Jorgenson, Alissa

Abstract Background Coagulation markers are used to guide clinical anticoagulation decisions. We aimed to identify circulating metabolites that are associated with coagulation markers in children with congenital heart disease (CHD). Methods Plasma samples were separated from whole blood under consistent conditions. Untargeted metabolomic data were measured in plasma from up to 203 young patients (age range: 0 days-24 years) with CHD before cardiac surgery. Coagulation markers included activated partial thromboplastin time (aPTT), prothrombin time (PT), and activated clotting time (ACT). Weighted Gene Co-expression Network Analysis (WGCNA) was performed to explore metabolite modules (clusters). Associations of metabolites with the coagulation markers were assessed cross-sectionally with regression models, with false discovery rate (FDR) correction for multiple comparison. Associations between coagulation markers and ‘eigenmetabolites’ from WGCNA modules were assessed by correlation analysis. Results A total of 776 metabolites were included in the final analysis. Among these, 20 metabolites were associated with PT and one (valine) with ACT (FDR q value < 0.05). Among the metabolites associated with PT, the top three were retinol, 1-palmitoyl-GPI (16:0), and X-25371 (identity unknown). One module from WGCNA with metabolites from the lipid super pathway was correlated with PT (P = 0.004). Conclusion In this first attempt to identify novel metabolites for coagulation markers, we report 21 metabolites associated with PT or ACT in children with CHD. Future studies are needed to replicate these findings in independent cohorts and to elucidate the biological mechanisms linking these metabolites to hemostatic regulation.

BACKGROUND: Thrombosis is a major complication after cardiac surgery in children with congenital heart disease. The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with thrombosis after surgery in children with congenital heart disease. METHODS: In this prospective cohort study, all blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range, 0 days–18 years) with congenital heart disease undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model. RESULTS: Out of 1115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 25 children (12.3%) developed thrombosis. Among the 776 metabolites, 175 were significantly associated with thrombosis (false discovery rate Q <0.05). The top 3 metabolites showing the strongest associations with thrombosis were eicosapentaenoate, stearidonate, and andro steroid monosulfate C 19 H 28 O 6 S (false discovery rate, 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism and glycerophospholipid metabolism were enriched (false discovery rate, 0.003 for both) and had significant impact on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.969 in the training sample (70% of the total sample) and 0.833 in the testing sample (the remaining 30%). CONCLUSIONS: We have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm these findings and examine the mechanistic pathways to thrombosis.

ABSTRACTObjectivesThe congenital lung malformation volume ratio (CVR) is a prenatal ultrasound measurement that parameterizes congenital lung malformation (CLM) size. The aims of this study were to use serial measurements to create estimated growth curves of fetal CVR for asymptomatic and symptomatic neonates with CLM and to investigate whether a discriminant prognostic model based on these measurements could predict accurately which fetuses with CLM will require invasive respiratory support at delivery and should therefore be delivered at a tertiary‐care facility.MethodsThis was a retrospective study of fetuses diagnosed prenatally with CLM at three tertiary‐care children's hospitals between 2009 and 2016. Those with two or more sonographic measurements of CVR were included. Serial fetal CVR measurements were used to create estimated growth curves for neonates with and those without respiratory symptoms at delivery, defined as requiring invasive respiratory support for the first 24 h after delivery. A discriminant model based on serial CVR measurements was used to calculate the dynamic probability of the need for invasive respiratory support. The performance of this model overall and in preterm and term neonates was compared with those using maximum CVR thresholds of 1.0 and 1.6.ResultsOf the 147 neonates meeting the inclusion criteria, 16 (10.9%) required postnatal invasive respiratory support. The estimated CVR growth curve models showed different growth trajectories for asymptomatic and symptomatic neonates, with significantly higher CVR in symptomatic neonates, and values peaking late in the second trimester at around 25 weeks' gestation in asymptomatic neonates. All prognostic methods had high accuracy for the prediction of the need for invasive respiratory support in term neonates, but the discriminant model had the best performance overall (area under the receiver–operating characteristics curve (AUC) = 0.88) and in the preterm population (AUC = 0.85).ConclusionsThe estimated CVR growth curves showed different growth patterns in asymptomatic and symptomatic neonates with CLM. The dynamic discriminant model performed well overall and particularly in neonates that were carried to term. Development of an externally validated clinical tool based on this analysis could be useful in determining the site of delivery for fetuses with CLM. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.