Three-dimensional (3D) echocardiography directly assesses right ventricular (RV) volumes without geometric assumptions, despite the complex shape of the right ventricle, and accordingly is more accurate and reproducible than the two-dimensional methodology, which is able to measure only surrogate parameters of RV function. Volumetric analysis has been hampered by frequent inability to clearly visualize RV endocardium, especially the RV free wall, in 3D echocardiographic images. The aim of this study was to test the hypothesis that RV contrast enhancement during 3D echocardiographic imaging would improve the accuracy of RV volume and function analysis.
Thirty patients with a wide range of RV size and function and image quality underwent transthoracic 3D echocardiography with and without contrast enhancement and cardiovascular magnetic resonance imaging on the same day. RV end-diastolic and end-systolic volumes and ejection fraction were measured from contrast-enhanced and nonenhanced 3D echocardiographic images and compared with cardiovascular magnetic resonance reference values using linear regression and Bland-Altman analyses. Blinded repeated measurements were performed to assess measurement variability.
RV contrast enhancement was feasible in all patients. RV volumes obtained both with and without contrast enhancement correlated highly with cardiovascular magnetic resonance (end-diastolic volume, r = 0.90 and r = 0.92; end-systolic volume, r = 0.92 and r = 0.94, respectively), but the correlation for ejection fraction was better with contrast ( r = 0.87 vs r = 0.70). Biases were smaller with contrast for all three parameters (end-diastolic volume, −16 ± 23 vs −36 ± 25 mL; end-systolic volume, −10 ± 16 vs −23 ± 18 mL; ejection fraction, −0.7 ± 5.5% vs −2.7 ± 8.1% of the mean measured values), reflecting improved accuracy. Also, measurement reproducibility was improved by contrast enhancement.
Contrast enhancement improves the visualization of RV endocardial borders, resulting in more accurate and reproducible 3D echocardiographic measurements of RV size and function. This approach may be particularly useful in patients with suboptimal image quality.
We hypothesized that contrast enhancement during 3D echocardiographic imaging would improve the accuracy of RV volume and function analysis.
This hypothesis was tested by comparing measurements obtained from nonenhanced and contrast-enhanced images against cardiac magnetic resonance reference images.
Contrast enhancement improved the visualization of RV endocardial borders, resulting in more accurate and more reproducible measurements.
This approach may be particularly useful in patients with suboptimal image quality.
Right ventricular (RV) size and function are known to be major determinants of clinical status and long-term outcomes in patients with different cardiovascular pathologies. Cardiovascular magnetic resonance (CMR) imaging is accepted as the reference standard for RV volumes and RV ejection fraction (RVEF) measurements because of its high myocardium-blood signal ratio. Although two-dimensional (2D) echocardiography–derived parameters recommended in the chamber quantification guidelines are able to measure only surrogate parameters of RV function, three-dimensional (3D) echocardiography directly assesses RV volumes without relying on geometric assumptions regarding the complex shape of the chamber and accordingly is more accurate and reproducible than the 2D approach. This is the reason why the most recent guidelines recommend 3D echocardiographic analysis of RV size and function whenever possible. However, this 3D volumetric analysis has been hampered by difficulties acquiring consistently high-quality data sets. Specifically, the endocardial blood-tissue interface of the anterior and lateral segments of the RV free wall and RV outflow tract (RVOT) are frequently suboptimally visualized.
Contrast-enhancing agents are an established means to improve the delineation of left ventricular (LV) endocardial borders, particularly in patients with suboptimal-quality images. Despite the routine use of contrast agents for LV opacification, these agents are not currently used for clinical RV assessment, even in patients with suboptimal visualization of the RV free wall. Although the feasibility of this approach was demonstrated more than a decade ago with 2D echocardiographic imaging, reports on contrast-enhanced 3D echocardiographic evaluation of RV size and function are extremely sparse. This is despite the fact that for some of these patients, accurate assessment of RV size and function is critical for their clinical management.
Our hypothesis was that contrast enhancement during RV-focused 3D acquisition would result in more accurate and reproducible analysis of RV size and function, especially in patients with suboptimal-quality images. Accordingly, our goal was to test the accuracy and reproducibility of contrast-enhanced versus nonenhanced 3D echocardiographic images using CMR as the reference standard.
Patient Population and Study Design
Thirty patients in sinus rhythm with a wide range of RV size and function were prospectively studied (42% women; mean age, 67 ± 16 years; mean body surface area, 2.0 ± 0.2 m 2 ). These patients were referred for CMR for clinical indications and agreed to undergo transthoracic 3D echocardiographic imaging in addition. Patients were selected to include a similar number with good and with suboptimal visualization of the RV endocardial border in the 3D echocardiographic images. Of the 30 patients, 22 (73%) had dilated cardiomyopathy, 11 (37%) had systemic hypertension, seven (23%) had pulmonary arterial hypertension, six (20%) had coronary artery disease, three (10%) had simple congenital heart disease, and one (3%) had end-stage renal disease.
Three-dimensional echocardiographic imaging with and without contrast-enhancing agents was performed immediately after CMR image acquisition to minimize the impact of changing loading conditions. RV end-diastolic volume (EDV) and end-systolic volume (ESV) and RVEF were measured from 3D echocardiographic images, both with and without contrast-enhancing agents, using the same analysis technique and compared with CMR reference values obtained using the standard disk-summation technique. The study was approved by the institutional review board of the University of Chicago Medical Center, and informed consent was obtained from each patient.
CMR Imaging and Analysis
CMR was performed on a 1.5-T scanner (Philips, Best, the Netherlands) with a five-channel cardiac coil. A steady-state free-precession dynamic gradient-echo sequence was used to obtain cine loops, during approximately 5-sec breath holds (repetition time, 3.0 msec; echo time, 1.6 msec; flip angle, 60°; temporal resolution, ∼30–40 msec). In all patients, six to 10 short-axis slices were obtained from the ventricular base to the apex (6-mm slice thickness, 4-mm gaps). These images were analyzed offline using commercial software (Medis Medical Imaging, Leiden, the Netherlands). In each slice, endocardial contours were manually traced at end-diastole and end-systole by an investigator experienced with CMR-based chamber quantification (Society for Cardiovascular Magnetic Resonance level III training), who was blinded to echocardiographic data. On the most basal slices, the right ventricle was differentiated from the right atrium by advancing the cine loop frame by frame throughout systole. If the cavity became smaller and the myocardium thicker, the slice was included in the RV volume, whereas portions of the cavity that became larger and did not show wall thickening were considered part of the right atrium. Endocardial trabeculae were included in the RV cavity. Disk summation was used to calculate EDV and ESV, and RVEF was calculated using the standard formula.
Transthoracic 3D Echocardiographic Imaging
RV-focused 3D echocardiographic data sets that included the entire right ventricle in the pyramidal scan volume were acquired by an experienced sonographer using the iE33 or EPIC imaging systems equipped with an S5 transducer (Philips Healthcare, Andover, MA). Simultaneous real-time short-axis multiplanar reconstruction was used at the time of image acquisition to ensure optimal visualization of the RV free wall ( Figure 1 ). Imaging settings were optimized to obtain RV full-volume images with clear endocardial border and high frame rate (24 ± 5 Hz) by minimizing the depth and the width of the imaging sector. The same imaging settings were used with contrast enhancement, resulting in similar frame rates (22 ± 5 Hz; P > .05). Three-dimensional echocardiographic data sets were stored digitally and used for offline analysis, with the reader blinded to CMR data. The quality of the nonenhanced 3D echocardiographic images was rated as optimal or suboptimal by an expert reader on the basis of the visualization of the RV free wall.
Contrast enhancement was achieved using injection of Lumason (Bracco, Monroe Township, NJ; 1.5- to 2-mL intravenous bolus for each acquisition). To overcome the fast contrast washout from the right ventricle, imaging settings were optimized before the injection, and acquisition was performed as soon as the right ventricle was fully opacified. In addition to the default contrast settings (mechanical index, 0.28 ± 0.07), 3D echocardiographic simultaneous real-time short-axis multiplanar reconstruction planes were used to ensure optimal visualization of the RV free wall, as well as the anterior segments and RVOT, which are frequently not well visualized without contrast enhancement. Figure 1 shows an example of a good-quality 3D RV data set without contrast ( left ), in which endocardial border definition further improved with contrast enhancement ( right ). Figure 2 shows an example of a suboptimal-quality 3D RV data set, in which the endocardial border was poorly visualized without contrast ( left ) but was considerably improved by contrast enhancement ( right ), specially for the RV free-wall anterior and lateral segments.
Three-Dimensional Echocardiographic Analysis
Both contrast-enhanced and nonenhanced 3D echocardiographic data sets were analyzed (4D RV-Function 2.0, a module of TomTec-Arena; TomTec Imaging Systems, Unterschleissheim, Germany) to measure RV volumes and RVEF using a semiautomated algorithm that was recently validated against CMR reference. The first steps of analysis involved manual definition of the LV and RV long axes at end-diastole in both apical two- and four-chamber views ( Figures 3 A and 3B), LV outflow tract diameter in the apical three-chamber view ( Figure 3 C, top ), anterior and posterior junction points of the RV free wall with the interventricular septum, and the longest dimension of the RV cavity between the septum and the free wall, both in a single short-axis view ( Figure 3 C, bottom ).
These anatomic landmarks were used to automatically extract from the 3D echocardiographic data set the RV-focused four-chamber view, a series of short-axis views from base to apex, and an RVOT view for both end-systole and end-diastole ( Figures 4 A–4C, top and bottom , respectively), and to generate a 3D model of the right ventricle ( Figure 4 D). This RV 3D endocardial surface was then tracked throughout the cardiac cycle using speckle-tracking technology ( Figure 4 E), while manual fine-tuning was performed interactively to optimize the boundary position as necessary. Three-dimensional volumes over time were then numerically computed from the dynamic surface model and used to determine EDV, ESV, and RVEF.
EDV, ESV, and EF measurements from 3D echocardiographic images both with and without contrast enhancement were compared with the CMR reference values. These intertechnique comparisons included linear regression with Pearson’s correlation and Bland-Altman analyses to assess the mean intertechnique differences (biases) and limits of agreement (±2 SDs of the mean difference) with the CMR reference. These analyses were repeated in the subgroup of patients with suboptimal image quality.
Measurements with and without contrast-enhancing agents were repeated by two readers for purposes of reproducibility analysis for the entire study group. This included repeated measurements by the same observer, at least 1 month later, as well as measurements by a second independent observer, both blinded to all prior measurements. Interobserver and intraobserver variability were calculated as an absolute difference between the corresponding pair of repeated measurements as a percentage of their mean in each patient and then averaged over the entire study group.
Data are expressed as mean ± SD. P values < .05 were considered to indicate statistical significance. Intertechnique differences were tested for significance using paired two-tailed t tests. In addition, the biases relative to CMR were compared to better appreciate the level of intertechnique agreement.
Of the 30 study patients enrolled using the aforementioned criteria, the quality of the nonenhanced 3D echocardiographic images was rated as optimal in 14 patients and suboptimal in the remaining 16. Contrast-enhanced imaging of the right ventricle was feasible in all 30 patients and resulted in visible improvement in the definition of the free wall segments in patients with suboptimal visualization without contrast. The acquired 3D data sets were suitable for analysis in all patients.
Table 1 shows the summary of the RV size and function indices measured by CMR and 3D echocardiographic analyses both with and without contrast, as well as the results of the intertechnique comparisons, including correlation coefficients and Bland-Altman biases.
|Measurement||CMR||Echocardiography, no contrast||P value between echocardiography biases||Echocardiography with contrast|
|Mean ± SD||Mean ± SD||r value to CMR||Bias to CMR, mean ± SD||Mean ± SD||r value to CMR||Bias to CMR, mean ± SD|
|EDV (mL)||192 ± 56||156 ± 49||0.90||−36 ± 25||.00||176 ± 46||0.92||−16 ± 23|
|ESV (mL)||103 ± 44||79 ± 35||0.92||−23 ± 18||.00||92 ± 36||0.94||−10 ± 16|
|RVEF (%)||47.7 ± 10||50.5 ± 11||0.70||2.7 ± 8.1||.25||48.4 ± 11||0.87||0.7 ± 5.5|
Without contrast enhancement, EDV and ESV showed good intertechnique correlations with CMR, as reflected by r values of 0.90 and 0.92, respectively ( Table 1 , Figures 5 and 6 , left , top ), but only a moderate correlation for RVEF ( r = 0.70; Figure 7 , left , top ). Importantly, 3D echocardiography without contrast significantly underestimated both EDV and ESV, while only a minimal bias was noted for RVEF ( Table 1 , Figures 5–7 , left , bottom ). The 95% limits of agreement were relatively wide for all three parameters (−86 to +14 mL for EDV, −59 to +13 mL for ESV, and –13% to +19% for RVEF).