Higher sFlt-1 Research Articles

Lead exposure and association with angiogenic factors and hypertensive disorders of pregnancy.

Lead exposure has been associated with hypertensive disorders of pregnancy. Angiogenic factors, including soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF), are aberrant in preeclampsia, but have not been correlated with lead levels. We evaluated the association of lead exposure with angiogenic factors. This cross sectional study utilized a convenience sample of singleton pregnancies ≥34weeks' gestation. Blood lead and angiogenic factors were measured before delivery; bone lead was measured postpartum. We dichotomized bone and blood lead into the top tertile versus the bottom tertiles and used log-binomial regression to assess the association between lead and a high angiogenic ratio. The outcomes were high sFlt1 to PlGF ratio and development of a hypertensive disorder of pregnancy. We enrolled 102 participants, of whom 98 had at least one lead measurement and an angiogenic factor result. Median bone lead was 3.8 ug/g (2.0 - 6.6) and median blood lead was 0.2 ug/dL (0.2 - 0.4). Incidence of hypertensive disorders of pregnancy was 31%. When comparing the highest tertile of bone lead to the bottom two tertiles, there was no association with a high sFlt1/PlGF ratio or hypertensive disorders of pregnancy. Similar results were observed for the exposure of blood lead. Lead exposure was not an important contributor to an elevated angiogenic factor ratio or hypertensive disorders of pregnancy in our U.S. However, lead exposure was modest in our population and we cannot exclude a relationship with hypertensive disorders of pregnancy.

MZe786 Rescues Cardiac Mitochondrial Activity in High sFlt-1 and Low HO-1 Environment.

Hypertensive disorder in pregnancy is a major cause of maternal and perinatal mortality worldwide. Women who have had preeclampsia are at three to four times higher risk in later life of developing high blood pressure and heart disease. Soluble Flt-1 (sFlt-1) is elevated in preeclampsia and may remain high postpartum in women with a history of preeclampsia. Heme oxygenase-1 (Hmox1/HO-1) exerts protective effects against oxidative stimuli and is compromised in the placenta of pregnant women with preeclampsia. We hypothesized that sFlt-1 inhibits cardiac mitochondrial activity in HO-1 deficient mice. HO-1 haplo-insufficient mice (Hmox1+/−) were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) or control virus (Ad-CMV). Subsequently, they were treated daily with either placebo or MZe786 for six days, when the heart tissue was harvested to assess cardiac mitochondrial activity. Here, we show that the loss of HO-1 disturbed cardiac mitochondrial respiration and reduced mitochondrial biogenesis. The overexpression of sFlt-1 resulted in the inhibition of the cardiac mitochondrial activity in Hmox1+/− mice. The present study demonstrates that the hydrogen sulfide (H2S) releasing molecule, MZe786, rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defense in Hmox1−/− mice and in Hmox1+/− mice exposed to a high sFlt-1 environment.

857: Angiogenic factors and prediction for ischemic placental disease in future pregnancies

Conditions of ischemic placental disease (IPD), including preeclampsia, abruption, and intrauterine growth restriction, often recur in subsequent pregnancies. Angiogenic factors have been associated with adverse outcomes in the concurrent pregnancy, but have not been studied as predictors of pregnancy outcomes in subsequent pregnancies. We hypothesized that elevated angiogenic factors in an index pregnancy would be associated with a recurrence of IPD. We conducted a retrospective cohort study of singleton pregnant patients who had angiogenic factors measured in an index pregnancy and experienced a subsequent pregnancy at the same institution. Patients with IPD in the index pregnancy were included. An elevated ratio of soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) was defined as greater than or equal to 85. The primary outcome was IPD in a subsequent pregnancy, which was a composite of preeclampsia, abruption, small for gestational age (SGA), and intrauterine fetal demise. Secondary outcomes included the components of IPD with severe SGA. Data are presented as median (interquartile range) or proportion, and log-binomial regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI). We included 90 patients in the analysis. The sFlt1/P1GF ratio was elevated in 29% of participants. Those with an elevated ratio were more likely to be nulliparous (88% vs. 71%) in the index pregnancy, and less likely to have chronic hypertension (0% vs. 6%). Overall, the recurrence of IPD in the study was 28%, with a non-significant difference in risk based on a high sFlt-1/P1GF ratio RR 0.47 (95% CI 0.18-1.2) compared to a low ratio. Similarly, we did not find an association between a high ratio and any of the components of IPD. A high sFlt1/P1GF ratio in an index pregnancy is not associated with a higher risk of IPD in a subsequent pregnancy and does not improve on risk prediction noted in prior studies. This study is limited overall by a small sample size and may reflect selection bias of a healthier population.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Angiogenic factors during pregnancy in Asian women with elevated blood pressure in early pregnancy and the risk of preeclampsia: a longitudinal cohort study

ObjectiveIt remains unclear what roles placenta-originated angiogenic factors play in the pathogenesis of preeclampsia among hypertensive women. We compared maternal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor...

Association of serum angiogenic factors with bronchopulmonary dysplasia. The ANGIODYS cohort study.

Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cord blood angiogenic factors (sFlt-1, placental growth factor [PlGF], soluble endogline [sEng], transforming growth factor β [TGF-beta]) and their association with moderate and severe bronchopulmonary dysplasia (BPD) in very preterm growth-restricted infants. Prospective monocentric cohort study. Twenty-four mother-child dyads featuring antepartum preeclampsia, intra-uterine growth restriction (IUGR) and birth before 30 weeks' gestation were included. This ensured a 80% power to test whether sFlt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD. Four pro/anti-angiogenic factors from two pathways (sFlt-1, PlGF and sEng, TGF-beta) were measured in maternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates' cord blood. Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks' postmenstrual age. sFlt-1 levels were positively correlated in maternal serum and cord blood (rs = 0.83, p < .001) but levels of PlGF and TGF-beta and its receptor sEng were not. Among all the factors studied in cord and maternal blood, none was associated with BPD. In IUGR preterm babies born before 30 weeks' gestation from preeclamptic mothers, serum sFlt-1, PlGF and sEng, TGF-β levels were not correlated with BPD. The increased BPD risk in preterm neonates born from preeclamptic mothers cannot be related to high sFlt-1 levels.

Abnormal expression and clinical significance of 25-hydroxyvitamin D and sFlt-1 in patients with preeclampsia.

ObjectiveTo determine the association between levels of serum 25-hydroxyvitamin D (25[OH]D) and soluble fms-like tyrosine kinase 1 (sFlt-1) in patients with preeclampsia.MethodsClinical and demographic data were collected from patients with preeclampsia and healthy pregnant controls. Serum 25(OH)D and sFlt-1 levels were evaluated by enzyme-linked immunosorbent assay and their correlations were determined using Spearman’s rank correlation coefficient. Associations between serum 25(OH)D and sFlt-1 levels and disease severity and clinical parameters were evaluated.ResultsSignificantly lower serum 25(OH)D and higher sFlt-1 levels were observed in patients with preeclampsia (n = 100) versus controls (n = 100), and 25(OH)D was inversely correlated with sFlt-1 in patients with preeclampsia. Serum 25(OH)D levels were reduced, while sFlt-1 concentration was increased in patients with severe versus mild preeclampsia. Serum 25(OH)D levels were reduced in late-onset versus early-onset severe preeclampsia. Patients with preeclampsia who had lower serum 25(OH)D or elevated sFlt-1 levels showed significantly higher blood pressure indexes versus those with higher 25(OH)D or lower sFlt-1.ConclusionsLow serum 25(OH)D and high sFlt-1 may be candidate biomarkers for preeclampsia diagnosis and prognosis.

Role of vascular growth factors as a regulator of angiogenesis processes at the stage of implantation potential formation in women with uterine factor infertility

Despite the broad discussion of clinical significance, the features of the etiopathogenesis of impaired implantation potential in women with uterine sinechias are described in individual works, there is no unanimous opinion on this issue among researchers. The objective: to find out the diagnostic value of a number of markers of the functional state of the endothelium and the level of individual induction angiogenesis in the formation of implantation potential in women with uterine infertility. Materials and methods. The evaluation of the endometrium was performed in 36 women with uterine senechias (first group) and 30 patients with long-term infertility and reproductive loss in history (second group). The control group included 20 healthy patients. This stage of scientific research was conducted taking into account the complex of instrumental methods – ultrasound, histological examination of endometrial biopsies obtained by hysteroscopy intervention, and/or fractional scissors in the dynamics of the menstrual cycle. The design of the study envisaged the study and evaluation of the level of individual factors of angiogenesis, in particular: vascular endothelial growth factor (VEGF-1), as well as antiangiogenic growth factor sFlt-1 and their fluctuations in the preconception phase in serum and cervical mucus. Results. The conducted researches allow to assert, that practically in all patients with uterine sinechia in the complex examination the predominance of the morphological picture of chronic endometritis, hyperplasia and endometrial polyposis, as well as inferior secretory transformation of the endometrium is established. The evaluation of the results of the histological study made it possible to diagnose the presence of hyperplastic processes in 36.1%, the so-called thin endometrium was verified at 19.4%, and the endometrium atrophy was found in 13.9% of the histological findings. The results obtained were demonstrated at the preconception stage in the reduction of VEGF-1 and the high anti-angiogenic growth factor sFlt-1: the level of said transmitter in the group of women with uterine senechias was 63% higher in controls than controls (2.8-fold) (p&lt;0,05). Thus, in the case of deep pathomorphological lesions of the endometrium, at the stage of preconception preparation, there is a marked shift in the balance of vascular growth factors towards the increase in the concentration of antiangiogenic markers – sFlt-1, which is evidence of more severe impingement potential impairment in this category of patients. Conclusions. The level of vascular-endothelial growth factor in serum and cervical secretion as well as the estimation of the angiogenic factor may be early prognostic markers that characterize the initial signs of trophoblast invasion, occurring long before implantation impairment and clinical manifestation of non-compliance. It provides an opportunity to predict damage to the endometrium and its vascular network and can be used to control the effectiveness of preventive measures and the effectiveness of preconception training in women at risk for the implementation of possible underdeveloped pregnancy. Key words: uterine senechia, chronic endometritis, growth factors, angiogenic coefficient.

Urinary trace metals, maternal circulating angiogenic biomarkers, and preeclampsia: a single-contaminant and mixture-based approach

BackgroundExposures to toxic metals and deficiencies in essential metals disrupt placentation and may contribute to preeclampsia. However, effects of exposure to combinations of metals remain unknown.ObjectiveWe investigated the relationship between urinary trace metals, circulating angiogenic biomarkers, and preeclampsia using the LIFECODES birth cohort.MethodsUrine samples collected during pregnancy were analyzed for 17 trace metals and plasma samples were analyzed for soluble fms-like tyrosine-1 (sFlt-1) and placental growth factor (PlGF). Cox proportional hazard models were used to estimate the hazard ratios (HR) of preeclampsia associated with urinary trace metals. Linear regression models were used to estimate the relationship between urinary trace metals and angiogenic biomarkers. Principal components analysis (PCA) was used to identify groups of metals and interactions between principal components (PCs) loaded by toxic and essential metals were examined.ResultsIn single-contaminant models, several toxic and essential metals were associated with lower PlGF and higher sFlt-1/PlGF ratio. Detection of urinary chromium was associated with preeclampsia: HR (95% Confidence Interval [CI]) = 3.48 (1.02, 11.8) and an IQR-increase in urinary selenium was associated with reduced risk of preeclampsia (HR: 0.28, 95% CI: 0.08, 0.94). Using PCA, 3 PCs were identified, characterized by essential metals (PC1), toxic metals (PC2), and seafood-associated metals (PC3). PC1 and PC2 were associated with lower PlGF levels, but not preeclampsia risk in the overall cohort.ConclusionsTrace urinary metals may be associated with adverse profiles of angiogenic biomarkers and preeclampsia.

In utero sFlt-1 exposure differentially affects gene expression patterns in fetal liver.

The soluble fms-like tyrosine kinase factor 1 (sFlt-1) is a major contributor to antiangiogenesis during preeclampsia. However, little is known about the effects of sFlt-1 on fetal health. In this study we aim to evaluate the effects of the sFlt-1 concentration during pregnancy on fetal liver physiology. We used adenoviral gene delivery in Sprague-Dawley dams (seven females, 10 weeks old) during mid-gestation (gestational day 8) with adenovirus overexpressing sFlt-1, and age-matched controls (six females, 10 weeks old) with empty adenoviral virus in order to quantify the sFlt-1 concentrations in pregnant dams. Dams exposed to adenoviral sFlt-1 delivery were subdivided into a low (n=4) and high sFlt-1 (n=3) group based on host response to the virus. One-way analysis of variance showed that fetuses (five per dam) exposed to high sFlt-1 concentrations in utero show fetal growth restriction (1.84±0.043 g high sFlt-1 v. 2.32±0.036 g control; mean (M)±s.e.m.; P&lt;0.001), without hypertension or proteinuria in the dams. In continuation, the microarray analysis of the fetal liver of the high sFlt-1 group showed significant enrichment of key genes for fatty acid metabolism and Ppara targets. In addition, using pyrosequencing, we found that the Ppara enrichment in the high sFlt-1 group is accompanied by decreased methylation of its promoter (1.89±0.097 mean % methylation in high sFlt-1 v. 2.26±0.095 mean % methylation in control, M±s.e.m., P&lt;0.02). Our data show that high sFlt-1 concentrations during pregnancy have detrimental effects on the fatty acid metabolism genes and the Ppara targets in the fetal liver.

Status of sFlt‐1 in Pregnant Women with Preeclampsia and its Impact on GRP78 in Trophoblast Cells

IntroductionsFlt‐1 is secreted in large amounts by placental trophoblasts, released into maternal circulation and reduces bioavailability of angiogenic molecule, VEGF. Plenty of evidence suggest that production of excess sFlt‐1 is a consequence of placental hypoxia leading to stressed placenta noted in preeclampsia (PE). Placental stress has been categorized into oxidative, immunologic and endoplasmic reticulum (ER) stress. Placental ER stress arises due to failure of unfolded protein response (UPR) affects its central regulator, GRP78, which dissociates from transmembrane sensors, PERK like ER kinase, IRE1 (Inositol‐Requiring Enzyme 1) and ATF6 (Activated Transcription Factor 6). The present study was aimed to unravel whether sFlt‐1 had any correlation with GRP78. Also, in vitro experiments were performed to explore effect of sFlt‐1 on GRP78.MethodsSera from 60 recruited women [(30 PE patients and 30 Normotensive, Non‐proteinuric (NT, NP; controls)] were used to estimate levels of sFlt‐1 and GRP78 proteins (ELISA; R and D system). Trophoblast cells (BeWo cells; human choriocarcinoma cell line) were subjected to various treatments with varying sFlt‐1 concentrations and expression of GRP78 was analysed using immunofluorescence (IF), western blot and qRT‐PCR at 8, 14 and 24 hours. The BeWo cells of group 1 and group 2 were exposed to sera from normotensive pregnant women (low sFlt‐1), and preeclamptic pregnant women (high sFlt‐1). The BeWo cells of group 3 were exposed to normotensive sera with recombinant sFlt‐1 (NT+re‐sFlt‐1). Statistical tests used were Paired t, Pearson correlation coefficient, One‐way ANOVA, Kruskal‐Wallis, Wilcoxon signed‐rank.ResultsSerum sFlt‐1 levels were found to be significantly elevated in women with preeclampsia [11295.25 (2936.2–37818) pg/ml] than in controls [2936.2 (1180.43–6706.6) pg/ml] (p=0.0001). GRP78 levels were also raised significantly in PE patients (1103.26 ± 104.27) ng/ml as compared to controls (1018.61 ± 125.51) ng/ml (p=0.023). Patients with increased sFlt‐1 in their sera had higher GRP78 levels suggesting a positive correlation. Significant expression of GRP78 was observed at 8 h when BeWo cells were treated with PE sera and NT sera with recombinant sFlt‐1 by IF. GRP78 expression was observed as early as 8 h, reached peak at 14 h, started diminishing after 14 h and was significantly upregulated when BeWo cells were treated with PE sera as compared to NT sera at both protein (p&lt;0.0001) and mRNA (p&lt;0.0001) levels. Expression of GRP78 was significantly raised at 8 and 14 h when BeWo cells were treated with NT+re‐sFlt‐1 as compared to NT sera at both protein (p&lt;0.0001) and mRNA (p&lt;0.0001) levels.ConclusionPositive correlation was observed between increased maternal serum levels of sFlt‐1 and GRP78 in preeclamptic patients. Upregulation of GRP78 in trophoblast cells exposed to group 2 and 3 indicate towards an important role which may be played by sFlt‐1 in inducing ER stress in Preeclampsia.Ethical clearance IESC/T‐323Support or Funding InformationA‐159 AIIMS, New DelhiThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

266. Demographic characteristics and angiogenic profile in relation to fetal sex

Introduction Fetal sex has been shown to alter maternal milieu, with patients carrying a male fetus having an altered inflammatory response in pregnancy. Angiogenic biomarkers sFlt1 and PlGF are associated with preeclampsia, however the difference in angiogenic profile with respect to the fetal sex is not previously analyzed. Methods In this retrospective cohort analysis, women with preeclampsia and normal pregnancy were enrolled upon admission to labor and delivery. Blood samples were collected and were assessed for angiogenic factors using an automated platform. Clinical and demographic information was abstracted from medical records and presented as median (interquartile range) or n (%). Results A total of 299 normotensive and 130 women with preeclampsia were enrolled. Equal number of patients had male fetuses among preeclampsia and normotensive parturients (55.9% and 50.2% respectively). Among both normotensive and women with preeclampsia, no difference was observed in demographic characteristics between male and female fetuses, including age (normotensive), body mass index, smoking or racial status, blood pressure, gestation age at delivery or birthweight (all p > 0.10). Normotensive mothers carrying a male fetus had significantly high sFlt1 (3168 [IQR: 2160–4945] vs 2678 [IQR: 1752–4271]; p = 0.01), lower PlGF (175 [IQR: 97–367] vs 215 [IQR: 124–426]; p = 0.09), and higher sFlt/PlGF ratios (18 [IQR: 7–44] vs 12 [IQR: 5–30]; p = 0.01). This difference between fetal sexes was not observed in the angiogenic profile of patients with preeclampsia; however, we did observe a higher maternal age (27 vs 24 years, p = 0.03) and rates of cesarean section, among patients with male fetuses in this cohort (54.7%vs 37.3%; p = 0.04). Conclusion Our study demonstrates that normotensive women carrying a male fetus have significantly worse angiogenic profile as compared to those carrying a female fetus. No such relationship exists for preeclamptic pregnancies. Further studies are needed to elucidate this mechanism.

247. Effect of aspirin on soluble Fms-like tyrosine kinase-1 levels and placental growth factor in women with suspected or confirmed preeclampsia

Background Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms-like tyrosine kinase-1) and decreased placental growth factor (PlGF) levels. Low-dose aspirin use is recommended for the prevention of preeclampsia in high-risk women, although its exact pathogenic mechanism remains unknown. Preclinical studies have shown that aspirin decreases sFlt-1 secretion in vitro. Our aim is to investigate whether aspirin use affects sFlt-1 and PlGF in women with confirmed or suspected preeclampsia. Methods A prospective cohort study was conducted involving 430 women. Of these women, 45 took aspirin for 10 to 32 (median 23) days before sFlt-1 and PlGF measurement. Measurements were only made once at study entry, between weeks 20 and 41 (median 33) weeks. Results Women using aspirin at study entry were compared to either all women not using aspirin, or given that sFlt-1 and PlGF alter with advancing gestation, to gestational age-matched women not using aspirin. We aimed at obtaining 2 gestational age-matched non-users for each individual drug user. Aspirin use tended to lower sFlt-1/PlGF ratio (p = 0.05), but this trend was mitigated when matched with gestational age-matched controls (p > 0.05). With regard to other drugs affecting sFlt-1, PPI use was associated with lower sFlt-1 levels both when compared with all non-PPI users and with 80 gestational age-matched controls. No sFlt-1/PlGF factor alterations were observed in women using ferrous fumarate or macrogol while, and as expected, women using antihypertensive medication displayed higher sFlt-1 levels and lower PlGF levels. The PPI use-associated decrease in sFlt-1 was independent of the application of aspirin or antihypertensive drugs. Rates of pregnancy complications for aspirin users were not different from non-aspirin users. Discussion Treatment with aspirin does not associate with lower sFlt-1 or altered PlGF levels. Larger studies are required to further elucidate the pathogenic role of aspirin in the prevention of preeclampsia.

Gebe sıçanlara bevacizumab uygulayarak preeklampsi çalışmalarında kullanılabilecek deneysel hayvan modeli oluşturulabilir.

INTRODUCTION: To develop a rat model of preeclampsia by administering bevacizumab, an angiogenesis inhibitor. METHODS: Sixteen pregnant rats were randomly allocated to intraperitoneal injection of 10 mg/kg bevacizumab or 0.1 cc intraperitoneal serum physiologic on the 4th and 8th days of gestation. Blood pressure, body weight, and proteinuria were measured on both day 0 (D0) and day 20 (D20). Blood samples were collected on D20 for analysis, including for determining vascular endothelial growth factor (VEGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) levels. On the same day, the mice were euthanized, the placentas and pups were weighted, and the angiogenesis markers and microvessel density were evaluated using immunohistochemical methods. RESULTS: Lower serum VEGF (p = 0.038) and higher SFlt-1 (p = 0.015) levels were observed in bevacizumab-treated pregnant rats. Bevacizumab-treated pregnant rats had significantly higher systolic (p = 0.050) and diastolic (p = 0.046) blood pressures compared to the controls. Additionally, the bevacizumab group showed a significant increase in proteinuria on D20 compared to that on D0 (p = 0.026). Although higher serum AST, ALT, BUN, and creatinine levels and renal glomerular endotheliosis scores as well as lower placental VEGF and microvessel density were noted in bevacizumab-treated rats, these differences were not statistically significant (p > 0.05 for each). DISCUSSION AND CONCLUSION: The promising results of this trial show that bevacizumab treatment in pregnant rats might provide a model to study human preeclampsia

Fetal—Not Maternal—APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry

Black Americans are at increased risk for preeclampsia. Genetic variants in apolipoprotein L1 (APOL1) account for much of the increased risk for kidney disease in blacks. APOL1 is expressed in human placenta and transgenic mice expressing APOL1 develop preeclampsia. We evaluated the role of APOL1 variants in human preeclampsia. We determined maternal and fetal APOL1 genotypes in black women with preeclampsia in two populations. At Einstein Montefiore Center (EMC) Affiliated Hospitals, we studied 121 pregnancies in black women with preeclampsia. At University of Tennessee Health Science Center (UTHSC), we studied 93 pregnancies in black women with preeclampsia and 793 pregnancies without preeclampsia. We measured serum markers of preeclampsia soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Fetal APOL1 high-risk (HR) genotype was associated with preeclampsia, with odds ratios at EMC and UTHSC of 1.84 (95% CI 1.11, 2.93) and 1.92 (95% CI 1.05, 3.49), respectively. Maternal APOL1 HR genotype was not associated with preeclampsia. Mothers with the fetal APOL1 HR genotype had more cerebral or visual disturbances (63% versus 37%, p = 0.04). In addition, fetal APOL1 HR genotype was associated with a higher sFLT-1/PlGF ratio at birth (p = 0.04). Fetal APOL1 high-risk genotype increases the risk for preeclampsia, likely by adversely affecting placental function. Further research is needed to assess whether APOL1 genetic testing can predict preeclampsia and improve pregnancy outcomes.

Prévention de la pré-éclampsie en 2018 en population générale et chez la femme lupique : à l’aube d’une médecine personnalisée ?

Pre-eclampsia prevention represents a major public health issue, as this vasculo-placental disorder generates a great burden of foeto-maternal morbi-mortality. Aspirin has proved its efficacy in primary and secondary pre-eclampsia prevention, especially when it is given at 150mg per day bedtime before 15 weeks of gestation to high-risk women. In the English trial ASPRE, high-risk women were identified by an algorithm taking into account angiogenic biomarkers ascertained at the end of first trimester of pregnancy. This article focuses on physiopathological mechanisms and risk factors of pre-eclampsia and on the interest of early angiogenic biomarkers dosing during pregnancy, for the assessment of pre-eclampsia risk. Unlike Great Britain or Israel, cost-effectiveness of this algorithm in general population has not been assessed in France. Finally, systemic lupus erythematous is at high risk of vasculo-placental disorders. Although few studies of angiogenic biomarkers dosing during lupus pregnancies identified a correlation between high sFlt1 levels at the end of first trimester and subsequent onset of severe vasculo-placental disorders, with a very good negative predictive value of sFtl1. Angiogenic biomarkers ascertainment for screening of vasculo-placental disorders in pregnant women with systemic lupus erythematous could allow targeting at best women needing an aspirin treatment and a closer monitoring.

Angiogenic factors in pregnancies of women with antiphospholipid syndrome and systemic lupus erythematosus

ObjectivesAn imbalance of angiogenic placental factors such as endoglin, soluble fms-like tyrosine kinase 1(sFlt-1) and placental growth factor (PlGF) has been implicated in the pathophysiology of preeclampsia. This study aimed to evaluate serum levels of sFlt-1, PlGF and endoglin in women with primary and secondary antiphospholipid Syndrome (APS) and systemic lupus erythematosus (SLE) longitudinally through pregnancy. Material and MethodsSerum levels of sFlt-1, PlGF and endoglin were measured prospectively at 4-week intervals (from gestational weeks 12–36) in 17 women with primary APS (PAPS), 18 women with secondary APS (SAPS), and 23 women with SLE. Results6/17 (35%) of women with PAPS, 3/18 (17%) of women with SAPS, and 2/23 (9%) of women with SLE developed early-onset preeclampsia. Women who developed preeclampsia had significantly higher mean sFlt-1 and endoglin levels, higher sFlt-1/PlGF ratios, and lower mean PlGF-levels than women who did not. These changes became statistically significant at 12 weeks for sFlt-1, PlGF and endoglin. DiscussionEndoglin, sFlt-1 and PlGF are potential early screening parameters for the development of preeclampsia in pregnant women with autoimmune diseases like APS and SLE.

The role of prognostic assessment with biomarkers in chronic kidney disease: a narrative review

Chronic kidney disease (CKD) is associated with high morbidity and mortality. In the past, residual kidney function in CKD patients was assessed by serum creatinine-based equations. However, due to low accuracy of those calculations there is a need for alternative biomarkers. As cardiovascular disease is a major cause of increased mortality in patients with CKD novel biomarkers to estimate risk of cardiovascular death are vital. We reviewed articles approaching beta-trace protein, beta-2 microglobulin (B2MG) and cystatin C as alternative biomarkers to estimate glomerular filtration rate (GFR) in CKD patients. Furthermore, we included recent publications showing the role of high sensitive troponin and sFlt-1 in assessment of progressing cardiovascular disease in patients with renal failure as well as the role of inflammatory biomarkers in those patients. Lastly, we present basic research regarding the role of APOL1 gene variants, suPAR and αvβ3 integrin on decline of renal function. Measuring GFR with serum creatinine and cystatin C seems to be more accurate than equations based on beta-trace protein and B2MG. Beta-trace protein however, seems to be a predictive marker to assess risk of end-stage renal disease. A recent study showed that serum sFlt-1 levels after heparin injection could predict cardiovascular mortality in patients with chronic renal failure. High sensitive troponin is a recently introduced biomarker measuring myocardial damage in acute myocardial infarction (MI) and can predict short-term all cause death in patients with reduced GFR. Progression of renal disease is attributed to increased inflammation levels and can be predicted by measuring proinflammatory biomarkers such as TNF-receptor 1, TNF-receptor 2 and KIM-1. We gave an updated review of novel biomarkers in CKD. While some have proven useful in certain situations it is unclear whether one single biomarker for assessing renal function or predicting mortality in patients with renal failure can be found.

Clinical Implications

HomeHypertensionVol. 71, No. 2Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published1 Feb 2018https://doi.org/10.1161/HYPERTENSIONAHA.117.10771Hypertension. 2018;71:217Metabolic Predictors of Vascular Change (p 237)Download figureDownload PowerPointAortic stiffness increases with age and contributes to the pathogenesis of hypertension and cardiovascular disease. In previous cross-sectional studies, metabolic traits were associated with aortic stiffness and mean arterial pressure. We examined whether metabolic traits at baseline and their changes over time were associated with changes in vascular function longitudinally. Vascular and metabolic traits were examined in 5779 middle-aged participants attending sequential examinations of the Framingham Heart Study cohorts (mean follow-up, 5.9±0.6 years). Multivariable regression was used to relate changes in vascular measures to changes in body mass index, serum lipids, and blood glucose. Aortic stiffness measures and pressure pulsatility increased, whereas mean arterial pressure decreased, suggesting that factors other than distending pressure may have contributed to the increase in aortic stiffness. Interindividual variation in the longitudinal changes of arterial stiffness (carotid-femoral pulse wave velocity) and mean arterial pressure were explained more by changes in metabolic traits than by baseline metabolic trait levels, consistent with the concept that modification of metabolic factors may mitigate arterial stiffness over time.Unattended Blood Pressure Measurement (p 243)Download figureDownload PowerPointDo you remember your reaction when looking at your angry math teacher? Or your reaction meeting the most beautiful girl in class on the schoolyard? In both cases, your blood pressure (BP) probably increased. The person that measures someone’s BP—either frightening or attractive—affects BP as well. The technique of unattended BP measurement is intended to minimize this alert reaction. Although the protocol did not really call for it, several study centers in the SPRINT study (Systolic Blood Pressure Intervention Trial) measured BP in an unattended manner, leading to a controversial discussion on the generalizability of the trial’s findings. The discussion was heated by an article from Filipovský et al reporting a 16 mm Hg difference in measurement techniques in a hypertension center. It is noteworthy that there is convincing evidence from the 80s that BP substantially decreases from the first visit of a new doctor to the following ones. So, what about the disparity of unattended versus attended BP in a familiar medical environment? Our study shows that the difference between measurements is low in a general practitioner setting. These findings make it improbable that the BP values in SPRINT substantially underestimate office BP values in primary care. It is currently being discussed whether unattended BP measurement should serve as the new gold standard for the assessment of office BP. The differences of the present data and those of Filipovský et al suggest that it may indeed be wise to implement this approach in secondary or tertiary care institutions, whereas it is dispensible in a general practitioner setting.sFlt-1/PlGF Ratio in Prediction of Preeclampsia (p 306)Download figureDownload PowerPointA substantial body of evidence suggests that angiogenic factors (sFlt-1 [soluble FMS-like tyrosine kinase-1] and PlGF [placenta growth factor]) could be useful biomarkers for prediction, diagnosis, and prognosis of preeclampsia from 24 to 37 weeks gestation. In this group, the sFlt-1/PlGF ratio has a very high negative predictive value for ruling out preeclampsia and its positive predictive value, whereas lower than the negative predictive value, outperforms current clinical tools. We conducted a meta-analysis of studies using sFlt-1/PlGF ratio to predict development of preeclampsia. The pooled sensitivity was 80% (95% confidence interval [CI], 0.68–0.88); pooled specificity 92% (95% CI, 0.87–0.96); and area under the curve 0.94 (95% CI, 0.91–0.95). With positive and negative likelihood ratios of 10.5 (95% CI, 6.2–18.0) and 0.22 (95% CI, 0.13–0.35), respectively, the probability of developing preeclampsia increased to 78% with a positive test compared with 7% with a negative test. Importantly, all included studies showed a high negative predictive value (10/15 studies reporting negative predictive value >98.5%). These results have important clinical implications. A low sFlt-1/PlGF ratio is a strong negative predictor of disease <37 weeks, allowing safe discharge or decreased surveillance. Concomitantly, a high sFlt-1/PlGF ratio could help prioritize patient care (transfer to tertiary centers or increased surveillance). The use of angiogenic factors for ruling out preeclampsia is used throughout Europe and was recently approved for pregnancies <35 weeks in the United Kingdom. The effective segregation of patients in a disease with an unpredictable course, which has substantial maternal and fetal morbidity and mortality, could have important clinical benefits. Previous Back to top Next FiguresReferencesRelatedDetails February 2018Vol 71, Issue 2 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.117.10771 Originally publishedFebruary 1, 2018 PDF download Advertisement

An sFlt-1:PlGF ratio of 655 is not a reliable cut-off value for predicting perinatal outcomes in women with preeclampsia.

The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is increased in preeclampsia. This study evaluated perinatal outcomes in cases with an sFlt-1:PlGF ratio above 655. We retrospectively analyzed data from all consecutive women with singleton pregnancies who presented with clinically manifest preeclampsia and underwent immediate sFlt-1:PlGF assessment. Cases with an sFlt-1:PlGF ratio ≥ 655 were matched 1:1 for gestational age to controls with a ratio < 655. The 5-min Apgar score and the arterial cord pH. There was a significant association of sFlt-1:PlGF ratios ≥ 655 with fetal distress (40% in cases vs. 3.3% in controls; p < .01) and neonatal sepsis (23.3% vs. 0%; p = .02), but not with impaired Apgar score (9 vs. 9 at 5 min; p = .45) or lower arterial cord pH (7.24 ± 0.09 vs. 7.26 ± 0.08; p = .73). Perinatal mortality (20% vs. 16.7%; p = .9), intrauterine growth restriction (IUGR; 30% vs. 13.3%; p = .2), and small-for-gestational-age fetuses (SGA; 30% vs. 16.7%; p = .35) were proportionally distributed among cases and controls. IUGR and SGA diagnoses were most common in cases with sFlt1:PlGF ratios ≥ 1000, as was respiratory distress. An sFlt-1:PlGF ratio above 655 is not predictive of impaired perinatal outcomes, and insufficiently reliable for predicting outcomes in cases with clinical signs of preeclampsia. Our data suggest that an extremely high sFlt-1:PlGF ratio above 1000 might be more useful.