Elevations in Endothelin‐1 Predate and are Strongly Diagnostic for the Development of Human Preeclampsia

Abstract

Preeclampsia (PE), a hypertensive disorder in pregnancy, affects 5–7% of all U.S. pregnancies. It is a leading cause of worldwide obstetric mortality and is associated with 50,000 maternal and 500,000 neonatal deaths yearly. Additionally, PE is known to cause immediate and long‐term maternal‐fetal morbidity. The diagnosis, prevention, and treatment of preeclampsia are limited due to the fact that the mechanisms and physiologic antecedents are largely unknown. Endothelin‐1 (ET‐1) is a potent vasoconstrictor that may be mediating this vascular dysfunction as it is known to be implicated in hypertensive disease and endothelial dysfunction. We have shown that first trimester ET‐1 can be predictive of this, often late, pregnancy disease. It is unknown if ET‐1 is elevated at the time when human physiologic symptoms arise. The objective of this study was to determine the diagnostic characteristics of Endothelin‐1 in women who present for evaluation for PE. This was a nested case‐control study (IRB# 201611746) of pregnant women who were being evaluated at a single tertiary center for PE due to having signs or symptoms of PE (N=130; cases=78, controls=52). Excess plasma and urine from clinical samples used during the PE evaluation were collected. Using commercially available assays, ET‐1 was measured via ELISA and total protein concentration was measured via bicinchoninic acid assay. Reported ET‐1 measurements are reported as ET‐1/total protein (pg/g). Demographic and clinical data for the pregnancy and neonatal outcomes were obtained through the electronic medical record. Cases and controls were gestationally age matched. Women with a PE diagnosis had significantly lower gravidity, parity, and gestational age at delivery; their babies had a lower birthweight and higher admission rate to the NICU. Plasma ET‐1 was higher in patients with PE (Control=18.8 ± 1.3 vs. PE=25.9 ± 3.0 pg/g, p=0.03). Those with early onset PE (<34wks) also had a higher plasma ET‐1 compared to those diagnosed with late onset PE (>34wks) in comparison to controls (Early=38.3 ± 7.8 vs. Late=20.2 ± 2.1 vs. Control=18.8 ± 1.3 pg/g, p<0.001, ANOVA). Conversely, urine ET‐1 was lower in those with PE (Control=128.3 ± 23.5 vs. PE=56.3 ± 13.4 pg/g, p=0.01) and was also lower in patients with more severe disease (Early=24.8 ± 10.6 vs. Late=81.5 ± 19.6 vs. Control=128.3 ± 23.5 pg/g, p<0.011, ANOVA). ET‐1 urine plasma ratio (UPR) at the time of diagnosis strongly predicted PE (AUC=0.84, p=0.0025). In this high‐risk cohort (PE incidence=60%), the ET‐1 UPR at a cutoff of 3.4 pg/g exhibited a sensitivity=87%, specificity=83%, positive predictive value=87%, and negative predictive value=81%. ET‐1 UPR may prove to be a strong diagnostic tool for PE. Further, the differential expression of ET‐1 in plasma and urine according to disease severity suggests ET‐1 may play a role in PE pathogenesis.Support or Funding InformationAHA Postdoctoral Fellowship (SS), AHA SFRN in Hypertension (AB‐O, GP, MS), U of Iowa Women's Health Tissue Repository.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.