9ffcf1330ecb5edd12ed0fd1a7325f47 270608.pdf 85916f3017928e7ce36fe10353fd47be75df8f84 270608.pdf e3ca5f3fb50bbce85383c47f777d7a527dd0620e62ebd90eb6ea252b87f79e7d 270608.pdf Title: The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics Subject: Introduction: Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. Methods: We examined the pathophysiological pathways involved in early-onset preeclampsia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood samples, collected at the time of diagnosis from 14 preeclamptic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. Results: A clear difference between preeclamptic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R2X = 0.91, p = 0.002) and predictive ability (Q2Y = 0.72, p < 0.001). Finally, univariate analysis followed by 5% false discovery rate correction indicated 82 metabolites significantly altered, corresponding to six overrepresented pathways: (1) aminoacyl-tRNA biosynthesis; (2) arginine biosynthesis; (3) alanine, aspartate and glutamate metabolism; (4) D-glutamine and D-glutamate metabolism; (5) arginine and proline metabolism; and (6) histidine metabolism. Conclusion: Metabolomic analysis focusing specifically on the early-onset severe form of preeclampsia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preeclampsia. Keywords: early-onset preeclampsia; fetal growth restriction; LC-MS/MS; maternal serum; preeclampsia; metabolomics; severe preeclampsia Author: Lina Youssef, Francesca Crovetto, Rui Vasco Simoes, Jezid Miranda, Cristina Paules, Miquel Blasco, Marta Palomo, Héctor García-Calderó, Olga Tura-Ceide, Ana Paula Dantas, Virginia Hernandez-Gea, Pol Herrero, Núria Canela, Josep Maria Campistol, Joan Carles Garcia-Pagan, Maribel Diaz-Ricart, Eduard Gratacos and Fatima Crispi Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jan 10 01:41:31 2022 CET ModDate: Mon Jan 10 01:46:07 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1439649 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ARZHUS+VnURWPalladioL Type 1 Custom yes yes no 10 0 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edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Baseline and Perinatal Characteristics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Metabolomics Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Study Population Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Data Collection Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Maternal Blood Sampling Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Metabolomic Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Appendix A Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Children: Item: Title: Metabolomics Technique Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Info: Title: The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics Author: Lina Youssef, Francesca Crovetto, Rui Vasco Simoes, Jezid Miranda, Cristina Paules, Miquel Blasco, Marta Palomo, Héctor García-Calderó, Olga Tura-Ceide, Ana Paula Dantas, Virginia Hernandez-Gea, Pol Herrero, Núria Canela, Josep Maria Campistol, Joan Carles Garcia-Pagan, Maribel Diaz-Ricart, Eduard Gratacos and Fatima Crispi Subject: Introduction: Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. Methods: We examined the pathophysiological pathways involved in early-onset preeclampsia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood samples, collected at the time of diagnosis from 14 preeclamptic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. Results: A clear difference between preeclamptic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R2X = 0.91, p = 0.002) and predictive ability (Q2Y = 0.72, p < 0.001). Finally, univariate analysis followed by 5% false discovery rate correction indicated 82 metabolites significantly altered, corresponding to six overrepresented pathways: (1) aminoacyl-tRNA biosynthesis; (2) arginine biosynthesis; (3) alanine, aspartate and glutamate metabolism; (4) D-glutamine and D-glutamate metabolism; (5) arginine and proline metabolism; and (6) histidine metabolism. Conclusion: Metabolomic analysis focusing specifically on the early-onset severe form of preeclampsia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preeclampsia. 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