Pediatr Cardiol (2015) 36:20–26 DOI 10.1007/s00246-014-0959-6
ORIGINAL ARTICLE
Longitudinal Systolic Left Ventricular Function in Preterm and Term Neonates: Reference Values of the Mitral Annular Plane Systolic Excursion (MAPSE) and Calculation of z-Scores Martin Koestenberger • Bert Nagel • William Ravekes • Andreas Gamillscheg Corinna Binder • Alexander Avian • Jasmin Pansy • Gerhard Cvirn • Berndt Urlesberger
•
Received: 13 January 2014 / Accepted: 20 June 2014 / Published online: 31 July 2014 Ó Springer Science+Business Media New York 2014
Abstract The mitral annular plane systolic excursion (MAPSE) is a quick and reliable echocardiographic tool for assessing longitudinal left ventricular (LV) systolic function in children and adults. Because this parameter is affected by the LV longitudinal dimension, pediatric and adult normal values are not suitable for preterm and term neonates. A prospective study investigated a large group of preterm and term neonates [gestational age (GA), 26/0–6 to 40/0–6; birth weight (BW), 670–4,140 g]. The growth- and BW-related changes in MAPSE were determined to establish normal z-score values for preterm and term neonates. The MAPSE ranged from a mean of 0.36 ± 0.05 cm in preterm neonates with a GA of 26/0–6 to 0.56 ± 0.08 cm in term neonates with a GA of 40/0–6. The findings showed MAPSE, GA, and BW to be moderately
correlated. Pearson’s correlation coefficient was 0.56 for GA (MAPSE; p \ 0.001) and 0.58 for BW (MAPSE; p \ 0.001). The normal MAPSE values did not differ significantly between females and males (p = 0.946). The absolute values and z-scores of normal MAPSE values in healthy preterm and term neonates within the first 48 h of life were calculated, and percentile charts were established. Determination of LV function using MAPSE might be useful for vulnerable infants for whom a prolonged examination is inappropriate and for neonates with suboptimal visualization of the endocardium.
M. Koestenberger (&) B. Nagel A. Gamillscheg Division of Pediatric Cardiology, Department of Pediatrics, Medical University Graz, Auenbruggerplatz 34/2, 8036 Graz, Austria e-mail: [email protected]; [email protected]
Introduction
W. Ravekes Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA C. Binder J. Pansy B. Urlesberger Division of Neonatology, Department of Pediatrics, Medical University Graz, Graz, Austria A. Avian Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Graz, Austria G. Cvirn Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
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Keywords Mitral annular plane systolic excursion Left ventricular long-axis function Preterm Neonates Reference values Birth weight M-mode z-Score
The mitral annular plane systolic excursion (MAPSE) is reported to correlate well with left ventricular ejection fraction (LVEF) in adults [7, 28]. Findings have shown MAPSE, an M-mode—derived measure of longitudinal LV function [21], to be an important parameter of the global LV function in premature infants as well [8, 33]. The morphology of the preterm heart shows a thinner walled left ventricle (LV) and a functionally hypertrophied right ventricle (RV) [32]. After birth, ductal shunting rapidly changes from balanced to left-to-right shunting, with a responsive increase in LV stroke volume [26, 27]. Especially in cases of noncooperative and vulnerable infants for whom prolonged examination may be inappropriate or in cases involving an endocardium that is suboptimal for tracing, determination of the MAPSE may be a useful technique. However, the MAPSE is growth dependent.
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Normal MAPSE values in healthy children have been published recently [17]. Eriksen et al. [9] have shown that the annulus excursion of both atrioventricular (AV) valves varies with ventricular size and that the MAPSE as well as tissue Doppler imaging (TDI) parameters may be useful and easily available methods for the evaluation of LV function. Changes in systolic LV function determined by MAPSE in the early neonatal period may give sufficient information about LV function in preterm and term neonates. The MAPSE is not a measure of the percentage of LV long-axis shortening, so smaller persons with a smaller LV may have a smaller MAPSE. For full assessment of changes in the systolic LV function of patients with congenital heart defects (CHD), healthy neonates, and neonates with sepsis or asphyxia and need for cooling, requires sufficient quantitative reference data. Therefore, reference values for neonates and determination of the effect of gestational week and birth weight (BW) are crucial. We therefore undertook a prospective study to determine normal values for MAPSE within the first 48 h of life in correlation with week of gestation and BW and to calculate normal z-score values in a cohort of 261 preterm and term neonates (ages, 26/0–6 to 40/0–6 weeks of gestation).
Materials and Methods Patient Population The patients were selected from individuals referred to the neonatal intensive care unit for observation or to our cardiology service for evaluation of a heart murmur or a family history of heart disease during the first 2 days of life. The gestational age (GA) was determined from the last menstrual period and confirmed by accurate estimation obtained by the patients’ obstetricians. The criteria for inclusion in the study specified that the measured LVEF (Simpson’s method) had to be higher than 60 %, the LV fractional shortening (M-mode) had to be higher than 30 % in all patients, and a measured tricuspid annular plane systolic excursion had to be within the published agerelated normal z-score values [16]. Patients who were small for GA (SGA) at birth were excluded from the study. All infants with suspected malformations and those with suspected or proven sepsis or septic shock, asphyxia, or need for inotropic and chronotropic drugs also were excluded. The infants were classified as having proven early-onset sepsis (positive blood culture), clinical early-onset sepsis (negative blood culture but clinical signs of sepsis with a positive sepsis screen or a history of risk factors and antibiotic treatment C7 days), or a negative infectious status (negative blood culture, negative sepsis screen, antibiotic treatment B3 days) [29]. Septic shock was
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defined as sepsis in the presence of cardiovascular dysfunction. Arterial hypotension was defined as an oscillometric mean arterial blood pressure below 95 % limits, requiring treatment. Patients with suspected pulmonary hypertension were excluded from this study. Perinatal data including Apgar scores at 1 and 5 min, pH of the umbilical artery, and mode of delivery were recorded. For the purpose of the study only echocardiograms with an official reading of a completely normal study were accepted for analysis except for patent foramen ovale (PFO) with a diameter of 2 mm or less. None of our patients had a diagnosis of a hemodynamically significant persistent ductus arteriosus (PDA). A PDA was diagnosed as hemodynamically important if it fulfilled the following three echocardiographic criteria: a left atrium-to-aortic root diameter ratio of 1.4 or greater, an internal ductal diameter greater than 1.4 mm/kg, and a left pulmonary artery enddiastolic flow greater than 0.2 m/s. The PDA constricts quickly after birth, but findings have shown some shunting to be commonly apparent on color Doppler mapping during the first 12–24 h of life [10]. In all our preterm infants younger than 29 gestational weeks, a standard prophylactic indomethacin administration was started on day 1. Some of the patients were included in previous studies [16, 18]. We included only infants with a healthy respiratory condition. All infants older than 28 gestational weeks who had any need of supplemental oxygen were excluded from the study. For infants younger than 28 gestational weeks, the definition of a ‘‘healthy respiratory condition’’ may become difficult. For this group of infants, noninvasive respiratory support with nasal continuous positive airway pressure (CPAP) often is necessary for maintenance of adequate functional residual capacity [5]. We included only premature infants with the need for nasal CPAP or supplemental oxygen who had a fraction of inspired oxygen (FiO2) lower than 0.3. All infants with supplemental oxygen whose FiO2 exceeded 0.3 and those who had a need for intubation and mechanical ventilation were excluded from the study. Furthermore, all infants with any suspected anomalies of airways also were excluded. Echocardiographic Techniques Echocardiographic examination was performed within 48 h after birth by two experienced echocardiographers (M.K.; B.N.). Echocardiograms were performed with echocardiographic systems (iE33; Philips, Andover, MA, USA) using a transducer of 12–4 MHz. The images were recorded digitally and later analyzed by one of the investigators (M.K.) using offline software (Xcelera Echo; Philips Medical Systems, Eindhoven, The Netherlands). For determination of the LVEF, we used the modified Simpson’s method, which is the most commonly used and
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recommended method [19]. The MAPSE was measured using the standard M-mode technique, with the cursor placed at the lateral site of the annulus from the apical fourchamber view [35]. The long-axis excursion of the lateral mitral ring was measured by determining the distance between the nadirs of the annulus motion profile corresponding to the maximal backward excursion of the mitral ring from the apex, defined as the point of maximal upward excursion. Care was taken to align the sample volume as vertically as possible with respect to the cardiac apex. To determine interobserver variability, data were measured by two observers (M.K.; B.N.) blinded to the results of each other. Intraobserver variability was considered among 24 participants by repeating measurements on two occasions. Inter- and intraobserver variabilities were examined with an intraclass correlation coefficient (ICC). Statistical Analysis All data (from 3 to 5 consecutive beats) were measured by two well-trained observers (M.K.; B.N.) and averaged. Data are presented as means ± standard deviations (SD). Regression was used to estimate MAPSE from GA, BW, and sex. In a first step, the correlation structure between continuous variables and MAPSE was examined with the Pearson correlation coefficient. Furthermore, group differences in MAPSE between male and female neonates were examined using the t test. Eligible variables with a significant correlation or significant group differences were chosen for further evaluation. Therefore, models using linear relations were tested. The White test and the Breusch-Pagan test were used to test for heteroscedasticity. When significant heteroscedasticity was detected, weighted least-square methods were used. To test for normal distribution of z-scores, the Anderson–Darling test and the Kolmogorov–Smirnov test were used. For data analysis, SPSS 20 (SPSS, Inc., Chicago, IL, USA) and SAS 9.2 (REG and MODEL procedure; SAS Institute, Cary, NC, USA) were used. A p value lower than 0.05 was considered statistically significant. Ethics This study complied with all institutional guidelines related to patient confidentiality and research ethics including institutional review board approval. Prospective written parental consent was obtained. There are no financial or other potentially conflicting relationships to report.
Results The study group consisted of 327 patients (171 males and 156 females), with a GA range of 26 ? 0 to 40 ? 6 weeks.
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Pediatr Cardiol (2015) 36:20–26 Table 1 Characteristics of the study group Gestational age (weeks)
Median (Range)
34 (26–40)
Birth weight (kg)
Median (Range)
2.33 (0.67–2.14)
Males (% of all)
n
133 (51)
Caesarean section
n
104
Apgars at 1 min
Mean ± 2 SD
8.7 ± 0.45
Apgars at 5 min
Mean ± 2 SD
9.3 ± 0.27
pH umbilical artery
Mean
7.28
PDA
n
93
PFO
n
135
N-CPAP
n
46
PEEP(NCPAP)
Range
3.0–5.0
The range of GA and of BW, the sex of preterm and term neonates, Apgar scores of 1 and 5 min (mean ± standard deviation), number of patients with residual shunting on a PDA smaller than 1.5 mm in size, number of patients with a PFO smaller than 2 mm in size, number of patients delivered by cesarean section, number of patients with nasal CPAP support, the PEEP under CPAP therapy, and the pH of the umbilical artery are given BW birth weight, CPAP continuous positive airway pressure, GA gestational age, PFO patent foramen ovale, PDA persistent ductus arteriosus, PEEP positive end-expiratory pressure, wks weeks, kg kilogram, n number of patients, SD standard deviation
After the exclusion of neonates who did not meet the inclusion criteria, 261 newborns (132 males and 129 females) with GAs ranging from 26/0–6 to 40/0–6 weeks and BWs ranging from 670 to 4,140 g were available for statistical analysis. The MAPSE ranged from a mean of 0.36 ± 0.05 cm in preterm neonates with a GA of 26/0–6 weeks to 0.56 ± 0.08 cm in neonates with a GA of 40/0–6 weeks. The inter- and intraobserver variabilities were found to be good for MAPSE, with ICCs of 0.96 [95 % confidence interval (CI), 0.94–0.98; p \ 0.01] and 0.97 (95 % CI, 0.95–0.99; p [ 0.01). The characteristics of the study group are presented in Table 1. The age-related z-scores ± 2 and ± 3 standard deviations for MAPSE are shown in Table 2. A representative M-mode image of the MAPSE (neonate with a GA of 29/3 weeks) with normal RV and LV function is shown in Fig. 1. The MAPSE values, measured within 48 h of life, increased in a linear way from a GA of 26/0–6 to a GA of 40/0–6. Birth weight, MAPSE, and GA were moderately correlated: Pearson’s correlation coefficient was 0.56 for GA–MAPSE (p \ 0.001), 0.58 for GA–BW (p \ 0.001), and 0.89 for BW–MAPSE (p \ 0.001). The female and male neonates had comparable MAPSE values (p = 0.946). Because of the strong correlation between GA and BW, two separate models were calculated. The regression equation relating GA (weeks) and MAPSE (cm) for calculation of the predicted MAPSE (MAPSEpred) for a given GA is MAPSEpred = 0.039 ? 0.013 9 GA. The GA-related z-scores for MAPSE are shown in Table 2. The
Pediatr Cardiol (2015) 36:20–26
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Table 2 Classification table for the MAPSE values GA (week)
n
Observed -3z
-2z
Mean
?2z
?32 0.51
26
11
0.21
0.26
0.36
0.46
27
10
0.24
0.28
0.38
0.48
0.53
23
12
0.17
0.25
0.4
0.55
0.62
29
13
0.23
0.29
0.42
0.54
0.6
30
14
0.18
0.26
0.42
0.58
0.66
31
15
0.26
0.32
0.45
0.58
0.65
32
15
0.19
0.27
0.43
0.59
0.67
33
22
0.14
0.24
0.44
0.64
0.74
34
23
0.3
0.36
0.48
0.6
0.66
35
10
0.26
0.34
0.49
0.64
0.72
36 37
17 13
0.25 0.22
0.33 0.31
0.48 0.5
0.63 0.68
0.71 0.77
38
32
0.35
0.41
0.53
0.65
0.71
39
39
0.22
0.32
0.52
0.71
0.81
40
15
0.31
0.4
0.56
0.73
0.81
-3z
-2z
Mean
?2z
?32 0.54
BW (kg)
n
Observed
0.8
10
0.2
0.26
0.37
0.48
1
13
0.21
0.26
0.35
0.45
0.5
1.2
25
0.23
0.29
0.4
0.51
0.57
1.4
15
0.29
0.35
0.47
0.58
0.64
1.6
20
0.13
0.23
0.42
0.62
0.72
1.8
13
0.21
0.29
0.44
0.59
0.67
2
15
0.23
0.3
0.44
0.59
0.66
2.2
17
0.27
0.33
0.47
0.6
0.67
2.4
22
0.25
0.33
0.5
0.66
0.74
2.6
14
0.31
0.38
0.51
0.63
0.7
2.8
15
0.25
0.33
0.49
0.65
0.73
3
17
0.21
0.3
0.48
0.65
0.74
3.2
24
0.26
0.35
0.53
0.71
0.8
3.4 3.6
15 13
0.31 0.33
0.38 0.4
0.52 0.53
0.66 0.67
0.74 0.74
3.8
7
0.4
0.46
0.58
0.7
0.77
4
6
0.25
0.36
0.57
0.78
0.89
The values in the classification table are shown as follows. (A) For each GA, the observed and predicted means and ±2z and ±3z are presented. (B) For the BW, the observed and predicted means and ±2z and ±3z are presented BW birth weight, GA gestational age, MAPSE mitral annular plane systolic excursion
regression equation relating BW (kg) and MAPSE (cm) is MAPSEpred = 0.331 ? 0.060 9 BW. The BW-related zscores ± 2z and ±3z for MAPSE are shown in Table 2. To investigate a possible effect of nasal CPAP therapy on MAPSE values, we determined the MAPSE in 10
Fig. 1 Apical four-chamber view. a The white broken line indicates the M-mode cursor placement at the free wall of the mitral annulus as recommended. b Representative M-mode image of the mitral annular plane systolic excursion (MAPSE) in a preterm infant (born in the 29/3 week of gestation) with normal right and left ventricular function. The absolute longitudinal displacement measure in centimeters (cm) is shown as the yellow line. The red line marks the upper measure point as the point of maximal upward excursion
Fig. 2 Gestational week versus observed mean value of mitral annular plane systolic excursion (MAPSE) ± 2 standard deviations (SDs) for gestational week versus MAPSE. The mean is indicated by the black solid line, the z-score ±2 by the black broken lines, and the z-score ± 3 by the black dotted lines
preterm neonates (GA, 26/0–6 to 28/0–6) without the need for nasal CPAP support and in 10 GA-matched preterm neonates receiving nasal CPAP therapy. The MAPSE values did not differ significantly between the two groups. The data for all the neonates were analyzed to draw GArelated ± two and three z-score values and BW-related ± two and three z-score values. Graphs demonstrating the mean value plus or minus two and three z-scores for
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Fig. 3 Birth weight versus observed mean value of mitral annular plane systolic excursion (MAPSE) ± 2 standard deviations (SD) for birth weight versus MAPSE. The mean is indicated by the black solid line, the z-score ± 2 by the black broken lines, and the z-score ± 3 by the black dotted lines
MAPSE versus GA and MAPSE versus BW are presented in Figs. 2 and 3, respectively.
Discussion To date, as part of the assessment of cardiac function in neonates, increasing attention has been paid to the longitudinal aspect of the LV function in the evaluation of LV systolic function. The apical displacement with shortening of the LV along its long axis can be measured by twodimensional echocardiography and M-mode. Conventional methods for assessing systolic LV function such as EF and fraction shortening (FS) are essentially independent of the weight despite a marked increase in the size of the LV during normal growth [13]. The LVEF is dependent on cavity size and shown to be biased by strict load dependency and low sensitivity to early impairment in fiber contractility [11]. The MAPSE is considered to be a reliable index of longitudinal function in children and adults, but it must be taken into account that the amount of displacement is affected by LV longitudinal dimension. Using tissue Doppler-derived strain and strain rate measurements during the first 28 days of life in preterm infants, Helfer et al. [12] showed that peak systolic strain measurements determined in preterm infants with a patent ductus arteriosus or a bronchopulmonary dysplasia reflect both an increased afterload and an increased preload. Intraobserver reproducibility deformation indices in neonates were shown to be adequate for myocardial velocity imaging parameters, whereas interobserver reproducibility were
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shown to be suboptimal, suggesting that these measurements should be used with caution in clinical practice [15]. Studies have shown that LV function parameters correlate with age in neonates and children [3, 4, 9, 25, 30]. In a recent study, Lee et al. [20] demonstrated that myocardial tissue velocities decrease significantly 5–12 h after birth in preterm infants. In a study comparing cardiac function measured by TDI, Ciccone et al. [4] demonstrated that myocardial velocities are higher in preterm than in term neonates. During the transition period from fetal to neonatal life, changes in LV myocardial performance were observed using TDI and speckle-tracking echocardiography [14, 31]. In preterm neonates, significant changes in myocardial function were observed immediately after PDA ligation, suggesting important changes in myocardial performance [6]. In neonates with asphyxia, findings have shown the LV systolic function to be decreased [34]. Also, neonates with congenital diaphragmatic hernia demonstrated impaired LV function, a finding shown to be associated with adverse outcomes in this group [1]. In addition, changes in TDI parameters during the first year of life were recently observed [2]. Therefore, it is crucial to have normal values for preterm and term neonates because normal pediatric and adult values do not apply for these patients. We found that MAPSE values increase with GA and BW. Due to developmental changes, it is accurate not to use a single value throughout the population but rather to reference the MAPSE to both GA and to BW for the best interpretation of the results. In this study, the MAPSE values were lower in preterm than in term neonates. Whether the markedly lower MAPSE in earlier weeks of gestation is solely a marker of growth-related changes within the study population or a sign of altered systolic function in younger GA neonates due to the immaturity of the LV musculature remains unclear. As expected, our normal values for MAPSE in the 40/0–6 term neonates were similar to the MAPSE normal reference values of infants available in the literature [17]. In the current study, no significant differences in MAPSE values were found between the male and female neonates. We did not find significant differences in the MAPSE values between 10 preterm neonates (GA, 26/0–6 to 28/0–6) without the need for nasal CPAP support and 12 GA-matched preterm neonates with CPAP therapy. This is in agreement with data from different groups demonstrating that CPAP therapy has only a small effect on M-mode measurements and does not change the cardiac output in preterm infants [24]. In conclusion, we have established normal reference values of MAPSE in preterm and term neonates within the first 48 h of life in terms of GA and BW that could serve as a reference database for preterm and term neonates with CHD and suspected LV dysfunction. The M-mode—
Pediatr Cardiol (2015) 36:20–26
derived MAPSE is a noninvasive method for evaluation of LV function that is an especially useful parameter in cases of noncooperative and vulnerable infants for whom a prolonged examination may be inappropriate or in cases involving an endocardium that is suboptimal for tracing. In the future, after more detailed validation, the MAPSE may be included in the targeted neonatal echocardiography guidelines [22] that allow neonatologists to assess the ventricular function in newborns.
Study Limitation A limitation of this study was that the MAPSE was measured only on the lateral site of the mitral annulus. We focused on the lateral wall in the four-chamber view because findings have shown this view to be reliable and easy to apply even in younger children [17]. A possible problem is that systolic translational motion of the heart may influence the values measured [23]. Although MAPSE is a good parameter for assessment of longitudinal LV systolic function, it does not take into account segmental LV function. We did not assess the effects of preload variations related to respiration. In neonatal clinical practice, it would be cumbersome to apply respiratory gaiting to this method on a routine basis. This study was conducted with a cross-sectional study design. Therefore, the data provided in this study should be used only for neonates within the first 48 h of life. This study was limited by the impossibility of defining ‘‘normal’’ respiratory support in premature neonates younger than 28 gestational weeks. For this study, we recruited only a relatively small number of preterm and term neonates for each gestational week and recognize that this reduced the power of our study to detect small changes in the MAPSE, increasing the likelihood of a type 2 error. We must state that it remains unclear how well MAPSE will perform as an index of systolic LV function in neonates with congenital heart disease (CHD) compared with other potential approaches (e.g., the myocardial performance index) or newer LV deformation parameters (e.g., the ventricular rotation) unless clinical studies prove its usefulness. Conflict of interest All authors state that there are no financial, personal or other relationships with other people or organizations that could inappropriately influence our work to disclose.
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ORIGINAL ARTICLE
Longitudinal Systolic Left Ventricular Function in Preterm and Term Neonates: Reference Values of the Mitral Annular Plane Systolic Excursion (MAPSE) and Calculation of z-Scores Martin Koestenberger • Bert Nagel • William Ravekes • Andreas Gamillscheg Corinna Binder • Alexander Avian • Jasmin Pansy • Gerhard Cvirn • Berndt Urlesberger
•
Received: 13 January 2014 / Accepted: 20 June 2014 / Published online: 31 July 2014 Ó Springer Science+Business Media New York 2014
Abstract The mitral annular plane systolic excursion (MAPSE) is a quick and reliable echocardiographic tool for assessing longitudinal left ventricular (LV) systolic function in children and adults. Because this parameter is affected by the LV longitudinal dimension, pediatric and adult normal values are not suitable for preterm and term neonates. A prospective study investigated a large group of preterm and term neonates [gestational age (GA), 26/0–6 to 40/0–6; birth weight (BW), 670–4,140 g]. The growth- and BW-related changes in MAPSE were determined to establish normal z-score values for preterm and term neonates. The MAPSE ranged from a mean of 0.36 ± 0.05 cm in preterm neonates with a GA of 26/0–6 to 0.56 ± 0.08 cm in term neonates with a GA of 40/0–6. The findings showed MAPSE, GA, and BW to be moderately
correlated. Pearson’s correlation coefficient was 0.56 for GA (MAPSE; p \ 0.001) and 0.58 for BW (MAPSE; p \ 0.001). The normal MAPSE values did not differ significantly between females and males (p = 0.946). The absolute values and z-scores of normal MAPSE values in healthy preterm and term neonates within the first 48 h of life were calculated, and percentile charts were established. Determination of LV function using MAPSE might be useful for vulnerable infants for whom a prolonged examination is inappropriate and for neonates with suboptimal visualization of the endocardium.
M. Koestenberger (&) B. Nagel A. Gamillscheg Division of Pediatric Cardiology, Department of Pediatrics, Medical University Graz, Auenbruggerplatz 34/2, 8036 Graz, Austria e-mail: [email protected]; [email protected]
Introduction
W. Ravekes Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA C. Binder J. Pansy B. Urlesberger Division of Neonatology, Department of Pediatrics, Medical University Graz, Graz, Austria A. Avian Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Graz, Austria G. Cvirn Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Graz, Austria
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Keywords Mitral annular plane systolic excursion Left ventricular long-axis function Preterm Neonates Reference values Birth weight M-mode z-Score
The mitral annular plane systolic excursion (MAPSE) is reported to correlate well with left ventricular ejection fraction (LVEF) in adults [7, 28]. Findings have shown MAPSE, an M-mode—derived measure of longitudinal LV function [21], to be an important parameter of the global LV function in premature infants as well [8, 33]. The morphology of the preterm heart shows a thinner walled left ventricle (LV) and a functionally hypertrophied right ventricle (RV) [32]. After birth, ductal shunting rapidly changes from balanced to left-to-right shunting, with a responsive increase in LV stroke volume [26, 27]. Especially in cases of noncooperative and vulnerable infants for whom prolonged examination may be inappropriate or in cases involving an endocardium that is suboptimal for tracing, determination of the MAPSE may be a useful technique. However, the MAPSE is growth dependent.
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Normal MAPSE values in healthy children have been published recently [17]. Eriksen et al. [9] have shown that the annulus excursion of both atrioventricular (AV) valves varies with ventricular size and that the MAPSE as well as tissue Doppler imaging (TDI) parameters may be useful and easily available methods for the evaluation of LV function. Changes in systolic LV function determined by MAPSE in the early neonatal period may give sufficient information about LV function in preterm and term neonates. The MAPSE is not a measure of the percentage of LV long-axis shortening, so smaller persons with a smaller LV may have a smaller MAPSE. For full assessment of changes in the systolic LV function of patients with congenital heart defects (CHD), healthy neonates, and neonates with sepsis or asphyxia and need for cooling, requires sufficient quantitative reference data. Therefore, reference values for neonates and determination of the effect of gestational week and birth weight (BW) are crucial. We therefore undertook a prospective study to determine normal values for MAPSE within the first 48 h of life in correlation with week of gestation and BW and to calculate normal z-score values in a cohort of 261 preterm and term neonates (ages, 26/0–6 to 40/0–6 weeks of gestation).
Materials and Methods Patient Population The patients were selected from individuals referred to the neonatal intensive care unit for observation or to our cardiology service for evaluation of a heart murmur or a family history of heart disease during the first 2 days of life. The gestational age (GA) was determined from the last menstrual period and confirmed by accurate estimation obtained by the patients’ obstetricians. The criteria for inclusion in the study specified that the measured LVEF (Simpson’s method) had to be higher than 60 %, the LV fractional shortening (M-mode) had to be higher than 30 % in all patients, and a measured tricuspid annular plane systolic excursion had to be within the published agerelated normal z-score values [16]. Patients who were small for GA (SGA) at birth were excluded from the study. All infants with suspected malformations and those with suspected or proven sepsis or septic shock, asphyxia, or need for inotropic and chronotropic drugs also were excluded. The infants were classified as having proven early-onset sepsis (positive blood culture), clinical early-onset sepsis (negative blood culture but clinical signs of sepsis with a positive sepsis screen or a history of risk factors and antibiotic treatment C7 days), or a negative infectious status (negative blood culture, negative sepsis screen, antibiotic treatment B3 days) [29]. Septic shock was
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defined as sepsis in the presence of cardiovascular dysfunction. Arterial hypotension was defined as an oscillometric mean arterial blood pressure below 95 % limits, requiring treatment. Patients with suspected pulmonary hypertension were excluded from this study. Perinatal data including Apgar scores at 1 and 5 min, pH of the umbilical artery, and mode of delivery were recorded. For the purpose of the study only echocardiograms with an official reading of a completely normal study were accepted for analysis except for patent foramen ovale (PFO) with a diameter of 2 mm or less. None of our patients had a diagnosis of a hemodynamically significant persistent ductus arteriosus (PDA). A PDA was diagnosed as hemodynamically important if it fulfilled the following three echocardiographic criteria: a left atrium-to-aortic root diameter ratio of 1.4 or greater, an internal ductal diameter greater than 1.4 mm/kg, and a left pulmonary artery enddiastolic flow greater than 0.2 m/s. The PDA constricts quickly after birth, but findings have shown some shunting to be commonly apparent on color Doppler mapping during the first 12–24 h of life [10]. In all our preterm infants younger than 29 gestational weeks, a standard prophylactic indomethacin administration was started on day 1. Some of the patients were included in previous studies [16, 18]. We included only infants with a healthy respiratory condition. All infants older than 28 gestational weeks who had any need of supplemental oxygen were excluded from the study. For infants younger than 28 gestational weeks, the definition of a ‘‘healthy respiratory condition’’ may become difficult. For this group of infants, noninvasive respiratory support with nasal continuous positive airway pressure (CPAP) often is necessary for maintenance of adequate functional residual capacity [5]. We included only premature infants with the need for nasal CPAP or supplemental oxygen who had a fraction of inspired oxygen (FiO2) lower than 0.3. All infants with supplemental oxygen whose FiO2 exceeded 0.3 and those who had a need for intubation and mechanical ventilation were excluded from the study. Furthermore, all infants with any suspected anomalies of airways also were excluded. Echocardiographic Techniques Echocardiographic examination was performed within 48 h after birth by two experienced echocardiographers (M.K.; B.N.). Echocardiograms were performed with echocardiographic systems (iE33; Philips, Andover, MA, USA) using a transducer of 12–4 MHz. The images were recorded digitally and later analyzed by one of the investigators (M.K.) using offline software (Xcelera Echo; Philips Medical Systems, Eindhoven, The Netherlands). For determination of the LVEF, we used the modified Simpson’s method, which is the most commonly used and
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recommended method [19]. The MAPSE was measured using the standard M-mode technique, with the cursor placed at the lateral site of the annulus from the apical fourchamber view [35]. The long-axis excursion of the lateral mitral ring was measured by determining the distance between the nadirs of the annulus motion profile corresponding to the maximal backward excursion of the mitral ring from the apex, defined as the point of maximal upward excursion. Care was taken to align the sample volume as vertically as possible with respect to the cardiac apex. To determine interobserver variability, data were measured by two observers (M.K.; B.N.) blinded to the results of each other. Intraobserver variability was considered among 24 participants by repeating measurements on two occasions. Inter- and intraobserver variabilities were examined with an intraclass correlation coefficient (ICC). Statistical Analysis All data (from 3 to 5 consecutive beats) were measured by two well-trained observers (M.K.; B.N.) and averaged. Data are presented as means ± standard deviations (SD). Regression was used to estimate MAPSE from GA, BW, and sex. In a first step, the correlation structure between continuous variables and MAPSE was examined with the Pearson correlation coefficient. Furthermore, group differences in MAPSE between male and female neonates were examined using the t test. Eligible variables with a significant correlation or significant group differences were chosen for further evaluation. Therefore, models using linear relations were tested. The White test and the Breusch-Pagan test were used to test for heteroscedasticity. When significant heteroscedasticity was detected, weighted least-square methods were used. To test for normal distribution of z-scores, the Anderson–Darling test and the Kolmogorov–Smirnov test were used. For data analysis, SPSS 20 (SPSS, Inc., Chicago, IL, USA) and SAS 9.2 (REG and MODEL procedure; SAS Institute, Cary, NC, USA) were used. A p value lower than 0.05 was considered statistically significant. Ethics This study complied with all institutional guidelines related to patient confidentiality and research ethics including institutional review board approval. Prospective written parental consent was obtained. There are no financial or other potentially conflicting relationships to report.
Results The study group consisted of 327 patients (171 males and 156 females), with a GA range of 26 ? 0 to 40 ? 6 weeks.
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Pediatr Cardiol (2015) 36:20–26 Table 1 Characteristics of the study group Gestational age (weeks)
Median (Range)
34 (26–40)
Birth weight (kg)
Median (Range)
2.33 (0.67–2.14)
Males (% of all)
n
133 (51)
Caesarean section
n
104
Apgars at 1 min
Mean ± 2 SD
8.7 ± 0.45
Apgars at 5 min
Mean ± 2 SD
9.3 ± 0.27
pH umbilical artery
Mean
7.28
PDA
n
93
PFO
n
135
N-CPAP
n
46
PEEP(NCPAP)
Range
3.0–5.0
The range of GA and of BW, the sex of preterm and term neonates, Apgar scores of 1 and 5 min (mean ± standard deviation), number of patients with residual shunting on a PDA smaller than 1.5 mm in size, number of patients with a PFO smaller than 2 mm in size, number of patients delivered by cesarean section, number of patients with nasal CPAP support, the PEEP under CPAP therapy, and the pH of the umbilical artery are given BW birth weight, CPAP continuous positive airway pressure, GA gestational age, PFO patent foramen ovale, PDA persistent ductus arteriosus, PEEP positive end-expiratory pressure, wks weeks, kg kilogram, n number of patients, SD standard deviation
After the exclusion of neonates who did not meet the inclusion criteria, 261 newborns (132 males and 129 females) with GAs ranging from 26/0–6 to 40/0–6 weeks and BWs ranging from 670 to 4,140 g were available for statistical analysis. The MAPSE ranged from a mean of 0.36 ± 0.05 cm in preterm neonates with a GA of 26/0–6 weeks to 0.56 ± 0.08 cm in neonates with a GA of 40/0–6 weeks. The inter- and intraobserver variabilities were found to be good for MAPSE, with ICCs of 0.96 [95 % confidence interval (CI), 0.94–0.98; p \ 0.01] and 0.97 (95 % CI, 0.95–0.99; p [ 0.01). The characteristics of the study group are presented in Table 1. The age-related z-scores ± 2 and ± 3 standard deviations for MAPSE are shown in Table 2. A representative M-mode image of the MAPSE (neonate with a GA of 29/3 weeks) with normal RV and LV function is shown in Fig. 1. The MAPSE values, measured within 48 h of life, increased in a linear way from a GA of 26/0–6 to a GA of 40/0–6. Birth weight, MAPSE, and GA were moderately correlated: Pearson’s correlation coefficient was 0.56 for GA–MAPSE (p \ 0.001), 0.58 for GA–BW (p \ 0.001), and 0.89 for BW–MAPSE (p \ 0.001). The female and male neonates had comparable MAPSE values (p = 0.946). Because of the strong correlation between GA and BW, two separate models were calculated. The regression equation relating GA (weeks) and MAPSE (cm) for calculation of the predicted MAPSE (MAPSEpred) for a given GA is MAPSEpred = 0.039 ? 0.013 9 GA. The GA-related z-scores for MAPSE are shown in Table 2. The
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Table 2 Classification table for the MAPSE values GA (week)
n
Observed -3z
-2z
Mean
?2z
?32 0.51
26
11
0.21
0.26
0.36
0.46
27
10
0.24
0.28
0.38
0.48
0.53
23
12
0.17
0.25
0.4
0.55
0.62
29
13
0.23
0.29
0.42
0.54
0.6
30
14
0.18
0.26
0.42
0.58
0.66
31
15
0.26
0.32
0.45
0.58
0.65
32
15
0.19
0.27
0.43
0.59
0.67
33
22
0.14
0.24
0.44
0.64
0.74
34
23
0.3
0.36
0.48
0.6
0.66
35
10
0.26
0.34
0.49
0.64
0.72
36 37
17 13
0.25 0.22
0.33 0.31
0.48 0.5
0.63 0.68
0.71 0.77
38
32
0.35
0.41
0.53
0.65
0.71
39
39
0.22
0.32
0.52
0.71
0.81
40
15
0.31
0.4
0.56
0.73
0.81
-3z
-2z
Mean
?2z
?32 0.54
BW (kg)
n
Observed
0.8
10
0.2
0.26
0.37
0.48
1
13
0.21
0.26
0.35
0.45
0.5
1.2
25
0.23
0.29
0.4
0.51
0.57
1.4
15
0.29
0.35
0.47
0.58
0.64
1.6
20
0.13
0.23
0.42
0.62
0.72
1.8
13
0.21
0.29
0.44
0.59
0.67
2
15
0.23
0.3
0.44
0.59
0.66
2.2
17
0.27
0.33
0.47
0.6
0.67
2.4
22
0.25
0.33
0.5
0.66
0.74
2.6
14
0.31
0.38
0.51
0.63
0.7
2.8
15
0.25
0.33
0.49
0.65
0.73
3
17
0.21
0.3
0.48
0.65
0.74
3.2
24
0.26
0.35
0.53
0.71
0.8
3.4 3.6
15 13
0.31 0.33
0.38 0.4
0.52 0.53
0.66 0.67
0.74 0.74
3.8
7
0.4
0.46
0.58
0.7
0.77
4
6
0.25
0.36
0.57
0.78
0.89
The values in the classification table are shown as follows. (A) For each GA, the observed and predicted means and ±2z and ±3z are presented. (B) For the BW, the observed and predicted means and ±2z and ±3z are presented BW birth weight, GA gestational age, MAPSE mitral annular plane systolic excursion
regression equation relating BW (kg) and MAPSE (cm) is MAPSEpred = 0.331 ? 0.060 9 BW. The BW-related zscores ± 2z and ±3z for MAPSE are shown in Table 2. To investigate a possible effect of nasal CPAP therapy on MAPSE values, we determined the MAPSE in 10
Fig. 1 Apical four-chamber view. a The white broken line indicates the M-mode cursor placement at the free wall of the mitral annulus as recommended. b Representative M-mode image of the mitral annular plane systolic excursion (MAPSE) in a preterm infant (born in the 29/3 week of gestation) with normal right and left ventricular function. The absolute longitudinal displacement measure in centimeters (cm) is shown as the yellow line. The red line marks the upper measure point as the point of maximal upward excursion
Fig. 2 Gestational week versus observed mean value of mitral annular plane systolic excursion (MAPSE) ± 2 standard deviations (SDs) for gestational week versus MAPSE. The mean is indicated by the black solid line, the z-score ±2 by the black broken lines, and the z-score ± 3 by the black dotted lines
preterm neonates (GA, 26/0–6 to 28/0–6) without the need for nasal CPAP support and in 10 GA-matched preterm neonates receiving nasal CPAP therapy. The MAPSE values did not differ significantly between the two groups. The data for all the neonates were analyzed to draw GArelated ± two and three z-score values and BW-related ± two and three z-score values. Graphs demonstrating the mean value plus or minus two and three z-scores for
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Fig. 3 Birth weight versus observed mean value of mitral annular plane systolic excursion (MAPSE) ± 2 standard deviations (SD) for birth weight versus MAPSE. The mean is indicated by the black solid line, the z-score ± 2 by the black broken lines, and the z-score ± 3 by the black dotted lines
MAPSE versus GA and MAPSE versus BW are presented in Figs. 2 and 3, respectively.
Discussion To date, as part of the assessment of cardiac function in neonates, increasing attention has been paid to the longitudinal aspect of the LV function in the evaluation of LV systolic function. The apical displacement with shortening of the LV along its long axis can be measured by twodimensional echocardiography and M-mode. Conventional methods for assessing systolic LV function such as EF and fraction shortening (FS) are essentially independent of the weight despite a marked increase in the size of the LV during normal growth [13]. The LVEF is dependent on cavity size and shown to be biased by strict load dependency and low sensitivity to early impairment in fiber contractility [11]. The MAPSE is considered to be a reliable index of longitudinal function in children and adults, but it must be taken into account that the amount of displacement is affected by LV longitudinal dimension. Using tissue Doppler-derived strain and strain rate measurements during the first 28 days of life in preterm infants, Helfer et al. [12] showed that peak systolic strain measurements determined in preterm infants with a patent ductus arteriosus or a bronchopulmonary dysplasia reflect both an increased afterload and an increased preload. Intraobserver reproducibility deformation indices in neonates were shown to be adequate for myocardial velocity imaging parameters, whereas interobserver reproducibility were
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shown to be suboptimal, suggesting that these measurements should be used with caution in clinical practice [15]. Studies have shown that LV function parameters correlate with age in neonates and children [3, 4, 9, 25, 30]. In a recent study, Lee et al. [20] demonstrated that myocardial tissue velocities decrease significantly 5–12 h after birth in preterm infants. In a study comparing cardiac function measured by TDI, Ciccone et al. [4] demonstrated that myocardial velocities are higher in preterm than in term neonates. During the transition period from fetal to neonatal life, changes in LV myocardial performance were observed using TDI and speckle-tracking echocardiography [14, 31]. In preterm neonates, significant changes in myocardial function were observed immediately after PDA ligation, suggesting important changes in myocardial performance [6]. In neonates with asphyxia, findings have shown the LV systolic function to be decreased [34]. Also, neonates with congenital diaphragmatic hernia demonstrated impaired LV function, a finding shown to be associated with adverse outcomes in this group [1]. In addition, changes in TDI parameters during the first year of life were recently observed [2]. Therefore, it is crucial to have normal values for preterm and term neonates because normal pediatric and adult values do not apply for these patients. We found that MAPSE values increase with GA and BW. Due to developmental changes, it is accurate not to use a single value throughout the population but rather to reference the MAPSE to both GA and to BW for the best interpretation of the results. In this study, the MAPSE values were lower in preterm than in term neonates. Whether the markedly lower MAPSE in earlier weeks of gestation is solely a marker of growth-related changes within the study population or a sign of altered systolic function in younger GA neonates due to the immaturity of the LV musculature remains unclear. As expected, our normal values for MAPSE in the 40/0–6 term neonates were similar to the MAPSE normal reference values of infants available in the literature [17]. In the current study, no significant differences in MAPSE values were found between the male and female neonates. We did not find significant differences in the MAPSE values between 10 preterm neonates (GA, 26/0–6 to 28/0–6) without the need for nasal CPAP support and 12 GA-matched preterm neonates with CPAP therapy. This is in agreement with data from different groups demonstrating that CPAP therapy has only a small effect on M-mode measurements and does not change the cardiac output in preterm infants [24]. In conclusion, we have established normal reference values of MAPSE in preterm and term neonates within the first 48 h of life in terms of GA and BW that could serve as a reference database for preterm and term neonates with CHD and suspected LV dysfunction. The M-mode—
Pediatr Cardiol (2015) 36:20–26
derived MAPSE is a noninvasive method for evaluation of LV function that is an especially useful parameter in cases of noncooperative and vulnerable infants for whom a prolonged examination may be inappropriate or in cases involving an endocardium that is suboptimal for tracing. In the future, after more detailed validation, the MAPSE may be included in the targeted neonatal echocardiography guidelines [22] that allow neonatologists to assess the ventricular function in newborns.
Study Limitation A limitation of this study was that the MAPSE was measured only on the lateral site of the mitral annulus. We focused on the lateral wall in the four-chamber view because findings have shown this view to be reliable and easy to apply even in younger children [17]. A possible problem is that systolic translational motion of the heart may influence the values measured [23]. Although MAPSE is a good parameter for assessment of longitudinal LV systolic function, it does not take into account segmental LV function. We did not assess the effects of preload variations related to respiration. In neonatal clinical practice, it would be cumbersome to apply respiratory gaiting to this method on a routine basis. This study was conducted with a cross-sectional study design. Therefore, the data provided in this study should be used only for neonates within the first 48 h of life. This study was limited by the impossibility of defining ‘‘normal’’ respiratory support in premature neonates younger than 28 gestational weeks. For this study, we recruited only a relatively small number of preterm and term neonates for each gestational week and recognize that this reduced the power of our study to detect small changes in the MAPSE, increasing the likelihood of a type 2 error. We must state that it remains unclear how well MAPSE will perform as an index of systolic LV function in neonates with congenital heart disease (CHD) compared with other potential approaches (e.g., the myocardial performance index) or newer LV deformation parameters (e.g., the ventricular rotation) unless clinical studies prove its usefulness. Conflict of interest All authors state that there are no financial, personal or other relationships with other people or organizations that could inappropriately influence our work to disclose.
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