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
Beshish, AJRCCM, in revision
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)
*
Beshish, AJRCCM, in revision
Adults Born Premature Unable to Augment Stroke Volume During Exercise
R e s t E x e r c is e5 0
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
SV
I (m
l/b
ea
t/m
2)
∆ S V I P = 0 .0 4
R e s t E x e r c is e2
4
6
8
1 0
1 2
C a rd ia c In d e xR e s p o n s e to E x e rc is e
CI
(L/m
in/m
2)
T erm
P re te rm
p = 0 .0 6
R e s t E x e r c is e6 0
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
Beshish, AJRCCM, in revision
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
6 0
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
8 0
9 0
1 0 0
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
Kristin Haraldsdottir, MS
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
Kristin Haraldsdottir, MS
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
8 0
S V i
ml/m
2
* * *
R e s t 7 0 % P m a x4 0
5 0
6 0
7 0
8 0
S V i M R I
ml/m
2
T erm
P re te rm
*
10 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 00
1 10
1 20
-6 0
-4 0
-2 0
0
H e a r t r a te re c o v e r y
s e c o n d s
be
ats
*
*
*
* *
• 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
(%
)
N o rm o x ia H y p e ro x ia
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
)
N o rm o x ia H y p e ro x ia
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)
N o rm o x ia H y p e ro x ia
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
e
(cm
H2
O/m
l)
N o rm o x ia H y p e ro x ia
p = 0 .0 1
p = 0 .0 5
Nx -
MN
x -F
Hx -
MH
x -F
0 .0 0
0 .0 5
0 .1 0
0 .1 5
0 .2 0
0 .2 5
E S P V R (E e s )
ES
PV
R (
mm
Hg
/ µl)
N o rm o x ia H y p e ro x ia
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
N o rm o x ia H y p e ro x ia
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
P o s tn a ta l A g e
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
P o s tn a ta l A g e
Ee
s/E
a
21 35 90 365
*
*
0
0
1
2
3
E S P V R
P o s tn a ta l A g e
ES
PV
R (
mm
Hg
/µl)
21 35 90 365
*
0
0 .0
0 .5
1 .0
1 .5
2 .0
E a
P o s tn a ta l A g e
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
N o rm o x ia H y p e ro x ia
***
***
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
N o rm o x ia H y p e ro x ia
**
*
*
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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