Maturational Patterns of Systolic Ventricular Deformation Mechanics by Two-Dimensional Speckle Tracking Echocardiography in Preterm Infants over the First Year of Age


Maturational Patterns of Systolic Ventricular Deformation 
Mechanics by Two-Dimensional Speckle Tracking 
Echocardiography in Preterm Infants over the First Year of Age

Philip T. Levy1,2, Afif EL-Khuffash3,4, Meghna D. Patel1, Colm R. Breatnach3, Adam T 
James3, Aura A. Sanchez5, Cristina Abuchabe1, Sarah R Rogal2, Mark R. Holland6, Patrick 
J McNamara7, Amish Jain8, Orla Franklin9, Luc Mertens10, Aaron Hamvas11, and Gautam K. 
Singh1

1Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA 
2Department of Pediatrics, Goryeb Children’s Hospital, Morristown, NJ, USA 3Department of 
Neonatology, The Rotunda Hospital, Dublin, Ireland 4School of Medicine (Department of 
Paediatrics), Royal College of Surgeons in Ireland, Dublin, Ireland 5Department of Pediatrics, 
University of Minnesota, Minneapolis, Minnesota, USA 6Department of Radiology and Imaging 
Sciences, Indiana University Purdue University, Indianapolis, IN, USA 7Division of Neonatology & 
Department of Physiology, The Hospital for Sick Children, Toronto, Canada 8Department of 
Paediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada 9Department of Cardiology, Our 
Lady's Children's Hospital Crumlin, Dublin, Ireland 10Division of Cardiology, The Labatt Family 
Heart Centre, The Hospital for Children, Toronto, Canada 11Pediatrics, Northwestern University 
Feinberg School of Medicine, Chicago, IL, USA

Abstract

Background—We aimed to determine the maturational changes in systolic ventricular strain 
mechanics by two-dimensional speckle tracking echocardiography in extreme preterm neonates 

from birth to one year of age, and discern the impact of common cardiopulmonary abnormalities 

on the deformation measures.

Methods—In a prospective multi-center study of 239 extreme preterm infants (< 29 weeks 
gestation at birth), left ventricle (LV) global longitudinal strain and systolic strain rate (GLS, 

GLSRs), interventricular septal wall (IVS) GLS and GLSRs, right ventricle free wall longitudinal 

S and SR (RV FWLS, FWLSRs), and segmental LS (SLS) in the RVFW, LVFW and IVS were 

serially measured at Days 1, 2, 5–7, 32 weeks and 36 weeks post-menstrual age (PMA), and one 

year corrected age (CA). Premature infants who developed bronchopulmonary dysplasia (BPD) or 

had echocardiographic findings of pulmonary hypertension (PH) were analyzed separately.

Correspondence Address: Philip T. Levy One Children’s place Campus Box 8116-NWT St. Louis, MO 63132 Phone: 314-454-6095 
Fax: 314-454-2561 levy_p@kids.wustl.edu.
Philip T. Levy and Afif El-Khuffash equally contributed to writing the first draft of the manuscript

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our 
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of 
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be 
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

HHS Public Access
Author manuscript
J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

Published in final edited form as:
J Am Soc Echocardiogr. 2017 July ; 30(7): 685–698.e1. doi:10.1016/j.echo.2017.03.003.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Results—In uncomplicated preterm infants (n=103, 48%), LV GLS and GLSRs remained 
unchanged from Day 5–7 to one year CA (p=0.60 and 0.59). RV FWLS, FWLSRs and IVS GLS 

and GLSR significantly increased over the same time period (p < 0.01 for all measures). A 

significant base-to-apex (highest to lowest) SLS gradient (p < 0.01) in the RVFW and a reverse 

apex-to-base gradient (p < 0.01) existed in the LVFW. In infants with BPD and/or PH (n=119, 

51%), RV FWLS and IVS GLS were significantly lower (p < 0.01), LV GLS and GLSRs were 

similar (p=0.56), and IVS SLS persisted as an RV dominant base-to-apex gradient from 32 weeks 

PMA to one year CA.

Conclusions—This study tracks the maturational patterns of global and regional deformation by 
2DSTE in extreme preterm infants from birth to one year CA. The maturational patterns are 

ventricular specific. BPD and PH leave a negative impact on RV and IVS strain, while LV strain 

remains stable.

Keywords

Cardiac function; Prematurity; Strain Imaging; Echocardiography

INTRODUCTION

Ventricular performance is an important prognostic determinant of clinical status and long-

term outcome in preterm neonates.1–3 Ventricular mechanics begin to undergo maturational 

changes in the early and late postnatal periods that can have a long-term impact on cardiac 

function beyond the first year of age.2,3 The exposure of an immature preterm heart to a 

sustained increase in hemodynamic load of postnatal circulation, at a time in the 

development when the heart primarily supports a low resistance circulation, induces 

myoarchitectural adaptation that may lead to ventricular remodeling.4,5 The proper 

evaluation of ventricular function in preterm infants by echocardiography has been limited 

by the lack of reliable quantitative parameters.1 Furthermore, there is paucity of longitudinal 

studies on prematurity-related alterations in the maturation of cardiac function beyond the 

early neonatal period. The establishment of sensitive indices of cardiac function in birth 

cohorts affected by prematurity and its common cardiorespiratory complications is a 

necessary prerequisite for the clinical adoption of a normative references patterns for use in 

evaluating pathologic changes and progression.

Myocardial strain is a measure of tissue deformation and strain rate is the rate at which 

deformation occurs. Longitudinal deformation by two-dimensional speckle tracking 

echocardiography (2DSTE) has been validated as a reproducible measure of ventricular 

function in premature infants.6–8 Initial data indicate that measuring deformation values in 

this population could have clinical implication, as they appears to have superior prognostic 

value for assessing and potentially predicting major adverse cardiopulmonary events when 

compared with conventional measurements (i.e. shortening and ejection fraction).9,10 

Maturational patterns of 2DSTE derived longitudinal strain measures during the transitional 

period through the first month of age have recently been established in preterm 

infants.7,8,11–14 However, the evolution of ventricular strain mechanics from birth to one 

year of age for clinical application has not been comprehensively described in a large 

longitudinal preterm cohort.13,15 Disturbances in myocardial function may also impact 

Levy et al. Page 2

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



neonatal morbidity and mortality, but there is limited information on how different 

prematurity associated cardiopulmonary conditions, such as bronchopulmonary dysplasia 

(BPD), pulmonary hypertension (PH), and a persistent patent ductus arteriosus (PDA), 

influence the normal changes in longitudinal cardiac function.16

Since the right ventricle (RV) and left ventricle (LV) are embryologically and structurally 

distinct and their functional roles change in the postnatal period,17 we hypothesized that (1) 

prematurity related maturational changes in RV and LV deformation measures would have 

uniquely different trajectories; and (2) prematurity associated cardiopulmonary conditions 

would influence changes differently in LV and RV mechanics. Accordingly, we aimed to 

determine the maturational (age- and weight-related) changes in LV, RV, and interventricular 

septum (IVS) strain mechanics by 2DSTE in healthy uncomplicated preterm infants not 

affected by significant cardiopulmonary abnormalities, and study the influence of the 

cardiopulmonary abnormalities on the maturational changes in myocardial deformational 

indices from birth through one year of corrected age (CA).

METHODS

Study Population

All data were prospectively obtained as part of an observational research study that included 

patients who were enrolled between August 2011 and January 2016 at hospitals affiliated 

with two academic institutions (Washington University School of Medicine, Saint Louis 

Children’s Hospital, and Royal College of Surgeons in Ireland, Rotunda Hospital). Two 

hundred and thirty nine preterm infants (born 23 0/7 to 28 6/7 weeks gestation) were 

recruited at birth and longitudinally followed until one year corrected age (CA). The preterm 

infants enrolled from the Washington University site were among infants participating in the 

Prematurity and Respiratory Outcomes Program (PROP, Clinical Trials number: 

NCT01435187).18 Infants with any suspected congenital anomalies of the airways, 

congenital heart disease (except atrial septal defects), chromosomal anomalies, intrauterine 

growth restriction (IUGR) or small for gestational age (SGA, birth weight < 10th centile for 

gestation) were excluded from the healthy uncomplicated cohort arm of the study.

At both centers, reference values and maturational patterns of RV fractional area of change 

from these cohorts have been recently published, but deformation imaging by 2DSTE has 

not been reported.19,20 At the Washington University School of Medicine site, a small 

proportion of the deformation data was previously used to test feasibility and 

reporducbility.6,21 At the Royal College of Surgeons in Ireland site, deformation imaging by 

tissue Doppler has been assessed in the transitional period and up to 36 weeks post-

menstrual age (PMA).11,22 The institutional review board of Washington University and the 

ethical committee on human research at Royal College of Surgeons approved the protocol. 

Written informed consent was obtained from the parents or guardians of all participants.

Inclusion Criteria in Uncomplicated Cohort

Only infants with ‘cardio-respiratory healthiness’ were classified as healthy uncomplicated 

infants in this study.19,23 In the early neonatal period, a large proportion of premature infants 

Levy et al. Page 3

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



present with acute respiratory failure that often require some sort of respiratory support up to 

36 weeks PMA, making it difficult to determine a true definition of ‘respiratory 

healthiness’.19,23 Respiratory disease syndrome and the need for invasive and non-invasive 

ventilation are common in extreme preterm birth in the early postnatal period. BPD, defined 

as the need for persistent supplemental oxygen support at 36 weeks’ PMA, is recognized as 

the most significant respiratory consequence of premature birth in the late postnatal 

period.24 If preterm infants still required any respiratory support at or beyond 36 weeks 

PMA, they were excluded from the uncomplicated cohort.24 We assessed for the 

contributions of BPD, as defined by a modified definition of the 2001 National Institutes of 

Health (NIH) BPD workshop24, in a sub-analysis.

Infants with any of the following echocardiographic signs of late onset PH, identified at any 

time point from 32 weeks PMA through one year CA were excluded: an estimated right 

ventricular systolic pressure (RVSP) greater than 40 mm Hg, a ratio of RVSP to systemic 

systolic blood pressure greater than 0.5, any cardiac shunt with bidirectional or right-to-left 

flow, unusual degree of right ventricular hypertrophy or dilatation, or ventricular septal wall 

flattening.19,25 They were assessed in a separate analysis. Since the incidence of PH ranges 

from 12–25% of infants with BPD26, we performed stepwise regression to analyze the 

influence of PH and BPD on ventricular strain patterns.

The significance of a PDA, and its impact on long term cardiorespiratory health, remain 

areas of ongoing debate in neonatology.27 Even the persistent patency of the PDA remains 

an ongoing clinical conundrum, as most premature neonates who fail to close their PDA in 

the first week of age or even by the time of discharge will undergo spontaneous closure a 

few weeks later.28 Prolonged patency is associated with numerous adverse outcomes, but the 

extent to which these adverse outcomes are attributable to the hemodynamic consequences 

of ductal patency, if at all, has not been established.29 However, infants with moderate to 

large PDA, based on its size relationship to the left pulmonary artery (LPA), have a 15 times 

greater likelihood of requiring treatment for clinically and hemodynamically significant 

PDA than those with small PDA.29,30 We, therefore, excluded any infant with a moderate to 

large hemodynamically significant PDA (hsPDA) in the first week of age, and any size PDA 

from 32 weeks and beyond, but a separate sub-analysis was performed for this cohort. For 

this study a hsPDA was defined as a PDA diameter of > 1.5 mm with the presence of flow 

reversal in the descending aorta and a left atrial to aortic root ratio (LA:Ao) of > 1.5.27 In 

addition, we used the relationship of the PDA to LPA to define size and clinical significance 

(large = PDA/LPA ratio > 1, moderate = PDA/LPA ratio < 1 but > 0.5, and small = 

PDA/LPA ratio < 0.5).30 Combined, these approaches allowed us to properly assess PDA 

characteristics, signs of pulmonary over circulation, and left heart-loading condition. Finally, 

infants that underwent pharmacological or surgical intervention at any time point in their 

neonatal course to close a PDA were also excluded from this cohort.

Echocardiographic Examination

Echocardiograms were performed at six time points from birth to one year CA, (Figure 1): at 

Washington University School of Medicine site, the echocardiograms were performed 

serially at Day 1 (n=30), Day 2, (n=30), 32 weeks PMA (n=117), 36 weeks PMA (n=117), 

Levy et al. Page 4

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



and one year CA (n=80). At the Royal College of Surgeons in Ireland site, echocardiograms 

were performed at Day 1 (n=102), Day 2, (n=102), Day 5–7 (n=98), and 36 weeks PMA 

(n=47), (Figure 1). We chose three time points in the first week of age to capture the 

physiological changes that occur during the transitional period in preterm infants. The 

timings of the echocardiograms at 32 weeks PMA, 36 weeks PMA and one year CA were 

carefully selected to avoid the early postnatal period of clinical and cardiopulmonary 

instability and early mortality associated with extreme preterm birth.6 Choosing to study all 

infants at a common PMA and CA optimizes the determination of the impact of gestational 

and chronological age on cardiac function at a specific developmental stage, and allows for 

the analysis of measures by post-gestational weeks from birth.6 The infants’ antenatal, 

delivery and demographic characteristic were obtained.

Echocardiograms were performed using the same commercially available ultrasound 

imaging system (Vivid 7 and 9; General Electric Medical Systems, Milwaukee, Wisconsin) 

at each center. One designated trained pediatric cardiac sonographer at each center obtained 

all the echocardiographic images using a phased array transducer (7.5–12 MHz).6 The 

echocardiographic images were acquired using a standardized image acquisition protocol in 

decubitus position during restful period without changing the position of the infant or 

disturbing the hemodynamic condition to minimize heart rate and respiratory variation 

during image acquisition.31 The image data were digitally stored in raw DICOM cine-loop 

format for offline analysis. Heart rate and blood pressure readings were recorded at the time 

of each echocardiogram.

Strain Analysis

Two-Dimensional Speckle Tracking Imaging—Myocardial mechanics were analyzed 
by the quantification of LV, RV, and IVS longitudinal strain (LS, %) and systolic strain rate 

(SRs, %/sec) using previously published image acquisition and data analysis protocols from 

our laboratories. 6,21 A frame rate to heart rate ratio (FR/HR) between 0.7 and 0.9 

frames/sec per bpm was utilized to optimize myocardial speckle tracking and mechanical 

event timing.21 LV global LS (LV GLS) and SRs (LV GLSRs) were calculated by averaging 

all values of the regional peak LS and SRs obtained from 17 segments in two-chamber, 

apical long-axis, and four- chamber apical views.32 RV free wall LS (RV FWLS) and SRs 

(RV FWLSRs) were calculated as the average of the three segmental longitudinal strain 

(SLS) measures in the RV FW from the RV focused apical four-chamber view.6 LV SLS at 

the apex, mid- and basal ventricular levels was calculated by averaging each segment from 

the two-chamber, apical long-axis, and four- chamber apical views of the LVFW. RV SLS 

was obtained from the segments at the apical, mid-ventricular, and basal levels of the RVFW 

from the RV focused apical 4-chamber view. Although IVS strain is incorporated in LV 

GLS, we decided to also measure IVS global and SLS with a new region of interest that only 

covered the width of the IVS from the trigonal crux at the basal septal side of the triannular 

plane to the apical point at the apical junction of the IVS and free walls.6 This separate 

region of interest would allow us to determine if the IVS strain has its own unique trajectory, 

distinct from the LV. In this model, IVS GLS is averaged from all the values obtained from 

9-segments in the two-chamber, apical long-axis, and four- chamber apical views along the 

IVS wall only. Peak strain for each index was measured as end-systolic strain at the closure 

Levy et al. Page 5

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



of the aortic valve.33 Two observers, who were blinded to the maternal and infant clinical 

and cardio-respiratory conditions, analyzed the strain imaging using vendor customized 

commercially available software (EchoPAC; General Electric Medical Systems, Waukesha, 

WI, USA, version 112).

Reproducibility of Strain imaging in Preterm Infants

We along with other groups have previously demonstrated that 2DSTE-derived LS imaging 

of the RV, LV, and IVS is highly feasible and reproducible in premature infants using 

specific cardiac image acquisition and postprocessing data analysis protocols.6–8,14,34,35 

These protocols have improved the image acquisition and reduced variance that has resulted 

in improved reliability of strain as measure of ventricular function in preterm infants. 

Reproducibility of SLS has not been comprehensively analyzed in preterm infants.7,14 We 

assessed SLS reproducibility using intra- and inter-observer variability analysis (Bland 

Altman plot analysis, intraclass correlation coefficient, and coefficient of variation) in 25% 

of the images at each time point. Two observers performed offline analysis using the same 

measurement protocol and were blinded to the patients’ clinical status, and one another.

Statistical Analysis

All data are expressed as mean ± SD or as percentages. Continuous variables of strain 

imaging were tested for normality using the Kolmogorov-Smirnov test and a histogram 

illustration of the data. Analysis of variance and student t tests were used to compare the 

changes in deformation values from birth to one year CA in the preterm infants and to 

compare the patterns between uncomplicated preterm infants and those with BPD, PH, 

and/or a persistent PDA, respectively. All outcome variables with non-normal distributions 

were analyzed in simple comparisons using Wilcoxon rank sum tests or Kruskal-Wallis one-

way analysis of variance for tests with more than two independent groups. Chi-square tests 

(or Fisher Exact test as appropriate) were used to assess the association between categorical 

variable. Two-way ANOVA with repeated measures was used to compare change over time 

between infants with and without BPD, PDA, and PH. Percentile charts (mean ± SD) were 

created using linear regression to assess the independent effect of postnatal age (in weeks) 

and weight (at time of echocardiogram) on each strain measurement, while adjusting for 

gestational age at birth and gender. Finally, generalized logistic regression models were 

developed to identify risk factors for BPD and/or PH at 36 weeks PMA using a stepwise 

variable selection.25 The statistical analysis was performed using SPSS version 14.0 (SPSS, 

Inc., Chicago, IL).

RESULTS

Study Population Characteristics

Two–hundred and thirty-nine infants with a median gestation of 27.0 weeks (IQR 26.0 – 

28.0) and birthweight of 960 g (IQR 800–1,138) were recruited in this study (137 patients 

from the Washington University site and 102 patients from the Royal College of Surgeon 

site). Of the 239 patients, 17 infants (7% with equal distribution amongst centers) died prior 

to hospital discharge and were excluded from the analysis, leaving 222 infants with data to 

be analyzed. Ninety-five (43%) were female and 182 (82%) were delivered by caesarean 

Levy et al. Page 6

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



section. Two hundred and thirteen (96%) received at least one course of antenatal steroids 

and all infants received postnatal surfactant replacement therapy. There were relatively lower 

rates of chorioamnionitis (n = 20, 9%), pre-eclampsia (n = 56, 25%) and antepartum 

hemorrhage (n = 38, 17%). Complete studies were available for >95% of infants on Days 1, 

2, 5–7, and at 32 weeks PMA. Fifty-eight infants were transferred to peripheral hospitals 

prior to 36 weeks PMA leaving 164 infants (74%) available for assessment at that time point 

(Figure 1). Although echocardiographic data was unavailable at 36 weeks for the transferred 

infants, their respiratory outcome data at 36 weeks PMA was obtained. At one year CA, 81 

(69% of the eligible infants from the Washington University cohort) returned for an 

echocardiogram. The clinical and demographic characteristics of the preterm patients are 

summarized and compared by time point in Table 1.

BPD was diagnosed in 52% of all infants (n=116/222). There were echocardiographic signs 

of PH in (15%) at 32 and 36 week PMA. On Day 5 – 7, 57 infants (58%) had a PDA of 

which 33 (34% of total cohort) were classified as hsPDA. None of the infants underwent 

PDA treatment during the first week of age. However, 66 infants (30%) eventually received 

pharmacological therapy and 26 (12%) underwent surgical intervention to close the PDA. Of 

the remaining infants who did not receive any intervention to augment its closure, a PDA 

was evident in 19 infants (16%) at 32 weeks PMA, 18 infants (16%) at 36 weeks PMA. 

None of the infants received inotropes or administration of inhaled nitric oxide. Therefore, 

after meeting all inclusion criteria, 103 patients (47%) infants were classified as “healthy 

uncomplicated preterm infants” (Figure 1). Table 2 compares the maternal and infant 

characteristics between those infants classified as healthy uncomplicated and infants 

classified with cardio-respiratory disease.

Maturational Patterns of Myocardial Strain in Uncomplicated Preterm Infants

In uncomplicated preterm infants (n=103), a time-specific maturational pattern revealed that 

RV FWLS and FWLSRs had stable pattern from Day 1 and 2 and their magnitudes increased 

by Day 5–7, p < 0.05. (Table 3). RV FWLS and FWLSRs continued increasing in magnitude 

from Day 5–7 to one year CA (−20.5% ± 3.2 to −27.2% ± 2.3, p < 0.01 and −2.7% ± 1.2 to 

−3.3 ± 0.3 p < 0.01, Figure 2A). IVS GLS and GLSRs followed the same pattern as RV 

strain mechanics (Figure 2B, Table 3). The magnitudes of LV GLS and LV LSRs increased 

from Day 1 to Day 5–7 (−18.4% ± 3.5 to −21.8% ± 3.2 and −1.8 1/s ± 0.3 to−2.4 1/s ± 0.4, p 

< 0.05 for both) and then remained stable through one year CA (−21.8% ± 3.3 to 21.1% 

± 0.4, p=0.56 and −1.9 ± 0.2 to −1.9 ± 0.7, Figure 2C).

Maturational changes in LV, RV, and IVS strain were further analyzed to produce percentile 

charts (mean ± 2 SD) related to gestational age at birth and postnatal age- and weight-related 

changes. RV FWLS and IVS GLS were linearly associated with gestational age (r=0.76 and 

0.77, p=0.001), while LV GLS and FWLS were not (r=0.34 and 0.44, p > 0.1). Step-wise 

regression analysis of the effects of gender, birth weight, change in postnatal weight, total 

oxygen days, length of stay, and common neonatal morbidities (necrotizing enterocolitis, 

intraventricular hemorrhage, and retinopathy of prematurity, Table 2) on maturation of LS 

revealed that at all time points increasing RV FWLS and IVS GLS were associated with both 

increasing weight (r = 0.76, 0.78. p < 0.01) and postnatal age (r = 0.78, 0.81, p < 0.01), 

Levy et al. Page 7

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Table 4. LV, RV, and IVS SRs imaging followed similar patterns as strain values, when 

adjusted for weight and postnatal age (Tables 4 and 5).

Maturational Patterns of Regional Myocardial Strain in Uncomplicated Preterm Infants

RV FW had a persistent base-to-apex SLS (highest to lowest) gradient from birth to one year 

CA (p < 0.001 at all time points). Similar to the RV FWLS, the magnitude of each SLS 

value at the basal-, mid-, and apical- ventricular regions increased throughout maturation (p 

< 0.001 for each level). IVS SLS had an initial base-to-apex gradient on Day 1 and Day 2 (p 

= 0.002 and p = 0.003, respectively) that switched to an apex-to-base gradient (highest to 

lowest) at Day 5–7 (p < 0.001) that persisted to one year CA (p < 0.001). LV FW had a 

stable apex-to-base longitudinal strain gradient over the same time period (p < 0.001 for all 

time points), (Table 6).

Confounding Cardiopulmonary Factors

BPD. Infants with BPD (n = 116, 52%) had a significantly lower gestational age than those 

without BPD [median (range); 25.7 (25.1 – 28.2) vs. 27.5 (24.6 – 27.6) weeks, p < 0.001] 

There were no significant differences in measures of LV, RV, or IVS strain and SRs between 

groups during the first week of age (all P < 0.19). However, the magnitude of RV FWLS and 

IVS GLS were significantly lower in preterm infants with BPD compared to uncomplicated 

preterm infants at 32 weeks (p=0.002 and p < 0.001, respectively), and these patterns 

persisted to one year CA (p < 0.001 for both, Figure 2A and 2B). The association between 

BPD and low RV FWLS (p = 0.024) and low IVS GLS (p = 0.015) remained significant 

when adjusting for gestational age, gender, and postnatal steroid use. Despite the differences 

between groups, the magnitudes of RV FWLS and IVS GLS increased, but at a slower rate 

from 32 weeks to one year CA in preterm infants with BPD (slope of change comparison 

between infants without BPD and with BPD for RV FWLS and IVS, 0.26% vs. 0.07, p< 

0.001 and 0.32% vs. 0.11, p< 0.001, respectively), (Figure 2A). RV FW maintained a base-

to-apex SLS gradient from 32 weeks to one year CA (p < 0.001 at each time point), but the 

magnitude of each segment was decreased in preterm infants with BPD compared to 

uncomplicated preterm infants (p=0.01). On the other hand, LV GLS, GLSr, FWLS, and 

FWLSRs all remained stable (p=0.56, p=0.62, p=0.59, p=0.45 respectively) with a persistent 

FW apex-to-base SL gradient in preterm infants with and without BPD at each time point (p 

< 0.01 for all), (Figure 2C). The individual IVS strain segments were decreased in premature 

infants with BPD when compared to uncomplicated preterm infants at all time points (p < 

0.05 for each segment at each time period), (Table 6). There was also a persistent base-to-

apex IVS SLS gradient (reflective of the RV pattern) by Day 5–7 (p < 0.01) that did not 

reverse to the expected apex-to-base IVS SLS gradient (reflective of the LV pattern) in 

infants with BPD, even by one year CA (p = 0.002), (Table 6). Gestational age at birth and a 

persistent IVS SLS base-apex-pattern at Day 5–7 were significantly associated with the 

development of BPD in this analysis, (RR, 1.15; 95% CI, 1.03–1.33, p=0.03 and RR, 1.23; 

95% CI, 1.09–1.40, p < 0.001, respectively).

Infants who received antenatal steroids had a higher LV GLS [−18.6 ± 3.5) vs. −16.4 ± 3.9) 

%, p=0.04] at Day 1. This relationship remained significant when adjusting for gestation on 

linear regression (β = 2.1, p=0.04), but disappeared after Day 1. Postnatal steroids were 

Levy et al. Page 8

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



administered in 35 infants (16%) at least one time during their hospital course. The majority 

(n=31/35, 88%) of the infants received postnatal steroids to treat lung disease beyond the 

first month of age, and these infants were also diagnosed with BPD. The four infants who 

did not develop BPD received steroids in the first month of age to facilitate a trial of 

extubation. There was no statistical difference in the maturational patterns of strain between 

those infants that did and did not receive postnatal steroids (p=0.45), although the study was 

not properly powered to answer this question.

PH—Based on echocardiographic evidence, we found an overall incidence of PH of 15% 
(n=17) at 32 weeks PMA, 9% (n=17) at 36 weeks PMA, and 1% (n=1) at one year CA. 

Overall, 71% (n=12) of the preterm infants with PH at 36 weeks PMA returned for follow 

up at one year CA, of whom 25% (n=3) did not carry a diagnosis of BPD. None of the 

infants with PH at 36 weeks PMA required oxygen or respiratory support at one year CA. 

LV GLS, GLSRs and FW SLS patterns were unchanged between the infants with and 

without the evidence of PH at 32 and 36 weeks PMA (p > 0.35 for all). All the infants with 

PH at 32 and 36 weeks PMA continued to have persistently decreased RV FWLS and IVS 

GLS (p=0.01 and p=0.002), with an altered IVS base-to-apex SLS gradient at one year CA 

(reflective of the RV pattern) when compared to those infants without PH, even after 

adjusting for the presence of BPD (β=2.9, p<0.001), (Table 6). The Day 5–7 risk factor of a 
persistent base-to-apex gradient (RR, 2.15; 95% CI, 1.18–4.33, p=0.02) was associated with 

late PH at 36 weeks PMA. There were three infants at 32 weeks PMA and 5 infants at 36 

weeks PMA that were not diagnosed with BPD, but had echocardiographic signs of PH. 

These infants also had lower values of RV FWLS and IVS GLS (p=0.02 and p=0.002), an 

IVS base-to-apex (reflective of the RV pattern) SLS gradient (p < 0.01), and preserved LV 

GLS (p=0.62) with an apex-to-base SLS gradient that persisted to one year CA (p < 0.001), 

when compared to uncomplicated infants..

PDA—The influence of a hsPDA present at Day 5 – 7 on the deformation measurements 
was assessed. Thirty-three infants (out of 98, 34%) were classified as having a hsPDA: their 

PDA diameter (3.1 [2.7 – 3.6] vs 0 [0 – 2.2] mm, p<0.001), and LA:Ao ratio [1.8 ± 0.3 vs. 

1.4 ± 0.3, p<0.001] were all higher than infants without a hsPDA (and all hsPDA infants had 

flow reversal in the abdominal aorta). On Day 5 – 7, infants with a hsPDA had higher LV 

GLS [−23.9% ± 2.4) vs. −20.6% ± 3.3), p<0.001] and higher RV FWLS [−22.6 ± 5.2) vs. 

−20.3 ± 4.3), p=0.04], Figure 3A and 3C). There was no difference in LV or RV SRs 

between the two groups (p > 0.52 for all measures) at any time points in the first week of age 

(Figure 3B and 3D). A hsPDA maintained its independent effect on LV GLS when adjusting 

for LV SRs (hsPDA β=2.7, p<0.001 and LV SRs β=5.0, p<0.001). However, the association 
between a hsPDA and RV FWLS was lost when adjusting for RV SRs (hsPDA β=2.1, p=0.1 
and RV SRs β=2.1, p=0.04). There was no difference in the maturational patterns of RV, LV, 
or IVS GLS or SLS between infants who still had PDA at 32 weeks PMA (n=25, 21%), 36 

weeks PMA (n=14, 12%), or one year CA (n=2, 2%), (adjusted for age, gender, and PDA 

size) and those who did not have PDA at these time points (p = 0.26, p= 0.32, p=0.29, 

respectively).

Levy et al. Page 9

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Feasibility and Reproducibility

The reproducibility analysis for RV, LV, and IVS SLS measures is summarized in Appendix 

1. The measurements were feasible in 89% of the images using the methods previously 

described by our group for image acquisition.6 For all measurements (intra- and inter-

observer variability), the bias ranged between 8% and 14%, coefficients of variations ranged 

between 9% and 16%, and intraclass correlation coefficient ranged between 0.81and 0.93.

DISCUSSION

In a prospective multi-center longitudinal study of a large cohort of premature infants (≤ 29 

weeks at birth), we evaluated ventricular mechanics with 2DSTE derived deformational 

indices from birth to one year CA to determine the maturational patterns of postnatal cardiac 

adaptation. The main findings of this study are that: (1) RV longitudinal strain has a distinct 

regional magnitude distribution with a base-to-apex gradient and an incremental progression, 

while LV strain has an apex-to-base magnitude gradient with relatively unchanged 

progression through the neonatal period and infancy in uncomplicated preterm infants; and 

(2) preterm infants who develop BPD and/or PH have similar LV strain patterns but with 

decreased magnitudes of RV and IVS strain that track lower to those in uncomplicated 

preterm infants through the late neonatal period and infancy, even after clinical resolution of 

BPD and PH.

The functional evaluation of each ventricle by echocardiography in preterm infants is an area 

of ongoing research, but has been limited by the lack of reliable quantitative parameters that 

can be used for the assessment of both RV and LV function.1 The complex three-

dimensional structure of the RV, with thin wall and high compliance, is evolutionally and 

embryologically different from the thick-walled and highly contractile LV. Despite these 

morphological differences, deformation imaging by 2DSTE has emerged as a reliable 

technique to assess global and regional myocardial function in each ventricle and permits a 

more direct assessment of myocardial function in preterm infants during this transitional 

period and through one year CA that could not be previously obtained with conventional 

modalities.9,10 In addition, deformation imaging has been mostly limited to the early 

postnatal period in preterm infants.1,6–8,10,12–14,16,21,35 We leveraged the large cohort of 

preterm infants in a multi-center format to study the impact of prematurity on the maturation 

of cardiac function in the preterm infants.18 This is the largest study to longitudinally assess 

strain imaging with 2DSTE in preterm infants up to one year CA. We showed that 

myocardial mechanics in both ventricles undergo unique longitudinal maturational changes 

in preterm infants, and that this maturation trajectory is influenced by body weight and age. 

We also studied the impact of different cardiopulmonary diseases’ influence on these 

adaptive processes.

Maturational Patterns of Ventricular Strain in Uncomplicated Preterm Infants

RV FWLS and IVS GLS—Myocardial function undergoes unique longitudinal changes in 
preterm infants that are specific to each ventricle. RV FWLS, and IVS GLS remained 

relatively stable from Day 1 to Day 2, but then physiologically increased from Day 5–7 to 

one-year CA. Nasu et al. found no change in RV strain patterns over the first 72 hours of age 

Levy et al. Page 10

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



(ranged between -19.0% and −22.0%).8 Schubert et al observed similar values in the first 

week of age (−20.5% ± 5.5).16 Interestingly, deformation indices were also higher in the RV 

than the LV beginning at 32 weeks PMA and persisting to one year CA, which is in 

concordance with previous studies in children and neonates.22,35,36 In this study, the 

increase of RV and IVS strain in uncomplicated preterm infants was influenced by both 

postnatal increase in weight (in grams) and post-gestational age (in weeks), Figure 3. The 

relative higher values of RV strain and its progressive increase throughout the late neonatal 

period and infancy (when compared to LV strain) is probably related to the more 

longitudinal orientation of RV fibers with a predominant longitudinal contraction pattern in 

the RV compared to the LV.6,32

The higher RV strain is also reflected in the increased metabolic demand of RV myocardium 

that leads to a larger percentage ratio of collagen matrix to myofibers when compared to the 

LV myocardium.37 Despite the overall reduction in cardiomyocyte endowment in the 

preterm neonate, the increased extracellular matrix (ECM) deposition in the RV and the 

changing postnatal loading conditions result in different properties of deformation between 

the LV and RV.5,17 The decreasing afterload that results from a postnatal drop in pulmonary 

vascular resistance also leads to an increase in RV deformation over time.19 In a small 

comparative study of preterm and term infants from birth to six months of age, Schubert et 

al. observed an increasing upward trend in RV and IVS strain values.16 In larger studies, 

both Hefler and Cerznick38 and James et al11,22 observed that tissue Doppler- derived RV 

and IVS strain values rose significantly from birth to 28 days of age and 36 weeks PMA, 

respectively. With 2DSTE-derived strain, Czernik et al. also observed a rise in IVS GLS over 

the first 28 days of age.14 Our findings are consistent with these recent reports that had 

shorter follow-up time.

LV GLS—Compared to RV strain patterns, LV GLS remained relatively unchanged from 
Day 5–7 through one year CA. We did observe an increase in LV GLS from Day 1 to Day 5–

7. LV strain values do not change markedly with age or heart rate in uncomplicated children, 

despite the alteration in loading conditions and changes in myocardial properties that occur 

during early childhood.39 There are a few studies in neonates that have demonstrated similar 

stable maturational pattern of global LV strain from birth through six months of 

age,8,11–14,16 however, none of these studies followed the infants to one year CA. Nasu et al. 

performed eight serial echocardiograms over the first 72 hours of age and demonstrated no 

change in LV strain.8 Czernik et al.14 and de Waal et al.12 each serially observed stable 

2DSTE-derived LV GLS in preterm infants from birth to 28 days of age. Hirose et al. 

demonstrated that clinically healthy preterm infants (delivered at < 30 weeks gestation) also 

have constant 2DSTE-derived LV strain measures from 28 days of age to near term 

equivalent age (3 months CA).13 Schubert et al. observed that in a small heterogeneous 

cohort of 25 preterm infants (16% had BPD, and 40% had septicemia), and 30 term infants 

that there was relatively uniform LV strain values from birth to six month of age.16 These 

results coincide with the findings of Helfer and Czernik38 and James et al11,22 whose groups 

used tissue Doppler-derived strain imaging to demonstrate relative stability in LV strain 

imaging in preterm infants from birth through 28 days and 36 weeks PMA, respectively. 

Two recent meta-analyses defined reference values of 2DSTE-derived LV GLS in health 

Levy et al. Page 11

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



term-born neonates that were also stable from birth to one year of age. 32,40 Although we 

observed a slight increase in LV GLS from Day 1 to Day 5–7, the impact of this early 

transitional period on LV strain patterns remains unclear from individual studies because of 

the variable methodologies and timings of scans employed in all those studies described 

above.

All of the previous studies in preterm infants only measured LV deformation from the apical 

four-chamber view.7,8,12–14,16 This is the first study to calculate the true “global” strain as an 

average from the three apical views.32 We further speculate that this difference is one reason 

for the disparity in reported values between studies, as well as the observed increase in LV 

GLS from Day 1 to Day 5–7 in our study. LV GLS is defined by different LV segmentation 

models, and it is recommended that each segment should be evaluated in multiple views to 

assess complete wall motion.31–33,41 Despite these recommendations, deformation imaging 

is still reported only from the apical 4- chamber view.32 However, despite that lack of 

uniform consensus on “which approach is more accurate or correlates more efficiently with 

health and disease,” it appears that by the end of the first week of age there is relative 

stability in LV strain patterns that persists throughout maturation, irrespective of which 

approach is utilized.32

Segmental LS—In the RVFW there is a base-to-apex SLS gradient that reflects the base-
to-apex alignment of the dominant deep longitudinal layers of the RV, and allows for greater 

longitudinal shortening.42 In this study and the report by Schubert et al.16 there was a base-

to-apex SLS gradient in the RVFW that was preserved throughout maturation. In the LVFW 

there exists an apex-to-base SLS gradient in children that occurs because of two primary 

reasons: (1) Torsional mechanisms of LV deformation is greatest toward the apex, as the 

right-handed helix in the subendocardium and the left-handed helix in the subepicardium 

converge toward the apex to form the “vortex of the double helical loop;” and (2) the electric 

excitation of cardiac motion begins in the apex and travels to the base.32,43 Coinciding with 

previous reports by Czernik et al.14 and de Waal et al.7, there existed a stable apex-to-base 

LV dominant SLS gradient in the LVFW that reflects the relatively constant geometry of the 

normal heart with maturation. In the IVS, there was also a persistent apex-to-base gradient 

(LV-dominant pattern32) in uncomplicated preterm infants that increased from Day 5–7 to 

one year CA. A series of meta-analysis defined similar reference ranges and physiological 

developmental patterns of SLS at the apical-, mid-, and basal- ventricular levels of the LV 

(apex-to-base) and RV (base-to-apex) FWs in healthy term-born children less than one year 

of age.32,42 Alteration of these “physiological” gradients have the potential to discern 

clinical changes in regional myocardial function in patients with different disease 

processes.32,42

Clinical Implications of Deformation Imaging in Neonates

Children with BPD and PH are much more likely than their gestational age counterparts to 

develop long-term respiratory morbidity that may affect the cardiovascular system.44 The 

extent to which prematurity-related alterations in cardiopulmonary structures affect their 

function has remained unclear due to the lack of early detection by a reliable biomarker of 

the disease, making the clinical management, intervention planning, and outcomes 

Levy et al. Page 12

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



prediction for these patients challenging.1 We believe evaluation of cardiac function in 

preterm infants by speckle-tracking deformation imaging may now provide a marker (that 

was not previously available with conventional imaging) to longitudinally track 

cardiopulmonary disease over the first year of age. With an accepted physiological 

maturation patterns of ventricular strain in uncomplicated preterm infants based on postnatal 

weight and age over the first year age, we feel that these myocardial deformation parameters 

can provide a valid basis that allows comparison among studies and between health and 

disease.1

BPD and Respiratory Support

Improved survival of extremely premature babies has led to increased recognition of RV 

dysfunction and IVS abnormalities in infants with BPD.19,25,26 In this study we found a 

significant decrease in RV FWLS and IVS GLS in infants with BPD compared to infants 

without BPD (uncomplicated preterm infant), which remained significant after adjusting for 

the gestational age at birth, gender, and postnatal steroid use. In preterm infants with BPD, 

the magnitude of RV FWLS increased from 32 weeks to one year CA, but remained lower 

and tracked inferior when compared to infants without BPD by one-year CA, even when 

they no longer displayed clinical evidence of lung disease with oxygen requirement or 

respiratory support. Helfer and Czernik observed that tissue Doppler-derived RV global 

strain measures increased over the first month of life, but the rate of increase was also slower 

in infants who developed BPD.38 These findings suggest that RV function, as characterized 

by deformation values, remains subnormal in infants with BPD.

In contrast to RV strain measure, LV GLS was preserved from Day 5–7 through one year 

CA, irrespective of neonatal lung status. Czernik et al. also demonstrated that LV GLS by 

2DSTE remained relatively constant from birth to 28 days of life in infants with and without 

BPD.14 Subtle differences in LV SLS values were seen at the mid-ventricular level in the 

early neonatal period that disappeared by one month of age.14 Similarly, James et al. 

demonstrated that BPD negatively impacted RV FWLS, but that LV tissue Doppler 

deformation values were unaffected by BPD.22 We also demonstrated that there was a 

preserved physiological segmental apex-to-base strain gradient in infants with and without 

BPD, suggesting that both global and regional longitudinal LV function remained preserved 

in the setting of lung disease. However, infants who developed BPD not only had decreased 

IVS GLS from 32 weeks PMA to one year CA, but a persistent base-to-apex (reflective of an 

RV dominant pattern) IVS strain gradient that never reversed, even by one year of age. 

Infants without BPD demonstrated an IVS apex-to-base SLS gradient, reflective of an 

LVFW pattern.

Mechanical ventilation can alter the pre- and after-load conditions and affect deformation 

values.14 In this study, 5% (n=12) of infants were on mechanical ventilation at 32 weeks 

PMA and 2% (n=4) of the infants at 36 weeks PMA. There were no infants on respiratory 

support at one year CA. We were unable to properly investigate the effect of mechanical 

ventilation on deformation changes because nearly all of the mechanically ventilated infants 

(85%, n=10) at 32 weeks and all infants at 36 weeks PMA developed BPD. We found an 

interesting association between the use of antenatal steroids and LV function on the first day 

Levy et al. Page 13

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



of age. Infants whose mothers received antenatal steroids had higher LV GLS and SRs, 

which was independent of gestation. No effect was observed on RV function. Preterm 

infants may suffer from a combination of adrenocortical insufficiency and down regulation 

of cardiovascular adrenergic receptors.45 Therefore, it is possible that the administration of 

antenatal steroids can reverse this phenomenon leading to improved function.

PH—We utilized a broad echocardiogram-based definition of PH described by Mourani et 
al.25 and found an overall incidence of PH of 15% at 32 weeks PMA and 9% at 36 weeks 

PMA. Infants with BPD had a higher incidence of PH at 32 weeks PMA (12% vs. 3%) and 

at 36 weeks PMA (10% vs. 5%) when compared to those infants without BPD. Infants with 

PH at 32 and 36 weeks PMA had lower values of RV FWLS and IVS GLS, with preserved 

LV GLS. IVS SLS displayed a persistent base-to-apex gradient (RV dominant) in infants 

with PH that did not reverse by 32 weeks PMA. The base-to-apex pattern that was present at 

Day 5–7 was associated with a higher risk of late PH. Mourani et al. observed that 

ventricular septal wall flattening at 7 days of age (as an early sign of pulmonary vascular 

disease) was also associated with increased risk of late PH.25

Similar to Mourani et al., we also found that 10% of infants without BPD had detectable 

pulmonary hypertension at 36-week corrected gestational age.25 The patterns of decreased 

RV FWLS and IVS GLS persisted in the infants without BPD, but with PH from 32 weeks 

to one year CA. As highlighted by Farrow et al., this observation suggests that a primary 

vascular injury coupled with RV dysfunction may occur in some extreme preterm infants, 

independent of the lung disease.26 Although we only observed that one infant had 

echocardiographic signs of PH at one year CA, the infants with PH on their 36 week PMA 

echocardiograms that returned for a one-year CA follow-up (n=12 of 17, none of which 

required oxygen or respiratory support at one year CA ) still had decreased RV FWLS and 

IVS GLS and altered SLS base-to-apex pattern. Interestingly 25% (n=3) of the infants with 

PH at 36 weeks PMA that returned at one year CA did not carry a diagnosis of BPD and the 

patterns of altered strain mechanics persisted in this small sub-cohort as well. These findings 

might suggest that while some of the mechanisms of BPD and PH overlap, impairments of 

the developing pulmonary circulation in the extreme preterm infant without BPD may not be 

severe enough to be clinically recognized as pulmonary hypertension, but may still lead to 

cardio-respiratory morbidity.46 Whether this PH is clinically significant alone or predicts 

long-term morbidity in infants with BPD will require further study.26

PDA—The true influence of persistent PDA on ventricular strain patterns beyond the early 
neonatal period is an area of ongoing research.14,16,22,35,38,47 Infants with a PDA 

accompanied by evidence of systemic hypoperfusion (diastolic flow reversal in the 

descending aorta, and pulmonary over-circulation (increased LA:Ao and increased ejection 

fraction) had a higher LV GLS by Day 5 – 7. However, LV SRs remained similar in the two 

groups. de Waal et al. also found higher LV GLS and SRs in infants with a PDA.12 It is well 

documented that a hsPDA significantly increases LV preload, and leads to an increase in LV 

output.48 The increase in preload is accompanied by an increase in S but not SRs. This adds 

further support to the relative lack of load dependency of SRs illustrated in animal models.49 

In our regression model, both hsPDA presence (and the accompanying increased preload), 

Levy et al. Page 14

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



and LV SRs (representative of inherent contractility) had an independent effect on LV GLS. 

Therefore, LV longitudinal strain measurements must be interpreted taking into 

consideration loading conditions.

In this study, the infants who did not undergo pharmacological or surgical intervention to 

augment closure of the PDA, but still had a persistent PDA beyond 32 weeks, did not show 

any differences in their strain values when compared to infants without a PDA. Furthermore, 

infants who received pharmacological or surgical intervention had relatively stable values of 

RV, LV, and IVS FWS and FWSRs values in the late postnatal period when compared to 

infants without a PDA. Schubert et al. also found no significant associations between the 

speckle-tracking outcome variables at three months of corrected age and the diagnosis of 

PDA.16 We suspect that the effects of a PDA on LV strain imaging during the transition 

period and early neonatal period that has been observed in previous studies, may either 

dissipate over time,35,38 may be more of a true reflection in myocardial diastolic 

performance,13 or are unlikely to be due solely to the presence of PDA.14 The importance of 

these findings is that they support the notion that most premature neonates who fail to close 

their PDA after the first week of age may likely not experience significant cardiac morbidity 

as evidence by similar LV and RV strain patterns.

Study Limitations and Future Directions

In this study we only evaluated longitudinal strain imaging, as the feasibility and 

reproducibility of radial and circumferential strain has not been fully described in preterm 

infants beyond the transitional period.7,22 Although longitudinal strain remains the most 

reproducible quantitative tool of the three to assess LV function in preterm infants during the 

transitional period and later neonatal period,6,7 future work is now needed to assess the 

feasibility and reproducibility of circumferential and radial deformation at multiple time 

points in the first year of age and understand their maturational patterns in the context of 

uncomplicated preterm infants and those exposed to a PDA, at risk for BPD and or PH.

Both systolic and diastolic strain rate imaging provide unique insight into myocardial 

contractility and loading conditions,22 but we did not assess early and late diastolic strain 

rate with 2DSTE, because they too lack reproducibility in preterm infants.6 Finally, we 

demonstrated reduced inter- and intra- variability of segmental strain data in the LVFW, 

RVFW and IVS when compared to the reproducibility of global strain imaging in preterm 

infants.6 The difference in variability between global and regional strain may be due to the 

notion that in the small heart of a preterm infant each individual segment may not comprise 

a lot of speckles, and coupled with the elevated baseline heart rates in neonates, will lead to 

smoothing over of segments. To some extent, this may be mitigated by keeping the frame 

rate to heart rate ratio (FR/HR) between 0.7 and 0.9 frame/sec per bpm to optimize 

myocardial speckle tracking and mechanical event timing.21 However, until further 

validation of regional strain values is performed amongst different vendor platforms, its 

clinical use may be limited to the research arena.

Levy et al. Page 15

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



CONCLUSIONS

This study tracks the maturational patterns of ventricular mechanics with global and regional 

deformation imaging by 2DSTE in extreme preterm infants during the first year of age. The 

maturational patterns are ventricular specific. BPD and PH appear to leave a negative impact 

on RV and IVS strain, while LV strain remains stable through the first year of age, 

independent of birth weight, postnatal age, and clinical status. This study suggests that 

2DSTE derived strain can be used as a complementary modality to assess systolic 

ventricular function in neonates.

Acknowledgments

This study was supported by grants from Premature and Respiratory Outcomes Program (NIH 1U01 HL1014650, 
U01 HL101794), NIH R21 HL106417, Pediatric Physician Scientist Training Grant (NIH 5 T32 HD043010-09), 
and Postdoctoral Mentored Training Program in Clinical Investigation (NIH UL1 TR000448). Afif EL-Khuffash is 
funded by multiple sources: EU FP7/2007-2013 grant (agreement no. 260777, The HIP Trial); the Friends of the 
Rotunda Research Grant (Reference: FoR/EQUIPMENT/101572); Health Research Board Mother and Baby 
Clinical Trials Network Ireland (CTN-2014-10).

Abbreviations

2DSTE two-dimensional speckle tracking echocardiography

BPD bronchopulmonary dysplasia

CA corrected age

FWLS free wall longitudinal strain

GLS global longitudinal strain

IVS interventricular septum

LS longitudinal strain

LV left ventricle

PDA patent ductus arteriosus

PMA post-menstrual age

PH pulmonary hypertension

RV right ventricle

SRs systolic strain rate

References

1. Breatnach CR, Levy PT, James AT, Franklin O, El-Khuffash A. Novel echocardiography methods in 
the functional assessment of the newborn heart. Neonatology. 2016; 110:248–60. [PubMed: 
27287615] 

2. Lewandowski AJ, Bradlow WM, Augustine D, Davis EF, Francis J, Singhal A, et al. Right 
ventricular systolic dysfunction in young adults born preterm. Circulation. 2013; 128:713–20. 
[PubMed: 23940387] 

Levy et al. Page 16

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



3. Lewandowski AJ, Augustine D, Lamata P, Davis EF, Lazdam M, Francis J, et al. Preterm heart in 
adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, 
geometry, and function. Circulation. 2013; 127:197–206. [PubMed: 23224059] 

4. Kluckow M. Low systemic blood flow and pathophysiology of the preterm transitional circulation. 
Early Hum Dev. 2005; 81:429–37. [PubMed: 15935920] 

5. LeGRICE IJ. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue 
architecture in the dog. Am J Physiol. 1995; 269:H571–82. [PubMed: 7653621] 

6. Levy PT, Holland MR, Sekarski TJ, Hamvas A, Singh GK. Feasibility and reproducibility of 
systolic right ventricular strain measurement by speckle-tracking echocardiography in premature 
infants. J Am Soc Echocardiogr. 2013; 26:1201–13. [PubMed: 23880052] 

7. de Waal K, Lakkundi A, Othman F. Speckle tracking echocardiography in very preterm infants: 
feasibility and reference values. Early Hum Dev. 2014; 90:275–9. [PubMed: 24703298] 

8. Nasu Y, Oyama K, Nakano S, Matsumoto A, Soda W, Takahashi S, et al. Longitudinal systolic strain 
of the bilayered ventricular septum during the first 72 hours of life in preterm infants. J 
Echocardiogr. 2015; 13:90–9. [PubMed: 26184747] 

9. El-Khuffash AF, Jain A, Weisz D, Mertens L, McNamara PJ. Assessment and treatment of post 
patent ductus arteriosus ligation syndrome. J Pediatr. 2014; 165:46–52. [PubMed: 24814414] 

10. James AT, Corcoran JD, Hayes B, Franklin O, El-Khuffash A. The effect of antenatal magnesium 
sulfate on left ventricular afterload and myocardial function measured using deformation and 
rotational mechanics imaging. J Perinatol. 2015; 35:913–8. [PubMed: 26291779] 

11. James AT, Corcoran JD, Jain A, McNamara PJ, Mertens L, Franklin O, et al. Assessment of 
myocardial performance in preterm infants less than 29 weeks gestation during the transitional 
period. Early Hum Dev. 2014; 90:829–35. [PubMed: 25463828] 

12. de Waal K, Phad N, Lakkundi A, Tan P. Cardiac Function After the Immediate Transitional Period 
in Very Preterm Infants Using Speckle Tracking Analysis. Pediatr Cardiol. 2016; 37:295–303. 
[PubMed: 26472651] 

13. Hirose A, Khoo NS, Aziz K, Al-Rajaa N, van den Boom J, Savard W, et al. Evolution of Left 
Ventricular Function in the Preterm Infant. J Am Soc Echocardiogr. 2015; 28:302–8. [PubMed: 
25533193] 

14. Czernik C, Rhode S, Helfer S, Schmalisch G, Buhrer C, Schmitz L. Development of left 
ventricular longitudinal speckle tracking echocardiography in very low birth weight infants with 
and without bronchopulmonary dysplasia during the neonatal period. PLoS One. 2014; 9:e106504. 
[PubMed: 25184634] 

15. Levy PT, Singh GK. Challenges in Interpreting Deformation Values by Two-Dimensional Speckle-
Tracking Echocardiography in Preterm and Term Infants. J Am Soc Echocardiogr. 2017; 30:97–8. 
[PubMed: 27638237] 

16. Schubert U, Muller M, Abdul-Khaliq H, Norman M. Preterm Birth Is Associated with Altered 
Myocardial Function in Infancy. J Am Soc Echocardiogr. 2016; 29:670–8. [PubMed: 27156903] 

17. Spotnitz HM. Macro design, structure, and mechanics of the left ventricle. J Thorac Cardiovasc 
Surg. 2000; 119:1053–77. [PubMed: 10788831] 

18. Pryhuber GS, Maitre NL, Ballard RA, Cifelli D, Davis SD, Ellenberg JH, et al. Prematurity and 
respiratory outcomes program (PROP): study protocol of a prospective multicenter study of 
respiratory outcomes of preterm infants in the United States. BMC Pediatr. 2016; 15:37.

19. Levy PT, Dioneda B, Holland MR, Sekarski TJ, Lee CK, Mathur A, et al. Right Ventricular 
Function in Preterm and Term Neonates: Reference Values for Right Ventricle Areas and 
Fractional Area of Change. J Am Soc Echocardiogr. 2015; 28:559–69. [PubMed: 25753503] 

20. James AT, Corcoran JD, Franklin O, EL-Khuffash AF. Clinical utility of right ventricular fractional 
area change in preterm infants. Early Hum Dev. 2016; 92:19–23. [PubMed: 26619069] 

21. Sanchez AA, Levy PT, Sekarski TJ, Hamvas A, Holland MR, Singh GK. Effects of frame rate on 
two-dimensional speckle tracking-derived measurements of myocardial deformation in premature 
infants. Echocardiography. 2015; 32:839–47. [PubMed: 25109389] 

22. James AT, Corcoran JD, Breatnach CR, Franklin O, Mertens L, El-Khuffash A. Longitudinal 
Assessment of Left and Right Myocardial Function in Preterm Infants Using Strain and Strain 
Rate Imaging. Neonatology. 2015; 109:69–75. [PubMed: 26583602] 

Levy et al. Page 17

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



23. Koestenberger M, Nagel B, Ravekes W, Urlesberger B, Raith W, Avian A, et al. Systolic right 
ventricular function in preterm and term neonates: reference values of the tricuspid annular plane 
systolic excursion (TAPSE) in 258 patients and calculation of Z-score values. Neonatology. 2011; 
100:85–92. [PubMed: 21273793] 

24. Poindexter BB, Feng R, Schmidt B, Aschner JL, Ballard RA, Hamvas A, et al. Comparisons and 
Limitations of Current Definitions of Bronchopulmonary Dysplasia for the Prematurity and 
Respiratory Outcomes Program. Ann Am Thorac Soc. 2016; 12:1822–30.

25. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early Pulmonary 
Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia. Am J Respir Crit 
Care Med. 2015; 191:87–95. [PubMed: 25389562] 

26. Farrow KN, Steinhorn RH. Pulmonary Hypertension in Premature Infants. Sharpening the Tools of 
Detection. Am J Respir Crit Care Med. 2015; 191:12–4. [PubMed: 25551345] 

27. Weber SC, Weiss K, Bührer C, Hansmann G, Koehne P, Sallmon H. Natural History of Patent 
Ductus Arteriosus in Very Low Birth Weight Infants after Discharge. J Pediatr. 2015; 167:1149–
51. [PubMed: 26239928] 

28. Benitz WE. Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016; 137:1–6.

29. Ramos FG, Rosenfeld CR, Roy L, Koch J, Ramaciotti C. Echocardiographic predictors of 
symptomatic patent ductus arteriosus in extremely-low- birth-weight preterm neonates. J Perinatol. 
2010; 30:535–9. [PubMed: 20182434] 

30. Jain A, Shah PS. Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm 
Neonates. JAMA Pediatr. 2015; 169:863–72. [PubMed: 26168357] 

31. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for 
chamber quantification. J Am Soc Echocardiogr. 2015; 28:1–39. [PubMed: 25559473] 

32. Levy PT, Machefsky A, Sanchez AA, Patel MD, Rogal S, Fowler S, et al. Reference Ranges of 
Left Ventricular Strain Measures by Two-Dimensional Speckle-Tracking Echocardiography in 
Children: A Systematic Review and Meta-Analysis. J Am Soc Echocardiogr. 2016; 29:209–25. 
[PubMed: 26747685] 

33. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, et al. Definitions for a 
common standard for 2D speckle tracking echocardiography: consensus document of the 
EACVI/ASE/Industry Task Force to Standardize Deformation Imaging. J Am Soc Echocardiogr. 
2015; 28:183–93. [PubMed: 25623220] 

34. James A, Corcoran JD, Mertens L, Franklin O, El-Khuffash A. Left Ventricular Rotational 
Mechanics in Preterm Infants Less Than 29 Weeks' Gestation over the First Week after Birth. J 
Am Soc Echocardiogr. 2015; 28(7):808–817. [PubMed: 25819342] 

35. El-Khuffash AF, Jain A, Dragulescu A, McNamara PJ, Mertens L. Acute changes in myocardial 
systolic function in preterm infants undergoing patent ductus arteriosus ligation: a tissue Doppler 
and myocardial deformation study. J Am Soc Echocardiogr. 2012; 25:1058–67. [PubMed: 
22889993] 

36. Lorch SM, Ludomirsky A, Singh GK. Maturational and growth-related changes in left ventricular 
longitudinal strain and strain rate measured by two-dimensional speckle tracking 
echocardiography in healthy pediatric population. J Am Soc Echocardiogr. 2008; 21:1207–15. 
[PubMed: 18992672] 

37. Salih C, McCarthy KP, Ho SY. The fibrous matrix of ventricular myocardium in hypoplastic left 
heart syndrome: a quantitative and qualitative analysis. Ann Thorac Surg. 2004; 77:36–40. 
[PubMed: 14726030] 

38. Helfer S, Schmitz L, Bührer C, Czernik C. Tissue Doppler-Derived Strain and Strain Rate during 
the First 28 Days of Life in Very Low Birth Weight Infants. Echocardiography. 2014; 31:765–72. 
[PubMed: 24372717] 

39. Colan SD, Parness IA, Spevak PJ, Sanders SP. Developmental modulation of myocardial 
mechanics: age- and growth-related alterations in afterload and contractility. J Am Coll Cardiol. 
1992; 19:619–29. [PubMed: 1538019] 

40. Jashari H, Rydberg A, Ibrahimi P, Bajraktari G, Kryeziu L, Jashari F, et al. Normal ranges of left 
ventricular strain in children: a meta-analysis. Cardiovascular Ultrasound. 2015; 13:37. [PubMed: 
26250696] 

Levy et al. Page 18

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



41. Farsalinos KE, Daraban AM, Unlu S, Thomas JD, Badano LP, Voigt JU. Head-to-head comparison 
of global longitudinal strain measurements among nine different vendors. J Am Soc Echocardiogr. 
2015; 28:1171–81. [PubMed: 26209911] 

42. Levy PT, Sanchez A, Machefsky A, Fowler S, Holland MR, Singh GK. Normal ranges of right 
ventricular systolic and diastolic strain measures in children: a systematic review and meta-
analysis. J Am Soc Echocardiogr. 2014; 27:549–60. [PubMed: 24582163] 

43. Buckberg G, Hoffman JIE, Mahajan A, Saleh S, Coghlan C. Cardiac mechanics revisited: the 
relationship of cardiac architecture to ventricular function. Circulation. 2008; 118:2571–87. 
[PubMed: 19064692] 

44. Islam JY, Keller RL, Aschner JL, Hartert TV, Moore PE. Understanding the Short- and Long-Term 
Respiratory Outcomes of Prematurity and Bronchopulmonary Dysplasia. Am J Respir Crit Care 
Med. 2015; 19:134–56.

45. Quintos JB, Boney CM. Transient adrenal insufficiency in the premature newborn. Curr Opin 
Endocrinol Diabetes Obes. 2010; 17:8–12. [PubMed: 19881342] 

46. Mourani PM, Abman SH. Pulmonary Hypertension and Vascular Abnormalities in 
Bronchopulmonary Dysplasia. Clin Perinatol. 2015; 42:839–55. [PubMed: 26593082] 

47. Sehgal A, Doctor T, Menahem S. Cyclooxygenase Inhibitors in Preterm Infants With Patent Ductus 
Arteriosus: Effects on Cardiac and Vascular Indices. Pediatr Cardiol. 2014; 35:1429–36. [PubMed: 
24894898] 

48. El-Khuffash A, Weisz D, McNamara P. Reflections of the changes in patent ductus arteriosus 
management during the last 10 years. Arch Dis Child Fetal Neonatal Ed. 2016; 101:F474–8. 
[PubMed: 27118761] 

49. Ferferieva V, Van den Bergh A, Claus P, Jasaityte R, Veulemans P, Pellens M, et al. The relative 
value of strain and strain rate for defining intrinsic myocardial function. Am J Physiol Heart Circ 
Physiol. 2012; 302:H188–95. [PubMed: 22081696] 

Appendix 1. Reproducibility Analysis for Segmental Longitudinal Strain

Bland Altman Intraclass Correlation CV

Absolute Bias (%) LOA (95% CI) P (%)

Left ventricle

 Apex 11% −3.3 – 3.2 0.81 (0.69–0.88) 0.03 16.4%

 Mid-ventricle 9% −2.1 − 2.3 0.89 (0.85–0.91) 0.03 9.7%

 Base 8% −2.3 – 2.6 0.91 (0.86–0.93) 0.04 10.6%

Right Ventricle

 Apex 14% −3.5 – 3.0 0.83 (0.75–0.91) 0.03 15.4%

 Mid-ventricle 11% −2.1 – 2.5 0.87 (0.83–0.94) 0.04 8.7%

 Base 9% −2.3 – 2.6 0.93 (0.89–0.94) 0.03 8.6%

Interventricular Septum

 Apex 12% −3.1 – 3.2 0.84 (0.79–0.93) 0.04 13.4%

 Mid-ventricle 9% −2.6 − 2.2 0.89 (0.85–0.96) 0.03 9.7%

 Base 8% −2.3 – 2.6 0.92 (0.88–0.94) 0.01 8.6%

Levy et al. Page 19

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Highlights

• Two-dimensional speckle tracking echocardiography (2DSTE) derived 
myocardial strain is a feasible and reproducible imaging modality that can be 

used to characterize systolic ventricular function in premature infants.

• This study establishes ventricular specific systolic strain maturational patterns 
by 2DSTE in a large cohort of extreme preterm infants from birth through one 

year corrected age (CA).

• Common cardiopulmonary morbidities, such as bronchopulmonary dysplasia 
and pulmonary hypertension appear to leave a negative impact on RV strain, 

while LV strain remains stable through the first year of age.

• With the establishment of the range of maturational patterns of strain 
mechanics and associated variations up to one year CA, deformation imaging 

by 2DSTE may now be implemented in preterm infants as a means to identify 

cardiovascular compromise earlier, guide therapeutic intervention, monitor 

treatment response, and improve overall outcome.

Levy et al. Page 20

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Figure 1. Enrollment and follow-up of study participants
BPD, bronchopulmonary dysplasia; PH, pulmonary hypertension; PDA, patent ductus 

arteriosus.

*119/222 infants were excluded from the healthy uncomplicated cohort because they either 

were: a) diagnosed with BPD, defined as the requirement any respiratory support at 36 

weeks PMA, and based on a modified NIH workshop definition24; b) evidence of PH on 

echocardiogram at 32 and/or 36 weeks PMA, defined as any infant with any conventional 

echocardiographic signs identified, by an estimated RV systolic pressure > than 40 mm Hg, 

a ratio of RVSP to systemic blood pressure > than 0.5, any cardiac shunt with right-to-left 

flow, unusual degree of RV hypertrophy or dilatation, or any degree of ventricular septal 

wall flattening;25 or c) evidence of a hemodynamically significant PDA by Day 5–7, 

(defined by PDA characteristics, signs of pulmonary over circulation, and left heart-loading 

condition),30 or any PDA at 32 and 36 week PMA. There was significant overlap between 

these four categories.

** There were 239 infants recruited for this study (137 infants from the Washington 

University School of Medicine site in Saint Louis, USA and 102 infants from the Royal 

College of Surgeons in Ireland site in Dublin, Ireland). Echocardiograms were performed at 

Day 1 (n=30), Day 2 (n=30), 32 weeks PMA (n=117), 36 weeks PMA (n=117), and one year 

CA (n=81) in Saint Louis, USA. Echocardiograms were performed at Day 1 (n=102), Day 2 

(n=102), Day 5 (n=98), and 36 weeks PMA (n=47) in Dublin, Ireland.

Levy et al. Page 21

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Levy et al. Page 22

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Figure 2. Maturational patterns of Ventricular Deformation over the first year of age
(A) RV FW longitudinal strain (RV FWLS%): In all infants RV FWLS % increased from 

Day 5–7 to one year CA (p < 0.01). RV FWLS % was higher and tracked superior in the 

uncomplicated preterm infants (blue circles with blue solid line) when compared to the 

preterm infants who developed BPD (red squares, dotted red lines) on echocardiogram at the 

time of evaluation. (B) Interventricular septal (IVS) global longitudinal strain (GLS, %): In 

all infants IVS GLS increased from 32 weeks PMA to one year CA (p < 0.01). IVS GLS 

was higher and tracked superior in the uncomplicated preterm infants when compared to the 

preterm infants who developed BPD on echocardiogram at the time of evaluation. (C) LV 

global longitudinal strain (LV GLS): LV GLS was preserved and relatively unchanged from 

32 weeks PMA to one year CA (p=0.6), irrespective on neonatal cardiopulmonary disease.

Levy et al. Page 23

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Levy et al. Page 24

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



Figure 3. Left and right ventricle strain and systolic strain rate in infants with and without a 
hemodynamically significant patent ductus arteriosus on Day 5 – 7
(A) LV GLS. On Day 5 – 7, infants with a hsPDA30 (Green diamond, dotted green lines) had 

higher LV GLS than the healthy uncomplicated cohort (blue circle, solid blue line); (B) LV 

GLSRs. There was no difference in the magnitude of LV GLSRs between cohorts at any 

time point in the first week of age; (C) RV GLS. On Day 5 – 7, infants with a hsPDA (Green 

diamond, dotted green lines) had higher RV GLS than the healthy uncomplicated cohort 

(blue circle, solid blue line); (D) RV GLSr. There was no difference in the magnitude of RV 

GLSRs between cohorts at any time point in the first week of age.

*= p < 0.05. LV: Left ventricle; RV: Right ventricle; SRs: systolic strain rate; FWLS, free 

wall longitudinal strain; FWLSRs, free wall longitudinal systolic strain rate; GLS, global 

Levy et al. Page 25

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



longitudinal strain; GLSRs, global systolic longitudinal strain rate; hsPDA: 

hemodynamically significant patent ductus arteriosus.

Levy et al. Page 26

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.

A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 27

Ta
b

le
 1

D
em

og
ra

ph
ic

 a
nd

 c
li

ni
ca

l 
ch

ar
ac

te
ri

st
ic

s 
of

 p
re

te
rm

 i
nf

an
ts

 b
as

ed
 o

n 
ti

m
in

g 
of

 e
ch

oc
ar

di
og

ra
m

 e
va

lu
at

io
n

T
im

in
g 

of
 E

ch
oc

ar
d

io
gr

am
s

D
ay

 1
D

ay
 2

D
ay

 5
–7

32
 w

ee
k

s 
P

M
A

36
 w

ee
k

s 
P

M
A

O
n

e 
ye

ar
 C

A

T
ot

al
 #

 i
nf

an
ts

 a
t 

ea
ch

 t
im

e 
po

in
t 

*
13

2
13

2
98

11
7

15
4

81

H
ea

lt
hy

 u
nc

om
pl

ic
at

ed
 i

nf
an

ts
**

65
65

36
48

67
30

R
es

p
ir

at
or

y

 
R

R
 (

br
ea

th
s/

m
in

) 
**

50
 ±

 1
0

50
 ±

 1
0

50
 ±

 1
0

50
 ±

 1
0

51
 ±

 1
0

52
 ±

 9

 
In

va
si

ve
 M

ec
ha

ni
ca

l 
ve

nt
il

at
io

n
66

 (
49

%
)

43
 (

32
%

)
25

 (
25

%
)

6 
(5

%
)

4 
(3

%
)

0

 
B

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a
69

 (
59

%
)

69
 (

59
%

)
69

 (
59

%
)

69
 (

59
%

)
69

 (
59

%
)

49
 (

60
%

)

C
ar

d
io

va
sc

u
la

r

 
P

D
A

12
6 

(9
5%

)
11

4 
(8

6%
)

69
 (

70
%

)
19

 (
16

%
)

24
 (

16
%

)
0

 
hs

P
D

A
N

A
N

A
35

 (
34

%
)

N
A

N
A

N
A

 
P

ul
m

on
ar

y 
hy

pe
rt

en
si

on
N

A
N

A
17

 (
14

.5
%

)
17

 (
14

.5
%

)
17

 (
14

.5
%

)
1 

(1
%

)

 
H

R
 (

be
at

s/
m

in
ut

e)
 *

*
15

5 
±

 1
5

16
1 

±
 1

2
16

5 
±

 1
2

15
9 

±
 1

8
16

3 
±

 1
4

13
3 

±
 1

9

 
S

B
P

 (
m

m
 H

g)
 *

*
49

 ±
 1

0
53

 ±
 1

3
56

 ±
 1

0
68

 ±
 9

71
 ±

 8
83

 ±
 1

0

 
D

B
P

 (
m

m
 H

g)
 *

*
30

 ±
 8

30
 ±

 9
31

 ±
 9

42
 ±

 9
42

 ±
 9

62
 ±

 9

 
M

A
P

 (
m

m
 H

g)
 *

*
36

 ±
 6

38
 ±

 8
39

 ±
 9

48
 ±

 1
2

50
 ±

 1
2

59
 ±

 1
4

D
at

a 
ar

e 
pr

es
en

te
d 

as
 m

ea
n 

±
 S

D
, o

r 
nu

m
be

r 
(P

er
ce

nt
ag

e)
; 

N
A

, n
ot

 a
pp

li
ca

bl
e

P
M

A
, p

os
t-

m
en

st
ru

al
 a

ge
; 

C
A

, c
or

re
ct

ed
 a

ge

R
R

, r
es

pi
ra

to
ry

 r
at

e;
 H

R
, h

ea
rt

 r
at

e;
 S

B
P,

 S
ys

to
li

c 
B

lo
od

 P
re

ss
ur

e;
 D

B
P,

 D
ia

st
ol

ic
 B

lo
od

 P
re

ss
ur

e;
 M

A
P,

 m
ea

n 
ar

te
ri

al
 b

lo
od

 p
re

ss
ur

e

* T
he

re
 w

er
e 

23
9 

in
fa

nt
s 

re
cr

ui
te

d 
fo

r 
th

is
 s

tu
dy

 (
13

7 
in

fa
nt

s 
fr

om
 t

he
 W

as
hi

ng
to

n 
U

ni
ve

rs
it

y 
S

ch
oo

l 
of

 M
ed

ic
in

e 
si

te
 i

n 
S

ai
nt

 L
ou

is
, U

S
A

 a
nd

 1
02

 i
nf

an
ts

 f
ro

m
 t

he
 R

oy
al

 C
ol

le
ge

 o
f 

S
ur

ge
on

s 
in

 I
re

la
nd

 s
it

e 
in

 D
ub

li
n,

 I
re

la
nd

).
 E

ch
oc

ar
di

og
ra

m
s 

w
er

e 
pe

rf
or

m
ed

 a
t 

D
ay

 1
 (

n=
30

),
 D

ay
 2

 (
n=

30
),

 3
2 

w
ee

ks
 P

M
A

 (
n=

11
7)

, 3
6 

w
ee

ks
 P

M
A

 (
n=

11
7)

, a
nd

 o
ne

 y
ea

r 
C

A
 (

n=
81

) 
in

 S
ai

nt
 L

ou
is

. E
ch

oc
ar

di
og

ra
m

s 
w

er
e 

pe
rf

or
m

ed
 a

t 
D

ay
 1

 (
n=

10
2)

, D
ay

 2
 (

n=
10

2)
, D

ay
 5

 (
n=

98
),

 a
nd

 3
6 

w
ee

ks
 P

M
A

 (
n=

47
).

**
A

ll
 t

he
 d

em
og

ra
ph

ic
 a

nd
 c

li
ni

ca
l 

ch
ar

ac
te

ri
st

ic
s 

ar
e 

fr
om

 t
he

 u
nc

om
pl

ic
at

ed
 p

re
te

rm
 i

nf
an

ts
. T

he
 i

nf
an

ts
 e

xc
lu

de
d 

fr
om

 t
hi

s 
co

ho
rt

 i
nc

lu
de

d:

1.
M

od
er

at
e-

la
rg

e 
hs

P
D

A
 a

t 
D

ay
 5

–7
 o

r 
pr

es
en

ce
 o

f 
P

D
A

 a
t 

an
y 

ti
m

e 
po

in
t 

fr
om

 3
2 

w
ee

ks
 P

M
A

 t
o 

on
e 

ye
ar

 C
A

, o
r 

re
ce

iv
ed

 s
ur

gi
ca

l 
or

 m
ed

ic
al

 a
ug

m
en

ta
ti

on
 t

o 
cl

os
e 

P
D

A
. 1

8,
28

,2
9

2.
B

P
D

, r
eq

ui
ri

ng
 r

es
pi

ra
to

ry
 o

r 
ox

yg
en

 s
up

po
rt

 a
t 

36
 w

ee
ks

 P
M

A
.2

3

3.
E

ch
oc

ar
di

og
ra

ph
ic

 s
ig

ns
 o

f 
pu

lm
on

ar
y 

hy
pe

rt
en

si
on

 5
–7

 d
ay

s 
of

 a
ge

 a
nd

 b
ey

on
d.

24

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 28

Ta
b

le
 2

M
at

er
na

l 
an

d 
in

fa
nt

 c
ha

ra
ct

er
is

ti
c 

co
m

pa
ri

so
ns

 b
et

w
ee

n 
co

ho
rt

s

A
L

L
U

n
co

m
p

li
ca

te
d

 C
oh

or
t 

*
In

fa
n

ts
 w

it
h

 e
it

h
er

 B
P

D
, P

H
, a

n
d

/o
r 

P
D

A
P

 -
V

al
u

e

N
=

22
2

N
=

10
3

N
 =

 1
19

B
ir

th
w

ei
gh

t 
(g

)
89

5 
[7

67
,1

01
0]

96
0 

[8
05

,1
13

0]
88

0 
[7

50
,9

80
]

0.
00

7

B
ir

th
w

ei
gh

t 
st

ra
ta

 (
g)

 
50

0 
– 

74
9 

(n
=

43
)

65
0 

[5
95

,6
98

]
69

0 
[6

50
,7

00
]

64
0 

[5
78

.6
85

]
0.

13

 
75

0 
– 

99
9 

(n
=

90
)

88
0 

[8
20

,9
50

]
85

3 
[8

09
,9

40
]

89
0 

[8
30

,9
50

]
0.

47

 
10

00
 –

 1
25

0 
(n

=
89

)
11

25
 [

90
3,

12
55

]
11

40
 [

10
52

,1
26

5]
11

10
 [

10
45

,1
21

7]
0.

71

G
es

ta
ti

on
al

 a
ge

27
 [

26
,2

8]
27

 [
26

,2
8]

26
 [

25
,2

7]
<

 0
.0

1

G
en

de
r 

(f
em

al
e)

10
8 

(4
9%

)
60

 (
58

%
)

72
 (

60
%

)
0.

22

R
ac

e
0.

64

 
W

hi
te

15
6 

(7
0%

)
91

 (
82

%
)

68
 (

57
%

)

 
B

la
ck

63
 (

54
%

)
21

 (
20

%
)

39
 (

33
%

)

 
A

si
an

2 
(2

%
)

1 
(1

%
)

1 
(1

%
)

 
O

th
er

1 
(1

%
)

0
1 

(1
%

)

E
th

ni
ci

ty
0.

36

 
H

is
pa

ni
c 

or
 L

at
in

o
3 

(3
%

)
2 

(2
%

)
1 

(1
%

)

 
N

ot
 H

is
pa

ni
c 

or
 L

at
in

o
21

9 
(9

7%
)

10
1 

(9
8%

)
11

8 
(9

9%
)

M
at

er
na

l 
S

m
ok

in
g

28
11

 (
11

%
)

17
 (

14
%

)
0.

67

A
nt

en
at

al
 c

or
ti

co
st

er
oi

ds
19

7 
(8

9%
)

99
 (

96
%

)
98

 (
82

%
)

0.
76

S
ur

fa
ct

an
t 

R
ep

la
ce

m
en

t 
T

he
ra

py
22

2 
(1

00
%

)
10

3 
(1

00
%

)
11

9(
10

0%
)

0.
84

M
ul

ti
pl

es
14

 (
6%

)
3 

(3
%

)
11

 (
9%

)
0.

23

C
es

ar
ea

n 
se

ct
io

n
16

0 
(7

2%
)

75
 (

73
%

)
85

 (
71

%
)

0.
56

M
at

er
na

l 
co

m
pl

ic
at

io
ns

 
G

es
ta

ti
on

al
 D

M
10

 (
5%

)
7 

(7
%

)
3 

(3
%

)
0.

57

 
G

es
ta

ti
on

al
 H

T
N

35
 (

16
%

)
17

 (
17

%
)

18
 (

15
%

)
0.

28

 
P

ro
lo

ng
ed

 r
up

tu
re

 o
f 

m
em

br
an

es
38

 (
17

%
)

15
 (

15
%

)
23

 (
19

%
)

0.
58

 
C

ho
ri

oa
m

ni
on

it
is

20
 (

9%
)

10
 (

10
%

)
10

 (
8%

)
0.

51

 
P

re
ec

la
m

ps
ia

56
 (

25
%

)
26

 (
26

%
)

30
 (

25
%

)
0.

62

 
P

la
ce

nt
al

 A
br

up
ti

on
38

 (
17

%
)

17
 (

17
%

)
21

 (
18

%
)

0.
89

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 29

A
L

L
U

n
co

m
p

li
ca

te
d

 C
oh

or
t 

*
In

fa
n

ts
 w

it
h

 e
it

h
er

 B
P

D
, P

H
, a

n
d

/o
r 

P
D

A
P

 -
V

al
u

e

N
=

22
2

N
=

10
3

N
 =

 1
19

N
ec

ro
ti

zi
ng

 e
nt

er
oc

ol
it

is
21

 (
9%

)
11

 (
11

%
)

10
 (

8%
)

0.
53

R
O

P
 t

hr
es

ho
ld

 (
S

ta
ge

 2
 o

r 
hi

gh
er

)
43

 (
19

%
)

8 
(9

%
)

35
 (

29
%

)
0.

00
4

IV
H

 (
G

ra
de

 3
 o

r 
4)

28
 (

13
%

)
9 

(9
%

)
19

 (
16

%
)

0.
09

T
ot

al
 o

xy
ge

n 
da

ys
 (

N
IC

U
)

84
 [

40
,1

07
]

34
 [

19
,5

0]
92

 [
82

,1
15

]
<

 0
.0

01

L
en

gt
h 

of
 s

ta
y 

(N
IC

U
)

91
 [

76
,1

14
]

79
 [

64
,8

9]
98

 [
87

,1
19

]
<

 0
.0

01

D
at

a 
ar

e 
pr

es
en

te
d 

as
 m

ed
ia

n 
[i

nt
er

qu
ar

ti
le

 r
an

ge
],

 o
r 

nu
m

be
r 

(P
er

ce
nt

ag
e)

B
P

D
, b

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a;
 P

H
, p

ul
m

on
ar

y 
hy

pe
rt

en
si

on
; 

P
D

A
, p

at
en

t 
du

ct
us

 a
rt

er
io

su
s

R
O

P,
 r

et
in

op
at

hy
 o

f 
pr

em
at

ur
it

y;
 I

V
H

, i
nt

ra
ve

nt
ri

cu
la

r 
he

m
or

rh
ag

e

* H
ea

lt
hy

 u
nc

om
pl

ic
at

ed
 c

oh
or

t,
 d

ef
in

ed
 a

s 
pr

et
er

m
 i

nf
an

ts
 w

it
ho

ut
 b

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a,
 e

ch
oc

ar
di

og
ra

ph
ic

 s
ig

ns
 o

f 
pu

lm
on

ar
y 

hy
pe

rt
en

si
on

 a
t 

32
 o

r 
36

 w
ee

ks
 P

M
A

, a
nd

/o
r 

a 
he

m
od

yn
am

ic
al

ly
 

si
gn

if
ic

an
t 

pa
te

nt
 d

uc
tu

s 
ar

te
ri

os
us

 a
t 

D
ay

 5
–7

 o
r 

an
y 

si
ze

 P
D

A
 a

t 
32

 o
r 

36
 w

ee
ks

 P
M

A
.

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 30

Table 3

Deformation measurements over the first week of age.

Day 1 Day 2 Day 5 – 7 p

Entire cohort

Number of infants 132 132 98

 LV GLS (%) −18.4 ± 3.8 −20.5 ± 3.1* −21.8 ± 3.3* † <0.001

 LV GLSRs (1/s) −1.8 ± 0.4 −2.1 ± 0.4* −2.4 ± 0.4* † <0.001

 IVS GLS (%) −17.7 ± 2.1 −17.9 ± 2.1 −18.4 ± 2.1*† <0.001

 IVS GLSR (1/s) −1.7 ± 0.2 −1.8 ± 0.2 −1.9 ± 0.2† 0.16

 RV FWLS (%) −18.8 ± 4.7 −20.1 ± 5.1 −21.1 ± 4.7 0.05

 RV FWLSRs (1/s) −2.0 ± 0.6 −2.3 ± 0.7* −2.8 ± 0.6* † <0.001

Healthy uncomplicated cohort

Number of infants 65 65 36

 LV GLS (%) −18.4 ± 3.5 −20.3 ± 3.2* −20.7 ± 3.0 † <0.001

 LV GLSRs (1/s) −1.8 ± 0.3 −2.1 ± 0.3* −2.3 ± 0.4 † <0.001

 IVS GLS (%) −17.7 ± 2.1 −18.0 ± 2.1 −18.4 ± 2.1*† <0.001

 IVS GLSR (1/s) −1.7 ± 0.2 −1.8 ± 0.2 −1.9± 0.2† 0.12

 RV FWLS (%) −18.1 ± 4.0 −20.3 ± 3.2 −20.5 ± 3.2* 0.02

 RV FWLSRs (1/s) −1.9 ± 0.5 −2.2 ± 0.6 −2.7 ± 0.7† 0.004

Values are presented as mean (standard deviation). One way ANOVA with repeated measures was used to assess the change in values over time.

*
= p < 0.05 compared with previous day measurement;

†
= p < 0.05 compared with Day 1 measurement (with Bonferroni adjustment).

RV, right ventricle; LV, left ventricle; IVS, interventricular septum

FWLS, free wall longitudinal strain; FWLSRs, free wall longitudinal systolic strain rate

GLS, global longitudinal strain; GLSRs, global systolic longitudinal strain rate

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 31

Ta
b

le
 4

V
en

tr
ic

ul
ar

 d
ef

or
m

at
io

n 
in

 h
ea

lt
hy

 u
nc

om
pl

ic
at

ed
 p

re
te

rm
 i

nf
an

ts
 b

y 
w

ei
gh

t

W
ei

gh
t 

(K
il

og
ra

m
s)

In
fa

n
ts

 *
 (

n
)

R
V

 F
W

L
S

 (
%

)
R

V
 F

W
L

S
R

s 
(1

/s
ec

)
L

V
 G

L
S

 (
%

)
L

V
 G

L
S

R
s 

(1
/s

ec
)

IV
S

 G
L

S
 (

%
)

IV
S

 G
L

S
R

s 
(1

/s
ec

)

0.
5 

– 
0.

9
66

−
18

.8
 ±

 4
.7

−
2.

0 
±

 0
.6

−
19

.1
 ±

 2
.0

−
1.

8 
±

 0
.1

−
17

.7
 ±

 2
.1

−
1.

7 
±

 0
.2

1.
0 

– 
1.

4
82

−
20

.7
 ±

 0
.3

−
2.

5 
±

 0
.4

−
19

.4
 ±

 2
.1

−
1.

9 
±

 0
.2

−
18

.0
 ±

 2
.5

−
1.

9 
±

 0
.4

1.
5 

– 
1.

9
62

−
21

.5
 ±

 0
.8

−
2.

8 
±

 0
.3

−
20

.2
 ±

 0
.5

−
1.

9 
±

 0
.3

−
18

.4
 ±

 0
.3

−
2.

3 
±

 0
.3

2.
0 

– 
2.

4
50

−
23

.3
 ±

 3
.3

−
2.

8 
±

 0
.4

−
20

.6
 ±

 0
.6

−
1.

8 
±

 0
.4

−
19

.4
 ±

 1
.2

−
2.

2 
±

 0
.4

2.
5 

– 
2.

9
21

−
24

.0
 ±

 3
.6

−
3.

1 
±

 0
.5

−
20

.4
 ±

 0
.6

−
1.

9 
±

 0
.5

−
19

.3
 ±

 1
.6

−
2.

4 
±

 0
.5

8.
0 

–9
.0

16
−

27
.3

 ±
 2

.3
−

3.
2 

±
 0

.3
−

21
.1

 ±
 0

.4
−

1.
7 

±
 0

.6
−

21
.7

 ±
 0

.5
−

2.
6 

±
 0

.3

10
.0

 –
12

.0
14

−
27

.7
 ±

 2
.3

−
3.

5 
±

 0
.7

−
20

.1
 ±

 0
.4

−
1.

9 
±

 0
.7

−
22

.9
 ±

 1
.3

−
2.

6 
±

 0
.7

D
at

a 
ar

e 
pr

es
en

te
d 

as
 m

ea
n 

±
 S

D
.

* H
ea

lt
hy

 u
nc

om
pl

ic
at

ed
 c

oh
or

t,
 d

ef
in

ed
 a

s 
pr

et
er

m
 i

nf
an

ts
 w

it
ho

ut
 b

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a,
 e

ch
oc

ar
di

og
ra

ph
ic

 s
ig

ns
 o

f 
pu

lm
on

ar
y 

hy
pe

rt
en

si
on

 a
t 

32
 o

r 
36

 w
ee

ks
 P

M
A

, a
nd

/o
r 

a 
he

m
od

yn
am

ic
al

ly
 

si
gn

if
ic

an
t 

pa
te

nt
 d

uc
tu

s 
ar

te
ri

os
us

 a
t 

D
ay

 5
–7

 o
r 

an
y 

si
ze

 P
D

A
 a

t 
32

 o
r 

36
 w

ee
ks

 P
M

A
. A

t 
D

ay
 1

 t
he

re
 w

er
e 

n=
65

, D
ay

 2
, n

=
65

, D
ay

 5
–7

, n
=

36
, 3

2 
w

ee
ks

 P
M

A
, n

=
48

, 3
6 

w
ee

ks
 P

M
A

, n
=

67
, a

nd
 O

ne
 y

ea
r 

C
A

, n
=

30
.

R
V

, r
ig

ht
 v

en
tr

ic
le

; 
L

V
, l

ef
t 

ve
nt

ri
cl

e;
 I

V
S

, i
nt

er
ve

nt
ri

cu
la

r 
se

pt
um

F
W

L
S

, f
re

e 
w

al
l 

lo
ng

it
ud

in
al

 s
tr

ai
n;

 F
W

L
S

R
s,

 f
re

e 
w

al
l 

lo
ng

it
ud

in
al

 s
ys

to
li

c 
st

ra
in

 r
at

e

G
L

S
, g

lo
ba

l 
lo

ng
it

ud
in

al
 s

tr
ai

n;
 G

L
S

R
s,

 g
lo

ba
l 

sy
st

ol
ic

 l
on

gi
tu

di
na

l 
st

ra
in

 r
at

e

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 32

Ta
b

le
 5

V
en

tr
ic

ul
ar

 d
ef

or
m

at
io

n 
in

 u
nc

om
pl

ic
at

ed
 p

re
te

rm
 i

nf
an

ts
 b

y 
ag

e 
be

yo
nd

 t
he

 f
ir

st
 w

ee
k 

.

A
ge

 (
w

ee
k

s)
In

fa
n

ts
*  

(n
)

R
V

 F
W

L
S

 (
%

)
R

V
 F

W
L

S
R

s 
(1

/s
ec

)
L

V
 G

L
S

 (
%

)
L

V
 G

L
S

R
s 

(1
/s

ec
)

IV
S

 G
L

S
 (

%
)

IV
S

 G
L

S
R

s 
(1

/s
ec

)

4 
– 

6
40

−
21

.0
 ±

 2
.5

−
2.

3 
±

 0
.4

−
19

.7
 ±

 2
.3

−
1.

9 
±

 0
.3

−
17

.9
 ±

 2
.3

−
1.

8 
±

 0
.4

6 
– 

8
57

−
23

.2
 ±

 2
.8

−
2.

6 
±

 0
.5

−
20

.4
 ±

 2
.4

−
1.

9 
±

 0
.2

−
18

.9
 ±

 2
.0

−
2.

1 
±

 0
.3

9 
– 

11
18

−
22

.7
 ±

 2
.2

−
2.

7 
±

 0
.5

−
20

.0
 ±

 2
.3

−
1.

8 
±

 0
.2

−
19

.1
 ±

 1
.5

−
2.

4 
±

 0
.3

60
 –

 7
9

26
−

27
.5

 ±
 2

.4
−

2.
9 

±
 0

.5
−

21
.4

 ±
 2

.0
−

1.
9 

±
 0

.2
−

21
.4

 ±
 3

.0
−

2.
5 

±
 0

.4

80
 –

 9
9

4
−

28
.7

 ±
 2

.5
−

3.
5 

±
 0

.4
−

21
.1

 ±
 1

.6
−

1.
7 

±
 0

.3
−

22
.1

 ±
 2

.3
−

2.
6 

±
 0

.6

D
at

a 
ar

e 
pr

es
en

te
d 

as
 m

ea
n 

±
 S

D
.

* U
nc

om
pl

ic
at

ed
, d

ef
in

ed
 a

s 
in

fa
nt

s 
w

it
ho

ut
 b

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a,
 e

ch
oc

ar
di

og
ra

ph
ic

 s
ig

ns
 o

f 
pu

lm
on

ar
y 

hy
pe

rt
en

si
on

 a
t 

32
 o

r 
36

 w
ee

ks
. T

he
re

 w
er

e 
48

 u
nc

om
pl

ic
at

ed
 p

re
te

rm
 i

nf
an

ts
 a

t 
32

 w
ee

ks
 

P
M

A
, 6

7 
un

co
m

pl
ic

at
ed

 p
re

te
rm

 i
nf

an
ts

 a
t 

36
 w

ee
ks

P
M

A
, a

nd
 3

0 
un

co
m

pl
ic

at
ed

 p
re

te
rm

 i
nf

an
ts

 a
t 

on
e 

ye
ar

 C
A

. P
M

A
, a

nd
/o

r 
a 

he
m

od
yn

am
ic

al
ly

 s
ig

ni
fi

ca
nt

 p
at

en
t 

du
ct

us
 a

rt
er

io
su

s 
at

 D
ay

 5
–7

 o
r 

an
y 

si
ze

 P
D

A
 a

t 
32

 o
r 

36
 w

ee
ks

 P
M

A
.

R
V

, r
ig

ht
 v

en
tr

ic
le

; 
L

V
, l

ef
t 

ve
nt

ri
cl

e;
 I

V
S

, i
nt

er
ve

nt
ri

cu
la

r 
se

pt
um

F
W

L
S

, f
re

e 
w

al
l 

lo
ng

it
ud

in
al

 s
tr

ai
n;

 F
W

L
S

R
s,

 f
re

e 
w

al
l 

lo
ng

it
ud

in
al

 s
ys

to
li

c 
st

ra
in

 r
at

e

G
L

S
, g

lo
ba

l 
lo

ng
it

ud
in

al
 s

tr
ai

n;
 G

L
S

R
s,

 g
lo

ba
l 

sy
st

ol
ic

 l
on

gi
tu

di
na

l 
st

ra
in

 r
at

e

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.



A
u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t
A

u
th

o
r M

a
n
u
scrip

t

Levy et al. Page 33

Ta
b

le
 6

R
eg

io
na

l 
ve

nt
ri

cu
la

r 
de

fo
rm

at
io

n 
pa

tt
er

ns
 i

n 
pr

et
er

m
 i

nf
an

ts
 a

t 
on

e 
ye

ar
 c

or
re

ct
ed

 a
ge

B
as

e
M

id
-v

en
tr

ic
le

A
p

ex
P

 -
va

lu
e

H
ea

lt
h

y 
u

n
co

m
p

li
ca

te
d

 P
re

te
rm

 I
n

fa
n

ts
*

 
R

V
 S

L
S

 (
%

)
−

23
.1

 ±
 1

.6
−

24
.2

 ±
 2

.1
−

26
.7

 ±
 1

.9
<

 0
.0

1

 
L

V
 S

L
S

 (
%

)
−

21
.2

 ±
 2

.1
−

19
.4

 ±
 2

.1
−

18
.1

 ±
 1

.3
<

 0
.0

1

 
IV

S
 S

L
S

 (
%

)
−

19
.1

 ±
 1

.5
−

18
.9

 ±
 2

.0
−

17
.9

 ±
 2

.3
<

 0
.0

1

P
re

te
rm

 I
n

fa
n

ts
 w

it
h

 B
P

D
 a

n
d

/o
r 

P
H

 
R

V
 S

L
S

 (
%

)
−

20
.1

 ±
 1

.4
−

23
.2

 ±
 1

.3
−

24
.7

 ±
 2

.1
0.

01

 
L

V
 S

L
S

 (
%

)
−

20
.9

 ±
 2

.2
−

19
.2

 ±
 1

.1
−

18
.5

 ±
 2

.1
<

 0
.0

1

 
IV

S
 S

L
S

 (
%

)*
*

−
16

.1
 ±

 1
.8

−
17

.9
 ±

 2
.1

−
18

.1
 ±

 1
.9

<
 0

.0
1

D
at

a 
ar

e 
pr

es
en

te
d 

as
 m

ea
n 

±
 S

D
.

R
V

, r
ig

ht
 v

en
tr

ic
le

; 
L

V
, l

ef
t 

ve
nt

ri
cl

e;
 I

V
S

, i
nt

er
ve

nt
ri

cu
la

r 
se

pt
um

S
L

S
, s

eg
m

en
ta

l 
lo

ng
it

ud
in

al
 s

tr
ai

n

B
P

D
, b

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a;
 P

D
A

, p
at

en
t 

du
ct

us
 a

rt
er

io
su

s,

* H
ea

lt
hy

 u
nc

om
pl

ic
at

ed
, d

ef
in

ed
 a

s 
in

fa
nt

s 
w

it
ho

ut
 b

ro
nc

ho
pu

lm
on

ar
y 

dy
sp

la
si

a,
 e

ch
oc

ar
di

og
ra

ph
ic

 s
ig

ns
 o

f 
pu

lm
on

ar
y 

hy
pe

rt
en

si
on

 a
t 

32
 o

r 
36

 w
ee

ks
 P

M
A

, a
nd

/o
r 

a 
he

m
od

yn
am

ic
al

ly
 s

ig
ni

fi
ca

nt
 p

at
en

t 
du

ct
us

 a
rt

er
io

su
s 

at
 D

ay
 5

–7
 o

r 
an

y 
si

ze
 P

D
A

 a
t 

32
 o

r 
36

 w
ee

ks
 P

M
A

.

**
IV

S
 S

L
S

 w
it

h 
pr

et
er

m
 i

nf
an

ts
 w

it
h 

B
P

D
 a

nd
/o

r 
P

H
 r

em
ai

ns
 i

n 
an

 a
pe

x-
to

-b
as

e 
pa

tt
er

n 
(h

ig
he

st
 t

o 
lo

w
er

s)
, r

ef
le

ct
iv

e 
of

 R
V

 r
eg

io
na

l 
gr

ad
ie

nt
.

J Am Soc Echocardiogr. Author manuscript; available in PMC 2018 July 01.


	Abstract
	INTRODUCTION
	METHODS
	Study Population
	Inclusion Criteria in Uncomplicated Cohort
	Echocardiographic Examination
	Strain Analysis
	Two-Dimensional Speckle Tracking Imaging

	Reproducibility of Strain imaging in Preterm Infants
	Statistical Analysis

	RESULTS
	Study Population Characteristics
	Maturational Patterns of Myocardial Strain in Uncomplicated Preterm Infants
	Maturational Patterns of Regional Myocardial Strain in Uncomplicated Preterm Infants
	Confounding Cardiopulmonary Factors
	PH
	PDA

	Feasibility and Reproducibility

	DISCUSSION
	Maturational Patterns of Ventricular Strain in Uncomplicated Preterm Infants
	RV FWLS and IVS GLS
	LV GLS
	Segmental LS

	Clinical Implications of Deformation Imaging in Neonates
	BPD and Respiratory Support
	PH
	PDA

	Study Limitations and Future Directions

	CONCLUSIONS
	References
	Appendix 1. Reproducibility Analysis for Segmental Longitudinal Strain
	Table T7
	Figure 1
	Figure 2
	Figure 3
	Table 1
	Table 2
	Table 3
	Table 4
	Table 5
	Table 6