Alexander Jank

Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia

Background— Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. Methods and Results— We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. Conclusions— This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

Angiotensin II Type 1 Receptor Agonistic Antibodies Reflect Fundamental Alterations in the Uteroplacental Vasculature

Abnormal uterine perfusion detected by Doppler sonography reflects impaired trophoblast invasion, a factor involved in the pathogenesis of pregnancy complications such as preeclampsia or intrauterine growth retardation. Recent studies have demonstrated an autoantibody against the angiotensin type 1 (AT1) receptor in pregnant women with preeclampsia. Our aim was to determine whether the AT1 autoantibody precedes the clinical symptoms and is thus predictive of preeclampsia. We therefore detected this antibody in serum from second trimester pregnancies with abnormal uterine perfusion because these women show an indirect sign of inadequate trophoblast invasion. Then the AT1 autoantibody distribution/concentration was compared with that of women at term with or without pregnancy pathology. The AT1 autoantibody was already detectable in second trimester pregnant women with abnormal uterine perfusion before the clinical manifestation of preeclampsia (80%). However, it was also found in second trimester pregnant women with abnormal uterine perfusion who later developed intrauterine growth retardation (60%) or even had a normal course of pregnancy (62%). In the third trimester, the AT1 autoantibody was demonstrated in 89% of patients with manifest preeclampsia, 86% of those with manifest intrauterine growth retardation, and even in healthy pregnant women at term with a history of abnormal uterine perfusion in the second trimester. We conclude that the AT1 autoantibody is an early but nonspecific marker for preeclampsia. The generation of this antibody seems to be associated with distinct types of pregnancy disorders resulting from impaired placental development. The AT1 autoantibody may thus be causative for pathological uteroplacental perfusion.

Serum levels of the adipokine chemerin are increased in preeclampsia during and 6 months after pregnancy.

UNLABELLED Preeclampsia is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, chemerin was introduced as a novel adipokine inducing insulin resistance in vitro and in vivo. In the current study, we investigated serum concentrations of chemerin by ELISA in control and preeclampsia patients during pregnancy ( CONTROL n=37, preeclampsia: n=37) and 6 months after delivery ( CONTROL n=35, preeclampsia: n=36). Furthermore, the association between chemerin and markers of renal function, glucose and lipid metabolism, as well as inflammation was studied in pregnant patients. Median maternal chemerin concentrations were significantly elevated in preeclampsia patients (249.5 [range: 123.1-366.9] μg/l) as compared to controls (204.8 [138.5-280.8] μg/l) (p<0.001). Furthermore, chemerin serum levels positively correlated with blood pressure, creatinine, free fatty acids, cholesterol, triglycerides (TG), leptin, adiponectin, and C-reactive protein in univariate analyses. In multivariate analyses, TG and leptin remained independently associated with circulating chemerin. Interestingly, median chemerin concentrations 6 months after delivery remained significantly higher in former preeclampsia patients (196.0 [119.8-368.7] μg/l) as compared to controls (152.2 [102.8-216.4] μg/l). Taken together, maternal chemerin serum concentrations are significantly increased in preeclampsia during and after pregnancy. Furthermore, TG and leptin are independent predictors of circulating chemerin during pregnancy.

Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia

BACKGROUND Preeclampsia (PE) is a serious cardiovascular complication in pregnancy, which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Fibroblast growth factor (FGF)-21 was recently introduced as a novel adipokine improving glucose metabolism in vitro and in vivo. MATERIAL AND METHODS We investigated serum FGF-21 levels in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of FGF-21 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was elucidated in all individuals. RESULTS Median maternal FGF-21 serum concentrations adjusted for body mass index and gestational age at blood sampling were significantly, almost 3-fold increased in PE patients (309.6 ng/l) as compared to healthy, age-matched pregnant women (105.2 ng/l) (p<0.001). Furthermore, FGF-21 concentrations were independently and positively correlated with triglycerides whereas an independent and negative association was observed with glomerular filtration rate and low density lipoprotein (LDL) cholesterol in pregnant women. Moreover, FGF-21 serum levels significantly decreased in former PE patients 6 months after pregnancy approaching levels found in control patients. CONCLUSIONS Maternal FGF-21 serum concentrations are significantly increased in PE during pregnancy. Furthermore, triglycerides, glomerular filtration rate, and LDL cholesterol are independent predictors of circulating FGF-21 in pregnant women.

Serum levels of growth arrest specific protein 6 are increased in preeclampsia

Preeclampsia (PE) contributes to maternal and fetal morbidity and mortality worldwide. Moreover, it is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, growth arrest specific protein (Gas) 6 has been introduced as a novel metabolic risk factor with anti-angiogenic, pro-atherogenic, and pro-adipogenic properties. In the current study, we investigated serum concentrations of Gas6 in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of Gas6 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was assessed in all individuals. Median maternal Gas6 serum levels adjusted for body mass index and gestational age at blood sampling were significantly increased in PE patients (5.7 μg/l) as compared to healthy, age-matched pregnant women (4.6 μg/l) (p<0.05). Furthermore, Gas6 concentrations positively correlated with blood pressure, creatinine, free fatty acids, C-reactive protein, leptin, and adiponectin during pregnancy. Moreover, leptin and adiponectin remained independently associated with Gas6 levels in multivariate analysis. Gas6 serum levels 6 months after pregnancy were not significantly different between former PE and control patients. Taken together, maternal Gas6 serum concentrations are significantly increased in PE during pregnancy. Furthermore, the adipokines leptin and adiponectin are independent predictors of circulating Gas6 in pregnant women.

Angiotensin II Type 1 Receptor Has Impact on Murine Placentation

Impaired placentation is a key step in the pathogenesis of important pregnancy disorders such as preeclampsia and fetal growth restriction. A role of angiotensin II in placental development can be assumed from the expression of angiotensin receptors on trophoblast from the earliest stages of pregnancy. To understand the role of angiotensin II type 1 (AT1) receptors in placental development, we investigated placentae of AT1a-deficient mice early in pregnancy (day 13 postconception). The number of alive newborns was significantly reduced in AT1a-deficient mice caused by placental malformations in 30% of all utero-placental units. Importantly, no embryonic structure was observable within the uterine segments harboring the malformed placentae. Immunohistochemistry with an antibody against murine betahCG-equivalent stained homogeneously in almost all cells in the altered placentae indicating still an endocrine-active trophoblast. However, the typical structure of the murine wild-type placenta in spongiotrophoblast, giant cells, and labyrinth was abolished in malformed placental tissue deficient in the AT1a receptor. Recent epidemiological studies revealed the detrimental effect of an AT1 blockade for fetal outcome due to renal malformations and a reduced birth weight. For the latter, our findings provide an early mechanistic explanation. The lack in AT1 stimulation causes an impaired trophoblast maturation leading to impaired placental function.

Serum levels of the adipokine zinc-α2-glycoprotein are increased in preeclampsia

Background: Preeclampsia (PE) is associated with facets of the metabolic syndrome and an increased future metabolic and cardiovascular risk for mother and newborn. Recently, zinc-α2-glycoprotein (ZAG) has been proposed as a new adipokine involved in the pathogenesis of obesity. Aim: In the current study, we investigated ZAG serum levels in PE patients as compared to healthy gestational age-matched controls. Subjects and methods: We quantified serum concentrations of ZAG in patients with PE (no.=37) as compared to healthy gestational age-matched controls (no.=37) by enzyme-linked immunosorbent assay. Furthermore, association of this adipokine with renal function, glucose and lipid metabolism, as well as inflammation was studied. Results: Median serum ZAG levels were 1.4-fold higher in PE patients (58.8 mg/l) as compared to controls (41.9 mg/l) (p<0.01). Furthermore, circulating ZAG was positively correlated to systolic and diastolic blood pressure, creatinine, triglycerides, and leptin in univariate analyses. In multiple regression analysis, creatinine remained independently associated with ZAG. Conclusions: We demonstrate that maternal ZAG serum concentrations are significantly increased in PE. Furthermore, renal function is an independent predictor of circulating ZAG.

Relation between maternal angiogenic factors and utero-placental resistance in normal first- and second-trimester pregnancies.

Objective. Soluble endoglin (sEng) is a novel antiangiogenic protein and elevated sEng concentrations in maternal circulation are closely related to preeclampsia and HELLP syndrome. As the perfusion of the uterine arteries as well as the dynamics of angiogenic factors between first and second trimester have prognostic value regarding pregnancy outcome, it was the aim of this study to investigate the relation between maternal angiogenic factors and uterine Doppler parameters. Study design. The longitudinal study includes 50 normal pregnancies. Pulsatility index (PI) of the uterine arteries was detected by Doppler ultrasound in first and second trimester. In parallel, maternal sEng and soluble fms-like tyrosine kinase 1 (sFlt1) concentration was measured using ELISA. Results. In the first trimester, the sEng concentrations were 4.92 ± 1.36 ng/mL and the uterine PI was 1.14 ± 0.28. In the second trimester, the maternal sEng concentration decreased significantly to 3.99 ± 0.63 ng/mL (p < 0.05) which was associated by a decrease of the uterine PI to 0.78 ± 0.15 (p < 0.001). Soluble fms-like tyrosine kinase 1 concentrations did not differ significantly between first and second trimester (423 ± 333 vs. 444 ± 291 pg/mL). There was a significant negative correlation between sEng and uterine resistance in the second trimester (r = −0.416; p < 0.001). Conclusions. In normal pregnancy, parallel to the fall of utero-placental resistance, there is a physiological decline of the maternal sEng concentration between first and second trimester. In second trimester, there is a negative correlation between sEng and uterine Doppler parameters.

Effect of Terminated Fetal Circulation on Maternal Angiogenic Factors in Severe Early Preeclampsia

Background. Although intrauterine presence of the placenta is essential in the etiology of preeclampsia (PE), case reports showed that the viability of the fetus influences the clinical course of PE and the intensity of the clinical symptoms. Aim. We examined the course of angiogenic factors soluble fms-like tyrosine kinase-1 receptors (sFlt-1) and placental growth factor (PlGF) in a case of severe early PE in week 22 + 1 of gestation, when fetal termination was required to stabilize maternal condition. Results. The cessation of the feto-placental perfusion via fetocide led to a reduction of the maternal sFlt-1 concentration of 8.3% which was associated with a decline of the sFlt-1/PlGF ratio from 405 to 334. Nevertheless, the highest change of the angiogenic factors was detected after ejection of the fetus and placenta. Conclusions. Our observations implicate that neither a vital fetus nor an intact feto-placental component is an obligatory prerequisite for the angiogenic imbalance that is associated with the preeclamptic phenotype.

Effect of steroids on angiogenic factors in pregnant women with HELLP syndrome

No abstract available