EHD-03954; No of Pages 6 Early Human Development xxx (2014) xxx–xxx
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Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation Beate Horsberg Eriksen a,b,⁎, Eirik Nestaas c, Torstein Hole d,e, Knut Liestøl f, Asbjørn Støylen b,g, Drude Fugelseth h,i a
Department of Paediatrics, Møre and Romsdal Hospital Trust, NO-6026 Ålesund, Norway Department of Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Department of Paediatrics, Vestfold Hospital Trust, Tønsberg, Norway d Department of Medicine, Møre and Romsdal Hospital Trust, Ålesund, Norway e Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway f Institute of Informatics, University of Oslo, Norway g Department of Cardiology, St. Olavs Hospital, Trondheim, Norway h Department of Neonatal Intensive Care, Oslo University Hospital, Ullevål, Oslo, Norway i Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway b c
a r t i c l e
i n f o
Article history: Received 6 March 2014 Received in revised form 24 March 2014 Accepted 8 April 2014 Available online xxxx Keywords: Tissue Doppler imaging Mitral annular plane systolic excursion Tricuspid annular plane systolic excursion Echocardiography Postnatal transition
a b s t r a c t Background: Sparse knowledge exists on the differences in cardiac function between term and preterm infants. This study examines the impact of heart size, gestational age and postnatal maturation on myocardial function. Aim: To assess and compare serial echocardiographic indices of myocardial function in term and moderately preterm infants. Methods: Longitudinal, prospective, observational echocardiographic cohort study of 45 healthy term infants examined at day three and at 12–20 weeks postnatal age and 53 moderately preterm infants (gestational age 31–35 weeks) examined at day three and at term equivalent (4–10 weeks postnatal age). Outcomes: Primary: Systolic mitral and tricuspid annular plane excursions and annular peak systolic pulsed wave tissue Doppler (pwTDI) velocities. Secondary: Indices normalized for heart size. Results: On day three, all indices were higher in the term than in the preterm infants whereas normalized systolic pwTDI velocities were lower in the term infants and normalized excursions showed no difference. All indices increased with advanced postnatal age. The indices in term infants on day three were lower than in preterm infants at term equivalent, with and without normalization. After postnatal maturation in both groups, all indices were higher in the term group (except left pwTDI), whereas normalized indices showed no consistent pattern. Conclusions: Myocardial function indices increased with gestational age at birth and more profoundly with postnatal maturation. Serial examinations of non-normalized and normalized myocardial function indices showed no sustained differences between the preterm and the term infants. Normalization by heart size may be of value when assessing myocardial function in infants. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The myocardium in term infants is structurally more mature than that in premature infants and studies in preterm fetal lambs show that fetal myocytes are smaller, have fewer myofibrils per unit mass and a larger proportion of mononucleated cardiomyocytes compared to myocytes in lambs at term [1]. The mature and the immature myocardium may respond differently to the abrupt circulatory changes during fetal–neonatal transition [2]. ⁎ Corresponding author at: Department of Paediatrics, Møre and Romsdal Public Health Enterprize, NO-6026 Ålesund, Norway. Tel.: +47 70105000; fax: +47 70167654(55). E-mail address: [email protected] (B.H. Eriksen).
Functional or targeted echocardiography provides bedside information on the central circulation and cardiac function and is increasingly incorporated into clinical practise in neonatal intensive care units [3]. The information obtained may be useful for the diagnosis and treatment of hemodynamic compromise. Several studies have assessed parameters reflecting postnatal hemodynamic adaption [4–7], but few studies have focused directly on the cardiac function by quantifiable measures. By applying conventional echocardiography, mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) can be assessed as parameters of left and right ventricular longitudinal systolic shortening [8–10]. Newer echocardiographic indices based on tissue Doppler imaging (TDI) are increasingly applied in the evaluation of myocardial function in adults [11] is feasible in children
http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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B.H. Eriksen et al. / Early Human Development xxx (2014) xxx–xxx
recorded from the apical four-chamber view according to the methods described previously [26,27]. Default frame rate and tissue velocity range of ±0.16 cm/s were applied.
and infants [12–15]. A recently published review advocates its use in the pediatric age group [16]. Measures of myocardial wall velocities along the longitudinal axis of the left and right ventricles can be obtained by pulsed wave (pw) TDI, and peak annular systolic velocity is validated as a measure of ventricular longitudinal systolic function [17]. pwTDI indices are less load dependent than blood flow measurements [18] and the method provides assessment of myocardial function in case of poor endocardial definition or abnormal septal motion [11]. The size of cardiovascular structures increase during normal body growth and development [19,20]. Scaling or normalization to correct for size is therefore customary. However, linear correction by body size has shown to be inaccurate in children [21]. Recent studies in children have shown that atrioventricular excursions normalized for heart size are independent measures of systolic function [22,23]. Eidem et al. also found that pwTDI velocities strongly correlated to left ventricular end-diastolic length (LVEDL) [14]. Annular excursions and velocities normalized by LVEDL are indices of longitudinal myocardial function that might more readily be compared between hearts of different size [24,25]. We have recently shown that atrioventricular plane velocities by pwTDI and atrioventricular plane excursions by conventional echocardiography are related to heart size, gestational and postnatal age in moderately premature infants [26,27]. The aim of this study was to serially assess and compare selected indices of longitudinal systolic myocardial function in healthy term born infants and to study the relative impact of prematurity and postnatal maturation. Secondly, parameters adjusted for heart size, normalizing by LVEDL, were assessed and compared between the groups. Our hypothesis was that indices of myocardial function were dependent on both gestational age at birth and postnatal maturation.
Demographic data are reported as median (range) or number (percentage). Normally distributed continuous echocardiographic variables are expressed as means (95% CI). Independent sample t-tests were used when comparing means between groups and paired sample t-tests when comparing measurements within groups. Multiple regression analysis was used to test the effect of HR on the echocardiographic parameters. Two sided p-values b 0.05 were considered significant. Statistical analyses were performed using SPSS 19.0 for Windows (SPSS Inc., Chicago, IL, USA) or JMP 9.0 (SAS Institute).
2. Methods
3. Results
2.1. Study design and study population
3.1. Study population and demographic data
In this prospective, longitudinal, observational study, forty-five healthy term infants were enrolled from the Maternity Ward at Oslo University Hospital, Ullevål in 2005 [28]. They had been examined by echocardiography day three after birth and at three to four months of age. They were compared to 53 preterm infants (gestational age 31– 35 weeks) recruited from the Neonatal Intensive Care Unit at Ålesund Hospital (n = 40) and the Department of Neonatal Intensive Care at Oslo University Hospital, Ullevål (n = 13) from March 2009 until December 2010 and examined on day three after birth and at the time of term equivalent (±14 days). Infants with major congenital anomalies of any organ system were excluded. In the preterm group, infants requiring cardiovascular supportive treatment were excluded, whereas ventilator support was not an exclusion criterion. Results from the majority of the preterm group, on days one and two after birth, have been published earlier [26,27].
Patient characteristics of the two groups are shown in Tables 1 and 2. Eight patients in the term group and five in the preterm group were lost to follow up. Images with inferior quality were not analyzed. One term and three preterm infants had an insignificant muscular ventricular septal defect. Otherwise, all the participants had structurally normal hearts. There was no significant difference in postmenstrual age (PMA) in the term group day three and in the preterm group at term equivalent. The lowest HR was found for the term infants on day three (p b 0.001) (Table 2). LVEDL was larger in the term group day three than in the preterm group day three (p b 0.001), whereas LVEDL were similar between the term group day three and the preterm group at term equivalent. In the preterm group, two infants were treated with positive pressure ventilation and three with nasal continuous positive airway pressure (nCPAP) at day three.
2.2. Ethical considerations
3.2. Myocardial deformation indices
The studies were approved by the Scientific Committees in both hospitals and by the Regional Committees for Medical and Health Research Ethics (South-East and Mid-Norway). Written informed parental consent was obtained.
Table 3 shows all indices of myocardial function in both groups at the two different study points. All indices increased in the term group with growth and postnatal maturation from day three. Comparing both groups at day three, both S′ and excursions in all walls were higher in the term group (p b 0.05 and b 0,001, respectively). All measurements were lower in the term group at day three compared to the preterm group at term equivalent (p b 0.001). After postnatal growth and maturation in both groups, all indices were higher in the term infants than in the preterm infants (p b 0.001 and p b 0.05 for left MAPSE), but not statistically significant for left S′. Multiple regression analyses, adjusting for term or preterm birth, showed a moderate negative effect of HR only on left and septal MAPSE day three (R2 0.246 and 0.209, p b 0.001 and 0.019). Otherwise, no effect of HR on the myocardial
2.3. Image acquisition Vivid 7 (term group) and Vivid I or Vivid S6 (preterm group) ultrasound machines (GE Vingmed, Horten, Norway) and standard phase array multi-frequency transducers (7S probe, 3.5–8 MHz and 5S probe; 2.0–5.0 MHz) were used to perform the echocardiographic examinations. Structural normality of the heart was established. Images for assessment of pwTDI velocities and MAPSE and TAPSE were
2.4. Off-line analyses All images in both groups were analyzed by the same observer (BHE) during a period of a few months in 2010/2011 using the manufacturer's software (EchoPac PC version 108.1.5, SW, GE Vingmed, Horten, Norway). Lateral and septal MAPSE and TAPSE were measured in B-mode by M-mode tracings (Fig. 1), and peak systolic (S′) atrioventricular plane Doppler velocities were measured in pwTDI as previously described [26,27] (Fig. 2). LVEDL was measured in B-mode four-chamber images as the distance from the apical epicardium to the level of the septal attachment of the mitral valve. Parameters adjusted for heart size were obtained by dividing the indices by LVEDL. Heart rate (HR) was obtained from the mitral Doppler flow signal. All variables were calculated using the average of three cardiac cycles. 2.5. Statistics
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
B.H. Eriksen et al. / Early Human Development xxx (2014) xxx–xxx
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Fig. 1. Apical four-chamber view. Representative post-processed M-mode tracing of mitral septal annular plane excursion (MAPSE). Solid lines represent the position of the atrioventricular annular in systole and diastole. The longitudinal excursion is shown as a dotted line.
function indices was shown in any of the two groups and, thereby, HR did not explain the differences in myocardial function shown in Table 3. No effect of nCPAP but a small effect of positive pressure ventilation on septal S′ was found by regression analyses (R2 0.107, p = 0.037).
differences were smaller and not consistent (normalized left S′ and normalized left MAPSE were lower (p b 0.05) and normalized septal MAPSE was higher (p b 0.001) in the term group compared to the preterm group). 4. Discussion
3.3. Myocardial deformation indices adjusted for heart size Table 4 shows indices of myocardial function adjusted for heart size in both groups at the two study points. Also normalized indices in the term group increased with maturation from day three. Comparing both groups at day three, normalized S′ in all walls was lower in the term group (p b 0.05), while there were no differences in normalized excursion indices. Comparing the term group at day three with the preterm group at term equivalent, all normalized indices were lower in the term group (p b 0.001). After postnatal maturation in both groups the
This is the first study to compare serial analyses of myocardial function by tissue Doppler imaging and B-mode echocardiography in healthy term born and moderately preterm infants. Our longitudinal approach enables assessment of myocardial function and physiology with postnatal maturation as well as comparison between the groups at different gestational and postnatal ages. The systolic myocardial function indices increased significantly with increasing postnatal age in the healthy term infants as well as in the preterm infants, as we have shown previously [26,27]. In a cross-sectional
Fig. 2. Apical four-chamber view. Pulsed wave tissue Doppler recording of septal velocities. S′, peak systolic velocity.
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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Table 1 Patient characteristics.
Gender, n female/male Gestational age at birth, weeks Postnatal age at second examination, weeks Postmenstrual age at second examination, weeks Age at first examination, h 5 min Apgar score SGA, n (%)
Term group n = 45
Preterm group n = 53
22/23 41 (37–42) 14 (12–20) 55 (51–61) 59 (48–69) 9 (8–10) 0 (0)
25/28 34 (31–35) 7 (4–10) 40 (38–43) 63 (57–72) 9 (6–10) 18 (34)
Values are median (range) or number (%). SGA, small for gestational age. Age is rounded to the nearest week.
study by Mori et al., systolic shortening velocities increased during the first week of life [12] and Koestenberger and colleagues found that tricuspid S′ and week of gestation were strongly correlated [29]. TAPSE has been found to be strongly correlated to gestational age at birth [30] and MAPSE and TAPSE increase with increasing age in children [31,32]. Our mean values for equivalent gestational ages were comparable with the results from these large cross-sectional studies. In our study, all indices of myocardial function were significantly higher in the term than in the preterm group at three days of age. At this point, the two groups had different gestational age but equal postnatal age. Other cross-sectional studies have shown similar differences in left and right S′ between term and moderately preterm infants within the first few days of life [13,33,34]. The differences in myocardial function indices between the term and moderately preterm infants might suggest impaired myocardial function in the preterm group or might reflect natural physiological properties due to differences in myocardial postnatal maturation and heart size. At term equivalent, the preterm group had the same postmenstrual but more advanced postnatal age than the term group day three. Even though the groups had equal heart size at this point, all indices of ventricular function were significantly lower in the healthy term group compared to the preterm group and this seems to contradict the presence of systolic dysfunction in the preterm group at term equivalent, as compared to the newborn term neonates. The adaption to extra uterine life appears to commence at the time of birth. Studies in fetal lambs indicate that the postnatal change in myocardial growth pattern is triggered by increased concentrations of catecholamines, triiodothyronine and cortisol [1] and the catecholamine response at birth is found to be similar in preterm and term infants [35]. Thus, the neurohormonal stimulation starts at an earlier gestational age and in a more immature myocardium in preterm birth. The increase in myocardial mass seems to be achieved by myocytes hyperplasia prenatally and by hypertrophy postnatally [1]. Preterm birth itself might therefore alter the myocardial growth pattern. Despite comparable body weight and heart size, the heart rate was lower in the term group day three than in the preterm group at term equivalent. The preterm infants at term equivalent were examined in an outpatient setting when some were agitated and the increased heart rate might be due to a higher stress level in the preterm infants. However, we found that differences in HR between the gestational age
groups did not explain the differences in ventricular function indices. Previous studies have shown a negative or no correlation between HR and systolic pwTDI velocities [14,36]. In our previous studies in the preterm group HR had no significant effect on systolic pwTDI velocities or B-mode excursions [26,27]. Because body size influence ventricular function, the rapid growth typical of infancy and childhood has to be taken into consideration when evaluating cardiac function. Calculation of body surface area and establishment of z-scores are increasingly used as references values for cardiac dimensions and cardiac function indices in infants and children [30,31,37,38]. However, in newborn infants, body length is frequently inaccurate or missing in case of breach presentation where measure of length is often postponed. Dividing ventricular function indices by LVEDL might therefore be an alternative method of assessing global myocardial function [24]. Our previous study has shown low intra- and inter-variability for measures of LVEDL [27]. The longitudinal systolic ventricular shortening divided by heart size is equivalent to longitudinal myocardial strain [39]. At day three in both groups, there was no difference in normalized MAPSE and TAPSE and hence probably similar longitudinal strain in the two groups. Furthermore, S′ divided by heart size is equivalent to strain rate which is closely related to contractility [40]. At day three in both groups, normalization by LVEDL reversed the difference in S′. Therefore, one might argue that the preterm infants display a higher myocardial contractility at day three compared to the term group at day three, possibly due to a higher sympathetic tone in the preterm infants, also resulting in a higher HR. Higher normalized S′ in the preterm group day three might also indicate compensatory mechanisms in the preterm due to a smaller heart facing the neonatal circulation or different responsiveness in the more immature myocardium compared to the mature ventricles in the term born infants. Thus, when taking the influence of gestational age, heart size and postnatal maturation into account, this study cannot conclude with sustained differences in myocardial function between the gestational age groups. Our results suggest that differences in heart size may be an important explanation for differences in myocardial functional indices found in many studies. Furthermore, postnatal myocardial maturation may have a greater influence on the myocardial development than gestational age at birth. Overall, the term infants after postnatal maturation had the highest indices of myocardial function, the largest hearts and the most advanced gestational and postnatal age. All these factors are expected to contribute to advanced myocardial function. Awareness of the effects of growth, gestational age and postnatal age on myocardial function indices is imperative for future monitoring of infants with or without cardiac disease. 4.1. Limitations This study has some limitations. The sample size considered is small and clinically relevant findings could have been missed because of limited statistical power. The second examination was conducted at different postnatal ages in the two groups and this could influence some of the differences between the groups. Slight heterogeneity between the groups in respect to respiratory state at day three could affect the measurements, but our analyses revealed only a small effect
Table 2 Longitudinal patient characteristics.
No of participants Weight, kg1 HR, bpm2 LVEDL, mm2
Term group Day 3
Term group 3–4 months postnatal
Preterm group Day 3
Preterm group 7 weeks postnatal (term equivalent)
45 3.68 (2.86–4.60) 120 [114, 126] 35.5 [34.7, 36.3]
37 7.00 (4.88–8.80) 143 [139, 147]⁎⁎⁎ 42.4 [41.2, 43.6]⁎⁎⁎
53 1.93 (1.13–2.84) 143 [139, 147]⁎⁎⁎ 28.4 [27.6, 28.2]⁎⁎⁎
48 3.20 (2.33–4.54) 163 [158, 167]⁎⁎⁎ 36.2 [35.4, 37.0]
1 Median (range), 2Mean [95% CI]. HR, heart rate; and LVEDL, left ventricular end diastolic length. ⁎⁎⁎ p b 0.001 compared to term group day 3.
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
B.H. Eriksen et al. / Early Human Development xxx (2014) xxx–xxx
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Table 3 Atrioventricular peak systolic velocity and excursion in term and preterm infants day three and after postnatal maturation.
S′ cm/s S′ left S′ septum S′ right Excursion mm MAPSE left MAPSE septum TAPSE
Term Day 3
Term 3–4 months postnatal
Preterm Day 3
4.47 [4.20, 4.75] 4.31 [4.12, 4.50] 6.30 [6.00, 6.60]
6.23 [5.87, 6.60]⁎⁎⁎ 6.89 [6.57, 7.21]⁎⁎⁎ 11.06 [10.47, 11.65]⁎⁎⁎
4.04 [3.76, 4.32]⁎ 4.02 [3.81, 4,23]⁎ 5.71 [5.43, 5.99]⁎
5.23 [4.87, 5.58] 4.11 [3.90, 4.33] 8.20 [7.76, 8.65]
7.26 [6.88, 7.66]⁎⁎⁎ 7.16 [6.77, 7.55]⁎⁎⁎ 13.75 [13.14, 14.35]⁎⁎⁎
4.41 [4.15, 4.67]⁎⁎⁎ 3.54 [3.38, 3.71]⁎⁎⁎ 6.75 [6.39, 7.10]⁎⁎⁎
Preterm Term equivalent 7 weeks postnatal 5.88 [5.56, 6,20]⁎⁎⁎ 5.54 [5.23, 5.85]⁎⁎⁎ 9.47 [9.06, 9.88]⁎⁎⁎ 6.78 [6.50, 7.06]⁎⁎⁎ 5.19 [4.93, 5.45]⁎⁎⁎ 11.11 [10.60, 11.61]⁎⁎⁎
Mean [95% CI]. S′, peak systolic velocity; TAPSE, tricuspid annulus plane systolic excursion; and MAPSE, mitral annulus plane systolic excursion. ⁎⁎⁎ p b 0.001 compared to term group day 3. ⁎ p b 0.05 compared to term group day 3.
Table 4 Normalized atrioventricular peak systolic velocity and excursion in term and preterm infants day three and after postnatal maturation. Term Day 3 S′/LVEDL, s−1 S′ left/LVEDL S′ septum/LVEDL S′ right/LVEDL Excursion/LVEDL MAPSE left/LVEDL MAPSE septum/LVEDL TAPSE/LVEDL
Term 3–4 months postnatal
Preterm Day 3
Preterm Term equivalent, 7 weeks postnatal
1.30 [1.18, 1.42] 1.24 [1.16, 1.31] 1.79 [1.70, 1.88]
1.45 [1.35, 1.55]⁎ 1.66 [1.59, 1.73]⁎⁎⁎ 2.62 [2.46, 2.77]⁎⁎⁎
1.43 [1.31, 1.54]⁎ 1.42 [1.32, 1.51]⁎ 2.02 [1.90, 2.15]⁎
1.65 [1.56, 1.75]⁎⁎⁎ 1.55 [1.45, 1.64]⁎⁎⁎ 2.62 [2.52, 2.71]⁎⁎⁎
0.152 [0.140, 0.163] 0.120 [0.112, 0.129] 0.233 [0.220, 0.246]
0.174 [0.161, 0.186]⁎ 0.170 [0.159, 0.180]⁎⁎⁎ 0.322 [0.307, 0.337]⁎⁎⁎
0.155 [0.147. 0.164] 0.125 [0.119, 0.131] 0.237 [0.225, 0.249]
0.188 [0.180, 0.197]⁎⁎⁎ 0.144 [0.137, 0.150]⁎⁎⁎ 0.308 [0.295, 0.321]⁎⁎⁎
Mean [95% CI]. S′, peak systolic velocity; MAPSE, mitral annulus plane systolic excursion; TAPSE, tricuspid annulus plane systolic excursion; and LVEDL, left ventricular end diastolic length. ⁎⁎⁎ p b 0.001 compared to term group day 3. ⁎ p b 0.05 compared to term group day 3.
of positive pressure ventilation. The more advanced postnatal age in the preterm group at term equivalent compared to the term group day three might in itself affect the myocardial indices and disturb the direct comparison between the groups. Also, longer follow-up could have yielded more extensive differences or smoothed out differences between the groups. Normalizing by ventricular length introduces an additional measurement (LVEDL) that will increase the measurement variability of the composite parameter. This can reduce the advantage of normalization.
5. Conclusion Our study demonstrates differences in systolic myocardial function in healthy term born and moderately preterm infants. Systolic myocardial function was higher in the term group compared to the preterm group both in the late transitional phase and after postnatal maturation. However, normalizing the indices by LVEDL removed or reversed the differences at day three in favor of the preterm infants. At term equivalent in the preterm group, both non-normalized and normalized indices were higher compared to term infants at the same postmenstrual age, suggesting a larger effect of postnatal maturation than of gestational age at birth. Hence, by this longitudinal study approach there were no sustained differences in myocardial function between the groups. We suggest that heart size as well as gestational and postnatal age should be taken into consideration when comparing indices of myocardial function in infants. Further studies are needed to validate the clinical usefulness of these measurements in neonates with variable clinical conditions.
Conflict of interest statement None declared.
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Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation Beate Horsberg Eriksen a,b,⁎, Eirik Nestaas c, Torstein Hole d,e, Knut Liestøl f, Asbjørn Støylen b,g, Drude Fugelseth h,i a
Department of Paediatrics, Møre and Romsdal Hospital Trust, NO-6026 Ålesund, Norway Department of Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Department of Paediatrics, Vestfold Hospital Trust, Tønsberg, Norway d Department of Medicine, Møre and Romsdal Hospital Trust, Ålesund, Norway e Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway f Institute of Informatics, University of Oslo, Norway g Department of Cardiology, St. Olavs Hospital, Trondheim, Norway h Department of Neonatal Intensive Care, Oslo University Hospital, Ullevål, Oslo, Norway i Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway b c
a r t i c l e
i n f o
Article history: Received 6 March 2014 Received in revised form 24 March 2014 Accepted 8 April 2014 Available online xxxx Keywords: Tissue Doppler imaging Mitral annular plane systolic excursion Tricuspid annular plane systolic excursion Echocardiography Postnatal transition
a b s t r a c t Background: Sparse knowledge exists on the differences in cardiac function between term and preterm infants. This study examines the impact of heart size, gestational age and postnatal maturation on myocardial function. Aim: To assess and compare serial echocardiographic indices of myocardial function in term and moderately preterm infants. Methods: Longitudinal, prospective, observational echocardiographic cohort study of 45 healthy term infants examined at day three and at 12–20 weeks postnatal age and 53 moderately preterm infants (gestational age 31–35 weeks) examined at day three and at term equivalent (4–10 weeks postnatal age). Outcomes: Primary: Systolic mitral and tricuspid annular plane excursions and annular peak systolic pulsed wave tissue Doppler (pwTDI) velocities. Secondary: Indices normalized for heart size. Results: On day three, all indices were higher in the term than in the preterm infants whereas normalized systolic pwTDI velocities were lower in the term infants and normalized excursions showed no difference. All indices increased with advanced postnatal age. The indices in term infants on day three were lower than in preterm infants at term equivalent, with and without normalization. After postnatal maturation in both groups, all indices were higher in the term group (except left pwTDI), whereas normalized indices showed no consistent pattern. Conclusions: Myocardial function indices increased with gestational age at birth and more profoundly with postnatal maturation. Serial examinations of non-normalized and normalized myocardial function indices showed no sustained differences between the preterm and the term infants. Normalization by heart size may be of value when assessing myocardial function in infants. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The myocardium in term infants is structurally more mature than that in premature infants and studies in preterm fetal lambs show that fetal myocytes are smaller, have fewer myofibrils per unit mass and a larger proportion of mononucleated cardiomyocytes compared to myocytes in lambs at term [1]. The mature and the immature myocardium may respond differently to the abrupt circulatory changes during fetal–neonatal transition [2]. ⁎ Corresponding author at: Department of Paediatrics, Møre and Romsdal Public Health Enterprize, NO-6026 Ålesund, Norway. Tel.: +47 70105000; fax: +47 70167654(55). E-mail address: [email protected] (B.H. Eriksen).
Functional or targeted echocardiography provides bedside information on the central circulation and cardiac function and is increasingly incorporated into clinical practise in neonatal intensive care units [3]. The information obtained may be useful for the diagnosis and treatment of hemodynamic compromise. Several studies have assessed parameters reflecting postnatal hemodynamic adaption [4–7], but few studies have focused directly on the cardiac function by quantifiable measures. By applying conventional echocardiography, mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) can be assessed as parameters of left and right ventricular longitudinal systolic shortening [8–10]. Newer echocardiographic indices based on tissue Doppler imaging (TDI) are increasingly applied in the evaluation of myocardial function in adults [11] is feasible in children
http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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B.H. Eriksen et al. / Early Human Development xxx (2014) xxx–xxx
recorded from the apical four-chamber view according to the methods described previously [26,27]. Default frame rate and tissue velocity range of ±0.16 cm/s were applied.
and infants [12–15]. A recently published review advocates its use in the pediatric age group [16]. Measures of myocardial wall velocities along the longitudinal axis of the left and right ventricles can be obtained by pulsed wave (pw) TDI, and peak annular systolic velocity is validated as a measure of ventricular longitudinal systolic function [17]. pwTDI indices are less load dependent than blood flow measurements [18] and the method provides assessment of myocardial function in case of poor endocardial definition or abnormal septal motion [11]. The size of cardiovascular structures increase during normal body growth and development [19,20]. Scaling or normalization to correct for size is therefore customary. However, linear correction by body size has shown to be inaccurate in children [21]. Recent studies in children have shown that atrioventricular excursions normalized for heart size are independent measures of systolic function [22,23]. Eidem et al. also found that pwTDI velocities strongly correlated to left ventricular end-diastolic length (LVEDL) [14]. Annular excursions and velocities normalized by LVEDL are indices of longitudinal myocardial function that might more readily be compared between hearts of different size [24,25]. We have recently shown that atrioventricular plane velocities by pwTDI and atrioventricular plane excursions by conventional echocardiography are related to heart size, gestational and postnatal age in moderately premature infants [26,27]. The aim of this study was to serially assess and compare selected indices of longitudinal systolic myocardial function in healthy term born infants and to study the relative impact of prematurity and postnatal maturation. Secondly, parameters adjusted for heart size, normalizing by LVEDL, were assessed and compared between the groups. Our hypothesis was that indices of myocardial function were dependent on both gestational age at birth and postnatal maturation.
Demographic data are reported as median (range) or number (percentage). Normally distributed continuous echocardiographic variables are expressed as means (95% CI). Independent sample t-tests were used when comparing means between groups and paired sample t-tests when comparing measurements within groups. Multiple regression analysis was used to test the effect of HR on the echocardiographic parameters. Two sided p-values b 0.05 were considered significant. Statistical analyses were performed using SPSS 19.0 for Windows (SPSS Inc., Chicago, IL, USA) or JMP 9.0 (SAS Institute).
2. Methods
3. Results
2.1. Study design and study population
3.1. Study population and demographic data
In this prospective, longitudinal, observational study, forty-five healthy term infants were enrolled from the Maternity Ward at Oslo University Hospital, Ullevål in 2005 [28]. They had been examined by echocardiography day three after birth and at three to four months of age. They were compared to 53 preterm infants (gestational age 31– 35 weeks) recruited from the Neonatal Intensive Care Unit at Ålesund Hospital (n = 40) and the Department of Neonatal Intensive Care at Oslo University Hospital, Ullevål (n = 13) from March 2009 until December 2010 and examined on day three after birth and at the time of term equivalent (±14 days). Infants with major congenital anomalies of any organ system were excluded. In the preterm group, infants requiring cardiovascular supportive treatment were excluded, whereas ventilator support was not an exclusion criterion. Results from the majority of the preterm group, on days one and two after birth, have been published earlier [26,27].
Patient characteristics of the two groups are shown in Tables 1 and 2. Eight patients in the term group and five in the preterm group were lost to follow up. Images with inferior quality were not analyzed. One term and three preterm infants had an insignificant muscular ventricular septal defect. Otherwise, all the participants had structurally normal hearts. There was no significant difference in postmenstrual age (PMA) in the term group day three and in the preterm group at term equivalent. The lowest HR was found for the term infants on day three (p b 0.001) (Table 2). LVEDL was larger in the term group day three than in the preterm group day three (p b 0.001), whereas LVEDL were similar between the term group day three and the preterm group at term equivalent. In the preterm group, two infants were treated with positive pressure ventilation and three with nasal continuous positive airway pressure (nCPAP) at day three.
2.2. Ethical considerations
3.2. Myocardial deformation indices
The studies were approved by the Scientific Committees in both hospitals and by the Regional Committees for Medical and Health Research Ethics (South-East and Mid-Norway). Written informed parental consent was obtained.
Table 3 shows all indices of myocardial function in both groups at the two different study points. All indices increased in the term group with growth and postnatal maturation from day three. Comparing both groups at day three, both S′ and excursions in all walls were higher in the term group (p b 0.05 and b 0,001, respectively). All measurements were lower in the term group at day three compared to the preterm group at term equivalent (p b 0.001). After postnatal growth and maturation in both groups, all indices were higher in the term infants than in the preterm infants (p b 0.001 and p b 0.05 for left MAPSE), but not statistically significant for left S′. Multiple regression analyses, adjusting for term or preterm birth, showed a moderate negative effect of HR only on left and septal MAPSE day three (R2 0.246 and 0.209, p b 0.001 and 0.019). Otherwise, no effect of HR on the myocardial
2.3. Image acquisition Vivid 7 (term group) and Vivid I or Vivid S6 (preterm group) ultrasound machines (GE Vingmed, Horten, Norway) and standard phase array multi-frequency transducers (7S probe, 3.5–8 MHz and 5S probe; 2.0–5.0 MHz) were used to perform the echocardiographic examinations. Structural normality of the heart was established. Images for assessment of pwTDI velocities and MAPSE and TAPSE were
2.4. Off-line analyses All images in both groups were analyzed by the same observer (BHE) during a period of a few months in 2010/2011 using the manufacturer's software (EchoPac PC version 108.1.5, SW, GE Vingmed, Horten, Norway). Lateral and septal MAPSE and TAPSE were measured in B-mode by M-mode tracings (Fig. 1), and peak systolic (S′) atrioventricular plane Doppler velocities were measured in pwTDI as previously described [26,27] (Fig. 2). LVEDL was measured in B-mode four-chamber images as the distance from the apical epicardium to the level of the septal attachment of the mitral valve. Parameters adjusted for heart size were obtained by dividing the indices by LVEDL. Heart rate (HR) was obtained from the mitral Doppler flow signal. All variables were calculated using the average of three cardiac cycles. 2.5. Statistics
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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Fig. 1. Apical four-chamber view. Representative post-processed M-mode tracing of mitral septal annular plane excursion (MAPSE). Solid lines represent the position of the atrioventricular annular in systole and diastole. The longitudinal excursion is shown as a dotted line.
function indices was shown in any of the two groups and, thereby, HR did not explain the differences in myocardial function shown in Table 3. No effect of nCPAP but a small effect of positive pressure ventilation on septal S′ was found by regression analyses (R2 0.107, p = 0.037).
differences were smaller and not consistent (normalized left S′ and normalized left MAPSE were lower (p b 0.05) and normalized septal MAPSE was higher (p b 0.001) in the term group compared to the preterm group). 4. Discussion
3.3. Myocardial deformation indices adjusted for heart size Table 4 shows indices of myocardial function adjusted for heart size in both groups at the two study points. Also normalized indices in the term group increased with maturation from day three. Comparing both groups at day three, normalized S′ in all walls was lower in the term group (p b 0.05), while there were no differences in normalized excursion indices. Comparing the term group at day three with the preterm group at term equivalent, all normalized indices were lower in the term group (p b 0.001). After postnatal maturation in both groups the
This is the first study to compare serial analyses of myocardial function by tissue Doppler imaging and B-mode echocardiography in healthy term born and moderately preterm infants. Our longitudinal approach enables assessment of myocardial function and physiology with postnatal maturation as well as comparison between the groups at different gestational and postnatal ages. The systolic myocardial function indices increased significantly with increasing postnatal age in the healthy term infants as well as in the preterm infants, as we have shown previously [26,27]. In a cross-sectional
Fig. 2. Apical four-chamber view. Pulsed wave tissue Doppler recording of septal velocities. S′, peak systolic velocity.
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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Table 1 Patient characteristics.
Gender, n female/male Gestational age at birth, weeks Postnatal age at second examination, weeks Postmenstrual age at second examination, weeks Age at first examination, h 5 min Apgar score SGA, n (%)
Term group n = 45
Preterm group n = 53
22/23 41 (37–42) 14 (12–20) 55 (51–61) 59 (48–69) 9 (8–10) 0 (0)
25/28 34 (31–35) 7 (4–10) 40 (38–43) 63 (57–72) 9 (6–10) 18 (34)
Values are median (range) or number (%). SGA, small for gestational age. Age is rounded to the nearest week.
study by Mori et al., systolic shortening velocities increased during the first week of life [12] and Koestenberger and colleagues found that tricuspid S′ and week of gestation were strongly correlated [29]. TAPSE has been found to be strongly correlated to gestational age at birth [30] and MAPSE and TAPSE increase with increasing age in children [31,32]. Our mean values for equivalent gestational ages were comparable with the results from these large cross-sectional studies. In our study, all indices of myocardial function were significantly higher in the term than in the preterm group at three days of age. At this point, the two groups had different gestational age but equal postnatal age. Other cross-sectional studies have shown similar differences in left and right S′ between term and moderately preterm infants within the first few days of life [13,33,34]. The differences in myocardial function indices between the term and moderately preterm infants might suggest impaired myocardial function in the preterm group or might reflect natural physiological properties due to differences in myocardial postnatal maturation and heart size. At term equivalent, the preterm group had the same postmenstrual but more advanced postnatal age than the term group day three. Even though the groups had equal heart size at this point, all indices of ventricular function were significantly lower in the healthy term group compared to the preterm group and this seems to contradict the presence of systolic dysfunction in the preterm group at term equivalent, as compared to the newborn term neonates. The adaption to extra uterine life appears to commence at the time of birth. Studies in fetal lambs indicate that the postnatal change in myocardial growth pattern is triggered by increased concentrations of catecholamines, triiodothyronine and cortisol [1] and the catecholamine response at birth is found to be similar in preterm and term infants [35]. Thus, the neurohormonal stimulation starts at an earlier gestational age and in a more immature myocardium in preterm birth. The increase in myocardial mass seems to be achieved by myocytes hyperplasia prenatally and by hypertrophy postnatally [1]. Preterm birth itself might therefore alter the myocardial growth pattern. Despite comparable body weight and heart size, the heart rate was lower in the term group day three than in the preterm group at term equivalent. The preterm infants at term equivalent were examined in an outpatient setting when some were agitated and the increased heart rate might be due to a higher stress level in the preterm infants. However, we found that differences in HR between the gestational age
groups did not explain the differences in ventricular function indices. Previous studies have shown a negative or no correlation between HR and systolic pwTDI velocities [14,36]. In our previous studies in the preterm group HR had no significant effect on systolic pwTDI velocities or B-mode excursions [26,27]. Because body size influence ventricular function, the rapid growth typical of infancy and childhood has to be taken into consideration when evaluating cardiac function. Calculation of body surface area and establishment of z-scores are increasingly used as references values for cardiac dimensions and cardiac function indices in infants and children [30,31,37,38]. However, in newborn infants, body length is frequently inaccurate or missing in case of breach presentation where measure of length is often postponed. Dividing ventricular function indices by LVEDL might therefore be an alternative method of assessing global myocardial function [24]. Our previous study has shown low intra- and inter-variability for measures of LVEDL [27]. The longitudinal systolic ventricular shortening divided by heart size is equivalent to longitudinal myocardial strain [39]. At day three in both groups, there was no difference in normalized MAPSE and TAPSE and hence probably similar longitudinal strain in the two groups. Furthermore, S′ divided by heart size is equivalent to strain rate which is closely related to contractility [40]. At day three in both groups, normalization by LVEDL reversed the difference in S′. Therefore, one might argue that the preterm infants display a higher myocardial contractility at day three compared to the term group at day three, possibly due to a higher sympathetic tone in the preterm infants, also resulting in a higher HR. Higher normalized S′ in the preterm group day three might also indicate compensatory mechanisms in the preterm due to a smaller heart facing the neonatal circulation or different responsiveness in the more immature myocardium compared to the mature ventricles in the term born infants. Thus, when taking the influence of gestational age, heart size and postnatal maturation into account, this study cannot conclude with sustained differences in myocardial function between the gestational age groups. Our results suggest that differences in heart size may be an important explanation for differences in myocardial functional indices found in many studies. Furthermore, postnatal myocardial maturation may have a greater influence on the myocardial development than gestational age at birth. Overall, the term infants after postnatal maturation had the highest indices of myocardial function, the largest hearts and the most advanced gestational and postnatal age. All these factors are expected to contribute to advanced myocardial function. Awareness of the effects of growth, gestational age and postnatal age on myocardial function indices is imperative for future monitoring of infants with or without cardiac disease. 4.1. Limitations This study has some limitations. The sample size considered is small and clinically relevant findings could have been missed because of limited statistical power. The second examination was conducted at different postnatal ages in the two groups and this could influence some of the differences between the groups. Slight heterogeneity between the groups in respect to respiratory state at day three could affect the measurements, but our analyses revealed only a small effect
Table 2 Longitudinal patient characteristics.
No of participants Weight, kg1 HR, bpm2 LVEDL, mm2
Term group Day 3
Term group 3–4 months postnatal
Preterm group Day 3
Preterm group 7 weeks postnatal (term equivalent)
45 3.68 (2.86–4.60) 120 [114, 126] 35.5 [34.7, 36.3]
37 7.00 (4.88–8.80) 143 [139, 147]⁎⁎⁎ 42.4 [41.2, 43.6]⁎⁎⁎
53 1.93 (1.13–2.84) 143 [139, 147]⁎⁎⁎ 28.4 [27.6, 28.2]⁎⁎⁎
48 3.20 (2.33–4.54) 163 [158, 167]⁎⁎⁎ 36.2 [35.4, 37.0]
1 Median (range), 2Mean [95% CI]. HR, heart rate; and LVEDL, left ventricular end diastolic length. ⁎⁎⁎ p b 0.001 compared to term group day 3.
Please cite this article as: Eriksen BH, et al, Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.04.010
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Table 3 Atrioventricular peak systolic velocity and excursion in term and preterm infants day three and after postnatal maturation.
S′ cm/s S′ left S′ septum S′ right Excursion mm MAPSE left MAPSE septum TAPSE
Term Day 3
Term 3–4 months postnatal
Preterm Day 3
4.47 [4.20, 4.75] 4.31 [4.12, 4.50] 6.30 [6.00, 6.60]
6.23 [5.87, 6.60]⁎⁎⁎ 6.89 [6.57, 7.21]⁎⁎⁎ 11.06 [10.47, 11.65]⁎⁎⁎
4.04 [3.76, 4.32]⁎ 4.02 [3.81, 4,23]⁎ 5.71 [5.43, 5.99]⁎
5.23 [4.87, 5.58] 4.11 [3.90, 4.33] 8.20 [7.76, 8.65]
7.26 [6.88, 7.66]⁎⁎⁎ 7.16 [6.77, 7.55]⁎⁎⁎ 13.75 [13.14, 14.35]⁎⁎⁎
4.41 [4.15, 4.67]⁎⁎⁎ 3.54 [3.38, 3.71]⁎⁎⁎ 6.75 [6.39, 7.10]⁎⁎⁎
Preterm Term equivalent 7 weeks postnatal 5.88 [5.56, 6,20]⁎⁎⁎ 5.54 [5.23, 5.85]⁎⁎⁎ 9.47 [9.06, 9.88]⁎⁎⁎ 6.78 [6.50, 7.06]⁎⁎⁎ 5.19 [4.93, 5.45]⁎⁎⁎ 11.11 [10.60, 11.61]⁎⁎⁎
Mean [95% CI]. S′, peak systolic velocity; TAPSE, tricuspid annulus plane systolic excursion; and MAPSE, mitral annulus plane systolic excursion. ⁎⁎⁎ p b 0.001 compared to term group day 3. ⁎ p b 0.05 compared to term group day 3.
Table 4 Normalized atrioventricular peak systolic velocity and excursion in term and preterm infants day three and after postnatal maturation. Term Day 3 S′/LVEDL, s−1 S′ left/LVEDL S′ septum/LVEDL S′ right/LVEDL Excursion/LVEDL MAPSE left/LVEDL MAPSE septum/LVEDL TAPSE/LVEDL
Term 3–4 months postnatal
Preterm Day 3
Preterm Term equivalent, 7 weeks postnatal
1.30 [1.18, 1.42] 1.24 [1.16, 1.31] 1.79 [1.70, 1.88]
1.45 [1.35, 1.55]⁎ 1.66 [1.59, 1.73]⁎⁎⁎ 2.62 [2.46, 2.77]⁎⁎⁎
1.43 [1.31, 1.54]⁎ 1.42 [1.32, 1.51]⁎ 2.02 [1.90, 2.15]⁎
1.65 [1.56, 1.75]⁎⁎⁎ 1.55 [1.45, 1.64]⁎⁎⁎ 2.62 [2.52, 2.71]⁎⁎⁎
0.152 [0.140, 0.163] 0.120 [0.112, 0.129] 0.233 [0.220, 0.246]
0.174 [0.161, 0.186]⁎ 0.170 [0.159, 0.180]⁎⁎⁎ 0.322 [0.307, 0.337]⁎⁎⁎
0.155 [0.147. 0.164] 0.125 [0.119, 0.131] 0.237 [0.225, 0.249]
0.188 [0.180, 0.197]⁎⁎⁎ 0.144 [0.137, 0.150]⁎⁎⁎ 0.308 [0.295, 0.321]⁎⁎⁎
Mean [95% CI]. S′, peak systolic velocity; MAPSE, mitral annulus plane systolic excursion; TAPSE, tricuspid annulus plane systolic excursion; and LVEDL, left ventricular end diastolic length. ⁎⁎⁎ p b 0.001 compared to term group day 3. ⁎ p b 0.05 compared to term group day 3.
of positive pressure ventilation. The more advanced postnatal age in the preterm group at term equivalent compared to the term group day three might in itself affect the myocardial indices and disturb the direct comparison between the groups. Also, longer follow-up could have yielded more extensive differences or smoothed out differences between the groups. Normalizing by ventricular length introduces an additional measurement (LVEDL) that will increase the measurement variability of the composite parameter. This can reduce the advantage of normalization.
5. Conclusion Our study demonstrates differences in systolic myocardial function in healthy term born and moderately preterm infants. Systolic myocardial function was higher in the term group compared to the preterm group both in the late transitional phase and after postnatal maturation. However, normalizing the indices by LVEDL removed or reversed the differences at day three in favor of the preterm infants. At term equivalent in the preterm group, both non-normalized and normalized indices were higher compared to term infants at the same postmenstrual age, suggesting a larger effect of postnatal maturation than of gestational age at birth. Hence, by this longitudinal study approach there were no sustained differences in myocardial function between the groups. We suggest that heart size as well as gestational and postnatal age should be taken into consideration when comparing indices of myocardial function in infants. Further studies are needed to validate the clinical usefulness of these measurements in neonates with variable clinical conditions.
Conflict of interest statement None declared.
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