3/11/2017

1

Pulmonary Hypertension in Children with Lung Disease

Steven H. Abman, MDProfessor of Pediatrics

Director, Pediatric Heart Lung CenterUniversity of Colorado Denver School of Medicine

Children’s Hospital ColoradoAurora CO 80045 USA

Disclosures• Steven Abman, MD, has no direct conflicts of

interest but receives some funding for laboratory research from:

- Shire Pharmaceuticals- United Therapeutics

• Dr. Abman has also received funding for sponsoring educational activities from Malinckrodt (for the Young Investigator’s Forum) and has served as a scientific advisor for GlaxoSmithKline.

Objectives• To present the diversity and high frequency of

childhood lung diseases associated with pulmonary hypertension (PH) (Group 3 Disease);

• To highlight the importance of pulmonary vascular disease beyond the contribution to PH in many lung related disorders;

• To illustrate the potential impact of early identification of at risk children for disease prevention in Group 3 disorders.

WHO Classification of Pulmonary Hypertension (Nice)1. Pulmonary Arterial Hypertension

1.1 Idiopathic1.2 Heritable

1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown

1.3 Drug and Toxin-induced1.4 Associated with (APAH)

1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal Hypertension1.4.4 Congenital Heart Diseases1.4.5 Schistosomiasis

1’. PVOD and/or PCH1.1’’ Persistent PH of the Newborn (PPHN)2. PH due to left heart disease

2.1 LV Systolic dysfunction2.2 LV Diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathy

3. PH due to lung disease or hypoxemia 3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed

restrictive and obstructive pattern3.4 Sleep –disordered breathing3.5 Alveolar hypoventilation syndromes 3.6 Chronic exposure to high altitudes3.7 Developmental lung diseases

4. Chronic thromboembolic disease (CTEPH)5. PH with unclear/or multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher diseae, thyroid disorders

5.4 Others: tumor obstruction, fibrosingmediastinitis, chronic renal failure, segmental PH

(Simmoneau et al, JACC, 2013)

3/11/2017

2

Multifactorial Conditions Contribute to Pediatric Pulmonary Hypertensive Vascular Disorders

(adapted from del Cerro MJ et al. Pulmonary Circulation, 2011)

Chromosomal and Genetic Syndromes

Pathophysiologic Insults to the Developing Lung Developmental Abnormalities

or Preterm Birth

Registry Data on Pediatric PHVD by Nice Classification SystemNetherlands

(van Loon, 2011)

Spanish(del Cerro, 2014)

UK(Haworth,

2010)

TOPP(Berger, 2012)

Group 1(PAH)

87% 63% 80% 87%

Group 2(L Heart)

5% 13% NA 0%

Group 3(Lung)

8% 18% 13% 11%

Group 4(CTEPH)

< 1% 1% NA < 1%

Group 5(Systemic)

0 4% 7% < 1%

Survival of Children with Pulmonary Hypertension by Nice Classification

(del Cerro Marin M et al. Am j Respir Crit Care Med. 2014)

(n = 131)

(n = 27)(n = 37)

(n = 10)

Initial Pt # at

Pediatric Lung Diseases Associated with Pulmonary Hypertension

• Developmental Lung Disorders (DLD)• Childhood Interstitial Lung Disease (chILD)• “Genetic Disorders” (e.g., Down Syndrome)• Cystic Fibrosis• Collagen Vascular Disease (vasculitis, JIRA)• Chronic Hypoxia +/- “lung disease”

- Obstructive sleep apnea - Chest wall abnormalities- Neuromuscular disease

3/11/2017

3

Developmental Lung Diseases Associated with Pulmonary HypertensionDown Syndrome Alveolar Capillary Dysplasia Bronchopulmonary Dysplasia

Increased Lung Endostatin Gene Expression in the Human Fetus and Infant with Down Syndrome

(Galambos C et al. PLosOne, 2016 )

Neonatal Pulmonary Hypertension in ABCA3 Deficiency

3/11/2017

4

Perinatal Disruption of VEGF Signaling Impairs Lung Structure in Adult Rats

(Tim Le Cras et al, 2002)

Unique Features of Pulmonary Vascular Disease Associated with Lung Disease in Pediatrics

• Disruption of normal vascular growth, function and signaling (“angiocrines”) can critically impair distal airspace growth and contribute to abnormal lung structure during development;

• Maturational mechanisms that regulate vascular tone, reactivity and vascular wall structure in the neonate, infant and child differ from the adult lung;

• Relationships between pulmonary and bronchial circulations in the setting of lung disease.

• Potential for “preventive” strategies with early identification of at-risk newborns, infants and children (especially with BPD, CDH, DS, other lung diseases).

Pulmonary Vascular Disease in Bronchopulmonary Dysplasia

(Stenmark KR, Abman SH. Ann Rev Physiol, 2006)

Evolution of BPD after 50 Years

(Abman SH, Bancalari E, Jobe AH. Am J Respir Crit Care Med, 2017)

3/11/2017

5

Late Pulmonary Hypertension is Associated with Poor Survival in BPD

(adapted from Khemani et al, 2007)

Pulmonary Vascular Disease in BPD

Developing Lung Circulation

Lung InjuryHyperoxiaMechanical VentilationInfectionInflammationHypoxiaHemodynamics (PDA)

Epigenetic and Genetic Factors

Premature BirthIncomplete vascular growthImmature vascular functionDecreased antioxidant defenses

Abnormal FunctionHigh vascular toneAltered vasoreactivityImpaired metabolic function

Abnormal StructureSmooth muscle cell and

fibroblast hyperplasiaAltered extracellular matrix

Decreased GrowthAngiogenesis(Alveolarization)

Placental Dysfunction

Disruption of Angiogenesis Impairs Alveolarization in the Developing Lung

(Jakkula M et al Am J Physiol, 2000)

Control

VEGF Receptor Inhibition Impairs LungVascular Growth in Neonatal Rats

SU5416

(Jakkula M et al, Am J Physiol. 2000)

3/11/2017

6

Intrauterine Growth Restriction and the Risk of PH in BPD Infants

(Check et al, 2013)

Abnormal Placental Histopathology and the Development of BPD and PH in Preterm Infants

(Mestan K et al, Placenta, 2014)(MVU = maternal vascular underperfusion)

Cord Blood ECFC are Decreased at Birth in Preterm Infants who Develop BPD

(Baker CD et al. Eur Respir J, 2012) (Borghesi et al. Am J Respir Crit Care Med, 2009)

Elevated sFlt-1Early Changes in Maternal Anti-Angiogenic

Factors (sFlt-1) Predict Preeclampsia

(Maynard et al. J Clin Invest, 2013)

3/11/2017

7

Experimental Preeclampsia: Intra-amniotic sFlt-1 Impairs Lung Vascular and Alveolar Growth in Infant Rats

Saline sFlt-1

Increased EC apoptosis Pulmonary Hypertension

(Tang JR et al. Am J Physiol, 2011)

Control Antenatal sFlt-1Intra-amniotic sFlt-1 Disrupts Lung Vascular Growth

(Greg Seedorf)

Insulin-like Growth Factor-1 (IGF-1)and Diseases of Prematurity

• IGF-1 is pro-angiogenic and modulates VEGF activity in the developing retina (Lois Smith, Ann Hellstrom);

• Low IGF-1 levels associated with BPD.

(Beardsall K et al. J Pediatr 2014)

IGF-1/IGF BP-3 Therapy Improves Lung Growth and Prevents PH after Prenatal sFlt-1

sFlt-1+ IGF-1/IGF BP-3Control sFlt-1+ Saline

100µm100µm 100µm

+ +Alveolarization +

Right Ventricular HypertropyAlveolarization

3/11/2017

8

Pilot Clinical Study: Early IGF-1/IGFBP3 Treatment Reduces Severe BPD

29

8.5

48.9

19.2 21.3

8.2

32.7

10.2

44.9

0

25

50

75

100

No BPD Mild Moderate Severe

Full Analysis Set

rhIGF-1/rhIGFBP-3 Standard neonatal care

Infan

ts (%

)

53% reduction in severe BPD*

9.5

61.9

23.8

4.88.2

32.7

10.2

44.9

0

25

50

75

100

No BPD Mild Moderate Severe

Evaluable Set

rhIGF-1/rhIGFBP-3 Standard neonatal careInf

ants

(%)

89% reduction in severe BPD*

*Severe BPD defined as ≥30% oxygen or CPAP/mechanical ventilation at a PMA of 36 weeks.

(Presented by David Ley et al. 6 th Congress of the European Academy of Paediatric Societies (EAPS); 21–25 October 2016; Geneva, Swit zerland )

(n = 121)

Antenatal Vascular Origins of BPD

(Mandell EW, Abman SH, 2017)

• Lung and CV disease (BPD, CDH, DLD, COPD, PH, left heart disease, systemic hypertension)

• Retina (ROP)

• Brain (Brain Injury: IVH, PVL, stroke; abnormal brain development, neuro- cognitive impairment)

• Pancreas (IUGR, Diabetes, growth failure, poor nutrition)

• Liver (abnormal growth and development)

Disruption ofAngiogenic Signaling

Endothelial Progenitor CellsPro-angiogenic FactorsAnti-angiogenic Factors

Does Evidence of Early Pulmonary Vascular Disease Predict the Risk for

BPD in Preterm Infants?Approach:• Prospective study of preterm newborns between 500-1250

g BW• Serial echocardiograms at postnatal day 7 and at 36

weeks post menstrual age (PMA)• Blood samples collected for proteomic analysis of

angiogenic factors (SOMAmer® technology)• Clinical and echocardiographic data analyzed to identify

risk factors for BPD and late PH and late respiratory disease during infancy.

Early Pulmonary Vascular Disease Associated with Increased BPD Severity and Late PH

BPD Severity Late PH

(Mourani PM et al. Am J Respir Crit Care Med, 2015)

3/11/2017

9

Pulmonary Vascular Disease is Associated with Respiratory Outcomes During Infancy

(Mourani PM et al, unpublished)

Combined Pulmonary Vascular Disease and Mechanical Ventilation at Day 7 and Increased Risk for Late Respiratory Disease

Early Changes in Angiogenic Proteins are Associated with Subsequent Diagnosis of BPD

The overall p-value for all proteins in the pathway was significant (Fisher's combined test of FDR p-values = 0.008).

PIGFADAMTS-4

CDONCONA1B-ECGF

Semaphorin 3EGro-b/g

VEGF121PDGF-AA

CTAP-IIIPF-4

FGF-19HGFBLCvWFCNTN2BMP RIIVEGF sR3ROBO2

(Wagner B et al, PAS meeting. 2015)

Interim Summary: Early Pulmonary Vascular Disease and the Risk for BPD• Early signs of PVD at day 7 were strongly

associated with the subsequent diagnosis of BPD and PH.

• Late PVD was associated with prolonged mechanical ventilation and oxygen support, and worse respiratory outcomes during infancy.

• Early identification of preemies at risk for BPD and PH may enhance prevention and improve outcomes .

3/11/2017

10

Diagnostic Approach to Pulmonary Hypertension in Preterm Infants with BPD

(* PPHNet Recommendations)

Diagnostic Approach to Infants with Pulmonary Hypertension in BPD

• Evaluation of Underlying Lung Disease:- Prolonged monitoring of O2 (awake, asleep,

feeds)- PaCO2 – contribution to PH or marker of disease

severity, need for chronic (effective) ventilation?- Chronic aspiration (barium swallow, swallowing

study, pH probe, impedance study)- Sleep study- Structural airway disease: flexible bronchoscopy- Reactive airways disease- Chest CT Scan

• Cardiac Catheterization, Other Imaging Modalities

Increased Pulmonary Vasoconstrictor Response to Hypoxia in BPD

(Abman SH et al Pediatrics, 1985)

O2 Therapy for BPD: Recommendations

• Target O2 saturations at 92- 95% in setting of:- Pulmonary hypertension- Frequent cyanotic episodes- Recurrent apnea- Chronic respiratory distress with frequent exacerbations

(e.g.wheezing, infections, swings in FiO2)- Poor somatic growth - Feeding difficulties- Marked irritability, developmental issues

• O2 saturations above this level rarely indicated, and associated Pa O2 may be markedly elevated, leading to oxidative stress.

3/11/2017

11

Lower Targeted O2 Saturations Increase Mortality in IUGR Preterm Infants *

AGA Infants SGA Infants

(Walsh MC et al. JAMA Pediatrics, 2016)

* Post-hoc analysis of data from the SUPPORT trial

Persistent Fetal Intrapulmonary “Shunt Pathways” in Severe BPD

(Galambos C et al. Ann Am Thorac Soc. 2013)Artery: red Lymphatic: pinkVeins: blue Art. media: aquaAirway: green Vascular Channels: yellow

Intrapulmonary Shunt Vessels in BPD

(Galambos C et al. Ann Am Thorac Soc. 2013)

Chronic Sildenafil Therapy for Late Pulmonary Hypertension in CLD

(Mourani PM et al, J Peds, 2009 )

3/11/2017

12

Resolution of Pulmonary Hypertension in Infants with BPD

(An et al, Korean Circ J, 2010)

29 patients with PH and BPD

69% on drug therapy:- inhaled NO (45%)- sildenafil (62%)- bosentan (10%)- iloprost (14%)

14% mortality

Conclusions• Endothelial-derived “angiocrine signaling”

contributes to normal distal airspace growth in the developing lung;

• Early disruption of lung vascular growth with signs of PH is associated with high risk for BPD;

• Therapeutic strategies that preserve or enhance endothelial survival, growth and function after preterm birth may prevent PH and improve long-term respiratory outcomes.

Pediatric Heart Lung CenterClinical Care and Research

Laboratory Research