impaired right ventricular- pulmonary vascular ... › content › dam › sm ›...

Impaired Right Ventricular-Pulmonary Vascular Interactions in

Adults Born PrematureKara Goss, MD

Assistant Professor of Medicine and PediatricsDivision of Allergy, Pulmonary, and Critical Care Medicine

University of Wisconsin

Disclosures: None

When I grow up, I want to be a…?

http://www.nicuhelpinghands.org/

Outline

• Prematurity in the US– Definitions and epidemiology

• Long-term right ventricular and pulmonary vascular outcomes after preterm birth– Newborn Lung Project Cohort

– Insights from animal models

• Identify a history of premature birth as a risk factor for adult pulmonary hypertension and right ventricular dysfunction

• Incorporate screening for key components of birth history in the standard evaluation of pulmonary hypertension patients

Objectives

Incidence of Premature Birth Is Rising

http://mchb.hrsa.gov/chusa13/perinatal-health-status-indicators/p/preterm-birth.html

Incidence of Premature Birth Is Rising

Blencowe, Lancet 2012

• GESTATIONAL AGE:– Term: ≥37 wks– Moderate to late preterm: 32 to

• BIRTH WEIGHT:– Low birth weight (LBW):

• 1904: Dr. Martin Couney and the Coney Island “Child Incubator Exhibit”

The First US Neonatal Care Unit

• 1930s: Routine use of oxygen for cyanotic infants• 1960s: First NICUs opened, ventilators in infants with Respiratory

Distress Syndrome

“Growing Pains” in Neonatal Care

• 1980s: Initial trials of surfactant• 1990s: Routine use of surfactant, antenatal steroids, antenatal

antibiotics

Modern Neonatal Care

“Les Premes”RedM Photography by Red Méthot

https://www.facebook.com/pg/RedMPhoto/photos/?tab=album&album_id=679320625546362

Karine, born at 28 wksVincent, born at 31 wks Lexiani, born at 25 wksFelix, born at 24 wks

https://www.facebook.com/pg/RedMPhoto/photos/?tab=album&album_id=679320625546362

Advances in Neonatal CareImprove Mortality

NICHD Neonatal Research Network - 1986

Adapted from: Fanaroff, Seminars in Perinatology 2003

0

10

20

30

40

50

60

70

1988 1994 2000

Perc

ent M

orta

lity

Mortality

501-750 g751-1000 g1001-1500 gOverall

• BPD:– Persistent oxygen requirement

inappropriate for the GA– Arrest in alveolar and vascular

development

Major Neonatal Comorbidities:Bronchopulmonary Dysplasia

Thomas, born at 23 wks“Les Premes” Collection

8 mo with BPD, born at 28 wks

Coalson, Seminars in Neonatology 2003

24 wk stillborn infant38 wk infant, non-respiratory death

Premature Birth Is a Risk Factor of Neonatal Pulmonary Vascular Morbidity

Baker, Pediatr Allergy Immunol Pulmonol 2014.Mourani, AJRCCM 2015.

– Lower FEV1 and FEV25-75%– Increased respiratory symptoms– Increased airway obstruction/bronchial reactivity– Reduced diffusing capacity– Reduced exercise tolerance

– LACKING data on long term pulmonary vascular health

Vrijlandt, AJRCCM 2006.Gough, CHEST 2012.

Farrell, Ann Am Thorac Soc 2015.Islam, AJRCCM 2015.

Crump, Pediatrics 2011.

Adults Born Premature Demonstrate Poorer Respiratory Outcomes

Thebaud, PVRI Review 2010.

Alveolar and Vascular Development are Integrally Linked

Preterm Birth May Limit AdultPulmonary Vascular Endowment

TIMEFetal Childhood Neonatal Adulthood

VASC

ULA

R D

ENSI

TY

Normal Vascular Development and Aging

Disrupted Vascular

Development

Secondary Insults

Disrupted Vascular Development Leads to

Decreased Adult Pulmonary Vascular Endowment

Decreased Vascular Development Leads to

Increased Susceptibility to Secondary Insults

Risk Factors:PrenatalGeneticEpigeneticEnvironmental

Potential Insults:TobaccoHypoxiaInfection

Toxins

Goss, Pulmonary Circ 2017.

Lewandowski, Circulation 2013

Right Ventricular Systolic Dysfunction In Young Adults Born Preterm

Cardiac MRI in 102 adults born pretermAvg GA 30.3 wks; Assessed at 25.1 yr (23-28)

Premature Birth Increases Risk for Pulmonary Hypertension

Naumburg, Acta Paediatr 2015

Case control study of adults in the Swedish Pulmonary Arterial Hypertension Registry

• Newborn Lung Project Cohort– Neonates enrolled at birth from 6 NICUs in Wisconsin and Iowa– Years 1988-1990– Weight ≤ 1500 g – Average gestational age 28 wks

• Healthy controls• All subjects free from adult cardiopulmonary disease

Long-term Effects of Premature Birth on the Pulmonary Vasculature?

Palta M, J Peddiatr 1991; Palta M, Arch Pediatr Adolesc Med 1994; Palta M, J Pediatr 1998; Palta M, Arch Pediatr Adolesc Med 2000;

Palta M, Am J Epidemiol 2001; Palta M, Pediatr Pulmonol 2007; Farrell ET, Ann Am Thorac Soc 2015

• Visit 1:– Screening: PFT, VO2 Max (normoxia/hypoxia)

• Visit 2:– Exercise at 70% PMax during cardiac MRI

• Visit 3: – Exercise at 70% PMax during right heart cath

Long-term Effects of Premature Birth on the Pulmonary Vasculature?

Rest - ExerciseNormoxia - Hypoxia

Baseline Characteristics Term Preterm

Number of subjects (male) 10 (7) 11 (5)Age (years) 25.8 ± 0.8 26.9± 1.1*Weight (kg) 72.9 ± 9.8 69.4 ± 13.3Height (m) 1.8 ± 0.1 1.7 ± 0.1BMI (m2) 23.3 ± 1.6 23.4 ± 3.2Pulmonary functionFEV1 (L) 4.4 ± 1.0 3.7+/-0.7FEV1 % pred 101 ± 17 99 ± 21FVC (L) 5.4 ± 1.1 4.6 ± 0.8FVC % pred 108 ± 11 107 ± 19FEV1/FVC (%) 0.9 ± 0.3 0.8 ± 0.1DLCO (ml/min/Torr) 31.0 ± 7.0 23.9 ± 4.2*DLCO % pred 106 ± 16 90 ± 1*DLCO/ VA (ml/min/Torr/L) 5.2 ± 0.6 4.5 ± 0.5*DLCO/ VA %pred 113 ± 13 96 ± 11*Exercise testVO2peak(ml/min/kg) 54.4 ± 17.1 34.4 ± 6.6*Pmax (watt) 246 ± 45 184 ± 41*70% Pmax (watt) 179 ± 27 134 ± 23*

Neonatal Characteristics Neonatal Characteristics (n=11)

Gestational age (weeks) 28.2 ± 2.8Birth weight (g) 1071 ± 310.4Delivered by C-section (n) 9Singleton/multiple 5/6Received antenatal steroids 0Intubation at 24 hrs. (n) 9Received surfactant (n) 4Days on mechanical ventilation 16.6 ± 25.1Days on oxygen 96.3 ± 159.7Days in the NICU 63.8 ± 32.0BPD diagnosis (n) 5Persistent PDA (n) 8Acute pulmonary complications (n) 3Diagnosis of PH by echo in the NICU 0Discharge home on supplemental oxygen (n) 5

Adults Born Premature Have Elevated Resting Pulmonary Pressures

Arij Beshish, MBBCh

T e r m P r e te r m1 5

2 0

2 5

3 0

3 5

4 0

S y s to lic P A P R e s t

Pre

ss

ure

(m

mH

g)

*p = 0 .0 2

T e r m P r e te r m0

5

1 0

1 5

2 0

D ia s to lic P A P R e s t

Pre

ss

ure

(m

mH

g)

Term Preterm0

10

20

30

Mean PAP Rest

Pres

sure

(m

mH

g )

*p=0.04

Beshish, AJRCCM, in revision

2 2 2 4 2 6 2 8 3 0 3 2 3 40

1 0

2 0

3 0

G e s ta t io n a l A g e (w k s )

mP

AP

(m

mH

g)

r 2= 0 .2 7P = 0 .1 0

0 2 0 4 0 6 00

1 0

2 0

3 0

D a y s o n In v a s iv e V e n t ila t io n

mP

AP

(m

mH

g)

r 2= 0 .5 1P = 0 .0 1

0 5 1 0 1 5 2 0 2 50

1 0

2 0

3 0

D a y s o n N o n - in v a s iv e V e n t ila t io n

mP

AP

(m

mH

g)

r 2= 0 .0 7P = 0 .4 5

0 2 0 4 0 6 00

1 0

2 0

3 0

mP

AP

(m

mH

g)

r 2= 0 .6 9P = 0 .0 0 1

D a y s o n C o m b in e d In v a s iv ea n d N o n - in v a s iv e V e n t i la t io n

Neonatal Days on Ventilatory Support is Strongest Predictor of Adult PAP


Arij Beshish, MBBCh

Jacob Macdonald

Adults Born Premature Have a Stiffer Pulmonary Vascular Bed

T e r m P r e te r m0 .0

0 .1

0 .2

0 .3

P A M e a n V e lo c ity

Ve

loc

ity

(m

/s)

* Control Preterm

Term Preterm0.20

0.25

0.30

0.35

0.40

0.45

Pulmonary ArteryRelative Area Change

Rel

ativ

e ar

ea (

%)

*

Exercise Reveals Decreased Pulmonary Vascular Recruitability

Arij Beshish, MBBCh

R e s t E x e r c is e0 .0

0 .5

1 .0

1 .5

2 .0

2 .5

T o ta l P u lm o n a ry R e s is ta n c eR e s p o n s e to E x e rc is e

TP

VR

(m

mH

g/L

/min

)

*

T e rm

P re te rm

R e s t E x e r c is e1 0

1 5

2 0

2 5

M e a n P A PR e s p o n s e to E x e rc is e

mP

AP

(m

mH

g)

*


Adults Born Premature Unable to Augment Stroke Volume During Exercise


6 0

7 0

8 0

9 0

1 0 0

S tro k e V o lu m e In d e xR e s p o n s e to E x e rc is e

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I (m

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t/m

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∆ S V I P = 0 .0 4

R e s t E x e r c is e2

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(L/m

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P re te rm

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8 0

1 0 0

1 2 0

1 4 0

H e a rt R a teR e s p o n s e to E x e rc is e

HR

(b

ea

ts/m

in)

*

Arij Beshish, MBBCh


Smaller, Less Efficient RV inAdults Born Premature

Arij Beshish, MBBCh

Term Preterm Jacob Macdonald

Cardiac Flow Is Less Laminar in Adults Born Preterm

Male, GA 25 wksPA 30/19 (mPAP 23)

Male, GA 40 wksPA 23/10 (mPAP 15)

Term Preterm Jacob Macdonald

RV Filling Vortex Is Less Structuredin Adults Born Preterm

Jacob Macdonald

RV Energetically Less Efficientin Adults Born Preterm

Total kinetic energy in the RV was normalized by each subject’s stroke volume to evaluate energetic efficiency

Adults Born Premature Demonstrate Impaired Heart Rate Recovery

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 00

2 0

4 0

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H e a r t R a te R e c o v e ry(a b s o lu te )

S e c o n d s

He

art

Ra

te

(bp

m)

p = 0 .0 3

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0 1 2 06 0

7 0

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H e a rt R a te R e c o v e ry% m a x

s e c o n d sP

erc

en

t (

%)

C o n tro l

P re te rm** * * * * *

p = 0 .0 0 1

Kristin Haraldsdottir, MS

Haraldsdottir, JAP, in revision

Adults Born Premature Demonstrate Impaired Heart Rate Recovery


C o n tr o l P r e te r m 0

1 0

2 0

3 0

4 0

5 0

H R R 1 m in

be

ats

p = 0 .0 0 1

Haraldsdottir, JAP, in revision

Adolescents Born Preterm Appear to Have Similar Cardiac Dysfunction


R e s t 7 0 % P m a x 1 0 0 % P m a x 4 0

5 0

6 0

7 0

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ml/m

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ml/m

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s e c o n d s

be

ats

*

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• Adults born premature have:– Mild elevations in pulmonary arterial pressure– Stiffer pulmonary vasculature– Impaired cardiac response to exercise (SV limitation)

• Also seen in adolescent population– Impaired heart rate recovery after maximal exercise

Summary: Cardiopulmonary Impairment in Adults Born Premature

Premature Birth Associated with a Markedly Increased Risk for Heart Failure

Why such a marked increase risk for heart failure?

Right ventricular dysfunction out of proportion to degree of

pulmonary vascular disease?

Animal Models of Chronic Lung Disease of Prematurity

O’Reilly, AJP Lung 2014.Botting, Clin Exp Pharmacol Physiol 2012

Relevant for cardiac development as well? Timing of cardiac binucleationHuman: 32 weeks gestationRat: PND 4

Postnatal Hyperoxia Exposure in Rats Recapitulates the known RV-PV Phenotype in Humans

Goss, AJRCMB 2017.

N x-M

N x-F

H x-M

H x-F

0 .0

0 .1

0 .2

0 .3

R V H y p e r tro p h y

RV

/(L

V+

S)

N o rm o x ia H y p e ro x ia

p < 0 .0 0 1

p < 0 .0 1

p = 0 .0 6

N x-M

N x-F

H x-M

H x-F

0

2 0

4 0

6 0

8 0

R V E je c t io n F ra c tio n

Eje

ctio

n F

ract

ion

(%

)


p = 0 .0 1

p < 0 .0 1

N x-M

N x-F

H x-M

H x-F

0

1 0

2 0

3 0

4 0

R V S y s to lic P re s s u r e

Pre

ssu

re (

mm

Hg

)


p < 0 .0 0 1

p = 0 .0 0 5

N x-M

N x-F

H x-M

H x-F

0

5 0

1 0 0

1 5 0

2 0 0

C a rd ia c O u tp u t

CO

(m

L/m

in)


Postnatal Hyperoxia Exposure in Rats Results in RV Dysfunction and RV-PV Uncoupling

Goss, AJRCMB 2017.

Nx -

MN

x -F

Hx -

MH

x -F

0 .0 0

0 .0 5

0 .1 0

0 .1 5

A rte r ia l E la s ta n c e (E a )

Ela

sta

nc

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(cm

H2

O/m

l)


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p = 0 .0 5

Nx -

MN

x -F

Hx -

MH

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0 .0 5

0 .1 0

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0 .2 0

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E S P V R (E e s )

ES

PV

R (

mm

Hg

/ µl)


p = 0 .0 4

Nx -

MN

x -F

Hx -

MH

x -F

0

1

2

3

V e n tr ic u lo v a s c u la r C o u p lin g (E e s /E a )

Ee

s/E

a


p < 0 .0 1

p < 0 .0 1

p < 0 .0 0 1

• Adaptive RV hypertrophy gene expression persists– ↑ VEGF and Apelin, ↓ Hexokinase 1

• Absence of fibrosis or impaired autophagy

• BUT appear to have increased mitochondrial dysregulation– Increase in RV mitochondrial number– Decreased mitochondrial biogenesis – Evidence of mitochondrial DNA damage– Mitochondrial dysfunction not typical of rat PAB models

RV Dysfunction is “Out of Proportion” to a Mild Chronic Pressure Overload State

Goss, AJRCMB 2017.

Pulmonary Vascular Disease Stabilizes,Bimodal RV Dysfunction

0

0

2 0

4 0

6 0

R V S P

P o s tn a ta l A g e

RV

SP

(m

mH

g)

21 35 90 365

*

*

*

0

4 0

5 0

6 0

7 0

8 0

E F


Eje

cti

on

Fra

cti

on

(%

)

N o rm o x ia

H y p e ro x ia

21 35 90 365

*

*

7 14 21 90 365

0.0

0.2

0.4

0.6

0.8

Fulton Index

Postnatal Age

RV

/(L

V+

S)

*

*

**

Pulmonary Vascular Disease Stabilizes,Bimodal RV Dysfunction

0

0

2

4

6

R V -P V C o u p lin g


Ee

s/E

a

21 35 90 365

*

*

0

0

1

2

3

E S P V R


ES

PV

R (

mm

Hg

/µl)

21 35 90 365

*

0

0 .0

0 .5

1 .0

1 .5

2 .0

E a


Ea

(m

mH

g/m

l)

21 35 90 365

*

*

RV Dysfunction Due to Mitochondrial Dysfunction

Late RV Mitochondrial Dysfunction Caused by Accumulation of mtDNA Mutations

P 21

P 90

P 36 5

0 .7

0 .8

0 .9

1 .0

1 .1

1 .2

N D 4 :N D 1

Fo

ld I

nd

uc

tio

n

N o rm o x ia

H y p e ro x ia

** **

Males Females

Nor

mox

iaH

yper

oxia

N x-M

N x-F

H x-M

H x-F

0

5

1 0

1 5

2 0

C O X D e f ic ie n t C a rd io m y o c y te s

%

CO

X

De

fic

ien

t


***

***

p = 0 .0 9

N x-M

N x-F

H x-M

H x-F

0 .0

0 .5

1 .0

N D 4 :N D 1

Fo

ld C

ha

ng

e


**

*

*

Goss, AJRCMB 2017.

Accumulation of mtDNA Mutations Follows Increased Mitochondrial Biogenesis

P 21

P 90

P 36 5

0 .0

0 .5

1 .0

1 .5

2 .0

P P A R a

Fo

ld In

du

ctio

n

** **

P 21

P 90

P 36 5

0 .0

0 .5

1 .0

1 .5

2 .0

T F A M

Fo

ld In

du

ctio

n

*** ***

P 21

P 90

P 36 5

0 .0

0 .5

1 .0

1 .5

2 .0

2 .5

P G C 1 a

Fo

ld In

du

ctio

n** ***

P 21

P 90

P 36 5

0 .0

0 .5

1 .0

1 .5

2 .0

2 .5

P o ly m e r a s e G a m m a

Fo

ld In

du

ctio

n

N o rm o x ia

H y p e ro x ia

*** **

• Key concepts:– Predictive adaptive responses of the fetus to environmental

cues• Mismatch between prenatal and postnatal environments

“To survive in a stressful or nutrient-poor environment, a fetus must make “choices” about how to use scarce resources

in a way that maximizes the likelihood of survival in early life, even at the expense of greater susceptibility to chronic illnesses

and increased mortality in adulthood.”

The Barker Hypothesis: Developmental Origins of Heath and Disease

Wadhwa, Semin Reprod Med 2009

• Adults born preterm have elevated resting PAP– Increased pulmonary vascular stiffness– Decreased pulmonary vascular recruitability

• RV dysfunction out of proportion to pulmonary vascular disease– Inability to augment stroke volume– RV energetically less efficient, increased work– Animal studies suggest impaired mitochondrial function in RV

• Bimodal RV response likely to have implications for screening

Summary: Right Ventricular-Pulmonary Vascular Interactions in Adults Born Preterm

Acknowledgements

Funding: NHLBI R01 HL115061 (Eldridge), NHLBI R01 HL115061-03, Suppl(Eldridge/Goss), CTSA grant UL1TR000427 (Goss KL2), PHA Barst Award (Goss)

• Marlowe Eldridge, MD• Collaborators:

– Mari Palta, PhD (Newborn Lung Project)– Luke Lamers, MD (Peds Cardiology)– Chris François, MD (Radiology)– Oliver Wieban, PhD (Med Physics)– Alan McMillan, PhD (Radiology)– Naomi Chesler, PhD (Biomedical

Engineering)– Tim Hacker, PhD (CV Physiology Core)

• Lab Members: – Santosh Kumari, PhD– Arij Beshish, MBBCh– Greg Barton, PhD– Ruedi Braun, PhD– Kristin Haraldsdottir, MS– Laura Tetri, MD/PhD candidate– Jacob McDonald– Ashley Mulchrone– David Pegelow– The undergraduate army

Impaired Right Ventricular-Pulmonary Vascular Interactions in Adults Born PrematureWhen I grow up, I want to be a…?OutlineObjectivesIncidence of Premature Birth Is RisingSlide Number 6TerminologyTerminologyThe First US Neonatal Care Unit“Growing Pains” in Neonatal CareModern Neonatal CareAdvances in Neonatal Care�Improve MortalityMajor Neonatal Comorbidities:�Bronchopulmonary DysplasiaSlide Number 14Adults Born Premature Demonstrate Poorer Respiratory Outcomes Slide Number 16Preterm Birth May Limit Adult� Pulmonary Vascular EndowmentPreterm Birth May Limit Adult� Pulmonary Vascular EndowmentPreterm Birth May Limit Adult� Pulmonary Vascular EndowmentRight Ventricular Systolic Dysfunction In Young Adults Born PretermPremature Birth Increases Risk for Pulmonary HypertensionSlide Number 22Long-term Effects of Premature Birth on the Pulmonary Vasculature?Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Summary: Cardiopulmonary Impairment in Adults Born Premature Premature Birth Associated with a Markedly Increased Risk for Heart FailureSlide Number 41Slide Number 42Animal Models of �Chronic Lung Disease of PrematurityPostnatal Hyperoxia Exposure in Rats Recapitulates the known RV-PV Phenotype in HumansPostnatal Hyperoxia Exposure in Rats Results in �RV Dysfunction and RV-PV UncouplingSlide Number 46Slide Number 47Slide Number 48Slide Number 49Slide Number 50Slide Number 51Slide Number 52The Barker Hypothesis: �Developmental Origins of Heath and Disease�Slide Number 54Acknowledgements

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