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Real-Time Three-Dimensional Echocardiographic Assessment of Left Ventricular Systolic Dyssynchrony in Healthy Children
Real-Time Three-Dimensional Echocardiographic Assessment of Left Ventricular Systolic Dyssynchrony in Healthy Children Wei Cui, MD, Katheryn Gambetta, MD, Frank Zimmerman, MD, Anne Freter, RN, Lissa Sugeng, MD, Roberto Lang, MD, and David A. Roberson, MD, Oak Lawn and Chicago, Illinois
Background: The use of resynchronization therapy for the treatment of left ventricular (LV) systolic dysfunction in children has been expanding. Because QRS duration is not a reliable indicator of the presence or severity of dyssynchrony in every case, additional methods of quantitation of dyssynchrony are needed. The purpose of this study was threefold: (1) to define normal values for LV real-time quantitative three-dimensional echocardiographic (3DE) dyssynchrony indices (DIs), (2) to analyze the feasibility and observer variability of 3DE DIs in a wide range of children, and (3) to determine the effects of age, heart rate, body surface area, and LV end-diastolic volume on these parameters. Methods: The two specific parameters studied were the standard deviation of the time to minimum systolic volume for the number of segments analyzed and the time difference between the earliest and latest contracting segments. Both parameters were expressed as a percentage of the cardiac cycle length. Results: In 125 normal children aged 1 day to 19 years, adequate dyssynchrony studies were obtained in 102 (81.8%). The mean LV 3DE DIs expressed as the standard deviation of the time to minimum systolic volume for the number of segments analyzed were 1.16 6 0.58 for 16 segments, 1.01 6 0.60 for 12 segments, and 0.93 6 0.68 for 6 segments. The mean LV 3DE DIs expressed as the time difference between the earliest and latest contracting segments were 3.80 6 1.57 for 16 segments, 2.99 6 1.42 for 12 segments, and 2.27 6 1.35 for 6 segments. There were no effects of age, heart rate, body surface area, or LV end-diastolic volume on 3DE DIs. Intraobserver variability was 5.1%, and interobserver variability was 7.6%. Conclusion: Three-dimensional echocardiographic DI analysis is reproducible and feasible in most children. Three-dimensional echocardiographic DIs are not affected by growth-related parameters in children but are lower than previously reported adult values. (J Am Soc Echocardiogr 2010;23:1153-9.) Keywords: Dyssynchrony, Three-dimensional echocardiography
The use of resynchronization therapy for the treatment of left ventricular (LV) dyssynchronous systolic dysfunction in children has been expanding and includes temporary perioperative multisite pacing1,2 as well as chronic treatment of the failing ventricle in cardiomyopathy and in those with congenital heart disease.3,4 Because QRS duration is not a reliable indicator of the presence or severity of dyssynchrony in every case, particularly in children, additional methods of quantitation of dyssynchrony are needed.2 Reports of normal values for three-dimensional echocardiographically derived dyssynchrony indices (DIs) in children are limited by small sample size and lack of data in patients aged < 12 years.4-6 The purpose of this study was threefold (1) to define normal values for LV real-time From The Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, Illinois (W.C., F.Z., A.F., D.A.R.); Children’s Memorial Hospital, Chicago, Illinois (K.G.); and the University of Chicago Medical Center, Chicago, Illinois (L.S., R.L.). Reprint requests: David A. Roberson, MD, The Heart Institute for Children, Hope Children’s Hospital, 4440 W. 95th Street, Oak Lawn, IL 60453 (E-mail: david@ thic.com). 0894-7317/$36.00 Copyright 2010 by the American Society of Echocardiography. doi:10.1016/j.echo.2010.08.009
quantitative three-dimensional echocardiographic (3DE) DIs, (2) to analyze the feasibility and observer variability of 3DE DIs in a wide range of children, and (3) to determine the effects of age, heart rate (HR), body surface area (BSA), and LV end-diastolic volume (LVEDV) on these parameters.
METHODS Study Population The study population consisted of 125 normal children aged 1 day to 19 years. Appropriate subjects were defined as healthy children who were referred for evaluation of heart murmur, chest pain, or sports clearance. All had no histories of cardiovascular disease, no cardiac symptoms, normal blood pressure, normal electrocardiographic results with normal QRS durations, and normal results on complete standard two-dimensional, pulsed-wave Doppler, and color Doppler echocardiography. All had official interpretations of normal echocardiographic results for age, including small patent foramen ovales with trivial left-to-right shunt in younger patients, as read by the clinical echocardiography attending physicians, who were blinded to the 3DE findings. 1153
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Real-Time Three-Dimensional Echocardiography BSA = Body surface area Real-time three-dimensional echocardiography was performed DI = Dyssynchrony index using the iE33 ultrasound maHR = Heart rate chine (Philips Medical Systems, Andover, MA) with either the LV = Left ventricular X3-1 or the X7-2 transducer. LVEDV = Left ventricular endImages were optimized to obtain diastolic volume the entire left ventricle in the 3DE = Three-dimensional full-volume data set in the apical echocardiographic four-chamber view. Data sets were acquired using a fourheartbeat or seven-heartbeat acquisition setting during a period of stable HR, defined as the HR not changing during the acquisition time and varying by <3 beats/min for the 30 seconds before acquisition. Endexpiratory breath holding was performed when feasible. A minimum of four data sets were acquired in each subject, and the three highest quality data sets were selected for analysis. Data sets that excluded a portion of the left ventricle, had indistinct endocardial borders, or had stitch artifacts were excluded. Abbreviations
Data Analysis This study was prospectively planned and conducted. After threedimensional images were obtained as a real-time pyramidal volumetric data sets in full-volume acquisition mode, offline analysis was performed on a QLAB workstation (3DQ-Advanced; Philips Medical System). In each data set, the frame immediately before full closure of the mitral valve was selected as end-diastole, and the frame immediately before full closure of the aortic valve was selected as end-systole. Five anatomic landmarks were identified from apical two-chamber and four-chamber orthogonal views, which were extracted from the pyramidal data set in multiplanar reconstruction mode: two points to specify each edge of the mitral valve annulus in two-chamber and four-chamber views and one point to identify the LV apex. A cast of the LV cavity was then created using an automatic edge detection algorithm and divided into 16 segments, excluding the cardiac apex. Endocardial tracking was inspected on a frame-by-frame basis and manually edited as needed. A time-volume data curve for each of the segments over the cardiac cycle was generated and displayed automatically along with end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction. The time taken to reach minimum systolic volume for each of the 16 standard myocardial segments was calculated automatically. The systolic DI was defined as the standard deviation of these timings, expressed as a percentage of the RR interval (SD%). In addition, the maximum time difference of the time taken to reach minimum systolic volume between the earliest and latest contracting segments was calculated and expressed as a percentage of the RR interval (difference%). The same measurements were performed for 12 segments (six basal and six mid segments) and 6 segments (six basal segments only).
Reproducibility Analysis Interobserver variability was measured by evaluating 26 randomly selected data sets by two of the investigators. Intraobserver variability was measured by evaluating 26 randomly selected data sets twice by one investigator with a 2-month interval between the two analyses.
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Table 1 Demographic characteristics and 3DE LV volumes and EF derived from 102 normal children Variable
Range
Mean 6 SD
Age HR (beats/min) BSA (m2) EDV (mL) ESV (mL) SV (mL) EF (%)
1 day to 19 years 47–167 0.12–2.20 2.6–122.2 0.8–53.5 1.8–85.5 51.6–82.0
9.5 6 5.9 years 91 6 28 1.18 6 0.61 58.7 6 35.4 19.5 6 13.8 39.2 6 23.2 68.3 6 7.1
EDV, End-diastolic volume; EF, ejection fraction; ESV, end systolic volume; SV, stroke volume.
Figure 1 Dyssynchrony indices, left ventricular volumes, and time-volume curves. Statistical Analysis Continuous data are reported as mean 6 SD. DIs were analyzed by descriptive statistics, including lowest and highest values, mean, median, and percentile distribution. Skew and kurtosis analysis were used to evaluate the degree of symmetry and data distribution and the degree of peakness or flatness of the data distribution. Generalized linear model was performed to determine the effects of age, HR, BSA, and LVEDV on DIs. Bland-Altman analysis was used to examine intraobserver and interobserver variability.
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Table 2 Three-dimensional echocardiographic measurements of DIs SD%
Difference%
Variable
16 Segments
12 Segments
6 Segments
16 Segments
12 Segments
6 Segments
Range Mean 6 SD Median Skewness SE of skewness Kurtosis SE of kurtosis Percentiles 2.5 25 50 75 97.5
0.27–3.17 1.16 6 0.58 1.01 1.201 0.239 1.415 0.474
0.20–3.33 1.01 6 0.60 0.85 1.624 0.239 3.236 0.474
0.09–4.15 0.93 6 0.68 0.79 2.337 0.239 7.280 0.474
1.02–8.73 3.80 6 1.57 3.59 0.744 0.239 0.460 0.474
0.74–8.73 2.99 6 1.42 2.64 1.114 0.239 2.073 0.474
0.26–6.77 2.27 6 1.35 1.99 1.094 0.239 0.976 0.474
0.3103 0.7175 1.0100 1.4700 2.7925
0.2200 0.6500 0.8450 1.2750 3.0268
0.1473 0.5225 0.7850 1.0300 3.4572
1.3305 2.5875 3.5900 4.7450 7.5617
0.7700 2.0250 2.6400 3.8400 6.5515
0.3678 1.3250 1.9900 2.8800 5.6662
Statistical significance was declared when computed P values from two-sided tests were <.05. Analyses were performed using SPSS version 18.0 for Windows (SPSS, Inc., Chicago, IL). Ethics This study complied with all institutional requirements for patient confidentiality and safety, including institutional review board approval. There were no financial or other relationships present that may have biased the results or their interpretation.
RESULTS Feasibility of 3DE Acquisition, Demographic Characteristics, and 3DE LV Volumes In 23 of the 125 subjects (18.4%), it was not possible to derive 3DE DIs or 3DE volumetric analyses, because of inadequate visualization of LV segments due to body habitus, lack of patient cooperation, extensive respiratory motion, or stitch artifacts. Acquisition of real-time 3DE data sets was feasible in 102 subjects (81.8%). Therefore, the final quantitative study population encompassed 102 healthy children (54 male, 48 female; age range, 1 day to 19 years; mean age, 9.5 6 5.9 years). The age groups of these 102 children included 22 aged < 1 year, 18 aged 1 to 5 years, 37 aged 5 to 12 years, and 35 aged > 12 years. All 102 subjects were in sinus rhythm. HRs ranged from 47 to 167 beats/ minute (mean, 91 6 28 beats/min). Respiratory rates varied from 0 breaths/min with breath holding to 32 breaths/min in a neonate. No child aged < 5 years performed effective breath holding. In those unable to hold their breath, respiratory rates varied from 14 to 32 breaths/ min. BSAs ranged from 0.12 to 2.20 m2 (mean, 1.18 6 0.61 m2). By realtime 3DE imaging, LVEDVs ranged from 2.6 to 122.2 mL (mean, 58.7 6 35.4 mL), LV end-systolic volumes ranged from 0.8 to 53.5 mL (mean, 19.5 6 13.8 mL), LV stroke volumes ranged from 1.8 to 85.5 mL (mean, 39.2 6 23.2 mL), and LV ejection fractions ranged from 51.6% to 82.0% (mean, 68.3 6 7.1%) (Table 1, Figure 1). Frame rates varied from 16 to 62 frames/sec (from 16 to 39 frames/sec for fourbeat acquisition mode and from 23 to 62 frames/sec for seven-beat acquisition mode). Frame rates in patients aged < 1 year ranged from 39 to 62 frames/sec, in those aged 1 to 12 years from 27 to 48 frames/sec, and in those aged > 12 years from 18 to 30 frames/sec.
Normal Values and Distribution of DIs LV 3DE DIs expressed as SD% were 1.16 6 0.58 for 16 segments, 1.01 6 0.60 for 12 segments, and 0.93 6 0.68 for 6 segments. LV 3DE DIs expressed as difference% were 3.80 6 1.57 for 16 segments, 2.99 6 1.42 for 12 segments, and 2.27 6 1.35 for 6 segments. Results along with statistical descriptive analyses are summarized in Table 2. Figure 2 shows histograms representing the frequency distribution of SD% and difference% for 16, 12, and 6 segments. Effects of Growth Parameters on DIs There was no influence of age, BSA, HR, or LVEDV on DIs in normal children (Figures 3 and 4). Observer Variability From 26 randomly selected subjects, variability analysis of DIs expressed as SD% for the 16-segment model using the Bland-Altman method demonstrated intraobserver bias of 5.1% and interobserver bias of 7.6% (Figure 5). DISCUSSION This study included the largest sample size and ranges of age and body size so far reported in children. It more than doubles the number of reported pediatric cases. It also demonstrates the lack of effects of growth parameters, including LVEDV, throughout the pediatric age and size spectrum. In addition, we found that the distribution of DIs varied from normal, showing a significant positive (rightward) skew. These results therefore provide additional normal reference values for the 3DE measurement of synchrony throughout the pediatric population. Without correction for skew or kurtosis, we use 2.3% as the upper limit of normal (Z + 2) for LV 3DE DI expressed as SD%. Because the Z + 2 cutoff values were so similar for 16-segment, 12-segment, and 6-segment analysis, varying by only 0.1%, for practical clinical purposes, we define 3DE DI SD% > 2.3% as dyssynchronous in those aged < 18 years, regardless of the number of segments analyzed. In contrast, there is some variation in the difference% LV 3DE DI Z + 2 cutoff values for 16 segments (6.9%), 12 segments (5.8%), and 6 segments (5.0%). One might predict this variation in the difference
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Figure 2 Frequency distribution of DIs (SD% and difference%). % parameter on the basis of a more widespread time interval when one compares apical segments, which contract earlier, with basal segments, which contract later in the normal heart’s apical to basal activation sequence. Our results are concordant with those of prior studies involving children. Ten Harkel et al.5 studied 73 normal children aged 12 to 18 years using the same method and found highly synchronized 16-segment function, with SD% = 1.2 6 0.53, high feasibility, and low observer variability. SD% was independent of age, body weight, or body length. Baker et al.4 obtained a somewhat larger value of median 16-segment SD% of 2.1%, albeit in a small series including only nine normal children. In a study of both children and adults Sonne et al.6 found that those aged < 10 years had lower normal 3DE DI values. In agreement with these three studies, we found that 3DE DI values were not affected by age within the pediatric population, but they were lower (more synchronous) in children compared with reported adult normal values, which range from 4% to 8%.7-16 Similar to all of these pediatric and adult
studies, we found the 3DE DI technique rapid, feasible, and reproducible. Despite extensive study in adults with congestive heart failure, the relationships between QRS duration, mechanical dyssynchrony, and ventricular dysfunction remain complex and a matter of ongoing study. Bax et al.17 demonstrated that in experienced hands, the presence of echocardiographically demonstrated mechanical dyssynchrony predicts a response to resynchronization therapy. However, the results of the Predictors of Response to Cardiac Resynchronization Therapy trial18 demonstrated that the broad application of mechanical dyssynchrony analysis to predict response to therapy remains challenging. These issues are made even more complex and less well understood by the limited number of subjects studied, the limited number of studies, and the addition of a wide variety of congenital heart disease diagnoses. Reliable methods, careful analysis, and further detailed collaborative study of children with dyssynchrony are essential to develop methods to determine the presence and
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Figure 3 Effects of age, BSA, HR, and LVEDV on 16-segment DI (SD%).
Figure 4 Effects of age, BSA, HR, and LVEDV on 16-segment DI (difference%). severity of mechanical dyssynchrony, its relationship to QRS duration and ventricular function, how to predict and measure the response to therapy for both synchrony and ventricular function,
and how to direct optimal pacemaker lead placement19 and pacemaker settings. As in adults, it is probable that 3DE DI analysis will be one of several tools used to achieve these goals in children.
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Figure 5 Bland-Altman plots of intra-observer (left) and inter-observer (right) variability in 16-segment dyssynchrony index (SD %).
Technical and Acquisition Issues The choice of transducer was based primarily on patient body size. As a general guideline, the X7-2 transducer was used for patients weighing < 25 kg, the X3-1 transducer was used in those weighing > 40 kg, and the transducer providing the best image quality was used in the intermediate group. We did not notice any significant difference in image quality or frame rate between the two transducers, provided the appropriate transducer for body size was used. The range of frame rates was wide, from 16 to 62 frames/sec. In some patients under identical conditions, the four-beat acquisition frame rate was only 55% to 60% of the seven-beat format. Patient size also had an important effect on frame rate. The fastest frame rates were achieved in the smallest patients using the seven-beat format. We prefer the 16-segment model over the 12-segment or 6-segment model because it includes more segments of the heart. The fewer the number of segments imaged, the more heart segments would be excluded from analysis and the greater the possibility that significant dyssynchronous segments may go undetected. All three models are automatically generated by the software and therefore available in all cases. It was not the purpose of this study to determine which model is more accurate or best predicts response to resynchronization. The choice of four-segment versus seven-segment acquisition relies substantially on the patient’s ability to hold his or her breath, as well as trial and error. If breath holding was effective, we preferred the sevenbeat mode because of the faster frame rate. We acquired volume sets in both four-segment and seven-segment formats in each case, and we chose the ones with less apparent stitch artifacts. The four-beat acquisition time is shorter, so it may be better with more rapid respiration.
In contrast, the seven-beat acquisition takes longer, but the frame rate is often much faster and the image quality sometimes better, if stitch artifacts are absent. However, the interplay between these factors is not always predictable, so it is best to try both and choose the best image. The main challenge in applying this technique in children is the interplay between respiratory rate and HR versus four-beat or sevenbeat acquisition time and the echocardiographic frame rate. Respiratory motion artifacts are by far the major source of stitch artifacts and failure to obtain a reliable 3DE volume set. Inability to hold the breath and the fastest HRs encountered in patients aged < 5 years made the application of this version of 3DE synchrony analysis challenging in younger children. Quite importantly, from preliminary experience with the most recently developed system, in which there is a single-heartbeat acquisition at frame rates of 50 to 60 frames/sec in adult patients, we speculate that many of these problems will be resolved.
Study Limitations The study was limited by a fairly small number of subjects in the two groups aged < 5 years. Also, we did not compare the 3DE DI with other methods of synchrony analysis, such as echocardiographic strain imaging or magnetic resonance imaging tissue tagging. Both of these issues should be resolved before normal cutoff values can be firmly established. The 3DE DI technique is itself limited by several factors. A slow frame rate relative to the HR and the lack of respiratory gating or
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controlled breath holding are encountered in smaller children. Both of these problems introduce significant stitch artifacts and were the reason for the failure to obtain reliable data in the large majority of the 18.4% of children excluded from analysis because of poor image quality. Failure to reliably track one segment can induce major error in both the SD and difference calculations. Also, manual correction of one poorly tracked segment may induce minor errors in the tracking of adjacent segments.
CONCLUSIONS Three-dimensional echocardiographic DI analysis of the left ventricle is reproducible and feasible in most children. SD% and difference% were not affected by growth-related parameters in children but were lower than adult values. REFERENCES 1. Zimmerman F, Starr J, Koenig P, Smith P, Hijazi Z, Bacha E. Acute hemodynamic benefit of multisite pacing after congenital heart surgery. Ann Thorac Surg 2003;75:1775-80. 2. Bacha E, Zimmerman F, Mor-Avi V, Weinert L, Starr J, Sugeng L, et al. Ventricular resynchronization by multisite pacing improves myocardial performance in the postoperative single-ventricle patient. Ann Thorac Surg 2004;78:1678-83. 3. Dubin A, Janousek J, Rhee E, Striepe M, Cecchin F, Law I, et al. Resynchronization therapy in pediatric and congenital heart disease patients. J Am Coll Cardiol 2005;46:2277-83. 4. Baker G, Hlavacek A, Chessa K, Fleming D, Shirali G. Left ventricular dysfunction is associated with intraventricular dyssynchrony by 3-dimensional echocardiography in children. J Am Soc Echocardiogr 2008;21:230-3. 5. Ten Harkel A, Van Osch-Gevers M, Helbing W. Real-time transthoracic three dimensional echocardiography: normal reference data for left ventricular dyssynchrony in adolescents. J Am Soc Echocardiogr 2009;22: 933-8. 6. Sonne C, Sugeng L, Takeuchi M, Weinert L, Childers R, Watanabe N, et al. Real-time 3-dimensional echocardiographic assessment of left ventricular dyssynchrony—pitfalls in patients with dilated cardiomyopathy. J Am Coll Cardiol Img 2009;2:802-12. 7. Nagueh S. Mechanical dyssynchrony in congestive heart failure diagnostic and therapeutic implications. J Am Coll Cardiol 2008;51:18-22.
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8. Kass D. An epidemic of dyssynchrony: but what does it mean? J Am Coll Cardiol 2008;51:12-7. 9. Park S, Kim K, Jeon M, Lee C, Kim D, Park K, et al. Assessment of left ventricular asynchrony using volume time curves of 16 segments by real-time 3 dimensional echocardiography: comparison with tissue Doppler imaging. Eur J Heart Fail 2007;9:62-7. 10. Vitarelli A, Franciosa P, Conde Y, Cimino E, Nguyen B, Ciccaglione A, et al. Echocardiographic assessment of ventricular asynchrony in dilated cardiomyopathy and congenital heart disease: tools and hopes. J Am Soc Echocardiogr 2005;18:1424-39. 11. Horstman J, Monaghan M, Gill E. Intraventricular dyssynchrony assessment by real-time three dimensional echocardiography. Cardiol Clin 2007;25:253-60. 12. Takeuchi M, Jacobs A, Sugeng L, Nishikage T, Nakai H, Weinert L, et al. Assessment of left ventricular dyssynchrony with real time 3-dimensional echocardiography: comparison with Doppler tissue imaging. J Am Soc Echocardiogr 2007;20:1321-9. 13. Kapetanakis S, Kearney M, Siva A, Gall N, Cooklin M, Monaghan M. Realtime three dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation 2005;112: 992-1000. 14. Burgess M, Jenkins C, Chan J, Marwick T. Measurement of left ventricular dyssynchrony in patients with ischaemic cardiomyopathy: a comparison of real-time three dimensional and tissue Doppler echocardiography. Heart 2007;93:1191-6. 15. Soliman O, van Dalen B, Nemes A, van der Zwaan H, Vletter W, ten Cate F, et al. Quantification of left ventricular systolic dyssynchrony by real-time three-dimensional echocardiography. J Am Soc Echocardiogr 2009;22:232-9. 16. Gimenes V, Vieira M, Andrade M, Pinheiro J, Hotta V, Mathias W. Standard values for real-time transthoracic three-dimensional echocardiographic dyssynchrony indexes in a normal population. J Am Soc Echocardiogr 2008;21:1229-35. 17. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44: 1834-40. 18. Yu CM, Abraham WT, Bax J, Chung E, Fedewa M, Ghio S, et al. Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design. Am Heart J 2005;149:600-5. 19. Derval N, Steendijk P, Gula LJ, Deplagne A, Laborderie J, Sacher F, et al. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricle wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol 2010;55:566-75.
Background: The use of resynchronization therapy for the treatment of left ventricular (LV) systolic dysfunction in children has been expanding. Because QRS duration is not a reliable indicator of the presence or severity of dyssynchrony in every case, additional methods of quantitation of dyssynchrony are needed. The purpose of this study was threefold: (1) to define normal values for LV real-time quantitative three-dimensional echocardiographic (3DE) dyssynchrony indices (DIs), (2) to analyze the feasibility and observer variability of 3DE DIs in a wide range of children, and (3) to determine the effects of age, heart rate, body surface area, and LV end-diastolic volume on these parameters. Methods: The two specific parameters studied were the standard deviation of the time to minimum systolic volume for the number of segments analyzed and the time difference between the earliest and latest contracting segments. Both parameters were expressed as a percentage of the cardiac cycle length. Results: In 125 normal children aged 1 day to 19 years, adequate dyssynchrony studies were obtained in 102 (81.8%). The mean LV 3DE DIs expressed as the standard deviation of the time to minimum systolic volume for the number of segments analyzed were 1.16 6 0.58 for 16 segments, 1.01 6 0.60 for 12 segments, and 0.93 6 0.68 for 6 segments. The mean LV 3DE DIs expressed as the time difference between the earliest and latest contracting segments were 3.80 6 1.57 for 16 segments, 2.99 6 1.42 for 12 segments, and 2.27 6 1.35 for 6 segments. There were no effects of age, heart rate, body surface area, or LV end-diastolic volume on 3DE DIs. Intraobserver variability was 5.1%, and interobserver variability was 7.6%. Conclusion: Three-dimensional echocardiographic DI analysis is reproducible and feasible in most children. Three-dimensional echocardiographic DIs are not affected by growth-related parameters in children but are lower than previously reported adult values. (J Am Soc Echocardiogr 2010;23:1153-9.) Keywords: Dyssynchrony, Three-dimensional echocardiography
The use of resynchronization therapy for the treatment of left ventricular (LV) dyssynchronous systolic dysfunction in children has been expanding and includes temporary perioperative multisite pacing1,2 as well as chronic treatment of the failing ventricle in cardiomyopathy and in those with congenital heart disease.3,4 Because QRS duration is not a reliable indicator of the presence or severity of dyssynchrony in every case, particularly in children, additional methods of quantitation of dyssynchrony are needed.2 Reports of normal values for three-dimensional echocardiographically derived dyssynchrony indices (DIs) in children are limited by small sample size and lack of data in patients aged < 12 years.4-6 The purpose of this study was threefold (1) to define normal values for LV real-time From The Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, Illinois (W.C., F.Z., A.F., D.A.R.); Children’s Memorial Hospital, Chicago, Illinois (K.G.); and the University of Chicago Medical Center, Chicago, Illinois (L.S., R.L.). Reprint requests: David A. Roberson, MD, The Heart Institute for Children, Hope Children’s Hospital, 4440 W. 95th Street, Oak Lawn, IL 60453 (E-mail: david@ thic.com). 0894-7317/$36.00 Copyright 2010 by the American Society of Echocardiography. doi:10.1016/j.echo.2010.08.009
quantitative three-dimensional echocardiographic (3DE) DIs, (2) to analyze the feasibility and observer variability of 3DE DIs in a wide range of children, and (3) to determine the effects of age, heart rate (HR), body surface area (BSA), and LV end-diastolic volume (LVEDV) on these parameters.
METHODS Study Population The study population consisted of 125 normal children aged 1 day to 19 years. Appropriate subjects were defined as healthy children who were referred for evaluation of heart murmur, chest pain, or sports clearance. All had no histories of cardiovascular disease, no cardiac symptoms, normal blood pressure, normal electrocardiographic results with normal QRS durations, and normal results on complete standard two-dimensional, pulsed-wave Doppler, and color Doppler echocardiography. All had official interpretations of normal echocardiographic results for age, including small patent foramen ovales with trivial left-to-right shunt in younger patients, as read by the clinical echocardiography attending physicians, who were blinded to the 3DE findings. 1153
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Real-Time Three-Dimensional Echocardiography BSA = Body surface area Real-time three-dimensional echocardiography was performed DI = Dyssynchrony index using the iE33 ultrasound maHR = Heart rate chine (Philips Medical Systems, Andover, MA) with either the LV = Left ventricular X3-1 or the X7-2 transducer. LVEDV = Left ventricular endImages were optimized to obtain diastolic volume the entire left ventricle in the 3DE = Three-dimensional full-volume data set in the apical echocardiographic four-chamber view. Data sets were acquired using a fourheartbeat or seven-heartbeat acquisition setting during a period of stable HR, defined as the HR not changing during the acquisition time and varying by <3 beats/min for the 30 seconds before acquisition. Endexpiratory breath holding was performed when feasible. A minimum of four data sets were acquired in each subject, and the three highest quality data sets were selected for analysis. Data sets that excluded a portion of the left ventricle, had indistinct endocardial borders, or had stitch artifacts were excluded. Abbreviations
Data Analysis This study was prospectively planned and conducted. After threedimensional images were obtained as a real-time pyramidal volumetric data sets in full-volume acquisition mode, offline analysis was performed on a QLAB workstation (3DQ-Advanced; Philips Medical System). In each data set, the frame immediately before full closure of the mitral valve was selected as end-diastole, and the frame immediately before full closure of the aortic valve was selected as end-systole. Five anatomic landmarks were identified from apical two-chamber and four-chamber orthogonal views, which were extracted from the pyramidal data set in multiplanar reconstruction mode: two points to specify each edge of the mitral valve annulus in two-chamber and four-chamber views and one point to identify the LV apex. A cast of the LV cavity was then created using an automatic edge detection algorithm and divided into 16 segments, excluding the cardiac apex. Endocardial tracking was inspected on a frame-by-frame basis and manually edited as needed. A time-volume data curve for each of the segments over the cardiac cycle was generated and displayed automatically along with end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction. The time taken to reach minimum systolic volume for each of the 16 standard myocardial segments was calculated automatically. The systolic DI was defined as the standard deviation of these timings, expressed as a percentage of the RR interval (SD%). In addition, the maximum time difference of the time taken to reach minimum systolic volume between the earliest and latest contracting segments was calculated and expressed as a percentage of the RR interval (difference%). The same measurements were performed for 12 segments (six basal and six mid segments) and 6 segments (six basal segments only).
Reproducibility Analysis Interobserver variability was measured by evaluating 26 randomly selected data sets by two of the investigators. Intraobserver variability was measured by evaluating 26 randomly selected data sets twice by one investigator with a 2-month interval between the two analyses.
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Table 1 Demographic characteristics and 3DE LV volumes and EF derived from 102 normal children Variable
Range
Mean 6 SD
Age HR (beats/min) BSA (m2) EDV (mL) ESV (mL) SV (mL) EF (%)
1 day to 19 years 47–167 0.12–2.20 2.6–122.2 0.8–53.5 1.8–85.5 51.6–82.0
9.5 6 5.9 years 91 6 28 1.18 6 0.61 58.7 6 35.4 19.5 6 13.8 39.2 6 23.2 68.3 6 7.1
EDV, End-diastolic volume; EF, ejection fraction; ESV, end systolic volume; SV, stroke volume.
Figure 1 Dyssynchrony indices, left ventricular volumes, and time-volume curves. Statistical Analysis Continuous data are reported as mean 6 SD. DIs were analyzed by descriptive statistics, including lowest and highest values, mean, median, and percentile distribution. Skew and kurtosis analysis were used to evaluate the degree of symmetry and data distribution and the degree of peakness or flatness of the data distribution. Generalized linear model was performed to determine the effects of age, HR, BSA, and LVEDV on DIs. Bland-Altman analysis was used to examine intraobserver and interobserver variability.
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Table 2 Three-dimensional echocardiographic measurements of DIs SD%
Difference%
Variable
16 Segments
12 Segments
6 Segments
16 Segments
12 Segments
6 Segments
Range Mean 6 SD Median Skewness SE of skewness Kurtosis SE of kurtosis Percentiles 2.5 25 50 75 97.5
0.27–3.17 1.16 6 0.58 1.01 1.201 0.239 1.415 0.474
0.20–3.33 1.01 6 0.60 0.85 1.624 0.239 3.236 0.474
0.09–4.15 0.93 6 0.68 0.79 2.337 0.239 7.280 0.474
1.02–8.73 3.80 6 1.57 3.59 0.744 0.239 0.460 0.474
0.74–8.73 2.99 6 1.42 2.64 1.114 0.239 2.073 0.474
0.26–6.77 2.27 6 1.35 1.99 1.094 0.239 0.976 0.474
0.3103 0.7175 1.0100 1.4700 2.7925
0.2200 0.6500 0.8450 1.2750 3.0268
0.1473 0.5225 0.7850 1.0300 3.4572
1.3305 2.5875 3.5900 4.7450 7.5617
0.7700 2.0250 2.6400 3.8400 6.5515
0.3678 1.3250 1.9900 2.8800 5.6662
Statistical significance was declared when computed P values from two-sided tests were <.05. Analyses were performed using SPSS version 18.0 for Windows (SPSS, Inc., Chicago, IL). Ethics This study complied with all institutional requirements for patient confidentiality and safety, including institutional review board approval. There were no financial or other relationships present that may have biased the results or their interpretation.
RESULTS Feasibility of 3DE Acquisition, Demographic Characteristics, and 3DE LV Volumes In 23 of the 125 subjects (18.4%), it was not possible to derive 3DE DIs or 3DE volumetric analyses, because of inadequate visualization of LV segments due to body habitus, lack of patient cooperation, extensive respiratory motion, or stitch artifacts. Acquisition of real-time 3DE data sets was feasible in 102 subjects (81.8%). Therefore, the final quantitative study population encompassed 102 healthy children (54 male, 48 female; age range, 1 day to 19 years; mean age, 9.5 6 5.9 years). The age groups of these 102 children included 22 aged < 1 year, 18 aged 1 to 5 years, 37 aged 5 to 12 years, and 35 aged > 12 years. All 102 subjects were in sinus rhythm. HRs ranged from 47 to 167 beats/ minute (mean, 91 6 28 beats/min). Respiratory rates varied from 0 breaths/min with breath holding to 32 breaths/min in a neonate. No child aged < 5 years performed effective breath holding. In those unable to hold their breath, respiratory rates varied from 14 to 32 breaths/ min. BSAs ranged from 0.12 to 2.20 m2 (mean, 1.18 6 0.61 m2). By realtime 3DE imaging, LVEDVs ranged from 2.6 to 122.2 mL (mean, 58.7 6 35.4 mL), LV end-systolic volumes ranged from 0.8 to 53.5 mL (mean, 19.5 6 13.8 mL), LV stroke volumes ranged from 1.8 to 85.5 mL (mean, 39.2 6 23.2 mL), and LV ejection fractions ranged from 51.6% to 82.0% (mean, 68.3 6 7.1%) (Table 1, Figure 1). Frame rates varied from 16 to 62 frames/sec (from 16 to 39 frames/sec for fourbeat acquisition mode and from 23 to 62 frames/sec for seven-beat acquisition mode). Frame rates in patients aged < 1 year ranged from 39 to 62 frames/sec, in those aged 1 to 12 years from 27 to 48 frames/sec, and in those aged > 12 years from 18 to 30 frames/sec.
Normal Values and Distribution of DIs LV 3DE DIs expressed as SD% were 1.16 6 0.58 for 16 segments, 1.01 6 0.60 for 12 segments, and 0.93 6 0.68 for 6 segments. LV 3DE DIs expressed as difference% were 3.80 6 1.57 for 16 segments, 2.99 6 1.42 for 12 segments, and 2.27 6 1.35 for 6 segments. Results along with statistical descriptive analyses are summarized in Table 2. Figure 2 shows histograms representing the frequency distribution of SD% and difference% for 16, 12, and 6 segments. Effects of Growth Parameters on DIs There was no influence of age, BSA, HR, or LVEDV on DIs in normal children (Figures 3 and 4). Observer Variability From 26 randomly selected subjects, variability analysis of DIs expressed as SD% for the 16-segment model using the Bland-Altman method demonstrated intraobserver bias of 5.1% and interobserver bias of 7.6% (Figure 5). DISCUSSION This study included the largest sample size and ranges of age and body size so far reported in children. It more than doubles the number of reported pediatric cases. It also demonstrates the lack of effects of growth parameters, including LVEDV, throughout the pediatric age and size spectrum. In addition, we found that the distribution of DIs varied from normal, showing a significant positive (rightward) skew. These results therefore provide additional normal reference values for the 3DE measurement of synchrony throughout the pediatric population. Without correction for skew or kurtosis, we use 2.3% as the upper limit of normal (Z + 2) for LV 3DE DI expressed as SD%. Because the Z + 2 cutoff values were so similar for 16-segment, 12-segment, and 6-segment analysis, varying by only 0.1%, for practical clinical purposes, we define 3DE DI SD% > 2.3% as dyssynchronous in those aged < 18 years, regardless of the number of segments analyzed. In contrast, there is some variation in the difference% LV 3DE DI Z + 2 cutoff values for 16 segments (6.9%), 12 segments (5.8%), and 6 segments (5.0%). One might predict this variation in the difference
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Figure 2 Frequency distribution of DIs (SD% and difference%). % parameter on the basis of a more widespread time interval when one compares apical segments, which contract earlier, with basal segments, which contract later in the normal heart’s apical to basal activation sequence. Our results are concordant with those of prior studies involving children. Ten Harkel et al.5 studied 73 normal children aged 12 to 18 years using the same method and found highly synchronized 16-segment function, with SD% = 1.2 6 0.53, high feasibility, and low observer variability. SD% was independent of age, body weight, or body length. Baker et al.4 obtained a somewhat larger value of median 16-segment SD% of 2.1%, albeit in a small series including only nine normal children. In a study of both children and adults Sonne et al.6 found that those aged < 10 years had lower normal 3DE DI values. In agreement with these three studies, we found that 3DE DI values were not affected by age within the pediatric population, but they were lower (more synchronous) in children compared with reported adult normal values, which range from 4% to 8%.7-16 Similar to all of these pediatric and adult
studies, we found the 3DE DI technique rapid, feasible, and reproducible. Despite extensive study in adults with congestive heart failure, the relationships between QRS duration, mechanical dyssynchrony, and ventricular dysfunction remain complex and a matter of ongoing study. Bax et al.17 demonstrated that in experienced hands, the presence of echocardiographically demonstrated mechanical dyssynchrony predicts a response to resynchronization therapy. However, the results of the Predictors of Response to Cardiac Resynchronization Therapy trial18 demonstrated that the broad application of mechanical dyssynchrony analysis to predict response to therapy remains challenging. These issues are made even more complex and less well understood by the limited number of subjects studied, the limited number of studies, and the addition of a wide variety of congenital heart disease diagnoses. Reliable methods, careful analysis, and further detailed collaborative study of children with dyssynchrony are essential to develop methods to determine the presence and
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Figure 3 Effects of age, BSA, HR, and LVEDV on 16-segment DI (SD%).
Figure 4 Effects of age, BSA, HR, and LVEDV on 16-segment DI (difference%). severity of mechanical dyssynchrony, its relationship to QRS duration and ventricular function, how to predict and measure the response to therapy for both synchrony and ventricular function,
and how to direct optimal pacemaker lead placement19 and pacemaker settings. As in adults, it is probable that 3DE DI analysis will be one of several tools used to achieve these goals in children.
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Figure 5 Bland-Altman plots of intra-observer (left) and inter-observer (right) variability in 16-segment dyssynchrony index (SD %).
Technical and Acquisition Issues The choice of transducer was based primarily on patient body size. As a general guideline, the X7-2 transducer was used for patients weighing < 25 kg, the X3-1 transducer was used in those weighing > 40 kg, and the transducer providing the best image quality was used in the intermediate group. We did not notice any significant difference in image quality or frame rate between the two transducers, provided the appropriate transducer for body size was used. The range of frame rates was wide, from 16 to 62 frames/sec. In some patients under identical conditions, the four-beat acquisition frame rate was only 55% to 60% of the seven-beat format. Patient size also had an important effect on frame rate. The fastest frame rates were achieved in the smallest patients using the seven-beat format. We prefer the 16-segment model over the 12-segment or 6-segment model because it includes more segments of the heart. The fewer the number of segments imaged, the more heart segments would be excluded from analysis and the greater the possibility that significant dyssynchronous segments may go undetected. All three models are automatically generated by the software and therefore available in all cases. It was not the purpose of this study to determine which model is more accurate or best predicts response to resynchronization. The choice of four-segment versus seven-segment acquisition relies substantially on the patient’s ability to hold his or her breath, as well as trial and error. If breath holding was effective, we preferred the sevenbeat mode because of the faster frame rate. We acquired volume sets in both four-segment and seven-segment formats in each case, and we chose the ones with less apparent stitch artifacts. The four-beat acquisition time is shorter, so it may be better with more rapid respiration.
In contrast, the seven-beat acquisition takes longer, but the frame rate is often much faster and the image quality sometimes better, if stitch artifacts are absent. However, the interplay between these factors is not always predictable, so it is best to try both and choose the best image. The main challenge in applying this technique in children is the interplay between respiratory rate and HR versus four-beat or sevenbeat acquisition time and the echocardiographic frame rate. Respiratory motion artifacts are by far the major source of stitch artifacts and failure to obtain a reliable 3DE volume set. Inability to hold the breath and the fastest HRs encountered in patients aged < 5 years made the application of this version of 3DE synchrony analysis challenging in younger children. Quite importantly, from preliminary experience with the most recently developed system, in which there is a single-heartbeat acquisition at frame rates of 50 to 60 frames/sec in adult patients, we speculate that many of these problems will be resolved.
Study Limitations The study was limited by a fairly small number of subjects in the two groups aged < 5 years. Also, we did not compare the 3DE DI with other methods of synchrony analysis, such as echocardiographic strain imaging or magnetic resonance imaging tissue tagging. Both of these issues should be resolved before normal cutoff values can be firmly established. The 3DE DI technique is itself limited by several factors. A slow frame rate relative to the HR and the lack of respiratory gating or
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controlled breath holding are encountered in smaller children. Both of these problems introduce significant stitch artifacts and were the reason for the failure to obtain reliable data in the large majority of the 18.4% of children excluded from analysis because of poor image quality. Failure to reliably track one segment can induce major error in both the SD and difference calculations. Also, manual correction of one poorly tracked segment may induce minor errors in the tracking of adjacent segments.
CONCLUSIONS Three-dimensional echocardiographic DI analysis of the left ventricle is reproducible and feasible in most children. SD% and difference% were not affected by growth-related parameters in children but were lower than adult values. REFERENCES 1. Zimmerman F, Starr J, Koenig P, Smith P, Hijazi Z, Bacha E. Acute hemodynamic benefit of multisite pacing after congenital heart surgery. Ann Thorac Surg 2003;75:1775-80. 2. Bacha E, Zimmerman F, Mor-Avi V, Weinert L, Starr J, Sugeng L, et al. Ventricular resynchronization by multisite pacing improves myocardial performance in the postoperative single-ventricle patient. Ann Thorac Surg 2004;78:1678-83. 3. Dubin A, Janousek J, Rhee E, Striepe M, Cecchin F, Law I, et al. Resynchronization therapy in pediatric and congenital heart disease patients. J Am Coll Cardiol 2005;46:2277-83. 4. Baker G, Hlavacek A, Chessa K, Fleming D, Shirali G. Left ventricular dysfunction is associated with intraventricular dyssynchrony by 3-dimensional echocardiography in children. J Am Soc Echocardiogr 2008;21:230-3. 5. Ten Harkel A, Van Osch-Gevers M, Helbing W. Real-time transthoracic three dimensional echocardiography: normal reference data for left ventricular dyssynchrony in adolescents. J Am Soc Echocardiogr 2009;22: 933-8. 6. Sonne C, Sugeng L, Takeuchi M, Weinert L, Childers R, Watanabe N, et al. Real-time 3-dimensional echocardiographic assessment of left ventricular dyssynchrony—pitfalls in patients with dilated cardiomyopathy. J Am Coll Cardiol Img 2009;2:802-12. 7. Nagueh S. Mechanical dyssynchrony in congestive heart failure diagnostic and therapeutic implications. J Am Coll Cardiol 2008;51:18-22.
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8. Kass D. An epidemic of dyssynchrony: but what does it mean? J Am Coll Cardiol 2008;51:12-7. 9. Park S, Kim K, Jeon M, Lee C, Kim D, Park K, et al. Assessment of left ventricular asynchrony using volume time curves of 16 segments by real-time 3 dimensional echocardiography: comparison with tissue Doppler imaging. Eur J Heart Fail 2007;9:62-7. 10. Vitarelli A, Franciosa P, Conde Y, Cimino E, Nguyen B, Ciccaglione A, et al. Echocardiographic assessment of ventricular asynchrony in dilated cardiomyopathy and congenital heart disease: tools and hopes. J Am Soc Echocardiogr 2005;18:1424-39. 11. Horstman J, Monaghan M, Gill E. Intraventricular dyssynchrony assessment by real-time three dimensional echocardiography. Cardiol Clin 2007;25:253-60. 12. Takeuchi M, Jacobs A, Sugeng L, Nishikage T, Nakai H, Weinert L, et al. Assessment of left ventricular dyssynchrony with real time 3-dimensional echocardiography: comparison with Doppler tissue imaging. J Am Soc Echocardiogr 2007;20:1321-9. 13. Kapetanakis S, Kearney M, Siva A, Gall N, Cooklin M, Monaghan M. Realtime three dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation 2005;112: 992-1000. 14. Burgess M, Jenkins C, Chan J, Marwick T. Measurement of left ventricular dyssynchrony in patients with ischaemic cardiomyopathy: a comparison of real-time three dimensional and tissue Doppler echocardiography. Heart 2007;93:1191-6. 15. Soliman O, van Dalen B, Nemes A, van der Zwaan H, Vletter W, ten Cate F, et al. Quantification of left ventricular systolic dyssynchrony by real-time three-dimensional echocardiography. J Am Soc Echocardiogr 2009;22:232-9. 16. Gimenes V, Vieira M, Andrade M, Pinheiro J, Hotta V, Mathias W. Standard values for real-time transthoracic three-dimensional echocardiographic dyssynchrony indexes in a normal population. J Am Soc Echocardiogr 2008;21:1229-35. 17. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44: 1834-40. 18. Yu CM, Abraham WT, Bax J, Chung E, Fedewa M, Ghio S, et al. Predictors of response to cardiac resynchronization therapy (PROSPECT)—study design. Am Heart J 2005;149:600-5. 19. Derval N, Steendijk P, Gula LJ, Deplagne A, Laborderie J, Sacher F, et al. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricle wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol 2010;55:566-75.