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

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

Apr 14, 2023 296 likes •378 views

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

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Placental & Perinatal Influences

  • n Lung Development

Karen Mestan, MD 12th International Conference Neonatal & Childhood Pulmonary Vascular Disease March 8, 2019 Conflict of Interest Disclosures for

Karen Mestan, M.D.

Grant/Research Support

ViaCord/Perkin-Elmer: Investigator-initiated research grant NHLBI: R01 HL139798

Consultant Nothing to disclose Speakers Bureau Nothing to disclose Stock Shareholder Nothing to disclose Other (identify) Nothing to disclose

(Typical) Case Presentation

  • 40 y.o. G2P0, uncomplicated

medical and prenatal history.

  • Presents to L&D at 28 3/7 weeks

with preterm labor.

  • Admitted for severe preeclampsia.
  • Ultrasound w/ Doppler concerning

for reverse end diastolic flow.

  • C-section for worsening

biophysical profile.

  • 28 weeks gestation male infant.
  • Birth weight 695 grams, SGA (5th percentile).

(Atypical) Clinical Course

  • Apgars 4, 6, 8.
  • Small but mighty…
  • Uncomplicated 1st week,

extubated to non-invasive respiratory support.

  • Serial echocardiograms:

mild pulmonary hypertension at 2 weeks, moderate at 1 month, severe by 5 months

  • f age.
  • Pulmonary hypertension

consult: Sildenafil, serial echocardiograms, BNP.

  • Cardiac catheterization, nitric oxide, bosentan, treprostinil.

BPD-Associated Pulmonary Hypertension

  • Progressive respiratory

insufficiency.

  • CPAP +6  Intubated.
  • Worsening pulmonary

hypertension, cardiopulmonary instability.

  • Tracheostomy and G-tube.
  • ASD closure.
  • Escalating mechanical vent

support (despite happy).

  • Discharged home at 13 months.
  • Presented to ER at 20 months.

Bronchopulmonary Dysplasia (BPD)

  • Most common chronic lung

disease of infancy: 10,000 new U.S. cases annually.

  • Incidence is increasing.
  • Severe BPD 40% of

premature infants born <28 weeks.

  • Increasing morbidity and

mortality.

  • Increased risk for long-term

cardiopulmonary disease and neurodevelopmental problems.

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BPD-Associated Pulmonary Hypertension

  • Persistently elevated

pulmonary arterial pressures, right-sided heart failure.

  • Affects up to one third of

infants with BPD.

  • Four-fold increased risk of

death.

  • Two-year mortality rate of

33-48% mortality.

  • Highly unpredictable clinical course and outcomes.
  • Substantial resources and socioemotional impact on families.

New BPD:

  • -pulmonary vascular remodeling
  • -intimal thickening, mural hypertrophy

Classic pathology at autopsy:

  • -necrotizing bronchiolitis
  • -squamous metaplasia
  • -inflammatory cells
  • -structural damage / fibrosis

Does BPD-PH begin before birth? To what extent? WHY should we care?

BPD-Associated Pulmonary Hypertension Fetal Origins of BPD-Associated Pulmonary Hypertension

Preterm Birth

BPD

Pulmonary Hypertension

Oxygen Nitric Oxide Caffeine Mechanical Ventilation Steroids Diuretics Maternal Factors Placental Factors Newer Therapies? Screening? Diagnosis? Surveillance? CPAP Surgical Interventions?

  • Maternal Preeclampsia and BPD:

– Yes: Rocha, et al. 2018. Large multicenter study, Portugal. – Yes: Tagliaferro, et al. 2019. 10-year single center cohort, US. – No: Soliman, et al. 2017. 3-year, <32 weeks, CA.

  • Fetal growth restriction:

– Bose, et al. Pediatrics 2009, ELGAN cohort, US. – Sehgal, et al. 2019, Pulmonary vascular disease begins early. – Consistent with previous clinical observations of PPHN in term and late preterm infants born small-for-gestational age (SGA).

Fetal Origins of BPD-Associated Pulmonary Hypertension Fetal Growth Restriction in BPD-Associated Pulmonary Hypertension

Berkelhamer, et al. Seminars in Perinatology 2013

Percent

PH No PH 20 40 60 80 100

<10th 10-24th 25-49th 50-74th 75-89th >=90th Even infants with mild FGR are at risk. What is the threshold? Occult biomarkers?

Anatomy of the Human Placenta

Decidua Basalis Fetal Circulation Chorionic Plate

Intervillous Space

Spiral Arteries

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Four Domains of Placental Histopathology

Acute Inflammation Chronic Inflammation Maternal Vascular Underperfusion Fetal Vascular Pathology

Maternal: Choriodeciduitis, Subchorionitis, Chorionitis, Chorioamnionitis, Necrotizing chorioamnionitis Fetal: Umbilical phlebitis, Chorionic vasculitis, Umbilical arteritis, Necrotizing funisitis Villitis Deciduitis with plasma cells Chorioamnionitis Marginating choriodeciduitis Decidual perivasculitis Intervillositis Vessels: Fibrinoid necrosis/ Acute atherosis, Muscularized BP Arteries, Mural Hypertrophy Villi: Syncytial knots, Villous agglutination, Distal villous hypoplasia/Small terminal villi Chorionic thrombi Stem villous thrombus Umbilical vessel thrombi Fetal thrombotic vasculopathy Avascular villi

Placental Maternal Vascular Underperfusion Predicts BPD-Associated Pulmonary Hypertension

Placental Lesion No BPD or PH N=165 BPD only N=84 BPD-PH N=34 P Any MVU Severe MVU 56 (34) 6 (4) 43 (51)* 9 (11) 22 (65)* 6 (18) 0.001 0.01 Vessel changes: FN/AA MBPA MHMA Villous changes: Infarcts Increased syncytial knots Villous agglutination Increased perivillous fibrin DVH/STV 6 (4) 16 (10) 10 (6) 10 (6) 53 (32) 4 (2) 7 (4) 36 (22) 8 (10) 12 (14) 9 (11) 14 (17) 39 (46) 4 (5) 2 (2) 36 (43)* 8 (24)** 10 (29)* 6 (18) 4 (12) 20 (59)* 2 (6) 2 (6) 18 (53)** 0.001 0.01 0.07 0.02 0.01 0.36 0.67 <0.001 *P<0.01, **P<0.001, versus controls Mestan, et al. Placenta 2014

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.

Placental Lesions of MVU

DVH/STV (Distal villous hypoplasia/small terminal villi) Small, round villi. Long villi due to lack of branching. Wide intervillous space.

Placental Maternal Vascular Underperfusion

MVU Reduced blood flow to the intervillous space

Abnormal implantation Preeclampsia Intrauterine growth restriction Stillbirth

“Mirror Images”

Pulmonary vessels with medial/intimal wall thickening Narrowed pulmonary arteries, alveolar disease FN/AA MBPA DVH/STV

Decreased Placental Villous Vascularity Predicts BPD-Associated Pulmonary Hypertension

# of Vessels per Villous Mean per patient no PH PH

2 4 6 8 10

*

Non-PH placenta Placenta of PH infant Yallapragada, et al. Pediatr Dev Pathol, 2016

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Placental MVU  BPD-Associated PH

  • 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?

What is the mechanism?

Cord Blood Studies of BPD-Associated Pulmonary Hypertension

YOU ARE HERE Cord Blood ≈ Placental Blood  Fetal Transition

Clinical Database: Maternal, Perinatal Neonatal, Outpatient Biospecimens: Cord Blood, Placenta Tissues, RNA/DNA, Cells Study Design: Open Cohort, Multiple Outcomes

TIME & PATIENCE (and patients!) N>6,000 Clinical Epidemiology Biochemical Markers Biomarker Interactions Placental Markers Cell & Animal Models

The Prentice Birth Cohort  NU CORD Cord Blood & Placental Tissue Biorepository

L&D, NICU Nursing Recruitment

Cord Blood Biomarkers of Placental MVU

Differential associations of 15 biomarkers of angiogenesis with 4 domains of placental histology. Simultaneous measurement via Luminex xMAP platform.

Mestan, et al. J Peds 2017

Decreased Cord Blood Placental Growth Factor (PIGF) and G-CSF Predict BPD-Associated PH

*P<0.05; **P<0.001 versus PH at 36 weeks Mestan, et al. J Peds 2017

PIGF G-CSF

G-CSF ↔ Placental Growth Factor (PIGF)

  • G-CSF serves as a mediator of

PIGF expression by regulating release of monocyte progenitors through which PIGF induces angiogenesis. Pipp, et al. 2003

  • Cord blood (fetal) monocytes

circulate during pregnancy and at birth. Bharat, et al. 2016 The placenta and lung share common circulating progenitor cells during fetal development, which predispose to parallel abnormal placental & pulmonary vascular development.

iMNC

Dysregulated angiogenesis  BPD-PH PIGF Hypoxia G-CSF

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Fetal Monocyte Heterogeneity with Placental MVU & Fetal Growth Restriction

  • MVU-FGR-

(Controls)

  • MVU+FGR-

(MVU only)

  • MVU+FGR+

(Severe exposure)

The Fetal Monocyte Transcriptome

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 FGR-Exposed Fetal Monocytes

900 differentially expressed genes (P<0.001). 100 genes linked to immunity and inflammation. HIF-1α, VEGF significantly upregulated in FGR group.

VEGFA and VEGFR1 Expression

* P<0.05 vs. No MVU No VEGFR1 expression in classical monocyte subset.

VEGFA and VEGFR1 Expression

* P<0.05 No PIGF expression in either monocyte subset.

Decreased Migration of MVU-exposed Fetal Monocytes

Placental Growth Factor (PIGF)

* * * P<0.05 v. PBS Chemotaxis assay of pooled monocytes

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Summary

  • BPD-associated pulmonary hypertension may begin before birth.
  • Placental MVU is a predictor of BPD-PH.
  • Mechanisms of placenta-lung crosstalk may include:
  • -Changes in fetal monocyte progenitor cell heterogeneity.
  • -Differences in monocyte gene expression and function.
  • -Paracrine effects from PIGF, G-CSF, and others.
  • Identification of these targets may lead to new approaches and

therapies in the management and prevention of PH disease.

Upcoming Studies and Future Directions:

Monocytes:

  • In vitro studies of fetal monocytes

(hypoxiahyperoxia).

  • Reconstitution of monocytes in

humanized (GM-CSF knock-in) mouse model.

Biomarker development:

  • Cord blood and placental

metabolomics/adductomics.

Beyond BPD-PH:

  • Placental regulation of PH disease in

CDH? CHD? Hypothesis: Healthy non-MVU exposed monocytes will attenuate PH disease.

The Team…

Collaborators & Contributors:

  • Prentice NICU, Labor & Delivery

Staff

  • Juanita Saqibuddin, RN

Research Nurse

  • Kelli Stephens, RN

Research Nurse

  • Rob Birkett, BS

Lab Manager

  • Kathy Farrow, MD, PhD

Neonatology

  • Andrew Franklin, MD

Neonatology Fellow PGY-6

  • Monti Sharma, MD

Neonatology Fellow PGY-4

  • Suchitra Swaminathan, PhD

NU Flow Cytometry Core

  • Hiam Abdala-Valencia, PhD

Pulmonary-Critical Care/Genomics

  • Alexander Misharin, MD, PhD

Pulmonary-Critical Care

  • Bill Grobman, MD, MBA

Maternal-Fetal Medicine

  • Linda Ernst, MD

Perinatal Pathology

  • Nina Gotteiner, MD

Cardiology

  • Nic Porta, MD

Neonatology/Pulmonary Hypertension Funding: R01 HL139798 Viacord/Perkin Elmer Northwestern Memorial Foundation Stanley Manne Children’s Research Institute of Chicago

Thank You!