Background
The accuracy of echocardiography in evaluating left ventricular contractility has not been validated in children. The objective of this study was to compare echocardiographic measures of contractility with those derived from pressure-volume loop (PVL) analysis in children.
Methods
Patients with relatively normal loading conditions undergoing routine left heart catheterization were prospectively enrolled. PVLs were obtained via conductance catheters. The gold-standard measure of contractility, end-systolic elastance (Ees), was obtained via balloon occlusion of one or both vena cavae. Echocardiograms were performed immediately after PVL analysis under the same anesthetic conditions. Single-beat estimations of echocardiographic Ees were calculated using four different methods. These estimates were calculated using a combination of noninvasive blood pressure readings, ventricular volumes derived from three-dimensional echocardiography, and Doppler time intervals.
Results
Of 24 patients, 18 patients were heart transplant recipients, and six patients had small patent ductus arteriosus or small coronary fistulae. The mean age was 9.1 ± 5.6 years. The average invasive Ees was 3.04 ± 1.65 mm Hg/mL. Invasive Ees correlated best with echocardiographic Ees by the method of Tanoue ( r = 0.85, P < .01), with a mean difference of −0.07 mm Hg/mL (95% limits of agreement, −2.0 to 1.4 mm Hg/mL).
Conclusions
Echocardiographic estimates of Ees correlate well with gold-standard measures obtained via conductance catheters in children with relatively normal loading conditions. The use of these noninvasive measures in accurately assessing left ventricular contractility appears promising and merits further study in children.
Highlights
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The objective of this study was to compare echocardiographic measures of contractility with those derived from PVL analysis in children.
- •
Noninvasive estimations of Ees correlate well with invasive gold-standard methods in children with biventricular circulation and relatively normal loading conditions.
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The use of these noninvasive estimates of Ees in accurately assessing LV contractility appears promising and merits further study in children.
The advanced assessment of left ventricular (LV) mechanics in the pediatric population has the potential to provide valuable insights into the natural history and results of medical and surgical interventions in patients with congenital heart disease. However, such an assessment is rarely performed in children, because of the invasive nature of the studies that are required to carry out pressure-volume loop (PVL) analysis. As such, the development of accurate noninvasive indices of myocardial mechanics has long been a goal in pediatric echocardiography.
LV end-systolic elastance (Ees) is a load-independent measure of myocardial contractility, defined as the slope of the end-systolic pressure-volume relationship. The ratio of arterial elastance (Ea) to Ees (Ea/Ees) is the reference-standard measure of ventriculoarterial coupling, as it describes the interaction between myocardial performance and vascular function. A number of studies have been performed in animals and humans attempting to develop noninvasive estimates of these measures. Few studies have been performed attempting to independently validate these methods in adults. However, it is clear that adult data supporting the accuracy of noninvasive assessments of myocardial mechanics may not be applicable in children. As such, before these noninvasive measures can be used in children, they should be validated against the reference standard.
The goal of this study was to assess the validity of echocardiographic indices of contractility and ventriculoarterial coupling by direct comparison with reference-standard indices derived from PVL analysis in children. We hypothesized that noninvasive estimates of Ees and Ea/Ees would correlate well with invasive Ees and Ea/Ees, respectively.
Methods
Children (<21 years of age) with biventricular circulation undergoing clinically indicated diagnostic left heart catheterization were recruited prospectively. Exclusion criteria were (1) medical status for which participation in the study presented more than minimal risk as determined by the attending physician, (2) nonsinus rhythm, (3) right-sided cardiac pathology (tetralogy of Fallot, atrial septal defect, etc), and (4) significantly abnormal loading conditions (ratio of pulmonary to systemic blood flow > 1.5 or LV outflow tract gradient > 15 mm Hg); a significant left-to-right shunt would adversely affect conductance catheter volume calibration and LV outflow tract obstruction would significantly affect the noninvasive estimation of LV pressure. Therefore, patients with significantly abnormal loading conditions were excluded, keeping the study population relatively homogenous. The protocol was approved by our institutional review board. Informed consent was obtained from the parents or legal guardians of minors and from participants ≥18 years of age.
Study Catheterization and PVL Analysis Protocol
All patients underwent general anesthesia per institutional protocol. All study data were collected after the patient’s primary diagnostic and interventional procedures. A 4-Fr high-fidelity microconductance catheter (CD Leycom, Zoetermeer, The Netherlands) was placed in the apex of the left ventricle via the femoral approach. The conductance catheter’s micromanometer was calibrated in normal saline for 15 sec before placement. PVLs were volume calibrated using hypertonic saline to account for parallel conductance. Conductance catheter volumes have been shown to correlate well with cardiac magnetic resonance imaging volumes, though they do underestimate absolute volumes. Cardiac output was determined by thermodilution. Conductance electrodes outside of the ventricle were excluded from analysis. Preload reduction was achieved via balloon occlusion of one or both vena cavae. Ees was then calculated using the iterative regression method. Invasive Ea was calculated as end-systolic pressure divided by invasive stroke volume. All PVL data were recorded in triplicate over 10 sec during an expiratory breath hold. Microconductance data were recorded at a sampling rate of 250 Hz. Invasive data were obtained using standard equipment approved for use in human subjects (INCA intracardiac analyzer; CD Leycom). PVL analysis was performed offline using specialized software (ConductNT version 3.18; CD Leycom).
Echocardiographic Acquisition and Analysis Protocol
Echocardiograms were obtained immediately after PVL analysis under the same anesthetic conditions using a Philips iE33 system (Philips Medical Systems, Andover, MA). Echocardiograms were sent uncompressed and at native frame rates to the encrypted server for analysis. All measurements were made offline by a single blinded reviewer (S.M.C.) and averaged over three beats. Ventricular volumes and ejection fraction used in the calculation of Ees were derived from three-dimensional (3D) echocardiography (QLAB version 9.0; Philips Medical Systems). Electrocardiographically gated 3D echocardiographic volumes were acquired during expiratory breath hold over four beats, and the subvolumes were stitched together. The average frame rate of the 3D echocardiographic volumes was 29.7 ± 5.1 frames/sec, with an average heart rate during acquisition of 86.8 ± 17.2 beats/min.
Single-beat estimations of echocardiographic Ees (Ees sb ) were calculated using four different methods, which have been previously validated in adult patients. Method 1 (Ees sb1 ), method 2 (Ees sb2 ), and method 3 (Ees sb3 ) use echocardiographic ventricular volumes, Doppler time intervals, and blood pressure cuff measurements to estimate Ees. In addition, Ees sb2 and Ees sb3 require an estimation of ventricular end-diastolic pressure. Method 4 (Ees sb4 ) is a simpler method that requires only echocardiographic ventricular volumes and blood pressure cuff measurements to estimate Ees. Please see the Appendix for details on the methods to calculate these Ees sb estimates.
Echocardiographic Ea was calculated as (0.9 × systolic blood pressure)/(3D echocardiographic stroke volume). A second set of calculations of Ees and Ea was made using two-dimensional (2D) echocardiography by calculating volumes using the 5/6 area-length method. Noninvasive blood pressures (systolic, diastolic, and mean) were obtained supine at the time of echocardiography by automated sphygmomanometer and averaged over three measurements. Intra- and interobserver variability of Ees sb was assessed in 50% of studies by observers blinded to the original measurements.
Statistical Analysis
The agreement between invasive Ees and echocardiographic Ees sb was expressed as percentage error of invasive Ees, (Ees sb − Ees)/Ees, with 95% limits of agreement (±1.96 × SD). One-sample t tests were used to determine if the percentage error of the mean was statistically significantly different from zero to assess if the noninvasive measure systematically over- or underestimated the invasive measure. Differential bias (e.g., increased error in estimation as the absolute value of the measure increases) in the accuracy of Ees sb estimation versus invasive Ees was tested using linear regression. This procedure was repeated for invasive Ea versus echocardiographic Ea and for invasive Ea/Ees versus echocardiographic Ea/Ees. Pearson’s correlation was calculated to evaluate for a linear relationship between invasive and echocardiographic measures. Intra- and interobserver variability of Ees sb was reported using intraclass correlation coefficients assessing absolute agreement and by calculating the absolute value of the percentage error of the mean (observation 2 − observation 1)/[(observation 2 + observation 1)/2]. P values < .05 were considered to indicate statistical significance. All statistical analyses were performed using IBM SPSS Statistics version 22 (IBM, Armonk, NY).
Results
Twenty-four patients were enrolled; 18 patients were heart transplant recipients, five patients had trivial or small patent ductus arteriosus, and one had a small coronary fistula. All patients with patent ductus arteriosus and coronary fistula underwent successful intervention. No heart transplantation patients had evidence of coronary artery disease. Demographic, clinical, and catheterization data from these patients are presented in Table 1 . A representative PVL during preload reduction and the resulting end-systolic pressure-volume relationship is shown in Figure 1 .
| Variable | Value |
|---|---|
| Age (y) | 9.6 ± 5.8 |
| Female, n (%) | 12 (50%) |
| Height (cm) | 126 (58.1) |
| Weight (kg) | 32.9 (36.4) |
| BSA (m 2 ) | 0.96 (0.85) |
| Systolic blood pressure (mm Hg) | 88 ± 9 |
| Diastolic blood pressure (mm Hg) | 47 ± 7 |
| Baseline heart rate (beats/min) | 86 ± 18 |
| Oxygen saturation | 99 (2.8) |
| EDP (mm Hg) | 10.6 ± 3.3 |
| Cardiac index (L/min/m 2 ) | 3.5 ± 1.2 |
| MvO 2 (%) | 75 ± 5 |
| Rp (Wood units) | 1.8 ± 0.7 |
| Rs (Wood units) | 19.2 ± 6.0 |
| Qp/Qs | 1.03 ± 0.21 |
| Ees (mm Hg/mL) | 2.9 ± 1.6 |
| Ea (mm Hg/mL) | 2.2 ± 0.9 |
| Ea/Ees | 0.88 ± 0.35 |
Three-Dimensional Echocardiographic Agreement with Invasive Measures: Ees
Descriptive echocardiographic estimates of 3D echocardiographic Ees are reported in Table 2 . Correlations and agreement between invasive and echocardiographic Ees are reported in Table 3 . Bland-Altman plots displaying agreement between invasive and echocardiographic estimation of Ees are shown in Figure 2 . Ees sb1 , Ees sb2 , and Ees sb3 all systematically overestimated invasive Ees. Only Ees sb4 showed good agreement with invasive Ees. There was positive differential bias when estimating Ees (i.e., error increased as Ees increased) using Ees sb1 ( R 2 = 0.58, P < .01), Ees sb2 ( R 2 = 0.52, P < .01), and Ees sb3 ( R 2 = 0.44, P < .01). There was negative differential bias when using Ees sb4 ( R 2 = 0.34, P < .01). Scatterplots and correlations between invasive and echocardiographic estimates of Ees are displayed in Figure 3 . In general, correlations between invasive and all echocardiographic Ees sb estimates were strong. Results of observer variability analysis for Ees sb methods and their components can be found in Table 4 .
| Ees method | Echocardiographic Ees | Echocardiographic Ea/Ees |
|---|---|---|
| Ees sb1 (mm Hg/mL) | 5.3 ± 2.9 | 0.59 ± 0.16 |
| Ees sb2 (mm Hg/mL) | 4.3 ± 3.1 | 0.85 ± 0.41 |
| Ees sb3 (mm Hg/mL) | 4.0 ± 2.8 | 0.90 ± 0.43 |
| Ees sb4 (mm Hg/mL) | 2.5 ± 1.1 | 1.17 ± 0.40 |
| 3D echocardiographic method | Echocardiographic vs invasive Ees | |
|---|---|---|
| Correlation coefficient | Percentage error of invasive Ees (95% LoA) | |
| SB1 | 0.84 ∗ | 91% (−1.2 to 5.8 mm Hg/mL) † |
| SB2 | 0.79 ∗ | 51% (−2.5 to 5.4 mm−Hg/mL) † |
| SB3 | 0.79 ∗ | 42% (−2.3 to 4.7 mm−Hg/mL) † |
| SB4 | 0.85 ∗ | −0.7% (−2.0 to 1.4 mm Hg/mL) |
† Percentage error is statistically significantly different from zero ( P < .05).
| Measure | Intraobserver ICC | Intraobserver % error of the mean | Interobserver ICC | Interobserver % error of the mean |
|---|---|---|---|---|
| Ees sb1 | 0.93 | 8% | 0.87 | 12% |
| Ees sb2 | 0.85 | 13% | 0.82 | 19% |
| Ees sb3 | 0.87 | 13% | 0.84 | 15% |
| Ees sb4 | 0.98 | 6% | 0.92 | 10% |
| EDV | 0.99 | 4% | 0.98 | 12% |
| ESV | 0.99 | 4% | 0.98 | 10% |
| PEP | 0.84 | 10% | 0.73 | 21% |
| ET | 0.94 | 3% | 0.88 | 3% |
Three-Dimensional Echocardiographic Agreement with Invasive Measures: Ea
Mean echocardiographic Ea was 3.0 ± 1.3 mm Hg/mL. The correlation between invasive and echocardiographic Ea was r = 0.94 ( P < .01). Echocardiographic Ea systematically overestimated invasive Ea by 33.4% (95% limits of agreement, −0.32 to 1.81 mm Hg/mL; P < .01), because of positive differential bias. That is, as Ea increased, the difference between invasive and 3D echocardiography increased ( r = 0.84, P < .01).
Three-Dimensional Echocardiographic Agreement with Invasive Measures: Ea/Ees
Descriptive echocardiographic estimates of 3D echocardiographic Ea/Ees are reported in Table 2 . Correlations and agreement between invasive and echocardiographic Ees and Ea/Ees are reported in Table 5 .
| 3D echocardiographic method | Echocardiographic vs invasive Ea/Ees | |
|---|---|---|
| Correlation coefficient | Percentage error of invasive Ea/Ees (95% LoA) | |
| SB1 | 0.60 ∗ | −21% (−0.89 to 0.39) † |
| SB2 | −0.27 | 9% (−0.88 to 0.87) |
| SB3 | 0.32 | 14% (−0.80 to 0.89) |
| SB4 | 0.60 ∗ | 46% (−0.37 to 0.95) † |
† Percentage error is statistically significantly different from zero ( P < .05).
Agreement with Invasive Measures: Ventricular Volumes, Ejection Fraction, and End-Systolic Pressure
To assess for sources of disagreement between invasive and noninvasive Ees, we evaluated the agreement between invasive and noninvasive ventricular volumes, ejection fraction, and end-systolic pressure. Results can be found in Appendix Table 1 . There were better correlations between invasive versus noninvasive ventricular volumes than between invasive versus noninvasive ejection fraction and end-systolic pressure. Noninvasive measures tended to underestimate ventricular volumes and ejection fraction compared with invasive analysis.
Two-Dimensional Echocardiographic Agreement with Invasive Measures: Ees, Ea, and Ea/Ees
Correlations and agreement between invasive and 2D echocardiographic Ees and Ea/Ees are reported in Appendix Table 2 . The correlation between invasive and 2D echocardiographic Ea was r = 0.90 ( P < .01). Two-dimensional echocardiographic Ea systematically overestimated invasive Ea by 21.3% (95% limits of agreement, −0.70 to 1.75 mm Hg/mL; P < .01). In general, Ees, Ea, and Ea/Ees estimates by 2D echocardiography were comparable with estimates obtained by 3D echocardiography.
Results
Twenty-four patients were enrolled; 18 patients were heart transplant recipients, five patients had trivial or small patent ductus arteriosus, and one had a small coronary fistula. All patients with patent ductus arteriosus and coronary fistula underwent successful intervention. No heart transplantation patients had evidence of coronary artery disease. Demographic, clinical, and catheterization data from these patients are presented in Table 1 . A representative PVL during preload reduction and the resulting end-systolic pressure-volume relationship is shown in Figure 1 .
| Variable | Value |
|---|---|
| Age (y) | 9.6 ± 5.8 |
| Female, n (%) | 12 (50%) |
| Height (cm) | 126 (58.1) |
| Weight (kg) | 32.9 (36.4) |
| BSA (m 2 ) | 0.96 (0.85) |
| Systolic blood pressure (mm Hg) | 88 ± 9 |
| Diastolic blood pressure (mm Hg) | 47 ± 7 |
| Baseline heart rate (beats/min) | 86 ± 18 |
| Oxygen saturation | 99 (2.8) |
| EDP (mm Hg) | 10.6 ± 3.3 |
| Cardiac index (L/min/m 2 ) | 3.5 ± 1.2 |
| MvO 2 (%) | 75 ± 5 |
| Rp (Wood units) | 1.8 ± 0.7 |
| Rs (Wood units) | 19.2 ± 6.0 |
| Qp/Qs | 1.03 ± 0.21 |
| Ees (mm Hg/mL) | 2.9 ± 1.6 |
| Ea (mm Hg/mL) | 2.2 ± 0.9 |
| Ea/Ees | 0.88 ± 0.35 |
Three-Dimensional Echocardiographic Agreement with Invasive Measures: Ees
Descriptive echocardiographic estimates of 3D echocardiographic Ees are reported in Table 2 . Correlations and agreement between invasive and echocardiographic Ees are reported in Table 3 . Bland-Altman plots displaying agreement between invasive and echocardiographic estimation of Ees are shown in Figure 2 . Ees sb1 , Ees sb2 , and Ees sb3 all systematically overestimated invasive Ees. Only Ees sb4 showed good agreement with invasive Ees. There was positive differential bias when estimating Ees (i.e., error increased as Ees increased) using Ees sb1 ( R 2 = 0.58, P < .01), Ees sb2 ( R 2 = 0.52, P < .01), and Ees sb3 ( R 2 = 0.44, P < .01). There was negative differential bias when using Ees sb4 ( R 2 = 0.34, P < .01). Scatterplots and correlations between invasive and echocardiographic estimates of Ees are displayed in Figure 3 . In general, correlations between invasive and all echocardiographic Ees sb estimates were strong. Results of observer variability analysis for Ees sb methods and their components can be found in Table 4 .
| Ees method | Echocardiographic Ees | Echocardiographic Ea/Ees |
|---|---|---|
| Ees sb1 (mm Hg/mL) | 5.3 ± 2.9 | 0.59 ± 0.16 |
| Ees sb2 (mm Hg/mL) | 4.3 ± 3.1 | 0.85 ± 0.41 |
| Ees sb3 (mm Hg/mL) | 4.0 ± 2.8 | 0.90 ± 0.43 |
| Ees sb4 (mm Hg/mL) | 2.5 ± 1.1 | 1.17 ± 0.40 |
| 3D echocardiographic method | Echocardiographic vs invasive Ees | |
|---|---|---|
| Correlation coefficient | Percentage error of invasive Ees (95% LoA) | |
| SB1 | 0.84 ∗ | 91% (−1.2 to 5.8 mm Hg/mL) † |
| SB2 | 0.79 ∗ | 51% (−2.5 to 5.4 mm−Hg/mL) † |
| SB3 | 0.79 ∗ | 42% (−2.3 to 4.7 mm−Hg/mL) † |
| SB4 | 0.85 ∗ | −0.7% (−2.0 to 1.4 mm Hg/mL) |
† Percentage error is statistically significantly different from zero ( P < .05).
| Measure | Intraobserver ICC | Intraobserver % error of the mean | Interobserver ICC | Interobserver % error of the mean |
|---|---|---|---|---|
| Ees sb1 | 0.93 | 8% | 0.87 | 12% |
| Ees sb2 | 0.85 | 13% | 0.82 | 19% |
| Ees sb3 | 0.87 | 13% | 0.84 | 15% |
| Ees sb4 | 0.98 | 6% | 0.92 | 10% |
| EDV | 0.99 | 4% | 0.98 | 12% |
| ESV | 0.99 | 4% | 0.98 | 10% |
| PEP | 0.84 | 10% | 0.73 | 21% |
| ET | 0.94 | 3% | 0.88 | 3% |
Three-Dimensional Echocardiographic Agreement with Invasive Measures: Ea
Mean echocardiographic Ea was 3.0 ± 1.3 mm Hg/mL. The correlation between invasive and echocardiographic Ea was r = 0.94 ( P < .01). Echocardiographic Ea systematically overestimated invasive Ea by 33.4% (95% limits of agreement, −0.32 to 1.81 mm Hg/mL; P < .01), because of positive differential bias. That is, as Ea increased, the difference between invasive and 3D echocardiography increased ( r = 0.84, P < .01).
Three-Dimensional Echocardiographic Agreement with Invasive Measures: Ea/Ees
Descriptive echocardiographic estimates of 3D echocardiographic Ea/Ees are reported in Table 2 . Correlations and agreement between invasive and echocardiographic Ees and Ea/Ees are reported in Table 5 .
| 3D echocardiographic method | Echocardiographic vs invasive Ea/Ees | |
|---|---|---|
| Correlation coefficient | Percentage error of invasive Ea/Ees (95% LoA) | |
| SB1 | 0.60 ∗ | −21% (−0.89 to 0.39) † |
| SB2 | −0.27 | 9% (−0.88 to 0.87) |
| SB3 | 0.32 | 14% (−0.80 to 0.89) |
| SB4 | 0.60 ∗ | 46% (−0.37 to 0.95) † |
† Percentage error is statistically significantly different from zero ( P < .05).
Agreement with Invasive Measures: Ventricular Volumes, Ejection Fraction, and End-Systolic Pressure
To assess for sources of disagreement between invasive and noninvasive Ees, we evaluated the agreement between invasive and noninvasive ventricular volumes, ejection fraction, and end-systolic pressure. Results can be found in Appendix Table 1 . There were better correlations between invasive versus noninvasive ventricular volumes than between invasive versus noninvasive ejection fraction and end-systolic pressure. Noninvasive measures tended to underestimate ventricular volumes and ejection fraction compared with invasive analysis.
Two-Dimensional Echocardiographic Agreement with Invasive Measures: Ees, Ea, and Ea/Ees
Correlations and agreement between invasive and 2D echocardiographic Ees and Ea/Ees are reported in Appendix Table 2 . The correlation between invasive and 2D echocardiographic Ea was r = 0.90 ( P < .01). Two-dimensional echocardiographic Ea systematically overestimated invasive Ea by 21.3% (95% limits of agreement, −0.70 to 1.75 mm Hg/mL; P < .01). In general, Ees, Ea, and Ea/Ees estimates by 2D echocardiography were comparable with estimates obtained by 3D echocardiography.
Discussion
To our knowledge, this is the first study to comprehensively evaluate the correlation and agreement of echocardiographic versus invasive measures of contractility and systolic pump function using gold-standard methods for PVL acquisition in children. The main findings of this study are that all four methods of 3D echocardiographic estimation of Ees show strong correlation with PVL-derived Ees, but only 3D echocardiographic Ees sb4 showed good agreement with invasive Ees.
The purpose of measuring noninvasive 3D echocardiographic Ees sb is to detect abnormal contractility in children. Our results beg the question: do the 3DE Ees sb methods with good correlation but poor agreement with invasive Ees hold the potential to accurately assess contractility in this population? It seems clear, with good correlation, that Ees sb will be able to classify children as having normal or abnormal contractility regardless of absolute value. However, because of poor agreement, normal values established using invasive methods will not be applicable to noninvasive methods. Therefore, new normative values will need to be established using these 3D echocardiographic methods.
Because all Ees sb methods showed good correlation with invasive Ees, determining the most robust method for clinical use will rely on other characteristics of these methods. For example, compared with Ees sb2 and Ees sb3 , Ees sb1 , and Ees sb4 appear to have better observer reliability and correlate with invasive Ea/Ees when assessing ventriculoarterial coupling by echocardiography. Therefore, Ees sb1 and Ees sb4 appear to hold the most promise. Although Ees sb4 is simple to calculate and shows good agreement with invasive Ees, it makes the assumption that the volume intercept of the end-systolic pressure-volume relationship is zero. It may also be quite susceptible to changes in loading conditions because it relies on only two load-sensitive components: systolic blood pressure and end-systolic volume. Ees sb1 may be more load insensitive because of its reliance on relatively insensitive Doppler time intervals. However, its complexity makes it more difficult to calculate. The number of factors in the formula also add “noise” that increases its observer variability. In addition, assumptions in the calculation do not hold in certain disease processes, such as ischemic cardiomyopathy. To determine the ideal method for estimating 3D echocardiographic Ees sb , future studies should assess these methods’ ability to predict patient outcomes and their accuracy during altered loading or inotropic states to make a more accurate assessment of their utility.
Although the correlation between Ees sb and invasive Ees was good for all methods, single-beat methods 1, 2, and 3 demonstrated significant systematic overestimation of Ees. This is likely related to the intrinsic nature of performing these measurements in children. These three methods were developed in adults and use time intervals, such as preejection period. In children, whose heart rates are significantly higher than those of adults, these time intervals become quite short and likely contribute to the overestimation of Ees. In addition, as contractility improves the preejection period shortens, likely leading to the positive differential bias in increasing overestimation of Ees sb1 , Ees sb2 , and Ees sb3 with higher invasive Ees. Moreover, because of the poor measurement resolution of short Doppler time intervals, these measurements have high observer variability. In contrast, the only method with no time interval incorporated into the equation, Ees sb4 , showed good agreement with invasive Ees. Another source of error in Ees sb methods 2 and 3 is the need to estimate LV end-diastolic pressure. Although we have shown good correlation between multiple methods of noninvasive Ees sb estimation and PVL-derived Ees in children with relatively normal loading conditions, the development of more accurate methods to estimate Ees sb in children may be prudent.
A number of studies purport the accuracy of invasive single-beat estimation of Ees. However, each study uses a different method to calculate Ees sb , leaving clinicians and researchers with little guidance on the most robust method. Similar patterns are found when these methods are translated noninvasively. Studies attempting to independently validate noninvasively derived Ees sb are rare. Yotti et al . assessed the correlation between Ees sb1 and Ees sb4 versus Ees derived from PVL analysis in adults. They found a poor correlation between Ees sb4 and invasive Ees and no correlation between Ees sb1 and invasive Ees, findings that are different from those of the present study. Disparate results between these two studies may be due to a number of reasons. First, their population was quite heterogeneous in their diagnoses and loading conditions. These formulas were developed in animals and adult humans with relatively normal loading conditions. Abnormal loading conditions are known to produce inaccuracies in the estimation of Ees sb , which likely contributed to the poor correlation between Ees sb and invasive Ees in the previous study. Second, ventricular volumes were assessed using the 2D biplane Simpson method, which has shown to be less accurate and to have greater observer variability compared with 3D echocardiography. Finally, the time and method of blood pressure measurement was not reported in the study, leading to concerns about more sources of error.
We found only a modest correlation between invasive and 3D echocardiographic Ea/Ees. This was likely because there were small, but compounded, sources of error in the measurements needed to estimate 3D echocardiographic Ea/Ees, such as the error seen in estimating end-systolic pressure using blood-pressure cuff. This is consistent with previous studies. Some groups have estimated Ees sb using arterial tonometry to estimate end-systolic pressure more accurately. This method merits further study in children. In addition, measurement of ventricular volumes and ejection fraction for Ees sb estimation may be more accurately measured using cardiac magnetic resonance imaging; however, such methodology does not lend itself to validation using simultaneous conductance derived PVL analysis.
Clinical Implications
The validation of the noninvasive assessment of Ees and Ea/Ees has the potential to provide important insights into disease progression and response to treatment in patients with congenital heart disease, many of whom spend their lives at risk for heart failure. With a constant preload, Ea/Ees is directly related to ejection fraction. Therefore, we can use Ea and Ees to assist in management decisions. For example, in a patient with dilated cardiomyopathy and a reduced ejection fraction, if Ea is elevated and Ees is in a relatively normal range, but cannot compensate for the high Ea enough to result in a normal ejection fraction, it would seem reasonable to treat with medications designed to decrease afterload. Alternatively, if the patient had Ea in the low or normal range and low Ees, it would seem clear that this patient would benefit from inotropic support to improve ejection fraction.
Ea and Ees have been shown to be associated with mortality, B-type natriuretic peptide, and exercise performance in adults with cardiovascular disease. In addition, they can be used to elucidate the mechanism of improvement in heart failure symptoms after therapy. This is important in pediatrics because children with heart failure have not shown the same response to heart failure therapy as adults. Investigating Ea and Ees may allow us to gain insight into the pathophysiology behind the lack of efficacy of standard heart failure therapies in children.
Limitations
The study population was relatively small; our results may deserve validation in a larger cohort. The majority of our patients were heart transplant recipients and therefore cannot be considered to have absolutely normal cardiac function or loading conditions. We did not perform repeated measures after a change in loading conditions or inotropic states, to avoid further complexity in the PVL catheterization procedure. To be applicable to the broader congenital heart disease population, 3D echocardiographic Ees sb methods should next be validated under differing loading conditions, inotropic states, and heart rates, as well as ventricular sizes, masses, and morphologies. Before clinical use, normative values need to be established, and the clinical utility of these measures needs to be validated by assessing their relationships to patient outcomes.
Conclusions
Noninvasive estimates of Ees sb derived from 3D echocardiography accurately represent invasive Ees derived from PVL analysis in children with normal loading conditions. The use of these noninvasive estimates of Ees in accurately assessing LV contractility appears promising and merits further study in children.
Appendix
Methods Used to Estimate 3D Echocardiographic Ees sb
Method 1 (Ees sb1 ) by Chen et al . :
Ees sb 1 = P d − ( E NDest × P s × 0.9 ) SV × E NDest ,
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