Calculation of Pediatric Left Ventricular Mass: Validation and Reference Values Using Real-Time Three-Dimensional Echocardiography

CLINICAL INVESTIGATIONS HEART DISEASE IN INFANTS, CHILDREN, ADOLESCENTS, AND YOUNG ADULTS

Calculation of Pediatric Left Ventricular Mass: Validation and Reference Values Using Real-Time Three-Dimensional Echocardiography Kai Thorsten Laser, MD, Britta Anna Houben, Hermann K€ orperich, PhD, Nikolaus Alexander Haas, MD, PhD, Andrea Kelter-Kl€ opping, Peter Barth, PhD, Wolfgang Burchert, MD, PhD, Robert DallaPozza, MD, PhD, Deniz Kececioglu, MD, PhD, and Ulrike Herberg, MD, Bad Oeynhausen, M€ unster, Munich, and Bonn, Germany

Background: Reference values for left ventricular mass (LVM) are important echocardiographic tools for the follow-up of pediatric patients with cardiac disease. Cardiac magnetic resonance (CMR) imaging is currently regarded as the gold standard. The aims of this study were to validate LVM calculated using real-time three-dimensional echocardiography (RT3DE) and to establish pediatric reference values. Methods: For validation, 40 subjects (20 patients) consecutively underwent CMR (3-T TX Achieva, 25 cardiac phases/slice) and RT3DE (iE33 or Vivid E9, four subvolumes) in a single-center approach. The quantification of CMR data by the disk summation method as standard (mean LVM, 84.2 6 53 g; range, 17.7–231.7 g) was compared with RT3DE. In a multicenter prospective design, 434 healthy children were investigated using standard software (LV-Analysis version 3.1). Results: In comparison with CMR, RT3DE provided a slight overestimation of LVM of only 2.5 6 11.3% (r = 0.990, intraclass correlation coefficient = 0.995), and there was low intraobserver (mean, 0.9 6 7.1%; scatter, 13.2% to 15.0%; r = 0.996; intraclass correlation coefficient = 0.998) and interobserver (mean, 1.5 6 9.3%; scatter, 17.2% to 20.1%; r = 0.993; intraclass correlation coefficient = 0.996) variability. Feasibility of the multicenter approach was 76%, resulting in 332 healthy children (median age, 10.0 years; range, 0–18 years; group I range, 0–6 years; group II range, 7–18 years) with data sets providing adequate image quality. LVM was correlated with sex (group II), age (r = 0.901), height (r = 0.881), weight (r = 0.876), and body surface area (r = 0.898). Unisex percentiles for 0 to 6 years of age and separated according to gender from 7 to 18 years of age were established. Mean calculation time for RT3DE was <3 min. Conclusions: In children, LVM calculation presuming excellent real-time three-dimensional echocardiographic data sets is accurate, quick, and reproducible. The percentiles provided are based on a large sample size and may be useful for clinical practice. (J Am Soc Echocardiogr 2015;28:275-83.) Keywords: Left ventricular mass, Echocardiography, 3D, Children, Congenital heart disease

From the Center for Congenital Heart Defects (K.T.L., N.A.H., D.K.) and the Institute of Radiology (H.K., P.B., W.B.), Heart and Diabetes Center Bad Oeynhausen, Ruhr University Bochum, Bad Oeynhausen, Germany; the €nster, Mu €nster, Germany (B.A.H.); Klinik Bad Oexen, Bad University of Mu Oeynhausen, Germany (A.K.-K.); the Department of Pediatric Cardiology, Ludwig Maximilian University of Munich, Munich, Germany (R.D.); and the Department of Pediatric Cardiology, University of Bonn, Bonn, Germany (U.H.). Drs Laser and Houben contributed equally to this work. This study was part of the project Validierung und Standardisierung der Echtzeit3D-Echokardiographie zur Funktionsanalyse von Herzkammern bei Kindern, € rdergemeinschaft Deutsche Kinderherzzentren (Project No. Wsponsored by Fo BN/M/BAD-009/2009). Reprint requests: Kai Thorsten Laser, MD, Center for Congenital Heart Defects, Heart and Diabetes Center, North Rhine-Westphalia, Ruhr University of Bochum, Georgstraße 11, D-32545 Bad Oeynhausen, Germany (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.11.008

The assessment of left ventricular (LV) mass (LVM) is a clinically important tool in patients with acquired or congenital heart disease. The combination of localized or global LV hypertrophy and dilatation has both diagnostic and prognostic implications.1-3 Morbidity and mortality in adult and pediatric patients are increased if LV preload and afterload are elevated.4-6 In this scenario, LVM is an important marker to modify treatment strategies such as drug therapy and percutaneous or surgical interventions.7,8 However, LVM can also be influenced by many physiologic factors that we do not primarily associate with a disease state, implying an expectable variation of LVM even among healthy subjects.9-12 Imaging modalities that can reliably assess this parameter are clinically important for further treatment and prognosis.13-15 Currently, cardiac magnetic resonance (CMR) imaging is the gold standard for the assessment of LV volumes and mass because of its accuracy, reproducibility, and independence of geometric assumptions.16,17 However, CMR cannot be used routinely in all clinical settings, because it is expensive, time consuming, in some cases even 275

276 Laser et al

contraindicated, and it may require anesthesiology in BSA = Body surface area smaller children. In comparison, echocardiography is quick, less CMR = Cardiac magnetic expensive, and widely available. resonance Not infrequently, sedation must ICC = Intraclass correlation be administered to minimize coefficient diagnostic errors,18 although in most cases there is no need for LV = Left ventricular it even if small children are LVM = Left ventricular mass investigated. Established twoRT3DE = Real-time threedimensional techniques are dimensional lacking in accuracy to determine echocardiography LVM because they rely on geometric assumptions and 3D = Three-dimensional use equations that cannot entirely compensate for the individual shape of a chamber.19-22 Therefore, real-time three-dimensional (3D) echocardiography (RT3DE) is a promising clinical alternative that has been proven in prior studies on adults, and improvements in hardware and evaluation software have played an important role in this field in recent years.23,24 The role of LVM measurements by RT3DE in pediatric patients has been investigated less extensively, but some studies have revealed progress regarding accuracy, reproducibility, and efficiency in normal as well as abnormally shaped ventricles.25,26 There is a need for pediatric reference values, because LVM changes during maturation. Currently, there are few valid pediatric normative data available. Many have been determined by CMR, include only small sample sizes, or are reliable for adults only.23,27-30 The aims of this study were to validate the accuracy and reproducibility of LVM using RT3DE compared with the gold standard of CMR using new quantification software and to establish reference values in a large cohort of healthy children. Abbreviations

METHODS Study Population and Design Validation Study. We prospectively carried out consecutive investigations by CMR and RT3DE in a single-center approach to assess the reproducibility and accuracy of LVM calculation by RT3DE in a group of 40 individuals. Ten patients with LV heart disease as well as 10 with abnormally shaped left ventricles (Table 1), who were referred for routine CMR because of congenital heart disease, were included, as well as 20 healthy children, who also participated in the referencevalues study. This selection was intended to display wide ranges of LVM, age, and shape. All investigations were carried out with the breath held; four patients were investigated under anesthesia. Reference-Values Study. For reference values, a prospective multicenter approach including three centers was performed after standardization of the acquisition procedure and interoperator training. Quantification of data was done in a core-laboratory design at one center. All healthy individuals mentioned in this study were in sinus rhythm, and cardiac disease was ruled out by history, physical examination, and echocardiography according to standard recommendations.31 Young children not able to hold their breath were examined under spontaneous breathing. For the creation of reference values for LVM with RT3DE, 434 healthy children were included from April 2011 to November 2013. Age, sex, weight, and height were measured before the exam-

Journal of the American Society of Echocardiography March 2015

Table 1 Demographic data from patients and healthy individuals for the validation of RT3DE versus CMR (n = 40) Variable

Sex (female) Age (y)

Value

19 2.3–43.9 (13.8 6 8.3) (median, 12.7)

Height (cm)

84.0–196.0 (151.3 6 27.9)

Weight (kg)

11.0–97.0 (49.4 6 25.3)

BSA (m2)

0.5–2.2 (1.4 6 0.5)

LVM by CMR (g)

17.7–231.7 (84.2 6 53.0)

LVM by RT3DE (g)

20.0–236.7 (86.0 6 53.7)

Data are expressed as number or as range (mean 6 SD).

ination, and body surface area (BSA) was calculated using the formula of Du Bois and Du Bois: body weight (kg)0.425  height (cm)0.725  0.007184. The study was approved by the local ethics institutional review committee (Registration No. 20/2011) and by the representative boards of all participating centers and conformed to the principles of the Declaration of Helsinki as well as German law. Informed written consent was obtained from all participants and/or their legal guardians before participation. RT3DE RT3DE was performed using iE33 (X7-2 or X5-1 transducer; Philips Medical Systems, Best, The Netherlands) or Vivid E9 (V4 transducer; GE Medical Systems, Milwaukee, WI) machines. Three real-time 3D echocardiographic volumes were acquired from an apical view with the LV apex next to the transducer, including the entire LV portion in the two-dimensional planning view using four subvolumes at 90 to 110 within a single end-expiratory breath-hold if possible to obtain one full-volume data set with a stable transducer position based on standard recommendations.32 The temporal resolution was between 17 and 65 volumes/sec, depending on angulation width, depth, transducer, age, and heart rate. Evaluation of Real-Time 3D Echocardiographic Data. The real-time 3D echocardiographic volume with the best image quality was imported into the Image Arena platform (version 4.6, build 4.6.2.12; TomTec, Unterschleißheim, Germany) and analyzed using 4D LV-Analysis version 3.1 (build 3.1.0.258661; TomTec). Briefly, after definition of end-diastolic and end-systolic frames, the fullvolume data set was adjusted using two-chamber, three-chamber, and four-chamber views, aligning the center of the mitral valve and apex of the left ventricle. After a first contour-tracking process, endocardial contour finding was manually revised if necessary, and the outer layer of the epicardium was manually determined (Figure 1). The myocardial volume was calculated from a connection between the epicardial and endocardial surface model mesh in systole multiplied by 1.053 g/mL, corresponding to the density of the myocardium.33 CMR Imaging Volumetric measurements were performed using a clinical 3.0-T whole-body magnetic resonance imaging system (Achieva 3.0T TX; Philips Medical Systems) equipped with parallel radiofrequency signal transmission technology to enhance image uniformity (maximum gradient performance, 80 mT/m; slew rate,

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Figure 1 Calculation of LVM by RT3DE. (A) Two-dimensional four-chamber, (B) two-chamber, (C) three-chamber, and (D) short-axis slices extracted from a representative real-time 3D echocardiographic data set with endocardial (yellow) and epicardial (red) borders of the left ventricular myocardium. AAo, Ascending aorta; LV, left ventricle; RV, right ventricle. 200 T/m/sec) using vector electrocardiography and respiratory motion gating. A 32-element phased-array receive-only surface coil was used for signal detection. To assess the LV and right ventricular volumes, a stack of 15 to 21 short-axis slices was acquired by applying a segmented multislice, multiphase vector electrocardiographically triggered steady-state free precession gradient-echo sequence (repetition time, 2.7 msec; echo time; 1.35 msec; excitation angle, 40 ; slice thickness, 5–6 mm; no slice gap; matrix size, 160  240; field of view, 384 mm; in-plane resolution, 1.6  1.6 mm; 25 cardiac phases under short breath-holding periods of <12 sec in duration). Evaluation of CMR Data. Quantification of the volumetric CMR data was performed offline on a workstation using the thresholdbased HDZ MR-Tools software package (HDZ, Bad Oeynhausen, Germany).34 LV muscle mass was calculated by summing the muscle areas and multiplying this by the slice thickness for all appropriate slices. Intracavitary trabeculations were excluded from the calculation of muscle mass to obtain an evaluation strategy comparable with RT3DE.

Statistical Analysis Real-time 3D echocardiographic and CMR data, respectively, were quantified by a different single expert blinded to the results of the other. For measurements of interobserver variability, another investigator was introduced after intensive interoperator training, again blinded to the results of the first investigator. Reproducibility was previously assessed extensively using the CMR HDZ MR-Tools software package.35 Intraobserver comparisons for RT3DE were performed in a second approach blinded to the results of the first quantification, >2 weeks apart. Analysis of Bland-Altman plotting was performed to quantify the agreement between CMR and RT3DE as well as intraand interobserver variability using the percentage of difference of the

investigations as a measure to address the problem of high variety of masses. The latter were also expressed by the intraclass correlation coefficient (ICC). Correlation analysis was undertaken using linear regression analysis and Pearson correlation using SPSS version 21 (SPSS, Inc, Chicago, IL). Descriptive statistics were obtained for all relevant continuous variables. Normal distribution was tested using the Kolmogorov-Smirnoff or Shapiro-Wilk test, depending on the sample size. The significance of the differences observed was tested using a two-sided paired Students t test. P values #.05 were considered statistically significant. For differences in homogeneity and/or the absence of normal distribution, the Mann-Whitney test was used as a nonparametric test. Reference centile curves were computed using Cole’s LMS method (lambda for the skew, mu for the median, and sigma for the coefficient of variation) in LMS version 1.27 software (Institute of Child Health, London, United Kingdom).36,37

RESULTS Validation Study All CMR and real-time 3D echocardiographic scans were completed successfully and could be included in the study. CMR evaluation of muscle mass provided a spectrum of 17.7 to 231.7 g (mean, 84.2 6 53 g; Table 1). Image analysis for RT3DE required a mean evaluation time of <3 min for the investigator after >10 data sets of training. Accuracy and Reproducibility of CMR versus RT3DE Comparison of the methods showed good agreement, with only a minimal overestimation of LVM using RT3DE at 2.5 6 11.3% (r = 0.990, ICC = 0.995; Figures 2A and 2B) and moderate scatter (20.1% to 25.1%). Intraobserver variability was low at only

278 Laser et al

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LVM was correlated with age (r = 0.901), weight (r = 0.876), height (r = 0.881), and BSA (r = 0.898). Comparative analysis between female and male children <7 years of age did not reveal significant differences (LVM in female vs male children, 41.7 6 16.6 vs 40.5 6 17.4 g; P = .70). Consequently, a subdivision into two age groups was made (group I, 0–6 years; group II, 7–18 years; Table 2). LVM in Children Aged 0 to 6 Years In group I, a continuous increase in LVM as an index of BSA (Figure 4A) plotted against age was observed. The slope of the curves decreased with increasing age. Normalization to height also revealed a continuous increase over age (Figure 4B). The relation to weight showed a different cluster, with a slight decrease in LVM indexed to weight from birth to the second year and again a slight increase to the maximum at the age of 5 years (Figure 4C). LVM in Children Aged 7 to 18 Years In group II, a continuous increase in LVM as an index of BSA was found in girls, with the slope becoming shallower in the last years investigated. Boys had significantly higher LVM (male vs female, 79.6 6 14.2 vs 75.4 6 17.9 g/m2; P < .05) in the corresponding group, with shallow sloping curves until the age of 10 years, becoming steeper until the age of 16 years, when the slope flattened again (Figure 5A). Plotting against LVM indexed to height revealed a relatively constant increase of curves during the whole range of ages, becoming flatter at the age of 16 years in girls. Again, percentiles became steeper in boys beginning at the age of 10 years, and the flattening of the curves was less pronounced in late adolescence. The difference between boys and girls was highly significant (male vs female, 0.74 6 0.16 vs 0.67 6 0.16 g/cm; P < .005; Figure 5B). LVM indexed to weight did not show gender differences (male vs female, 2.48 6 0.54 vs 2.45 6 0.54 g/kg; P = NS) and showed a continuous decline from 7 years until early adulthood. Scatters were slightly higher in boys from 10 to 15 years (Figure 5C). Figure 2 Comparison of LVM by CMR and RT3DE. (A) BlandAltman plot showing biases and limits of agreement (mean 6 2 SDs). (B) Regression plot with coefficient of correlation. D, Relative mean difference of the two observations. 0.9 6 7.1% (r = 0.996, ICC = 0.998), with acceptable scatter (13.2% to 15.0%; Figures 3A and 3B). Interobserver variability resulted in comparably low mean differences of 1.5 6 9.3% (r = 0.993; ICC = 0.996; scatter, 17.2% to 20.1%; Figures 3C and 3D). Reference-Values Study Feasibility. Three hundred thirty-two of the 434 data sets provided adequate image quality and therefore could be included in the study, which resulted in feasibility of 76%. The dropout of 102 data sets was due mainly to the miss of major parts of the myocardium (51 data sets; missing apex in 89%, other regions missed in 11%); too strong reflections by the pericardium, limiting border differentiation (five data sets); breathing artifacts, especially in smaller children (14 data sets); or a frame rate that was too low (32 data sets). Growth- and Sex-Dependent Interrelations of LVM. The entire group of healthy children was investigated concerning correlations (Table 2).

DISCUSSION This study presents the results of a multicenter approach designed to provide reference values for LVM in a population of healthy children using state-of-the-art RT3DE after validating new quantification software in a group of healthy individuals and patients with underlying cardiac disease representing a wide range of LVM. The major findings of our study are that the method is accurate, reproducible, and quick compared with CMR. The second important result is that young children aged <7 years did not show differences in LVM concerning gender, and thus they can be regarded as a unisex group, whereas older children show sex-related differences already proven by others. The third interesting finding is that the large sample size provides high correlations with demographic data, which facilitates the creation of percentiles. Validation of RT3DE Until now, CMR and cardiac computed tomography have been regarded as the gold standard for the calculation of cardiac LVM because of the higher accuracy and reproducibility they afford compared with conventional echocardiography.16,17,38,39 This study provides evidence that RT3DE using the above-mentioned calculation software can quantify LVM with high accuracy and

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Figure 3 (A,B) Intraobserver variability. LVM determined by observer 1: first and second investigation by RT3DE in comparison. (A) Bland-Altman plot on the left showing biases and limits of agreement (mean 6 2 SDs). (B) Regression plot on the right with coefficient of correlation. (C,D) Interobserver variability. LVM calculated by observers 1 and 2 applying RT3DE. (C) Bland-Altman plot on the left showing biases and limits of agreement (mean 6 2 SDs). (D) Regression plot with coefficient of correlation. D, Relative mean difference of the two observations. reproducibility according to the Bland-Altman, Pearson, and ICC statistics compared with CMR. Furthermore, the work flow presented is time saving and in this regard is superior to CMR, which is known to be more time consuming in the postprocessing phase.22 Importantly, we investigated a cohort of patients and healthy individuals who presented a wide range of LVM to provide valid data in smaller children with higher heart rates as well as in patients with concentric hypertrophy and abnormally shaped left ventricles, but among them, there were only very few with localized hypertrophy. Impact of Maturational Changes in LVM on Methodology of Assessment There are several circumstances that can influence cardiac LVM during maturation. Continuous growth is the most important, but the influence of hormone status during puberty also must be taken into account.40 Because of these differences, normalization of LVM has been carried out in many studies,28,41,42 and commonly used parameters are the mass index over BSA, height, and weight. Furthermore, the methodology of creating percentiles has the advantage of being free from linear relationships between cardiovascular parameters and physical data.37,43 In our study, correlations of LVM with BSA, age, height, and weight were equally

high. Therefore, percentiles were created with LVM normalized to BSA, height, and weight. This was reasonable not only for comparability with former studies22 but also to differentiate and visualize properly an LVM range of 6 to 197 g. Muscle Mass and Weight Interestingly, the highest indexed LVM to body weight was found in newborns, with another minor peak at the age of 5 years. Afterward, there was a continuous decrease in LVM indexed to weight with increasing age. This is of special interest because LV performance increases with birth because of the changeover from fetal to postpartum circulation. Ventricles are stiffer at birth and need time to adapt to develop and use their elastic properties. On the other hand, this observation may reflect that the relative growth of the heart muscle compared with body weight physiologically is slower until adolescence, an observation that has been reported in indexing LVM for weight as well as indexing for height.40,44 Influence of Gender The influence of gender is a topic often discussed in the literature. In our study, we used RT3DE with a large sample size and accuracy and

0.19–2.15 (1.16 6 0.47)

6.2–182.8 (83.3 6 39.2)

17–61 (28.1 6 7.1) 7.8–196.7 (94 6 48.2)

17–65 (28.4 6 7.2)

50–147 (85 6 20)

0.2–2.15 (1.2 6 0.51)

3.1–93 (38.5 6 22.0)

50–194 (138 6 36)

0–18 (9.8 6 5.4) (median, 10)

(n = 170)

Male

17–44 (26.4 6 5.2)

51–109 (78 6 12)

0.8–1.9 (1.34 6 0.29)

19.1–73 (42.8 6 14.2)

114–181 (150 6 17)

7–18 (12.1 6 3.4) (median, 12)

(n = 110)

Female, aged 7–18 y

1.43–4.25 (2.53 6 0.52)

1.30–4.61 (2.54 6 0.54)

LVMiWeight (g/kg)

1.30–4.61 (2.55 6 0.56) 1.42–3.86 (2.71 6 0.51)

0.16–1.10 (0.63 6 0.21) 0.13–0.63 (0.41 6 0.12)

LVMiBSA, LVM indexed to BSA; LVMiHeight, LVM indexed to height; LVMiWeight, LVM indexed to weight. *Significant gender difference (P < .05).

0.13–1.11 (0.58 6 0.19)

0.13–1.11 (0.61 6 0.2)

17–65 (27.9 6 6.6)

50–110 (76 6 12)

0.82–2.2 (1.5 6 0.35)

20.3–93 (49.6 6 17.4)

118–194 (158 6 20)

7–18 (12.9 6 3.2) (median, 13)

(n = 116)

Male, aged 7–18 y

1.43–4.25 (2.45 6 0.54)

0.31–1.11 (0.67 6 0.16)*

1.30–4.61 (2.48 6 0.54)

0.42–1.10 (0.74 6 0.16)

50.7–115.5 (79.6 6 14.2)

6.2–75.9 (40.8 6 16.8) 38.7–182.8 (101.5 6 31.3)* 53.7–196.7 (118.2 6 36.3)

20–61 (30.5 6 8.7)

66–160 (105 6 22)

0.19–1.0 (0.62 6 0.2)

2.6–26.4 (15.0 6 5.3)

47–127 (96 6 20)

0–6 (3.4 6 2.0) (median, 4)

(n = 106)

Aged 0–6 y

33.2–122.9 (73.1 6 15.7) 33.2–122.9 (71.5 6 15.2) 34.4–115.5 (74.8 6 16.0) 33.2–90.4 (63.4 6 13.5) 44.2–122.9 (75.4 6 14.9)*

6.2–197 (88.3 6 44.3)

17–65 (28.3 6 7.1)

51–160 (87 6 21)

0.19–1.9 (1.12 6 0.42)

2.6–93 (36.3 6 20)

50–160 (86 6 20)

47–181 (134 6 31) 2.57–73 (34.0 6 17.6)

47–194 (136 6 33)

0–18 (9.4 6 4.9) (median, 9)

0–18 (9.6 6 5.2) (median, 10)

(n = 162)

(n = 332)

LVMiHeight (g/cm)

LVMiBSA (g/m2)

LVM (g)

Volume rate (vol/sec)

Heart rate (beats/min)

BSA (m2)

Weight (kg)

Height (cm)

Age (y)

Variable

Female

All

Table 2 Demographic data from healthy children for the generation of reference values

280 Laser et al Journal of the American Society of Echocardiography March 2015

Figure 4 Unisex percentiles (Pc) for LVM using RT3DE in children aged 0 to 6 years. LVM normalized to BSA (A) (LVMiBSA), height (B) (LVMiHeight), and weight (C) (LVMiWeight) plotted against age.

reproducibility comparable with CMR. We found no gender difference in subjects aged <7 years and could detect gender differences only from 7 to 18 years of age, with a higher LVM in male children indexed to BSA and height. Indexing LVM to weight showed no gender differences, which underlines the role of growth in body

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Figure 5 Gender-specific percentiles (Pc) for LVM using RT3DE in children aged 7 to 18 years. LVM normalized to BSA (A) (LVMiBSA), height (B) (LVMiHeight), and weight (C) (LVMiWeight) plotted against age for girls (red) and boys (blue). height. These results are partially in agreement with those of Sarikouch et al.,27 who also found gender differences for total LVM in the age range 8 to 20 years for height and BSA using CMR. In contrast to our study, they also found differences in LVM indexed to weight, but they could not detect any gender differences in a subgroup for the ages of 8 to 15 years. In contrast, our study, using RT3DE, included a much larger sample size at a younger age, which might account for further gender differences even before puberty, as also reported by studies on other LV functional parameters.45-47

population with our group II, with which we used RT3DE. A good explanation for these differences is hard to find, as the latest studies on LVM using RT3DE have shown good agreement with CMR, as did our validation.23 Most probably, the sample size and the selection of individuals with differences in factors such as physical activity or body constitution account for the differences detected in LVM. At first glance, this may become less obvious when using the LMS methods to create percentiles because of smoothing between age classes of different sample sizes within the study population investigated.

Amount of LVM Achieving the comparability of studies is difficult in many cases because of differences in sample sizes, methods used for quantification, and study populations.23,27,28,48,49 This is one reason why we undertook the validation of our real-time 3D echocardiographic approach using the same methodologic CMR protocol as found in the study by Sarikouch et al.,27 except for the inclusion of the trabeculations to the LV cavity, to make the strategy parallel to the real-time 3D echocardiographic approach. Using CMR, Sarikouch et al. found lower indexed LVM values in a much smaller but comparable

Clinical Implications The reliability of reference values is necessary to differentiate physiology from pathology. Not only general maturational changes but also gender differences are becoming more important in the diagnostic and prognostic workup of children and adults with congenital heart disease.50 Although there are high correlations between LVM and weight, height, and BSA, under special conditions, it might be necessary to choose the appropriate index. In a study by Goble et al.,51 differences in absolute LVM at the age of 11 years were found between boys and girls, but girls were taller and heavier than boys

282 Laser et al

because of the onset of puberty. Another investigation with obese children revealed statistically differences of absolute LVM that could not be proven if normalized to BSA because of inappropriate body weight gain.52 In cases of high deviations of body weight or height, one possibility would be to use a ‘‘normalized’’ BSA for the age group and use the indexed LVM for BSA. Another alternative would be to use height-indexed LVM, especially in the case of obesity or anorexia. A gold standard for an adequate index in each situation has not yet been defined.19 Limitations Some limitations require discussion. Both methods used to quantify LVM by CMR and RT3DE lack precision because trabeculations are excluded, but the amount was not high. In the validation study, the CMR data sets demonstrated a mean value of 5.6% more LVM if trabeculations were included. Furthermore, we could only quantify the whole LVM but not the interventricular septum separately, and we did not include enough patients with asymmetric hypertrophy. Feasibility was 76% because of two major problems. The first is that an excellent image quality mandatory for accurate results depends on complete data sets without dropouts. In addition, strong reflections of the pericardial border make it difficult to define the myocardial borders in many data sets. Excellent cooperation was often difficult in young children, resulting in reduced feasibility. Validation could not be done in very young children with low values of LVM, as not enough of them were available to undergo CMR investigations under anesthesia. Interstudy reproducibility was not tested, but we found LVM quite robust, as it is calculated only in end-diastole and is therefore not influenced strongly by changes in heart rate or volume state. Finally, right ventricular mass was not assessed, because no quantification tool with comparable accuracy is currently available for RT3DE.

CONCLUSIONS Accurate and reproducible reference values for LV muscle mass were assessed by RT3DE using a large sample size of excellent data sets as a precondition. Maturational differences throughout childhood were found, which might be of great importance for clinical use.

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