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Title:   Author  item
                                            LA FRANO, MICHAEL - University Of Californiaitem
                                            FAHRMANN, JOHANNES - University Of Californiaitem
                                            GRAPOV, DMITRY - University Of Californiaitem
                                            FIEHN, OLIVER - University Of Californiaitem
                                            PEDERSEN, THERESA - University Of Californiaitem
                                            Newman, Johnitem
                                            UNDERWOOD, MARK - Uc Davis Medical Centeritem
                                            STEINHORN, ROBIN - University Of Californiaitem
                                            WEDGWOOD, STEPHEN - University Of California
  Submitted to: Metabolomics
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 1/30/2017
                                    Publication  Date: 2/13/2017
                                    Citation: La Frano, M.R., Fahrmann, J.F., Grapov, D., Fiehn, O., Pedersen, T.L., Newman, J.W., Underwood, M.A., Steinhorn, R.H., Wedgwood, S. 2017. Metabolic perturbations of postnatal growth restriction and hyperoxia-induced pulmonary hypertension in a bronchopulmonary dysplasia model. Metabolomics. 13:32. https://doi.org/10.1007/s11306-017-1170-6.DOI: https://doi.org/10.1007/s11306-017-1170-6                                                              
                                Interpretive Summary: Background: Pulmonary hypertension (PH) is a common consequence of bronchopulmonary dysplasia (BPD) and remains a primary contributor to sickness and death in preterm infants. Since no reliable diagnostic markers for PH exist, understanding the underlying perturbations that lead to the development of PH in the presence of BPD is of utmost importance. To look for a novel diagnostic PH marker, state-of-the-art analytics were used to perform a broad screen of metabolites in umbilical cord blood (UCB) plasma from preterm infants who did or did not subsequently develop PH. A total of 1656 unique chemical entities were detected of which 407 were identified. PH-associated metabolic perturbations were characterized by changes that suggest a reduced phospholipid biosynthesis capacity, an increase in vasodilatory lipid mediator destruction, and an increase in free fatty acids and certain triglyceride species, indicating subtle perterbations in lipid metabolism. Conversely, BPD presence and severity were positively associated with UCB choline, palmitoleic acid, and pro-inflammatory lipid mediators including prostaglandin E2 and a variety of linoleic acid oxidation products. Hazard ratio models identified total UCB free fatty acids and phosphatidylcholines as weak, yet promising independent risk markers for development of PH. In conclusion, this expansive evaluation of cord blood plasma identified compounds reflecting metabolism alterations that differentiate subjects both by BPD severity and PH development. Total UCB free fatty acids and phosphatidylcholines may serve as potential independent risk markers for PH development, but further studies are needed and warranted.
                                Technical Abstract: Background: Pulmonary hypertension (PH) is a common consequence of bronchopulmonary dysplasia (BPD) and remains a primary contributor to increased mortality and morbidity among preterm infants. There are no reliable markers for diagnosing PH. Understanding the underlying perturbations that lead to the development of PH in the presence of BPD is of utmost importance. 
Methods and Results: A multi-platform metabolomics approach using both untargeted and targeted methods was used to characterize metabolic perturbations in umbilical cord blood (UCB) plasma from preterm infants who did or did not develop subsequent PH. A total of 1656 features were detected of which 407 were annotated by metabolite structures. PH-associated metabolic perturbations were characterized by: 1) elevations in oxylipins derived from soluble epoxide hydrolase and non-enzymatic oxidation; 2) reductions in major choline-containing phosphopolipids suggesting alterations in pulmonary surfactant bioavailability; 3) elevations in free fatty acids and select triacylglycerides indicating altered lipid metabolism. UCB choline, palmitoleic acid, PGE1, PGE2, 9- and 13-HOTE, 9- and 13-HODE, and 9- and 13-KODE were found to be positively associated with BPD presence and severity. Cox proportional hazard ratio models identified total UCB free fatty acids (HR: 1.42 [C.I. 0.96–1.88]; p: 0.14 and 1.6 [C.I. 1.08-2.13]; p: 0.078 for univariate and multivariate analyses, respectively) and phosphatidylcholines (Hazard Ratio: 0.76 [C.I. 0.24-1.27]; p: 0.29) and 0.44 [C.I. -0.64-1.51]; p: 0.131 for univariate and multivariate analyses, respectively) as promising independent risk markers for development of PH.
Conclusions: This expansive evaluation of cord blood plasma identifies compounds reflecting altered metabolism that differentiate subjects both by BPD severity and PH development. Total UCB free fatty acids and phosphatidylcholines may serve as potential independent risk markers for PH development. Further studies are warranted.


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