Karen Mestan, M.D. ViaCord/Perkin-Elmer: Investigator-initiated - PDF document

2/28/2019 Placental & Perinatal Influences Conflict of Interest Disclosures for on Lung Development Karen Mestan, M.D. ViaCord/Perkin-Elmer: Investigator-initiated Grant/Research research grant Support NHLBI: R01 HL139798 Consultant Nothing to disclose Speakers Bureau Nothing to disclose Stock Shareholder Nothing to disclose Karen Mestan, MD Other (identify) Nothing to disclose 12 th International Conference Neonatal & Childhood Pulmonary Vascular Disease March 8, 2019 (Typical) Case Presentation (Atypical) Clinical Course • Apgars 4, 6, 8. • 40 y.o. G2P0, uncomplicated • Small but mighty… medical and prenatal history. Uncomplicated 1 st week, • • Presents to L&D at 28 3/7 weeks extubated to non-invasive with preterm labor. respiratory support. • Admitted for severe preeclampsia. • Serial echocardiograms: • Ultrasound w/ Doppler concerning mild pulmonary hypertension for reverse end diastolic flow. at 2 weeks, moderate at 1 • C-section for worsening month, severe by 5 months biophysical profile. of age. • Pulmonary hypertension • 28 weeks gestation male infant. consult: Sildenafil, serial Birth weight 695 grams, SGA (5 th percentile). • echocardiograms, BNP. • Cardiac catheterization, nitric oxide, bosentan, treprostinil. Bronchopulmonary Dysplasia (BPD) BPD-Associated Pulmonary Hypertension  Most common chronic lung • Progressive respiratory disease of infancy:  10,000 insufficiency. new U.S. cases annually. • CPAP +6  Intubated.  Incidence is increasing. • Worsening pulmonary Severe BPD  40% of  hypertension, cardiopulmonary premature infants born <28 instability. weeks. • Tracheostomy and G-tube.  Increasing morbidity and • ASD closure. mortality. • Escalating mechanical vent  Increased risk for long-term support (despite happy). cardiopulmonary disease • Discharged home at 13 months. and neurodevelopmental • Presented to ER at 20 months. problems. 1

2/28/2019 BPD-Associated Pulmonary Hypertension BPD-Associated Pulmonary Hypertension Classic pathology at autopsy:  Persistently elevated --necrotizing bronchiolitis pulmonary arterial pressures, right-sided --squamous metaplasia heart failure. --inflammatory cells  Affects up to one third of --structural damage / fibrosis infants with BPD. New BPD:  Four-fold increased risk of --pulmonary vascular remodeling death. --intimal thickening, mural hypertrophy  Two-year mortality rate of 33-48% mortality. Does BPD-PH begin before birth?  Highly unpredictable clinical course and outcomes. To what extent?  Substantial resources and socioemotional impact on families. WHY should we care? Fetal Origins of Fetal Origins of BPD-Associated Pulmonary Hypertension BPD-Associated Pulmonary Hypertension • Maternal Preeclampsia and BPD: Mechanical Maternal Steroids Ventilation – Yes: Rocha, et al. 2018. Large multicenter study, Portugal. Factors – Yes: Tagliaferro, et al. 2019. 10-year single center cohort, US. Oxygen CPAP Diuretics – No: Soliman, et al. 2017. 3-year, <32 weeks, CA. BPD Caffeine Preterm • Fetal growth restriction: Birth Pulmonary – Bose, et al. Pediatrics 2009, ELGAN cohort, US. Nitric Hypertension – Sehgal, et al. 2019, Pulmonary vascular disease begins early. Oxide Screening? – Consistent with previous clinical observations of PPHN in term Diagnosis? Placental and late preterm infants born small-for-gestational age (SGA). Surveillance? Surgical Newer Factors Interventions? Therapies? Anatomy of the Human Placenta Fetal Growth Restriction in BPD-Associated Pulmonary Hypertension Fetal Circulation 100 >=90th Intervillous 75-89th Chorionic Plate 80 Space 50-74th 25-49th Percent 60 10-24th <10th 40 Berkelhamer, et al. 20 Seminars in Perinatology 2013 0 PH No PH Decidua Basalis Even infants with mild FGR are at risk. Spiral What is the threshold? Arteries Occult biomarkers? 2

2/28/2019 Four Domains of Placental Histopathology Placental Maternal Vascular Underperfusion Predicts BPD-Associated Pulmonary Hypertension Maternal Acute Chronic Fetal Vascular Vascular Inflammation Inflammation Pathology Underperfusion Placental Lesion No BPD or PH BPD only BPD-PH P Maternal: Villitis Vessels: Chorionic thrombi N=165 N=84 N=34 Choriodeciduitis, Deciduitis with Fibrinoid necrosis/ Stem villous Subchorionitis, plasma cells Acute atherosis, thrombus Any MVU 56 (34) 43 (51)* 22 (65)* 0.001 Chorionitis, Chorioamnionitis Muscularized BP Umbilical vessel Severe MVU 6 (4) 9 (11) 6 (18) 0.01 Chorioamnionitis, Marginating Arteries, Mural thrombi Vessel changes: Necrotizing choriodeciduitis Hypertrophy Fetal thrombotic FN/AA 6 (4) 8 (10) 8 (24)** 0.001 chorioamnionitis Decidual vasculopathy Villi: MBPA 16 (10) 12 (14) 10 (29)* 0.01 perivasculitis Avascular villi Fetal: Syncytial knots, Intervillositis MHMA 10 (6) 9 (11) 6 (18) 0.07 Umbilical phlebitis, Villous agglutination, Chorionic vasculitis, Distal villous Villous changes: Umbilical arteritis, hypoplasia/Small Infarcts 10 (6) 14 (17) 4 (12) 0.02 Necrotizing funisitis terminal villi Increased syncytial knots 53 (32) 39 (46) 20 (59)* 0.01 Villous agglutination 4 (2) 4 (5) 2 (6) 0.36 Increased perivillous fibrin 7 (4) 2 (2) 2 (6) 0.67 DVH/STV 36 (22) 36 (43)* 18 (53)** <0.001 * P<0.01, **P<0.001, versus controls Mestan, et al. Placenta 2014 Placental Maternal Vascular Underperfusion Placental Lesions of MVU Reduced blood flow to the intervillous space FN/AA (Fibrinoid necrosis/acute atherosis) Degeneration of arterial smooth muscle in muscularized maternal arteries of the basal plate. MBPA (Muscularization of basal plate arteries) Persistence of smooth muscle cells in the wall of large spiral arteries in the basal plate. DVH/STV (Distal villous hypoplasia/small terminal villi) Small, round villi. Long villi due to MVU lack of branching. Wide intervillous space. Abnormal implantation Preeclampsia Intrauterine growth restriction Stillbirth Decreased Placental Villous Vascularity Predicts “Mirror Images” BPD-Associated Pulmonary Hypertension FN/AA Pulmonary # of Vessels per Villous vessels with medial/intimal 10 Mean per patient * wall thickening 8 6 Non-PH placenta MBPA 4 2 0 Narrowed no PH PH pulmonary arteries, alveolar Yallapragada, et al. Pediatr Dev Pathol, 2016 DVH/STV disease Placenta of PH infant 3

2/28/2019 Cord Blood Studies of Placental MVU  BPD-Associated PH BPD-Associated Pulmonary Hypertension What is the mechanism? YOU ARE HERE  Parallel development of placental and lung vasculature?  Stem/progenitor cell-mediated?  Epigenetic programming?  Chronic fetal hypoxia?  Perinatal hypoxia  hyperoxia?  Systemic effect?  Or specific to the lungs? Cord Blood ≈ Placental Blood  Fetal Transition The Prentice Birth Cohort  NU CORD Cord Blood Biomarkers of Placental MVU Cord Blood & Placental Tissue Biorepository Study Design: Open Cohort, Multiple Outcomes L&D, NICU Nursing Recruitment Biospecimens: Clinical Database : Cord Blood, Placenta Maternal, Perinatal Tissues, RNA/DNA, Cells Neonatal, Outpatient TIME & PATIENCE Differential associations of 15 biomarkers of angiogenesis with 4 domains of (and patients!) placental histology. Simultaneous measurement via Luminex xMAP platform. N>6,000 Mestan, et al. J Peds 2017 Placental Biomarker Cell & Animal Clinical Biochemical Markers Interactions Models Epidemiology Markers Decreased Cord Blood G-CSF ↔ Placental Growth Factor (PIGF) Placental Growth Factor (PIGF) and G-CSF Predict BPD-Associated PH • G-CSF serves as a mediator of Hypoxia PIGF expression by regulating G-CSF release of monocyte PIGF G-CSF PIGF progenitors through which PIGF induces angiogenesis. Pipp, et al. 2003 • Cord blood (fetal) monocytes iMNC circulate during pregnancy and at birth. Bharat, et al. 2016 Dysregulated angiogenesis  BPD-PH The placenta and lung share common circulating progenitor cells during fetal development, which predispose to parallel abnormal placental & pulmonary vascular development. *P<0.05; **P<0.001 versus PH at 36 weeks Mestan, et al. J Peds 2017 4

2/28/2019 Fetal Monocyte Heterogeneity with The Fetal Monocyte Transcriptome Placental MVU & Fetal Growth Restriction  MVU-FGR- (Controls)  MVU+FGR- (MVU only)  MVU+FGR+ (Severe exposure) Preliminary RNA-seq of classical monocytes (NextSeq 500, Illumina). Principal component analysis identifies two distinct profiles: Fetal Growth Restriction (red) and Non-FGR (blue). Differential Gene Expression in VEGFA and VEGFR1 Expression FGR-Exposed Fetal Monocytes * P<0.05 vs. No MVU 900 differentially expressed genes (P<0.001). 100 genes linked to immunity and inflammation. No VEGFR1 expression in classical monocyte subset. HIF-1α, VEGF significantly upregulated in FGR group. Decreased Migration of VEGFA and VEGFR1 Expression MVU-exposed Fetal Monocytes Chemotaxis assay of pooled monocytes * P<0.05 v. PBS * * * P<0.05 Placental Growth Factor (PIGF) No PIGF expression in either monocyte subset . 5