-1; Angiopoietin-2; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Fetal Blood; Gravidity; HELLP Syndrome; Humans; Keratin-18; Parity; Peptide Fragments; Pre-Eclampsia; Pregnancy; Pregnant Women

To compare maternal and umbilical venous big endothelin (big ET) and endothelin-1 (ET-1) levels of pregnancies complicated by severe preeclampsia (PE) or HELLP-syndrome to those of a well-matched normotensive pregnant control group.. We measured plasma levels of ET-1 and big ET in 16 patients with severe PE and 14 patients with HELLP-syndrome by commercially available RIAs and compared them with those of well-matched normotensive pregnant controls. Additionally, the umbilical venous ET-1 and big ET levels were determined in 10 corresponding newborns.. The plasma concentrations of ET-1 and big ET were significantly higher in patients with severe PE and especially in women with HELLP-syndrome when-compared with controls. The molar ratios of big ET to ET-1 were significantly lower in the two study groups. The levels of ET-1 and big ET were higher in umbilical venous plasma than in maternal plasma, but there were no significant differences in the umbilical venous concentrations between normotensive and by severe PE or HELLP-syndrome complicated pregnancies.. These findings suggest that ET-1 may be considered as a marker of endothelial injury in by severe preeclampsia or HELLP-syndrome complicated pregnancies. The increase of the ET-1 plasma levels may be due, at least in part, to changes in the conversion of big ET to ET-1 by the endothelin-converting enzyme.

Topics: Adult; Endothelin-1; Endothelins; Female; Fetal Blood; HELLP Syndrome; Humans; Immunoenzyme Techniques; Maternal Age; Pre-Eclampsia; Pregnancy; Pregnancy, High-Risk; Protein Precursors; Sensitivity and Specificity