Late Pulmonary Vascular LUNG VASCULAR & AIRWAY DENSITY Outcomes - - PowerPoint PPT Presentation

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Late Pulmonary Vascular Outcomes of Prematurity

Marlowe Eldridge, MD, FAAP Departments of Pediatrics, Kinesiology and Biomedical Engineering Director, Rankin Laboratory of Pulmonary Medicine University of Wisconsin-Madison

Disclosures: None

Preterm Birth May Limit Adult Lung Vascular & Airway Endowment

TIME Fetal Childhood Neonatal Adulthood LUNG VASCULAR & AIRWAY DENSITY

Normal Vascular & Airway Development and Aging

Disrupted Vascular Development Secondary Insults

Disrupted Development Leads to Decreased Adult Vascular & Airway Endowment Decreased Development Leads to Increased Susceptibility to Secondary Insults & Accelerated Lung Aging Risk Factors: Prenatal Genetic Epigenetic Environmental Potential Insults: Tobacco Hypoxia Infection Toxins Goss, Pulmonary Circ 2017.

Study Populations: New Born Lung Projects

Palta M, J Pediatr 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 al, Ann Am Thorac Soc 2015; Bates et al NEJM 2015; Haraldsdottir et al Physiol Reports 2018

The Newborn Lung Project 1 (NLP1) is a multicenter population-based cohort of preterm infants with birth weights ≤1500g born between 08/01/1988 (pre-surfactant era) and 06/30/1990 (surfactant era) admitted to 1 of 6 regional NICU’s in the states of Wisconsin and Iowa. Initial enrollment, included 1091 very low birth weight (VLBW)

• infants. 885 survived to discharge and consented for further follow-up and encompasses
• ur target recruitment list. This cohort has been studied serially at ages 5, 8, 10, 21 and

27 years. Healthy age-matched controls were recruited from the general population in the Madison area. Newborn Lung Project 2 (NLP2) is a multicenter population-base cohort of VLBW infants admitted to all 17 Wisconsin NICUs during birth years 2003-2004. Initial enrollment was 1479, at present 979 survived to age 2 and gave permission for follow-up. In addition 465 term-born subjects were recruited from the same hospitals during the same birth years at age 2 years. These 2 groups encompasses our target recruitment list.

Study Design

PA Sheeth

Screening Visit GPAQ PFT’s, DLCO Maximal exercise test Adults & Adolescents Visit #2 (CMRI) Cardiac MR at rest & exercise (70% Pmax) Adults & Adolescents Visit #3 (RHC) RV & PV pressures VE, VO2, VCO2 arterial & mixed venous BG’s at rest & during exercise (70% Pmax) PBF calculated from Fick equation Adults only

RV

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Anthropometric & Pulmonary Function Data

Term N=10 Preterm N=11 P value Anthropometric Data Age (years) 26.3 ± 0.9 27.3 ± 0.8 0.02 Sex (M/F) 7/3 5/6 0.26 Weight (kg) 72.8 ± 9.8 69.3 ± 13.3 0.45 Height (cm) 176.6 ± 7.8 170.0 ± 11.3 0.23 BMI (kg/m2) 23.3 ± 1.7 23.9 ± 3.0 0.66 Pulmonary Function Testing FVC (L) 5.4 ± 1.1 4.7 ± 0.7 0.16 – % predicted 103.8 ± 13.2 103.8 ± 16.6 0.73 FEV1 (L) 4.5 ± 1.0 3.8 ± 0.7 0.11 – % predicted 101.9 ± 15.1 99.1 ± 20.1 0.37 FEF25-75 (L/s) 4.5 ± 1.6 3.6 ± 1.2 0.24 – % predicted 98.3 ± 30.3 87.6 ± 32.6 0.45 FEV1/FVC 0.82 ± 0.06 0.80 ± 0.06 0.73 DLCO (ml/min/Torr) 32.4 ± 6.5 24.4 ± 4.3 0.004 – % predicted 97.8 ± 9.1 81.5 ± 6.4 <0.001 DLCO/VA (ml/min/Torr/L) 5.6 ± 0.8 4.7 ± 0.4 0.002 – % predicted 113.3 ± 18.0 96.3 ± 8.9 0.01

Arij Beshish, MBBCh, PhD

Exercise Capacity

Term N=10 Preterm N=11 P value Exercise Testing VO2max (L/min) 3.5 ± 0.7 2.6 ± 0.6 0.005 – % predicted 135.5 ± 31.7 112.4 ±3 7.0 0.17 VO2max (ml/kg/min) 50.0 ± 10.4 38.1 ± 8.6 0.01 Pmax (watts) 236.5 ± 48.9 187.7 ± 36.0 0.02 Pmax at 70% VO2max (watts) 172.8 ± 31.5 130.5 ± 24.6 0.005 GPAQ (MET/week) 3368 ± 2550 3420 ± 2006 0.79

Arij Beshish, MBBCh, PhD

Goss et al AJRCCM, in review, 2018 Farrell et al AATS, 2015 Males Females Males Females Neonatal Characteristics N (males) 11(5) Gestational age (weeks) 28.6 ± 2.7 (24 – 31) Birth weight (grams) 1087 ± 297 (675 – 1497) Apgar score at 1 minute 3 ± 2 Apgar score at 6 minutes 6 ± 2 Singleton/multiple birth 5/6 Received antenatal steroids Intubated at 24 hours of age (yes/no) 9/2 Received surfactant (yes/no) 2/9 Days of invasive ventilation 15.5 ± 17.7 (0 – 50) Days of noninvasive ventilation 3.9 ± 6.5 (0 – 22) Days on oxygen 93 ± 150 (1 – 514) Days in the NICU 64 ± 30 (33 – 107) BPD diagnosis at discharge (yes/no) 5/6 Persistent PDA (yes/no) 7/4 Diagnosis of PH by echo in NICU

Neonatal Characteristics

Goss et al AJRCCM, In review, 2018

Arij Beshish, MBBCh, PhD

Adults Born Premature Have Elevated Resting Pulmonary Vascular Pressures

mPAP (mmHg) sPAP (mmHg) dPAP (mmHg) Arij Beshish, MBBCh, PhD

Goss et al AJRCCM, in review, 2018

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Adults Born Premature have a Stiffer Pulmonary Vascular Bed

Arij Beshish, MBBCh, PhD

Goss et al AJRCCM, in review, 2018

(mPAP/SV) (mPAP/PBF)

Preterm subjects continue to have higher afterload and stiffer PA in response to exercise

Arij Beshish, MBBCh, PhD

Adults Born Premature Unable to Augment Stroke Volume During Exercise

Arij Beshish, MBBCh, PhD

Goss et al AJRCCM, in review, 2018

Adolescents Born Preterm have similar Cardiac Dysfunction

Kristin Haraldsdottir,MS

Haraldsdottir et al Pediatrics in review 2018

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Left: Cardiac output (CO) versus mean pulmonary artery pressure (mPAP) demonstrates a greater pulmonary vascular resistance (slope) for a given volume of pulmonary flow among preterm subjects. Right: Systolic right ventricular pressure (sRVP) versus stroke volume (SV) demonstrates a lower volume ejected for any RV pressure among preterm subjects.

Goss et al AJRCCM, in review, 2018

Pressure / Flow Relationships during Exercise

Arij Beshish, MBBCh, PhD

Neonatal Days on Ventilatory Support is Strongest Predictor of Adult PAP

Arij Beshish, MBBCh, PhD

Goss et al AJRCCM, in review, 2018

Pulmonary Blood Flow (PBF) and Mean Transit Time (MTT) in term and preterm populations indicate significantly shorter MTT (* p<0.02). Suggest stiff pulmonary vascular bed in preterm’s. May also suggest vascular simplification.

*

Shorter Mean Transit Time in Adults Born Preterm further supports stiffer pulmonary vascular bed

Luis Torres

PC VIPR or 4D Flow (phase contrast vastly-undersampled isotropic projection)

PA SVC IVC RV RA PA SVC IVC RV RA

PC VIPR is a UW-developed 4D phase contrast technique that extends flow encoding from 1 dimension to 3 dimensions. Kevin Johnson PhD UW Med Physics

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Further evidence for a stiffer pulmonary vascular beds in adults born preterm

Preterm

Term Preterm 0.20 0.25 0.30 0.35 0.40 0.45

Pulmonary Artery Relative Area Change

Relative area (%) *

Term Male, PA 23/10 (mPAP 15) Male, GA 25 wks PA 30/19 (mPAP 23)

Term Preterm

Jacob Macdonald

Cardiac Flow Is Less Laminar in Adults Born Preterm

Male, GA 25 wks PA 30/19 (mPAP 23) Male, GA 40 wks PA 23/10 (mPAP 15)

Term Preterm

Jacob Macdonald

RV Filling Vortex Is Less Structured in Adults Born Preterm

Term Preterm

Jacob Macdonald

RV Filling Vortex Is Less Structured in Adults Born Preterm

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Jacob Macdonald

RV Energetically Less Efficient in Adults Born Preterm

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

Macdonald et al J Cardiovascular MR 2018, in review

Representative image of the determination of right ventricular circumferential strain

Greg Barton, PhD

Adults Born Preterm have greater RV strain suggesting a hyperdynamic RV

Greg Barton, PhD

Preterms require a greater proportion of the cardiac cycle to reach peak systolic strain (45% vs 35%). During diastole, preterm demonstrate greater diastolic strain suggestive of altered relaxation kinetics or increased myocardial stiffness.

Strain based analysis further supports decreased RV efficiency

Greg Barton, PhD

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• Adults born premature have:
• Mild elevations in pulmonary arterial pressure
• Stiffer pulmonary vascular bed
• Impaired cardiac response to exercise (SV limitation)
• Evidence of diastolic dysfunction
• Reduced RV efficiency

Summary: Cardiopulmonary Impairment in Adults Born Premature Acknowledgements

Enthusiastic human subjects

Key Collaborators

Kara Goss MD (Medicine & Pediatrics) Mari Palta PhD (NLP, Biostatistics) Luke Lamars MD (Pediatrics)

Research Scientist

Emily Farrell, PhD (Pediatrics) Ruedi Braun PhD (pediatrics) Jens Eickhoff, PhD (Biostatistics)

Pre & Post-Doctoral Trainees

Arij Beshish, MBBCh, PhD (Pediatrics & Physiology) Kristin Haraldsdottir, MS (Pediatrics & Kinesiology) Laura Tetri, PhD (MD/PhD Program) Jacob McDonald, BS (Medical Physics) Luis Torres, BS (Medical Physics) Ashley Mulchrone, BS (Biomedical Engineering) Greg Barton, PhD (Pediatrics & Medical Physics)

Technical Support

David Pegelow, BS (Pediatrics)

Army of Graduate Students Funding:

NIH-NHLBI, RO1 HL086897 (Eldridge) NIH-NHLBI RO1 HL115061 (Eldridge) NIH-NHLBI RO1 HL115061-03:Suppl (Eldridge/Goss) CTSA grant UL1TR000427 (Goss:KL2) PHA Barst Award (Goss) Parker B. Francis Fellowship (Goss)

Heart & Lung Imaging Core

Oliver Wieban, PhD (Medical Physics) Sean Fain, PhD (Medical Physics) Chris François, MD (Radiology) Scott Nagle, MD, PhD (Radiology) Kevin Johnson, PhD (Medical Physics) Naomi Chesler PhD, Biomedical Engineering

Questions / Comments

Hybrid cardiac PET/MR

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Preterm subjects have decreased RV-PV coupling Premature Birth Increases Risk for Pulmonary Hypertension

Naumburg, Acta Paediatr 2015

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